DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
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CARDIOVASCULAR AND RENAL DRUGS
ADVISORY COMMITTEE
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90th MEETING
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Monday, May 1, 2000
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		The Advisory Committee met at 10:00 a.m., in the Masur Auditorium, Building 10, National Institutes of Health, 900 Rockville Pike, Rockville, Maryland, Dr. Robert Califf, Acting Chairman, presiding.
PRESENT:
		ROBERT CALIFF, M.D., Acting Chairman
	
		JOHN Di MARCO, M.D., Member

		THOMAS GRABOYS, M.D., Consumer
		   Representative

		ILEANA PINA, M.D., Member

PRESENT:

		JOHN C. STANDAERT, Executive Secretary

PARTICIPANTS:

		PAUL ARMSTRONG, M.D.
		JEFFREY BORER, M.D.
		THOMAS FLEMING, Ph.D.
		JOANN LINDENFELD, M.D.
		UDHO THADANI, M.D., FRCP
INVITED GUESTS:
		GEORGE BAKRIS, M.D.
		MARK MOLITCH, M.D.
FDA PARTICIPANTS:
		JAMES HUNG, Ph.D.
		RAYMOND LIPICKY, M.D.
		SHARI TARGUM, M.D.
		ROBERT TEMPLE, M.D.
SPONSOR REPRESENTATIVES:
		BARRY M. BRENNER, M.D.
		GILES DAGENAIS
		CARL FURBERG, M.D., Ph.D.
		HERTZEL GERSTEIN, M.D., M.Sc.
		THOMAS K. ROGERS, III, M.S.
SPONSOR REPRESENTATIVES (Continued):
		SALIM YUSUF, D.Phil., M.D.

C-O-N-T-E-N-T-S
	PAGE
Conflict of Interest Statement 	5
Sponsor's Presentation:
	Introduction, Thomas K. Rogers, III, M.S.	8
	HOPE Study Designs and Results, Salim
	Yusuf, D.Phil., M.D. 	11

	Clinical Strategies for Renal Protection,
	Barry M. Brenner, M.D. 	151

HOPE Results in Patients with Diabetes,
	Hertzel Gerstein, M.D., M.Sc.	178

Role of DSMB and Implications for Public Health,
	Carl Furberg, M.D., Ph.D. 	262

Discussion of Questions by the Advisory 
	Committee 	270

P-R-O-C-E-E-D-I-N-G-S
(10:04 a.m.)
		ACTING CHAIRMAN CALIFF:  Good morning.  I'm Rod Califf, and it's now time to start our Cardiovascular and Renal Drugs Advisory Committee meeting.
		This morning we have some invited guests and some new participants to this committee, in addition to the return of some old participants to help us out.  We'll have time to introduce everyone as we get into the discussion, but we'd like to open the meeting by asking if there's anyone who would like to make a public comment.
		(No response.)
		ACTING CHAIRMAN CALIFF:  Hearing no public comment, we'll now turn it over to Joan Standaert, who will acknowledge the conflicts.
		MS. STANDAERT:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Based on the submitted agenda and information provided by the participants, the Agency has determined that all reported interest in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.
		Drs. Milton Packer and Marvin Konstam have been excluded from participating in today's discussion and vote concerning Altace.
		Further, in accordance with 18 USC 208(b), full waivers have been granted to Drs. George Bakris, Thomas Fleming, Udho Thadani, Ileana Pina, Joann Lindenfeld, and Mark Molitch.  Copies of these waiver statements may be obtained by submitting a written request to FDA's Freedom of Information Office located in Room 12A30 of the Parklawn Building.
		In addition, we would like to disclose for the record that Drs. Robert Califf, Udho Thadani, and George Bakris have interests which do not constitute financial interest within the meaning of 18 USC 208(a), but which could create the appearance of a conflict.
		The agency has determined notwithstanding these interests, that the interests of the government in their participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.
		Therefore, Drs. Robert Califf, Udho Thadani, and George Bakris may participate fully in all matters relating to Altace.  
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.
		With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
		This concludes the conflict of interest statement for this meeting.
		I have been asked by the management of the auditorium to make a general announcement regarding food and drink in the auditorium.  They are concerned that people have been leaving papers and leaving the site in not too nice a condition.  So they are asking that you please respect the building and take all of your papers and everything that you bring with you back.
		ACTING CHAIRMAN CALIFF:  Thank you.
		We'll move on now with the presentation from the sponsor, and I think what we'll do is we'll hear from each speaker, each individual speaker, and then we'll let the panel ask questions of each individual.
		MR. ROGERS:  Good morning, Mr. Chairman, distinguished members of the panel.  We are pleased that today you will be considering a supplement to King Pharmaceuticals' NDA for Altace, or ramapril capsules.
		Altace has been approved for the treatment of hypertension sine 1991.  It is also indicated for the treatment of congestive heart failure in patients who have sustained acute myocardial infarctions.
		The supplemental application being considered today seeks approval of additional indications for Altace.  The proposed new indications are for the prevention of cardiovascular death, myocardial infarction, and stroke.
		Based upon positive comments from the FDA's review, all cause mortality has also been added to the indications shown on this slide.  Of course, we understand that the text of final labeling will be the result of meaningful discussions with the agency after the conclusion of today's meeting.
		The supplement is based upon the findings of the Heart Outcomes Prevention Evaluation Study, known as the HOPE study.  The study was conceived and independently conducted by Dr. Salim Yusuf of McMaster University and administered by members of the International Steering Committee for HOPE. 
		The study evaluated the long-term benefits of ramipril in an extremely large patient population that was followed for approximately four and one-half years.
		Today Drs. Yusuf, Brenner, Gerstein, and Furberg will present and discuss the findings of the study.  We're also joined today by additional consultants, Dr. Giles Dagenais, who was co-chair of the study, and by Dr. Craig Pratt.
		From a public health perspective, the implications of the HOPE Study are dramatic, and we are fortunate and appreciative that Dr. Yusuf persevered to obtain funding necessary to conduct an independent study of such magnitude and duration.  Dr. Yusuf will be our first presenter and will also facilitate further discussions as the morning proceeds.
		Thank you.
		ACTING CHAIRMAN CALIFF:  I'm assuming the panel has no questions at this point.
		Obviously in the redesign of this auditorium they didn't take us into consideration up here.  We're sort of packed in like sardines, but we'll make the best of --
		DR. FLEMING:  Rob, it's correct then that the labeling indication differs from what has just been sent to us on paper?
		ACTING CHAIRMAN CALIFF:  Only for the --
		DR. FLEMING:  All cause mortality?
		ACTING CHAIRMAN CALIFF:  -- all cause mortality.  That's correct.
		DR. YUSUF:  Dr. Califf, Dr. Lipicky, ladies and gentlemen, it's my pleasure on behalf of the HOPE Steering Committee and investigators to present to you the results of the study.
		HOPE stands for Heart Outcomes Prevention Evaluation Study.  It's a large, simple, randomized trial of ramipril ACE inhibitor and Vitamin E in patients at high risk for cardiovascular events.
		I'm not going to show you data related to Vitamin E.  Suffice to say that Vitamin E proved to be ineffective in this trial.  
		Now, as you all know, there is a long history of the evaluation of ACE inhibitors in cardiovascular disease going back some 20 years.  A series of trials initially high risk and sick patients were conducted.  This was initially in people with heart failure, and we know it reduces mortality and heart failure hospitalizations, and some of these trials also suggested a reduction in myocardial infarction which has not been fully accepted.
		There have been similar data in patients with asymptomatic LV dysfunction, post myocardial infarction, some data on acute myocardial infarction, and in diabetics at least in the literature there's a range of studies that have indicated a benefit on progression of renal disease.
		Looking at the literature amongst hypertensives, it seems to be similar in reducing clinical events likely to be better than calcium blockers in diabetics, and there's a meta analysis in press at the moment.
		However, there's a large body of people, those with other manifestations of coronary artery disease and without LV dysfunction or heart failure, those with strokes, those with peripheral arterial disease or other diabetics in which we do not know if ACE inhibitors prevent clinically important outcomes.
		The starting point for me in the design of HOPE was my experiences in the SOLVD trial.  In this trial of 6,700 people with low ejection fractions, half of whom had heart failure; the other had asymptomatic LV dysfunction; we had a surprising finding, and the finding was a reduction in myocardial infarction by about 23 percent, which was statistically significant and consistent in the two parts of the study.
		Nevertheless, these data generated a lot of interest, but was not seen to be convincing to most people.  When we looked at the literature and looking at the literature, we find epidemiological data that would suggest the possibility that modifying the renin angiotensin system may be helpful.  
		These are data from one such study by Mickey Alderman, where he took 2,000 hypertensives, treated them with diuretics, controlled their blood pressure, then profiled their renin levels, and whether they were smokers or nonsmokers, the risk of myocardial infarction increased with the risk or with the levels of renin; the same thing after controlling for cholesterol; the same thing after controlling for glucose.
		In addition, there were animal data, and these are one such studies, indicating in the radum (phonetic) centric artery that use of an ACE inhibitor decreases vascular wall thickening and also leads to dilatation of the artery.
		Victor Zahl (phonetic) has done a large amount of work in this area at the molecular level and has come up with a unifying hypothesis.  In this hypothesis, he thinks of the classical respecters as increasing oxidative stress in the vascular wall leading to endothelial dysfunction.  This then leads to a decrease in nitric oxide activity, and the secretion of a number of local mediators, including an increase in tissue ACE levels and adjutants in two levels.
		This has a prothombotic effect, an effect in stimulating inflammation in the vessel wall.  It could lead to vasoconstriction.  It could lead to hypertrophy both of the heart as well as the vessel wall, and my promote plaque rupture by inducing the secretion of various hormones, various enzymes that are proteolytic, such as the metallo-proteinasis (phonetic).
		So this was the basis on which several years ago, eight years ago, we embarked on this trial.  This is the summary of the study.  The main name of the study was to assess the effects of ramipril on Vitamin E or all Vitamin E versus its placebo on the primary composite endpoint of cardiovascular death, myocardial infarction or strokes.
		This was a randomized, double blind study utilizing a two-by-two factorial design.  We deliberately chose wide entry criteria.  The study was large, and it was simple.
		Nine and a half thousand patients were followed for about four to six years.  The study had high power to detect relative risk reductions in the primary endpoint in the range of 11 to 13 percent.  In addition, the study was designed specifically to examine the results in a few key subgroups and on a number of secondary endpoints.
		The study was organized in 267 hospitals in 19 countries in North and South America and in Europe, and it was coordinated by the Canadian Cardiovascular Collaboration Project Office at McMaster University in Hamilton, Canada.
		These are the key inclusion and exclusion criteria.  Patients over the age of 55 and at high risk of cardiovascular events, if they had any evidence of vascular disease, as long as they did not have markers of low risk or have heart failure.  This could be any evidence of coronary heart disease, strokes, or peripheral arterial disease, or if they were diabetics and in addition had one of the coronary risk factors or had vascular disease.
		We also excluded patients who had heart failure or those with low ejection fraction because that was clear proof of the value of ACE inhibitors in this population.
		In addition, if anybody was taking ACE inhibits for hypertension or any other reason, or they were on Vitamin E, they were excluded.
		These are the main outcomes of the study.  As stated before, the primary outcome was the composite of myocardial infarction, stroke or cardiovascular death.
		The secondary outcomes were the individual components of this composite, and in addition, we wanted to look at hospitalizations for unstable angina, hospitalizations for heart failure, total mortality, revascularization, overt nephropathy, and for the Vitamin E part, cancer, and that part of the study is still continuing.
		There were other outcomes that were prespecified, and these were two:  that with diabetic complications and other forms of heart failure, all forms of heart failure.
		In addition, the phones recorded at regular intervals cardiac arrest, worsening angina, and development of diabetes, but they were not prespecified as hypotheses in the protocol.
		These are the sample size and power calculations.   The study was due to get 8,000 patients by formal calculations, followed for three and a half years, and the event rate expected was about five percent per year.
		Using that, we would have high power to detect 15 to 17 percent risk reductions.  At the very beginning, we inflated the sample size by an additional 1,000 patients to overcome unexpected eventualities, such as lower event rates or poor compliance.
		In the end, we ended up with nine and a half thousand patients, followed for longer periods of time, and I shall explain to you why this happened.
		The original follow-up was meant to be to follow patients for three years after the first 18 months of recruitment so that the mean follow-up was going to be about 3.6 years.
		However, because of the consistent results from the anti-hypertensive trials and the cholesterol lowering trials, we were concerned that there would be a lag in the manifestations of the effects of ACE inhibitors because we were postulating an anti-atherosclerotic mechanism.
		So we thought perhaps the first two years we would have no treatment effect, and treatment would only -- the differences would only emerge later.  As you will see, we were wrong in this assumption, but nevertheless, this is the assumption that we in with.
		Furthermore, we had a lower event rate than expected.  Instead of five percent, we had 4.2 percent.
		The process by this decision was made was as follows.  It was made by the Steering Committee who had absolutely no knowledge of any of the blinded data other than the overall event rate.  We then requested and sought funding both from the Medical Research Council of Canada and from the sponsors in two steps, and we eventually managed to get a two year extension so that the mean follow-up would be comparable to that seen in the cholesterol lowering trials.
		There are certain additional aspects of the study organization that's worth pointing out.  In each country there were national coordinators and regional coordinators.
		In addition to the CCC project office in Hamilton, there were regional coordinating centers in Europe, in Brazil, and in Argentina.  These constituted the International Steering Committee.
		There were three important subcommittees.  Two of them were made of members of the Steering Committee and one was independent.  This committee, the Events Adjudication Committee, adjudicated all of the primary and prestated secondary endpoints blindly.
		In addition, the Data and Safety Monitoring Board, consisting of outside experts, independently reviewed the progress of the study.
		The study was funded through 14 sources.  What is listed here are the key sources.  The primary peer reviewed funding came from Medical Research Council of Canada and the Heart and Stroke Foundation of Ontario.
		The primary pharmaceutical funding came from Hoechst Marion Roussel in Canada and internationally.  Astra-Zeneca, King Pharmaceuticals were also major funders, as were contributions from the Vitamin E manufacturers.
		I should, however, stress that the study was independently designed, organized, conducted, analyzed, and reported by the Canadian Cardiovascular Collaboration and the HOPE Steering Committee, and the company only received the database after the publication of the results and the data being sent directly by us to the FDA.
		As you know, the study was terminated early because of clear evidence of benefit in favor of ramipril.  This occurred on March 22nd, when the Data Monitoring Committee recommended early terminations.
		On April 17th and 24, we presented the results to the investigator, and we had formally stated that all events up to April 15th would be counted.  Close-out visits were completed by August 1999.  Database was closed on November 1999 at which time vital status was ascertained in all but six out of the nine and a half thousand patients.  
		Non-fatal outcomes were ascertained in 99.3 percent of patients.  Adjudication was completed and possible in 99.9 percent of patients, and out of the 700,000 forms, 99.4 percent were declared clean.
		The data were first published electronically in the New England Journal on November 10th, 1999, and in print version in two papers, in January in the New England Journal and another one in the Lancet in the third week of January.
		Now, this is the process or screening and run-in.  Screening first.  Ten thousand seven hundred and ten patients were initially invited to an eligibility visit.  However, 134 were found to be ineligible at that time.  The vast majority of these were due to proteinuria or the use of ACE inhibitors, and a small number for using Vitamin E.
		Ten thousand five hundred and seventy-six, or 98.7 percent, were considered to be eligible and entered a run-in phase.  The run-in phase consisted initially of seven to ten days of two and a half milligrams of ramipril used in a single blind fashion, at the end of which creatinine and potassium were checked.
		This was then followed by a ten to 14-day period of placebo, which is also single blind.  Ten thousand five hundred and seventy-six patients entered the run-in, and 9,541 were randomized.  Approximately 1,000 were excluded after run-in.  The main reasons were due to nonadherence or the patient changing his or her mind.  A few patients had elevations of creatinine, cough, or hypotension or dizziness, and these are not mutually exclusive.
		Eventually we randomized nine and a half thousand patients to the overall program.  However, for the evaluation of ramipril, there was a sub-study, a secure sub-study, of 750 patients in which one third were also randomized to two and a half milligrams of ramipril, and that is this dose.
		So the main analysis of ramipril that I'll present to you is based on 9,300 patients.  However, the data adding this to this slightly strengthened the results and has no material impact on any conclusions we come to.
		These are the baseline characteristics.  There are two things to note:  first, that all the baseline characteristics were balanced.  The second thing to note are key findings.  The mean age was 66.  The blood pressure was 139 by 79.  The ankle-arm ratio was .98.  Heart rate was 69.  Body mass index was 28, and serum creatinine and potassium were as follows.
		This was a well treated group with about three quarters of patients receiving anti-platelet agents, four percent receiving anticoagulants.  Fifteen percent received diuretics for hypertension.  Forty percent received beta blockers.  Forty-six percent received calcium blockers, and about 29 percent receive cholesterol lowering agents, and this proportion increased over time as I'll show you in a minute.
		The key aspects of history as follows.  About two and a half thousand patients were women, making this one of the largest trials in cardiovascular disease to include women.  Eighty percent had coronary artery disease, out of which about 50 percent of the overall population had a remote myocardial infarction.  Eleven percent had cerebrovascular disease, and in 40 percent they either had clinical peripheral arterial disease or an abnormal ankle-arm blood pressure ratio.
		Forty-seven percent had hypertension, but these people have to have their blood pressures controlled before they enter the trial.  We were very much interested in the diabetic component and had a target of 40 percent of diabetics, but recruitment strategies insured that at least one third of the patients would be diabetics, and this is one of the larger trials of diabetes and cardiovascular prevention.
		These are the data on the change in concomitant drugs over time.  As you will see, three quarters of patients were on anti-platelets at the beginning.  At the end of the study you will see there is a slightly lower rate in the group receiving ramipril, and this is probably because there were more clinical events in this group compared to this group.
		Lipid lowering therapy increase in both groups and was nearly half by the end of the study.  Beta blocker use remained approximately constant, increasing in the placebo group and decreasing slightly in the ramipril use.
		Diuretic use increased in both groups, but to a greater extent in the placebo group.  Calcium channel blockers decreased in both groups, and that is consistent with the worldwide trend towards lower calcium blocker use.
		These are the data on adherence to the medications.  At one year, 85 percent of the patients receiving ramipril remained on study medications compared to 89 percent.  At four years, 68 percent compared to 71 percent.
		In addition, the proportion taking ACE inhibitors as an open label fashion was low in both groups, both at one year and at four years, but as you can see, it was higher in the placebo group compared to the control groups, compared to the ramipril group.
		These are the doses once a patient decided to take the medication.  These are the people who stopped taking the medication, and you will see in the majority of patients, if they were on the medication, they were tolerating and using the ten milligram dose.
		So we did achieve the goal that we wanted of getting the dose up to ten milligrams in the vast majority of patients.
		Now, these are the reasons why either ramipril or placebo was stopped.  Cough as a reason for stopping, as expected, was more common with ramipril, as was hypotension and dizziness.  There were lower rates of stopping blinded medication for hypertension because a clinical event occurred or for the use of non-study ACE inhibitors.
		This slide tells you -- summarizes data on the most important side effect that we are all concerned about about this class of agents.  During the run-in, there were five cases out of ten and a half thousand patients of angioneurotic edema.  All of them were mild and did not require hospitalizations.
		After randomization, there were 16 cases in the ramipril group compared to seven in the placebo group.  One was fatal in the ramipril group.  There was no such event in the placebo group.  There was one hospitalization here, none here.  Nobody required ventilation.
		We only had 141 patients who were blacks in the study, and they had no events in either the active or the placebo group.
		These are the primary results of the study.  The composite of myocardial infarction, stroke, and cardiovascular death.  There were 826 events in the placebo group.  That is 17.8 percent compared to 651 with ramipril, or 14 percent.  This represents a 22 percent relative risk reduction or relative risk, with relatively tight confidence limit, and it's clearly statistically significant.
		Each component of this primary was reduced, like cardiovascular deaths were reduced by 26 percent.  Myocardial infarction was reduced by 20 percent.  Strokes were reduced by 32 percent, and each of these three components was statistically significant.
		We postulated a neutral effect on non-cardiovascular deaths, and that's exactly what we found.  Overall, total mortality was reduced from 12.2 percent down to 10.4 percent, a 16 percent relative risk reduction.  That is also statistically significant.
		These are the survival curves for the composite primary endpoint, and you will see the curves diverge early and keep on diverging throughout the study.
		These are the data on myocardial infarction, and we see the same pattern of divergence and then continued divergence.
		These are data on strokes.  We again see a somewhat larger effect, but the same pattern of divergence within the first year and then continuing to go apart.
		Now, these are details of several vascular events.  These are the total number of strokes based on the previous slides, at 32 percent risk reduction with reasonably tight confidence intervals.
		In addition, we had a reduction in transient ischemic attacks, and if you take the composite of these two, that, too, is clearly reduced.
		Fatal strokes were reduced, as were non-fatal strokes.
		In addition, when you look at the types of strokes, you will see a significant reduction in ischemic strokes, a tendency towards lower hemorrhagic strokes, although these were less common, and strokes where we were not able to classify whether they were ischemic or hemorrhagic, but also tended to be lower with ramipril.
		These are data on the degree of disability and severity based in those having strokes.  You will see strokes that were associated with full recovery on nonlimiting were reduced.  Those that left the patient somewhat impaired was also lower, 56 down to 43.  Those that left the patient severely incapacitated or needing constant help was also lower, and these are the data that I showed you before on a reduction in fatal strokes.
		Therefore, the impact on strokes was across different types of strokes and different severities of strokes.
		These are the data on cardiovascular deaths.  Again, a divergence by about a year and continuing divergence throughout.  These are similar curves on total mortality, which again shows a slightly more delayed divergence, but then it keeps on diverging throughout the end of the study.
		Now, these are further details on the causes of death.  At the bottom are noncardiovascular deaths that I showed you.  At the top are the total cardiovascular deaths, which is where we found the difference, and we found that difference in myocardial infarction, in strokes, in a small trend towards heart failure deaths, little difference in documented arrhythmia, but there was also a clear difference in those with other cardiovascular deaths, and these are mainly periprocedural, either CABG surgery or PTCA or cardiac causes after noncardiac surgery.
		These data are on the primary composite endpoint stratified by the allocation to Vitamin E on no Vitamin E.  You can see in the half of the patients who were randomized to receive placebo for Vitamin E there is a clear benefit.  Similarly, in those receiving Vitamin E as the second randomization, there's a 21 percent risk reduction that is clearly significant.
		What this means is that if you divide the data into two random halves, we have clearly significant results in each of those two random halves.  
		It also means that the randomization to Vitamin E in no way interfered with the evaluation of ramipril compared to placebo, a point that I wish other sponsors would take note of.  It's a very efficient way of answering two questions for the price of one.
		Now, these are data on the subgroup analysis utilizing the primary endpoint.  We have pre-specified two sets of subgroup analysis to examine consistency, in those with cardiovascular disease and those without cardiovascular, those with diabetes and those without diabetes.
		As we only had about 1,100 people without cardiovascular disease, the event rates were lower in this group compared to the placebo group, but the relative risk reductions are consistent with the relative risk reductions seen in the overall study, which is what this dotted line is, although the confidence limits are wide, but nevertheless, they overlap, and the P value for interaction indicates no evidence of heterogeneity.  
		In those with diabetes and those without diabetes, in each of these two subgroups there is clear statistical significance compared to placebo, and again, no evidence of heterogeneity.
		These are data on other subgroups, and these are mainly being examined for consistency.  In those under the age of 65, those over the age of 65, the results were similar.  In men and women in both groups, the results were similar, and just to emphasize the point, we had two and a half thousand women, and the results in women by themselves are statistically significant, and because the upper confidence limit does not cross one.
		Those with hypertension history or those without hypertension history, the results are consistent.  Those with coronary artery disease, those without coronary artery disease, the results are consistent.
		Again, in those with a history of cerebral vascular disease, those without cerebral vascular disease, although we had only 1,000 people, this was a high risk subgroup, and again, the risk reductions are identical and there is no evidence of heterogeneity.
		In those with evidence of peripheral arterial disease and no peripheral arterial disease, similar results.  Those with micro albuminuria or no micro albuminuria at the randomization visit, similar results.
		So these three slides indicate to you that the results were consistent across many different subgroups and broad populations.
		These are the data on secondary outcomes.  We had a significant reduction in revascularization procedures, 18.4 percent down to 16 percent, representing a relative risk of .85, which is nominally significant.
		Hospitalizations for unstable angina, there was no impact, even overall or when we looked at the data in those who had ECG changes when they were hospitalized.  
		Hospitalizations for heart failure was numerically lower in the ramipril group compared to the placebo group at 13 percent risk reduction with wide confidence limit, and it's not statistically significant.
		These are the data on other outcomes that I had shown you in one of my earlier slides.  Complications related to diabetes mellitus was significantly lowered, and these data will be elaborated to a greater extent by Dr. Hertzel Gerstein.  So I request that you hold any questions on that for him.
		I will show you more data on heart failure, and heart failure, any manifestation of heart failure, was also significantly reduced by 23 percent with relatively tight confidence limits.
		Cardiac arrests were lower.  These are non-fatal cardiac arrests and are not counted in mortality.
		Worsening angina based on the patient's report was also lower, and much to our surprise, new diagnosis of diabetes mellitus was also lowered by 34 percent.
		These are the survival curves on revascularization.  You will see it took some time for the curves to diverge, and then it diverged throughout the duration of follow-up.  These are details on the types of revascularization.  You will see that coronary revascularizations were reduced by 17 percent, but there was also a similar trend towards reduced non-coronary revascularizations, such as peripheral angioplasty or surgery, limb amputation, or carotid endarterectomy.
		Now, before I show you further details on heart failure, I want to put the heart failure data in perspective.  As you know, heart failure and ACE inhibitors have a long history.  The first major trial in heart failure was done in the CONSENSUS 1 trial using an allopril (phonetic) in Class 4 heart failure some ten to 15 years ago.
		At that time, since we did not have a clear indication for the use of ACE inhibitors, when patients deteriorated, ACE inhibitors were hardly used, under ten percent of the patients.  I was easy, therefore, to show an impact on total mortality.
		By the time the SOLVD treatment trial was being done, we already had the results of consensus.  At that time we included people with low ejection fraction and heart failure, and in this study we saw an impact of mortality being reduced, but the risk reductions were smaller than this, and this may well be because of the lower risk patients, but also because of the higher rate of noncompliance.
		In addition, we showed an impact on heart failure hospitalization.  However, when we did the SOLVD prevention trial, which was being simultaneously run  as the treatment trial, when people deteriorated and had signs or symptoms of heart failure, up to 40 percent of patients received open label ACE inhibitors, and this was also a lower risk group which had low ejection fraction alone and no heart failure, and in this group we weren't able to show a clear reduction in mortality, but we showed a clear reduction in out-patient manifestations of heart failure and heart failure hospitalization.
		It is in this context that we should review the HOPE data.  The HOPE data included people without low ejection fraction, that is, preserved ejection fraction, and they had no heart failure.  
		When they deteriorated, they were allowed to use ACE inhibitors even if the patient did not reach a primary or second endpoint, and 60 percent of the people, when they developed heart failure as an out patient, received an ACE inhibitor, and we found a clear reduction in all manifestations of heart failure, and I'll show you those data now.
		These are the data that I've shown you before on heart failure hospitalizations.  There is a trend in favor, but it's not statistically significant.  These are the data on all manifestations of heart failure, including the ones that I showed you previously.
		You will see a 23 percent reduction.  That is clearly significant and keeps on diverging throughout the study, parallelling what we saw on other endpoints.
		These are further details.  This is the top line.  On all manifestations of heart failure, there's a 23 percent risk reduction with tight confidence limits.
		This was contributed due to a variety of different forms.  One is the use of open label ACE inhibitors for heart failure was also reduced by 28 percent.  When you take most of your manifestations, there's a 13 percent risk reduction, and when you take death, there's a 12 percent risk reduction.
		If you take the composite of cardiovascular death or all heart failure, there's a 24 percent risk reduction.  If you take the composite of cardiovascular death plus heart failure hospitalization, there's a 23 percent risk reduction.  That is significant, and all of these are consistent.
		There are two reasons to use the composites in formal statistical evaluation.  First, death is a competing event.  So when you take a secondary endpoint, it is methodologically more rigorous to use deaths plus heart failure hospitalization, although of course each of them contribute to the difference observed.
		The second reason is because -- gosh, I can't remember what the second reason is.  I'll go on.
		Now, these are data now on development of heart failure.  Sorry.  These are data now on the diagnosis of diabetes mellitus.  The way this was recorded was on an annual check box in the forms.  No tests were required, but I'll show you the data.  That's why you get these in steps annually.
		Remember this is a blinded study, and the total number of people unblinded in the study was under 20; is that right?  In five years.
		So essentially this diagnosis was being made unbiased, and there's a 34 percent risk reduction that is statistically significant.  
		These are further details of what the physician did when he or she diagnosed diabetes.  You will see oral agents were described in 53 patients in the ramipril group compared to 101 in the placebo group.  Insulin alone or in combination with oral agents, six here and four there.  And diet alone as a strategy was used in 43 patients in the ramipril group and 15 in the placebo group.
		Now, this study did not perform ejection fractions in everybody at baseline.  The protocol recommended that if you knew somebody had a low ejection fraction, please exclude them, but it wasn't demanded, given the fact this was an international study, and also the fact this was a cheap study.
		So, however, in 4,775 patients ejection fraction was available pre-randomization and was normal.  The mean ejection fraction was .59 in this group with this standard deviation.  The primary outcome was reduced from 18.8 percent to 13.9 percent, a 27 percent risk reduction, which is at least as large as what we saw in the overall population.
		Again, we see reductions in cardiovascular deaths, reductions in myocardial infarction, reductions in strokes, reductions in all manifestations of heart failure, and reductions in revascularization.
		So focusing just on the subgroups of patients where we know for sure have a preserve EF, the results are consistent and clear.  
		These are the data on blood pressure because one of the questions that could be asked is:  how much of the benefits can be explained due to blood pressure lowering?
		The first thing to note is that the blood pressure at entry was about 139 systolic by 79 diastolic.  That would not conventionally be called hypertension.  Some may call this borderline elevated blood pressure.
		You will see that in the middle of the trial, the difference in systolic blood pressure was just over three millimeters or just over -- this is about 1.8 millimeters diastolic.  So the difference in blood pressure was modest.
		Now, based on this and based on external data, we can project what degree of the benefit, what amount of the benefit can be explained by blood pressure lowering.
		Based upon previous trials of hypertensive patients who all had higher blood pressures coming into those trials, a ten to 15 millimeter difference in systolic blood pressure leads to a 40 percent lower stroke rates and a 15 percent lower myocardial infarction rates.
		We saw a 3.3 millimeter difference in systolic blood pressure.  Using these data, we would expect a 13 percent difference in strokes, but we saw a 32 percent reduction.
		We would have expected a five percent myocardial infarction reduction solely based on the blood pressure lowering, but we observed a somewhat larger effect.
		So we would be able to say or we would at least surmise that only a small proportion of the benefits are due to the blood pressure lowering effects of the agent and the rest may be due to other effects.
		This is further explored in the next few slides.  Here we divided people into quartiles by diastolic blood pressure and the next one by systolic.  So the quartiles we used were 70, 71 to 79, 80 to 85, and over 86.  We, in order to overcome regression to the mean, we calculated usual blood pressures, and interestingly the usual mean blood pressure in this group is higher than the cutoff, and the usual mean blood pressure here is lower than the cutoff.  That's just a methodological point.
		And you will see the relative risk reductions though are consistent across the four quartiles.
		The same holds true for systolic blood pressure.  The lower systolic blood pressure is, the blood pressure of under 124, 125 to 139, 140 to 150, or over 151, and you will see consistent reductions across the whole range, although it may appear visually there's a slightly higher benefit out here at the highest levels.
		Now, a third way that we looked at the data was to do a time dependent covariate analysis within our trial, adjusting for the observed reduction in blood pressure.  These are the unadjusted, crude results, a relative risk of .78.  After adjustment it was virtually unchanged.
		When we look at each of the individual components, you will see for myocardial infarction there is very little difference.  If anything, this is slightly more in favor of treatment, but for strokes you will see there is a slight attenuation of the benefit, and for cardiovascular deaths, again, there is only a slight attenuation of the benefit.
		So these three different approaches to the analysis suggest to us that the benefits are probably independent of blood pressure lowering.
		In my reserve slides, I have additional slides on atherosclerosis prevention, and if the committee would like to discuss it at a later time, I'd be happy to show them.
		Now, as a clinician, we were very pleased with the results of the study because as a clinician it meant this would be of great importance to my patients.
		If we treated 1,000 people for four years, we would prevent 18 deaths, 16 myocardial infarctions, and nine strokes for a total of 43 events, which means the number needed to treat to prevent one event is 23.  Since some of these occur in the same patients and to take into account overlapping events, the number of people in whom you'd prevent an event is 36, and the number needed to treat would be 28 people to prevent one event.
		As you know, there was 20 percent when it's noncompliant, and you can kind of crudely calculate what it might have theoretically looked had everybody taken the drugs.  Of course, that's theory.
		Now, in addition to these three major endpoints, a number of other clinically important endpoints or roles are prevented.  Now, if you put all of this into the equation, you will see 128 events were prevented in about 60 people, and the number needed to treat understandably gets smaller.
		Either analysis, the previous slide or this slide, indicates that clinically important and useful results have emerged.  
		Therefore, ladies and gentlemen, in conclusion, there is convincing evidence that ramipril prevents cardiovascular death, myocardial infarction, and strokes.  It prevents the need for revascularization.
		These benefits are consistently observed in a very broad range of high risk patients and in addition to other effective therapies.
		In addition to those observations, we found there was significant reductions in any manifestation of heart failure, in new diagnosis of diabetes, which was not prespecified, and in nephropathy, which Dr. Gerstein will devote an entire presentation to.
		The only major uncommon side effect or only common side effect is a five percent excess of cough.
		Thank you very much.
		ACTING CHAIRMAN CALIFF:  Okay.   What I'd like to suggest is that we focus the questions on the general study design, the organization of the study, and the primary results, and we save questions on diabetes and renal outcomes until those speakers present.
		And maybe we could just start, Udho, with you at your end and just work our way down and let everyone ask the questions that they have.
		DR. THADANI:  I suppose they purposely didn't allow me to speak into the microphone, no more questions.
		When I'm reviewing this, one of the issues you said the patients in the exclusion were not on ACE to be in the study, and yet the document I'm provided with from the FDA says they could not be withdrawn from ACE.
		Which is the truth now?  They could have been on ACE and they were withdrawn from the study and put in the study as long as they could be withdrawn?  Because --
		DR. YUSUF:  That's right.
		DR. THADANI:  -- there's a major issue there.
		DR. YUSUF:  Yeah, I think they could be withdrawn.  Is that right?  I mean --
		DR. THADANI:  But that could have important implications.  First of all, one of the exclusions you showed was the patients should not have been -- you know, patients in heart failure and ACE were excluded, and I think the assumption could be patients who were on ACE because of their heart failure, and if that is true, I'm not denying the results, but that could skew some of the results.
		If that is true, then some of the patients in heart failure actually could have been withdrawn from ACE for whatever reason, or for hypertension is possibility, and then that could have pushed the results in your favor because we know some of the patients did have low yields.
		I'm saying that --
		DR. YUSUF:  Can I answer the question?
		DR. THADANI:  Yeah, sure.
		DR. YUSUF:  I mean, it's a good question.
		We explicitly said that ACE inhibitors were indicated for two conditions and those patients should not be included:  those with heart failure and those with proteinuria. 
		So even if they were not on an ACE inhibitor, if they have heart failure, they can't get into the trial.  So that was stated right throughout.  In fact, that was an explicit decision by the steering committee.
		What I don't know is what proportion of the hypertensives were on ACE and were withdrawn and gotten.  I don't know the answer because of I don't think we recorded that.
		DR. THADANI:  I think it might have implication because even if your EF data is .5-something plus/minus .11 SD, so that if you allow two standard deviations, some of the patients are going to be below 40.
		DR. YUSUF:  No, no, no.
		DR. THADANI:  But it was .51.
		DR. YUSUF:  We actually -- let me -- let me take you through this.  We said anybody with an EF 40 percent or under should not be in the trial.  That was one.  I mean, take that into context.
		The other thing is .59, two standard deviations of .59 reduced by .11 is about .47.  Sure, there's still a tail of two and a half percent of people, but it starts to become increasingly unlikely.
		Now, let me also tell you we did a sub-study in 700-odd people where echoes were done consecutively, and in that only two percent of people had an EF under 14 percent.
		So I can't guarantee it is zero percent, but I can tell you it's going to be in that very low order.
		DR. THADANI:  The other important issue is the hypertension, the way JNC-6 guidelines are totally different now because hypertension is defined as 160, now is 140 and below.  So that incidence could change.
		DR. YUSUF:  Sure.
		DR. THADANI:  And if you look at the numbers, I think 50 percent of the population was hypertensive in the last slide you showed in the pressures above 140.  So there's a large number of patients who were hypertensive in the study.
		I realize the results are going in the right direction, but it has to be kept in mind.
		DR. YUSUF:  I think, you know, but ten years from now everybody in this trial will be considered to be hypertensive when we get JNC-8.
		DR. THADANI:  And, you know, one data you really do not show which I'm in the review, everybody talks about the aspirin-ACE interaction.  That's one of the issues --
		DR. YUSUF:  Sure.
		DR. THADANI:  -- I suppose we could discuss later on, and it seems like you also did not show where the patients came from.  A lot of patients came from Canada.  There are very few patients from the States, and the benefit is obviously because the sample size is greater there, at least the data I was given.
		Now, do you think that could be, although the data you do not show it, could be because of the integration rates are so different in the two countries regarding rewaspiration (phonetic), et cetera, would have impacted your results more so in Canada where it's, you know, waiting six months or one year for bypass, et cetera?
		DR. YUSUF:  Okay.  With the permission of the Chairman, can I show a back-up slide?
		ACTING CHAIRMAN CALIFF:  I think you should address both the --
		DR. YUSUF:  Sure.
		ACTING CHAIRMAN CALIFF:  -- aspirin interaction and the international difference.
		DR. YUSUF:  Can we have from our back-up slides, Angie -- well, just to be in the order that you are, can we have Slide 28 and then 29, please, first from the back-up?
		Okay.  This was an issue we examined, and the event rate was reduced.  The relative risk was .85 in those people taking aspirin, which is nearly 7,000 people.  Two and a half thousand people were not on aspirin.  In this group it was reduced by -- the relative risk was .59, and the interaction P value is quite significant.
		Now, two things to note.  First, this is significant on its own and for no reason would we say don't give aspirin.  Don't give aspirin and ACE inhibitors together.  We're going to say use them together so that there's an additive benefit.
		Now, the issue:  is this real or not?  We have done over 100 subgroups, and some of them will be real, and some of them may be, you know, due to the play of chance, and some of them may be even in subgroups where we think there is likely to be an effect.
		So we did two things.  If there is an aspirin interaction, it's likely to occur in other trials, and it could also occur on the other events in our trial that you expect treatment to have the benefit of.
		So we looked at revascularizations, and here, if anything, the effects are slightly greater in those on aspirin compared to those not on aspirin, no interaction P value.  On all heart failures the effects are similar, if anything greater here than here, and on nephropathy, which you will hear later, again, the effects are similar, slightly greater here, slightly smaller here, slightly greater there, but, again, there is no interaction on these.
		And if you take any of these outcomes, because in the end you will give treatment to prevent a number of different outcomes, you will see the relative risk is .83 compared to .74, numerically a bigger effect here, but in each case highly statistically significant benefit there, as well as there, and there is no interaction for between these events.
		We then did another thing because, as you know, I've been involved in coordinating a worldwide meta analysis of ACE inhibitor trials, and so we got data from not only HOPE, from SOLVD, SAVE, TRACE, and AIRE, and what we got was the individual data points.
		So we now have individual data points on 22,000 people on 7,000 events.  So this is now getting to be reasonable numbers to look at subgroups.
		On non-DETS (phonetic), you will see there's a 14 percent relative risk reduction here compared to 26 percent, nominally significant P value for interaction.
		Myocardial infarction, again, a somewhat greater effect there compared to here.  Again, significant, but note in no case does the confidence limits cross one.  So you would use it in those circumstances.
		But for strokes we don't see that.  For revascularizations, we don't see that.  For heart failure hospitalizations we don't see that, and when you take all of these together, you get a 20 percent risk reduction for those receiving aspirin for the effects of ramipril or for the effects of an ACE inhibitor, and those not receiving aspirin, there's a 30 percent effect, which is nominally significant.
		So there may be a weak quantitative interaction, but there is no qualitative interaction, and clearly based on these data, you would not withhold aspirin or ACE inhibitors should there be an indication to use it.
		ACTING CHAIRMAN CALIFF:  Can you address the international differences in outcome if there are any?
		DR. YUSUF:  Sure, I'd be happy to do that.
		Can we have Slide 16, please, of the back-ups?
		Okay.  This is the recruitment from different parts of the world.  You were right, Udho, that we had more people from Canada in the trial, and if you look at it, you'll think Canada is the most populous country in the world, but that would be a mistake.
		Five thousand seven hundred patients from Canada, 2,000 from Europe, 800 from the U.S., 730 from South America, and 300 from Mexico.  So this is about 1,000; this is 800; that's 2,000.  So there are reasonable numbers in each of these categories.
		What I'm showing you now is North America, and you will see in North America there's a clear reduction on the primary and the composite secondary.  In Europe there's a trend in favor, and remember European intervention rates are lower than North American intervention rates, and when you add the secondary endpoint, it's almost an identical effect.
		And Latin America, again, these are the results.  There is no evidence of heterogeneity by these categories.
		We also did it another way, and each of these ways are data dredging.  So just be cautious.  This is Canada, USA, Europe, Latin America, but remember the numbers in each now start to get small, and you will see the rates of interventions between USA and Canada were closer.  I won't say they were identical.  They were closer.  The lowest was here, and you will see these are the relative risk reductions for the primary, for the secondary, and the confidence limits overlap, and the interaction P values are certainly not significant.
		Now, remember these are data dredge.  We've been doing so many of them.  So at the very least we can say directionally the benefits are similar in different countries.  Of course, this trial was never set out to prove they were similar in each individual country.
		DR. THADANI:  I think you can probably come back to some more because one of the criteria for inclusion --
		DR. YUSUF:  Can we switch that off, please?  Thank you.
		DR. THADANI:  One of the criteria for inclusion is patients who did not have a previous MI could be entered in the trial provided they had a positive stress test or two SOCAD (phonetic), not one vessel, and it's possible that the intervention rate in the two countries are different because at least in our center they have got estimated depression of two millimeters.  With Italian (phonetic) positive, they are going to have some intervention.  So it might have some relevance.
		I'm not saying the totality of the result.  You have to keep that in mind.
		My last question before you go is how you define heart failure in this population when your secondary endpoint of hospitalization due to heart failure is not different because when the EFs are relatively preserved, I won't say normal, heart failure is not easy to diagnose.  So what was your definition of heart failure?
		DR. YUSUF:  Well, heart failure is tough to -- equally tough or equally easy to diagnose whether you have EF or not.
		DR. THADANI:  I realize.
		DR. YUSUF:  So it's not an EF criterion.  I think the hospitalization, there was a set of criteria.  I don't remember them offhand.  There was an adjudication.  There was a specific --
		DR. THADANI:  But it makes no difference in hospitalization due to heart failure?
		DR. YUSUF:  Well, there was a trend.
		DR. THADANI:  Yeah.
		DR. YUSUF:  Okay?  There was a trend.  Okay.  I think no difference does not accurately reflect the data.
		DR. THADANI:  It's a trend.
		DR. YUSUF:  And if you look at other forms of heart failure, that was a check box.  In the opinion of the investigator, based on a blinded -- remember there's a truly double blind trial with very few unblinding.  So there were check boxes for heart failure, and then they said whether an ACE inhibitor was used or not.  That's all there was.
		DR. THADANI:  My last question is the use of lipid lowering drugs.
		DR. YUSUF:  Right.
		DR. THADANI:  Especially the statens are fairly low.  These are high risk patients given the scenario of LDL cholesterol not required less than 100 probably.
		You think your results would be valid if everybody was given the risk reduction of stroke, given the risk reduction of revascularization and MIs with the lipid lowering recent trials?  Would it still hold or you need another trial to prove that this will be additive if the lipid reduction was more aggressive?
		DR. YUSUF:  Can I have my back-up Slide 32, please?  Actually 31 first and then we'll go to 32.
		This is 31.  We looked at these two therapies in addition to aspirin.  You're absolutely right.  It's a good question.  We know beta blockers save lives.  Lipid lowering also save lives.  So this is the results on the primary endpoint.  This is on the secondary endpoint.
		If they were taking beta blockers or no beta blockers, similar relative risk reduction, both for the primary and the secondary.  If they were taking lipid lowering medications, similar risk reductions both on the primary and the secondary.
		We also did a further analysis, and let's look at the next slide, and this is any of the above.  These are the three drugs that save lives, and remember aspirin, there was a nominal interaction.
		But if you take any one of these three, there is benefit in those, taking any of the above, 19 percent risk reduction, and here there's a 14 percent risk reduction if they weren't taking any, but I think that the entire thing is be contributed by aspirin.
		And you will see here on the secondary endpoint, which is more numerous, the relative risk reductions are identical or if you go to the subgroup taking all of the three.  So you've got a patient on a beta blocker or an aspirin and a lipid lowering.  You will see the relative risk reductions are similar, and there's no evidence of interaction.
		So I think although one could say that the benefits of ramipril are on top of the three other therapies we know that saves lives.
		DR. THADANI:  Thanks.
		DR. YUSUF:  Thank you.  
		Could you switch that off?
		ACTING CHAIRMAN CALIFF:  Okay.  Thanks, Dr. Thadani.
		Now, Dr. Fleming, do you have questions?
		DR. FLEMING:  Salim, I'd like to thank you for your terrific efforts in such a very informative and well conducted study.
		Some of the questions that I've had we've certainly got into.  I was interested in your subgroup analyses and some of the ones I was particularly interested in I didn't see, although you've begun to address them:  the issue of potential interaction by baseline aspirin use and by region.  You've begun to try to explain this.  
		It's interesting to me.  You've interpreted the results on aspirin use after you went back and looked at the meta analysis as there may be a weak quantitative interaction.  Even with your study alone the significance level is 002, and I realize this is in the context of many subgroup analyses.
		And you're right.  That has to be taken into account, but the meta analysis seems to strongly confirm there is absolutely a quantitative interaction.  Is it qualitative, i.e., is there still adequate evidence that there is benefit in those that are on aspirin?
		One of the ways that I'd be interested in getting additional insight beyond what you've presented there comes back to one of your earlier comments about competing risks.  And you had noted earlier that when you leave out, for example, certain events that are censored, that can create some difficulties, and in fact, it absolutely can statistically if we're looking at the primary endpoint, for example, of events that are death, stroke, and cardiovascular related deaths.
		By leaving out other deaths --
		DR. YUSUF:  Sure.
		DR. FLEMING:  -- those people who die for other causes aren't left out of the analysis.  They are, in fact, censored, and their future outcome is, in essence, in a Kaplan-Meier self-consistency approach estimated by other people who didn't die.
		So essentially if the two of us are moving along and we're matched in certain ways and I die and you don't, if I die from a non-CV related cause, I'm censored, and my subsequent risk of these events is represented by you, and it always leaves me completely uncomfortable to say what it is we're really estimating.
		DR. YUSUF:  Sure.
		DR. FLEMING:  So having said that, it is reassuring to see when you look at all cause mortality in the global analysis that results are so strong that even though you have, as you expected, essentially no difference in the non-CV related deaths, the results are still robust and positive.
		Where I begin to wonder a bit more though is when we start looking at these  two important interactions, and the first of these interactions is baseline aspirin use, yes versus no.
		Could you give us two analyses?  Could you show us the mortality data in those people who were on aspirin at baseline, and could you show us the endpoint I would have preferred, which is the composite endpoint of MI, stroke, and all cause mortality?
		Those two analyses --
		DR. YUSUF:  I don't have it.  I don't think we did it.  So --
		DR. FLEMING:  Could you -- these are really critical to interpreting the aspirin subgroup.  Could they be generated for us and presented before the votes?
		DR. YUSUF:  No, it's not possible to do that.
		DR. FLEMING:  Because it is interesting that in your analysis in those people who started on aspirin, and your point was you still have evidence to say there's benefit there.
		DR. YUSUF:  Un-huh.
		DR. FLEMING:  The relative risk estimate, I think, was .89, but the upper limit of the confidence interval was approaching one, and if you put the deaths in that were non-CV related --
		DR. YUSUF:  But, Tom, you know that's methodologically invalid for subgroup analysis.  I'm not talking of competing risk.  I accept your concept.
		DR. FLEMING:  Well, I'm talking competing risks here.  That's --
		DR. YUSUF:  Yeah, well, let me tell you the problem with subgroup analysis because you want to take your biggest delta, your most sensitive endpoint, and then do a subgroup analysis because, you know, you could say why didn't you add in cancers.  The reason we're not adding cancers is we don't expect an effect on cancers.  So it's meaningless to do a subgroup analysis on cancers.
		So my approach, for which I've written for 15 years on subgroup analysis, is take your most sensitive endpoint and then look for interactions in that, and that's what we've done.
		DR. FLEMING:  So if, in fact, the most sensitive endpoint is truly a statistically valid endpoint, the problem is censoring the deaths does not protect the --
		DR. YUSUF:  But, Tom, I think we could spend a lot of time on cost specific mortality.
		DR. FLEMING:  -- a statistically valid endpoint.  That's the problem.
		DR. YUSUF:  Well --
		DR. FLEMING:  And so it is fortunate in your composite analysis where you do show it to us, you do show us the analysis when you look at all cause mortality that it's significant.
		The concern that I have is when you see considerable evidence that there is, in fact, at least a qualitative or quantitative interaction, that it would be at least of interest to look at mortality in that group.
		DR. YUSUF:  Let me say one thing.  First, there is absolutely no indication of a qualitative interaction.  So we shouldn't use that term.
		There is a --
		DR. FLEMING:  Quantitative interaction.
		DR. YUSUF:  Quantitative, yes.
		DR. FLEMING:  There's clearly a quantitative interaction.
		DR. YUSUF:  Sure.
		DR. FLEMING:  The question is:  is it qualitative?  That's the question.
		DR. YUSUF:  Well --
		DR. FLEMING:  Let me move on because this is an analysis that unfortunately should have been done because it's certainly of interest to know whether or not when you include all cause -- you do include all cause mortality in your global analysis.  So it certainly would have been of interest --
		DR. YUSUF:  Actually I don't.  Nowhere do I include that.
		DR. FLEMING:  Well, you present us all cause mortality.
		DR. YUSUF:  As a curve.
		DR. FLEMING:  A global analysis.
		DR. YUSUF:  As a single curve.
		DR. FLEMING:  Right.
		DR. YUSUF:  Yeah.
		DR. FLEMING:  The second issue, and you've addressed the Canadian issue, and the tests for interactions that you showed us, actually you didn't show us the test for interaction on Canada versus non-Canada.  The non-Canadian sites seem to have consistently far less evidence of benefit.  The relative risk estimate in Canada of .71, in the U.S. .91, and in all non-Canadian sites is .89.
		So there is here, again -- there are issues of attempt to dissect noise from signal, but it's very interesting to see a fairly consistent evidence of much less effect outside of Canada.
		What is your best sense of what could be causing what would be maybe a threefold higher effect in Canada?
		DR. YUSUF:  I think I -- first, I do not accept there is a higher effect in Canada compared to the rest of the thing.  First, it's an extremely data derived analysis, and let us give you a scenario.
		The overall results were nonsignificant, and in Canada there was a striking result.  I don't think any of us could come to the conclusion that it works in Canada and doesn't work in the rest of the world.  We would base --
		DR. FLEMING:  So you're arguing that basically there really is no difference --
		DR. YUSUF:  Yes.
		DR. FLEMING:  -- in any factors in Canada versus, for example, delivery of care of supportive measures in the U.S.
		DR. YUSUF:  No, no.  What we're saying is there is no strong evidence that the treatment varies to a considerable extent by region.  I mean we can keep on dissecting this out, and I'm sure we'll find 50 centers where actually the treatment would go slightly the wrong way.
		DR. FLEMING:  Well, we're not looking for 50 centers.  We're looking for major groupings, and --
		DR. YUSUF:  But, Tom, I've already presented about 50 subgroup analyses.  Some things are going -- there was no hypothesis around this.  There is no pre-specified hypothesis.
		If you really wanted to address that question, I would say let's take the meta analysis of all the trials, 22,000 patients, and then look at it by region.  That would be interesting.
		DR. FLEMING:  And what did that show?
		DR. YUSUF:  We haven't done it.
		DR. FLEMING:  Okay.
		DR. YUSUF:  We haven't done it, but I can tell you what it's likely to show because the SOLVD trial was predominantly U.S.  The SAVE trial was substantially U.S.  The likelihood is that it will show that Canada and the rest of the world would be very similar results.
		ACTING CHAIRMAN CALIFF:  Just an editorial note here.   We're going to come back to this discussion later because certainly when it comes to the U.S. FDA, there are a host of international trials now with results that look sort of like this, and so we'll come back to the generalizable issue later.
		DR. FLEMING:  Let's do that.  Let me move on to the next -- the last of the separate issues:  race.  Could you show us the race?  You didn't show us the race subgroups, and give us any comments you have on those.
		DR. YUSUF:  I mean the race subgroups have even bigger problems because of the small numbers.  I'll show you the data, but just be very careful in interpreting them.
		Can we have Slide No. 20, please, back-up?
		Okay.  The commonest race in the study is white, Caucasian.  There was no hypothesis related to race when we went into the study, no attempt at sampling by race, and you will see if you look at that the relative risks overlap and the confidence limits overlap, and if you take the secondary endpoint, which in a sense is twice the number of events, this is primary plus secondary, not secondary alone.  You will see the relative risks are identical.
		Now, if you further subdivide, which is -- the first one itself I would say is methodologically problematic.  If you further subdivide, you're starting to get tiny numbers in many of the races, and it's all noise.  You know, it's all over the place.
		You will see for one endpoint it seems there's no effect.  Another endpoint, there is an effect, and vice versa out here.
		So I think, you know, really the totality of the data on the whole thing is what you really must emphasize, and all of these are interesting to look at, but they are so problematic with lack of power and the play of chance.
		DR. FLEMING:  It's absolutely true that one has to be cautious in interpreting subgroups because of the multiplicity of testing.  At the same time, to basically ignore what they say because of the multiplicity of testing is also a dissatisfying conclusion.
		DR. YUSUF:  Sure.
		DR. FLEMING:  I guess there are two things that are evident there.  One is how strikingly unrepresented the blacks were in this study, and the second is the relative risk estimate, granted in small numbers, is in the wrong direction.
		DR. YUSUF:  On one endpoint, not the other endpoint.
		DR. FLEMING:  Is there any -- are you suggesting that there's no other data from other related studies that would also suggest lack of benefit in blacks?
		DR. YUSUF:  It's very hard to get the data.  I'll tell you why.  We tried to do this before this because we have a meta analysis of the ACE inhibitor paper in press in the Lancet prior to this, and at the last minute this was an issue that came up.  We tried to get it.
		There are only 200 or 300 such patients in the SAVE trial.  There it seemed to be consistent out of 2,000, and in the SOLVD trials, on some endpoint the results were the same; other endpoints it wasn't.  The AIRE trial and the TRACE trial were done in Europe so that there are no blacks.
		So that if you take the world literature in blacks, it'll be about 600 or 700 people in randomized trials, long term treatment.
		DR. FLEMING:  And the overall conclusion there about relative risks in the meta analysis?
		DR. YUSUF:  I don't really know because I haven't done a meta analysis of HOPE plus the other ones.  I've done one with the other ones separately, and there is absolutely no hint of heterogeneity.
		DR. FLEMING:  Last question.  Why did you do the secure sub-study?  Obviously one answer is to look at the lower dose.  You did.  What was your intention in doing that when you designed the trial?
		DR. YUSUF:  Okay.  There were two things that happened.  First, the secure sub-study in our mind was primarily done to look at the effects on atherosclerosis.  We as investigators only wanted to study in the whole study one dose, ten milligrams.
		There was a very strong push from the marketing people to study two and a half milligrams.  In fact, they wanted the whole study at two and a half milligrams.
		We came to an impasse.  Secure the three dose thing was a compromise whereby we said, "Okay.  Let's test two and a half, as well, in a sub-study.  It won't hurt the main study."
		The argument was very simple.  You know, if you need 10,000 people to show an effect, you'd better go with your best dose, especially when you know the --
		DR. FLEMING:  So essentially to obtain at least some evidence as to whether there is a dose response.
		DR. YUSUF:  And would you like to see the secure data?  It's actually interesting.
		DR. FLEMING:  Well, you did show it to us.  You can show it again, sure.
		DR. YUSUF:  No, I haven't actually.
		DR. FLEMING:  You showed us in the book.
		DR. YUSUF:  Have we?  Okay.
		DR. FLEMING:  And it looked as though the effect was there in the lower dose.
		DR. YUSUF:  Yes, there is a trend, but there are some more interesting data actually worth looking at.
		Can we go to 39 on the back-up?
		Okay.  Now, this is the randomization and secure where a third went to ten milligrams, a third went to two and a half milligrams, a third went to placebo, and then there was the further randomization to Y2ME (phonetic).  I won't show you any data.
		Primary endpoint in this was progression of atherosclerosis using the carotid evaluation, and the next slide will show you the blood pressure changes.
		First, you would be interested.  The mean blood pressure was 131 systolic by 76 diastolic, even more normal.  The degree of blood pressure drop was small for both ramipril arms, but interestingly identical for both ramipril arms.  So although we used two different doses, the blood pressure lowering was the same.
		Now, these are the data on atherosclerosis progression.  You will see there was a dose dependent reduction of atherosclerosis progression, and this P value is one for trend, and this is showing that that's different from that.
		So using a trend analysis that's significant.  Using just this, this is significant.
		So we have this interesting observation that the low dose had the same effect on blood pressure as the full dose, yet had visually less of an effect on atherosclerosis progression.  So this actually helps us in thinking about the dissociation of the blood pressure effect with this atherosclerosis progression further.
		And the clinical events were very few.  Oh, sorry.  They switched that off.  Is there one more slide?
		DR. FLEMING:  That's the most important slide.
		DR. YUSUF:  Okay.  Actually there must be another slide.
		Here are the clinical -- well, it isn't the most important slide.  It's the least common event, and --
		DR. FLEMING:  That's the most important event.
		DR. YUSUF:  Yeah, that's why we did HOPE, Tom, you know,, and you will see the primary outcome, there's a trend towards a lower effect.  Again, it seems to be -- I mean, I don't know what you'd make of it.  It fits in, but it's in between this and this, and it would be too much if I made anything of this.
		I mean these are the data.
		DR. FLEMING:  Well, then essentially I come back.  What was your intention, again?  It shouldn't have been to be establishing blood pressure.  You have given appropriate arguments that blood pressure is not the mechanism through which the effects are mediated.
		DR. YUSUF:  Actually the primary endpoint was carotid atherosclerosis.  So we were interested in the clinical outcomes, not -- sorry.  We were interested in the atherosclerosis outcome and LV hypertrophy.  We haven't yet analyzed the LV hypertrophy data.
		So I hope I've answered your question clearly.  It was the B mode ultrasound, and we powered the study for that, which is going back as I -- it's not working backwards anyway.
		ACTING CHAIRMAN CALIFF:  Okay.  Tom, anymore questions?
		DR. FLEMING:  Not at this point.
		ACTING CHAIRMAN CALIFF:  Okay.  Dr. Armstrong.
		DR. ARMSTRONG:  Salim, could I just return to a couple of points and then raise a couple of others that my colleagues have identified?
		There is historic evidence for biologic plausibility about less of a blood pressure lowering effect in blacks and a higher frequency of angioedema.  As I understand it, none of the angioedema in the ramipril group occurred in blacks.  Please confirm.
		DR. YUSUF:  That's true.
		DR. ARMSTRONG:  And, secondly, do you have information on the blood pressure lowering in the black population in HOPE as it relates to the general population?
		DR. YUSUF:  Actually we haven't looked at it, Paul.  I don't know the answer to that.
		DR. ARMSTRONG:  The second point was that there is, as you know, biologic plausibility concerning the attenuation of the hematodynamic effects of ACE inhibitors with concurrent aspirin, and in relationship to the difference in the treatment effect, while still significant in the aspirin ramipril group, do you have information on the blood pressure in those patients as opposed to those not receiving aspirin in ramipril?
		DR. YUSUF:  Did we look at that?
		I don't think we've looked at that.  So I'm sorry.  We can't answer.
		But one little point that's worth noting.  I mean, yes, there was that interaction on the primary, but the event that is most closely linked to blood pressure and also most closely at least in my mind linked to hemodynamic changes is heart failure, and on heart failure it was the other way around.
		You know, we had a bigger effect on those who were on aspirin.
		DR. ARMSTRONG:  My third question relates to the issue of cigarette smoking, which is in the label for secondary rationale, and just to inquire as to the definition.  In other words, was any cigarette consumption perceived to be cigarette smoking since that's relevant to the label?
		DR. YUSUF:  What was the answer, Jackie?
		I don't know the answer.
		DR. ARMSTRONG:  So one or two cigarettes would qualify for this label.
		DR. YUSUF:  I think it was current smokers.
		DR. ARMSTRONG:  Okay.  The other question relates to the echo sub-study, and I recognize that you've taken care to try and address the issue of ejection fraction.  I continue to be surprised that in excess of half of the overall population in HOPE had a prior myocardial infarction, and yet the ejection fraction as reported is, you know, well up into the normal range, which raises in my mind the question as to whether the distribution of prior infarction in the sub-study that received echo cardiography was similar to the overall population.
		DR. YUSUF:  Do you have the baseline secure data, the secure paper with you?
		All I can say, I haven't looked at this specifically, but we wrote the paper, and it didn't seem to us there was any major differences in baseline characteristics in the secure because the secure was done in five centers, every consecutive patient.  So I --
		DR. ARMSTRONG:  I'm sorry.  I'm confused.
		DR. YUSUF:  I don't have the numbers with me.  So sorry.
		Is it 50 percent?  So it's the same.
		DR. ARMSTRONG:  Are you surprised that despite a population in excess of 50 percent with prior infarction that there would be normal ejection fractions?
		DR. YUSUF:  No, we deliberately excluded people, you see.  If they had a low EF, they would be excluded.  So obviously whatever value we have in EF is -- is sort of an artificial value.
		DR. ARMSTRONG:  I'm just a little surprised that with over half of the population with prior infarction their injection fractions are normal and wondered if the other half who hadn't had echo cardiography also had normal ejection fractions.
		There are two issues around dichotomy for unstable angina and heart failure that have been previously raised, and it would be helpful to me if you would just address them again, and that is since, again, revascularization is perceived as a secondary component of the label, yet unstable angina and unstable angina with electrocardiographic changes were not affects, could you comment on the reconciliation of those phenomena?
		DR. YUSUF:  I don't have a good explanation why unstable angina was not changed, and like you I'm puzzled actually.  We had a reduction in MI.  We had a reduction worsening angina, and we had a reduction revascularization.  So I don't understand that.
		DR. ARMSTRONG:  And I believe in SOLVD you had a reduction.
		DR. YUSUF:  That's right, but SAVE did not.  You know, it's -- you know, maybe it's not a good endpoint.  I don't know.
		DR. ARMSTRONG:  Okay.  Ordinarily hospitalization for heart failure tracks heart failure fairly well, but in this study it did not.  Comments?
		DR. YUSUF:  Well, it did, except that as soon as somebody got mild heart failure, they were given an ACE inhibitor, and the protocol allows it.  So directionally it tracks it.  Magnitude-wise it doesn't.
		So, for instance, we found a 27 percent impact on the earliest manifestation of heart failure.  Then if you take hospitalization as being more severe but a later manifestation, we only had a 13 or 14 percent effect.
		And if you take death, it was a smaller effect, and I think it is partly due to the fact at least because of the noncompliance.  Sixty percent were given ACE inhibitors when they got heart failure, and the protocol allowed that.
		DR. ARMSTRONG:  My final question, which may be a function of my imperfect memory, as I recall in SOLVD there was a statistically significant increase in the incidence of carcinoma, which was thought to be a chance finding in I thought it was colorectal, but I can't remember.
		And I understand that there's a similar trend in this study which is under observation.  Could you comment on --
		DR. YUSUF:  No.
		DR. ARMSTRONG:  -- this tricky issue associated with cancer and all cause mortality?  I'm having a little trouble understanding it.
		DR. YUSUF:  I think in this trial it will be fair to say there was a ten percent nonsignificant lower rate of cancers with ramipril compared to placebo, but it's nowhere near significant, and I don't recall us ever doing an analysis by site for ramipril.  No, we haven't even looked at it by site for ramipril.
		DR. ARMSTRONG:  Did you say lower or higher?
		DR. YUSUF:  I don't know where they got those numbers.
		DR. ARMSTRONG:  Nine colorectal cancers in ramipril and one in placebo?
		DR. YUSUF:  Can I see that?
		DR. THADANI:  It was the other way around.
		DR. YUSUF:  No, no, no.  I'm talking about overall cancers.  Okay?
		DR. ARMSTRONG:  And I was talking about the incidence of colorectal cancer in SOLVD and the incidence in --
		DR. YUSUF:  Actually in SOLVD there was a numerical excess, but it wasn't significant, and when you looked at the data in SOLVD, and it's there in the paper, we said it was unlikely to be real because it was from mouth down to rectum, and obviously mouth etiology is very different from rectum.
		The second thing is all those excesses in SOLVD occurred in the first two years, and cancer takes time to develop.  So we felt it was implausible.
		I can speak to SOLVD because I wrote the paper.  This one we actually -- "we," CCC -- didn't do any analysis beyond overall cancer.  So what you're seeing is what the FDA statistician has done.  We haven't done those analyses.
		DR. ARMSTRONG:  Thank you.
		ACTING CHAIRMAN CALIFF:  Dr. Lindenfeld.
		DR. YUSUF:  Okay.  That's worth pointing out, Paul.  It's based on AE reporting.  Now cancers weren't required to be reported.  So actually most of the cancers that occurred in the study weren't part of the AE file.  We know this because we -- for another part of the study this is an issue, and so we looked at cancers and pulled our cancers from every source.
		So I think that's an incomplete part of the data.
		DR. LINDENFELD:  Okay.  It's been a pleasure to listen to this data.  I want to go to a different issue for a minute.  One of the entry criteria was to be diabetics with a single risk factor, and yet the data is presented as all diabetics.
		DR. YUSUF:  Sure.
		DR. LINDENFELD:  I wonder if in the interest of people who may be using ramipril for this indication, could you show us the results in diabetics with no vascular disease?
		DR. YUSUF:  I don't have the slide, but Hertzel will address that issue.
		DR. LINDENFELD:  Okay.
		DR. YUSUF:  Dr. Gerstein in the next presentation.
		DR. LINDENFELD:  And then I guess at the same time maybe we could see what risk factors were in those diabetics, how many had, in fact, just a single risk factor and how many had multiple.
		DR. YUSUF:  Actually we don't know that, Joann.  I can't recall.  Did we ever do that analysis?  No, I don't think we've done that.
		DR. LINDENFELD:  Because I think that will be an important group to see, just in terms of indications.
		Again, in terms of entry, patients were entered for one of four reasons:  coronary disease, vascular disease, stroke, and then the diabetes indication.
		Do you have those divided by how many -- I recognize that many of these patients had one or more of the vascular complications, but was there a specific reason for entry?  
		In other words, what I'm getting back at is in a patient who's had a stroke and no other evidence of disease, do you know how many patients like that were entered for that reason or for the reason of peripheral vascular disease?
		DR. YUSUF:  What we have done is to look at the primary reason for entry.  I don't -- I'm afraid we didn't bring any slides on it, but the results are consistent.  What we have not done is how many people had stroke only or coronary artery disease only.  I don't think we ever did that analysis.
		DR. LINDENFELD:  I understand that this is a large group of patients, and we think of vascular disease similarly, but there have been studies where there appeared to be differences in benefits by -- such as Capri, for instance, in which there may have been differences in the --
		DR. YUSUF:  But here we have, you know, the same kind of Capri analysis I've actually shown you.
		DR. LINDENFELD:  Right.
		DR. YUSUF:  And there there's consistent benefit in all the groups.
		DR. LINDENFELD:  Okay, and then in terms of the blood pressure, I'd like to get back to that for just a minute.  Do you have the blood pressure draft?  You said that two years was three millimeters systolic and two diastolic approximately.
		DR. YUSUF:  Yeah, about 3.3 and 1.8.
		DR. LINDENFELD:  And then at the end of the study?
		DR. YUSUF:  It's about the same delta.  I just focused on the middle for presentation.  It was there on the slide.  It's actually slightly less towards the end because of noncompliance.
		DR. LINDENFELD:  And then in the ramipril 2.5 dose, do we know what the blood pressure drop was?
		DR. YUSUF:  It was on that curve.  It paralleled what ten did.  So it's about the same order of magnitude.
		DR. LINDENFELD:  About the same.
		DR. YUSUF:  About the same.  It may be off by a second decimal point, but it's about the same.
		DR. LINDENFELD:  Okay, but perhaps -- again, I know this is getting down to analysis that's difficult, but perhaps an intermediate effect with a similar --
		DR. YUSUF:  No, no.  Actually it was numerically slightly greater than the ten.
		DR. LINDENFELD:  I see.
		DR. YUSUF:  Although not significantly greater, but numerically in one case it was 3.5 at the lower dose and 3.3 at the higher dose.  So it was opposite to what you might have expected.
		DR. LINDENFELD:  And then just as a clarification, in our FDA booklet, the primary outcome events were adjudicated; is that correct?
		DR. YUSUF:  Yes, all the primary, secondary, heart failure, hospitalization, revascularizations, nephropathy, and unstable angina were also adjudicated.
		DR. LINDENFELD:  And then just as a comment, I think as we talk about race here, there is some data, albeit in small numbers, to suggest there might be differential effects.  
		DR. YUSUF:  Yes.
		DR. LINDENFELD:  For instance, in VHEFT (phonetic) there may have been a differential effect in blacks and heart failure, and I think the best study will show potentially a similar one.
		DR. YUSUF:  We actually -- Jay Kohn (phonetic) rang me when he had that analysis, and we  redid the SOLVD analysis, and we couldn't find it the way he did.  Then he asked for all kinds of combinations to try to get something close, and one out of seven or eight analyses hinted at it, but overall in SOLVD it's an analysis we've done.
		One of the problems with analyses like RACE, which is not a prespecified hypothesis in trials, is if you did many trials, in one or two of them there'll be an interesting trend, and if only the people who have the interesting trend reported, you have a biased impression of the literature because the others didn't report it because it was uninteresting.
		And I can tell you for SOLVD we've looked at it, and the reason we've never presented it is there was nothing interesting in it.
		DR. LINDENFELD:  Okay.
		ACTING CHAIRMAN CALIFF:  Dr. Borer.
		DR. BORER:  One of the very good things about sitting in the middle of the table with such a sharp group here is that by the time you get to me there's not much to ask, but I have a couple of questions anyway.
		First of all, you indicated a reduction in heart failure by whatever definition, heart failure development at any point during the study on ramipril.  I didn't see in any of the materials we received the definition used to identify heart failure.  I understood heart failure hospitalizations, and you showed a category of new use of angiotensin converting enzyme inhibitors as supportive evidence that heart failure was present, but how did you define new onset heart failure that didn't require hospitalization?
		DR. YUSUF:  I mean, it was basically at the discretion of the clinical investigator.  So he or she thought there was heart failure.  There was a check box.  So to be fair we didn't even ask was JVP elevated.  We said it was, and then we asked did you use ACE inhibitor or not, and you know, 60-odd percent used an ACE, initiated ACE inhibitors.
		So that's all the data we have, Jeff, and that's it.  That's what we have.
		DR. BORER:  Okay.  Similarly, with regard to peripheral arterial disease, the plan was to enter about ten percent of the patients, I guess, with peripheral arterial disease?
		DR. YUSUF:  No, we didn't have a quota for it.
		DR. BORER:  Well, there was some discussion for that, but it doesn't matter.  That's not important here.
		DR. YUSUF:  Yeah.
		DR. BORER:  The point is that there was the expectation that a certain percentage of patients might have or some proportion of patients might be entered with PAD.
		As I looked at the data, in fact, about half the patients had PAD, which was comforting to me to see, but I didn't understand the criterion because -- the criterion by which the diagnosis was made.
		The entry criteria included in addition to critical limb ischemia evidence, an ABI of less than .8, and I would assume that you didn't have an ABI of less than .8 or claudication or both in 50 percent of the patients, or did you?
		DR. YUSUF:  Okay.  There are two different things, and then I can show you some data as well.  The first is if they had clinical evidence of PAD, either symptoms or surgery or something else, then they're in.  Okay?  And if it's only symptoms they need the low ABI as well, so that it was both.
		Then we have data on ABI and everybody. Okay?  So I can show you the data both ways, clinical symptoms and just by ABI if you'd like.
		And can we see, yes, 33, Angie, please.  Thank you.
		Okay.  These are the data.  This is clinical PAD.  Okay.  So we had 1,700 people with some evidence of PAD clinically, and that's the risk reduction on the primary and the secondary.
		Then we took everybody, including these people, okay, and divided them into quartiles.  What's not included here are the people that we couldn't record ABI because they couldn't palpate the dosalisbeaters (phonetic) or the posterior tibial, but leaving that out, which is about 800 people, this is the rest of the people by quartiles.
		And you will see, you know, the relative risk is there right through our -- there's no evidence of interaction.
		DR. BORER:  Okay.  So the point is that about a quarter of the population had either an ABI that was relatively low plus --
		DR. YUSUF:  Can we switch the light off, please?
		DR. BORER:  -- plus or minus claudication, or they had had surgery, or they had angiography showing significant obstruction?
		DR. YUSUF:  Right, right.
		DR. BORER:  Okay.  Finally, I don't want to beat a horse that's already been riding for a great deal of time here, but I would like to get back to the race issue as well because I was concerned by it, too, for the same reasons that Tom indicated initially.
		It's true you didn't power the study to look at the impact of race, and it's true that the sample size of blacks particularly was very small.  Nonetheless, I too think that there is a potential biological basis for hypothesizing that there might be a difference in blacks and in others, and the labeling consideration here would be potentially important.
		Despite the very compelling pathophysiologic construct of Dr. Zow, we don't really know how ACE inhibitors cause their apparent clinical benefit in this setting, but we do know that renin levels vary within the population, and that by and large black people have lower renins than non-black people.
		And I wonder.  Do you have any information at all about renin levels in any part of the population, in any subpopulation, and can you look at the impact of this drug on the endpoints that are of interest here with regard -- as a function of that parameter?
		DR. YUSUF:  Jeff, that's a good question.  It's one of the many analyses we intended to do with stored bloods.  In three and a half thousand people we have stored bloods.  Now, the unfortunate part -- not the unfortunate part -- the reality is that those bloods are all collected in Canada.  So we wouldn't have many blacks in it.
		But we could look at it by measured renin levels, high, low, intermediate, and try to explore those questions, but it's one of those things that we intend to write a grant and raise money to do.
		One little point just worth noting.  You know, yes, on the primary endpoint in blacks.  Numerically the odds ratio was 1.59 with white confidence limits from .66 to 3.79.
		But if you look at the secondary endpoint, you get a relative risk of .70 with confidence limits that go from .38 to 1.3.  It's exactly the opposite.  It just emphasizes the unreliability of small numbers.  It will be incorrect for me to use the secondary endpoint to claim we have proof that it works in blacks.
		I mean, I'm glad Tom's nodding his head in agreement.  I think the point is we don't have many people there, and we shouldn't try to make too much of that subgroup.
		ACTING CHAIRMAN CALIFF:  Okay.  I'm going to reserve my questions until the end.
		John Di Marco.
		Bad luck with the microphones here.
		DR. Di MARCO:  Salim, a very nice presentation.  Can I ask you just a couple of questions?  Most of your events are myocardial infarction, and can you review for me how the diagnosis of myocardial infarction was made in this study which is carried out across the world and what your criteria were and what your events committee, you know, required for the diagnosis?
		DR. YUSUF:  Would you mind?  We have the ‑- we'll do two things.  One is I can give you what the events committee's criteria is, but the chairman of the events committee is Dr. Dagenais, and maybe, Giles, you'd like to come up to the microphone.
		I mean, we had very detailed criteria.
		DR. Di MARCO:  Part of the reason that comes up, because if you look at your deaths, the vast majority of your deaths are related to myocardial infarction, and you have very few sudden deaths.  You have a bunch of resuscitated cardiac arrests, but did you classify a sudden death as a myocardial infarction?
		DR. DAGENAIS:  No.  What we did was to use unexpected death, which was 24 hour.  It was at the 60 minute.  So it was unexpected cardiovascular death as a definition.  So we cannot say that this was really the death within one hour.  We didn't make that difference.
		DR. Di MARCO:  But what I'm just saying, were they classified --
		DR. YUSUF:  I've got the criteria here.  I can help you.  Unexpected deaths within 24 hours were classified as cardiovascular presumed MI.  Then we have fatal MI.  Then we have heart failure deaths.  Then we have post intervention deaths, and then we have documented arrythmia, and then dying either due to bradyarrythmia or tachyrhythmia.  Then we have a bunch of other categories for cardiovascular, but those are the ones that would be related to --
		DR. Di MARCO:  So someone found asleep dead in bed, how were they classified?
		DR. DAGENAIS:  Well, as unexpected cardiovascular death.
		DR. Di MARCO:  Well, in your table is that an MI?
		DR. DAGENAIS:  It was unexpected.  I mean it was classified as unexpected cardiovascular death.
		DR. Di MARCO:  Well, in the slide that was shown it says cardiovascular.  It says MI/heart failure, documented arrythmia and other cardiovascular.
		DR. DAGENAIS:  It was among the cardiovascular deaths.
		DR. YUSUF:  It would be in the other.  That is the point.
		DR. Di MARCO:  I thought you said all of those were post procedure, and most of those --
		DR. DAGENAIS:  All those were post procedure.
		DR. YUSUF:  Sorry.  Tell me what it is.
		It was an MI?  Okay.  It was an MI.
		DR. Di MARCO:  So a lot of the MIs were really sudden deaths.
		DR. YUSUF:  Yes, and for what it's worth, John, there is a significant reduction in sudden deaths, which patterns the reduction in cardiac arrest.
		ACTING CHAIRMAN CALIFF:  John, I can't resist as the Chair asking you this.  Can you really tell a sudden death from an MI death in someone that's having --
		DR. Di MARCO:  I think that's a terrible misclassification.  You know, I mean you can call it an MI, but it's -- I can't take the same statement that this reduces what I think is a myocardial infarction.  It may reduce a whole mess of cardiovascular events, but sudden at night most of the time is an arrhythmia that probably may be ischemically mediated, but may not.
		ACTING CHAIRMAN CALIFF:  Do you have any further questions?
		DR. Di MARCO:  No.
		ACTING CHAIRMAN CALIFF:  Ileana.
		DR. PINA:  Salim, thank you for a very nice presentation.  I want to go back to the heart failure issue, and I know it's been brought up now several times, but I think in your initial definition what you've excluded were patients who had demonstrated congestion as opposed to the broad spectrum of heart failure, and you did SOLVD, and you know how we found some of the prevention patients was by going through the FO lab and trying to find myocardial infarctions so we could pick up the low EFs.
		I am quite surprised at seeing this many patients with reasonable rejection fractions of 59.  Were those rejection fractions taken at any time or was it after an event or --
		DR. YUSUF:  Those were taken --
		DR. PINA:  -- anyone in the chart that had a --
		DR. YUSUF:  Those were taken at any time before randomization, and they shouldn't have been after that was done a further event and no further EFs that were below that.
		DR. PINA:  And in the concomitant medications, there seems to have been an increase in the use of several agents.  Diuretics went up, and it looked like they went up in placebo more than in the ramipril group.  Was that significant and were those the patients that developed the heart failure?
		DR. YUSUF:  I know it is significant, but I think it includes the people that developed the heart failure, and it also includes some hypertensives.  It's both.
		DR. PINA:  So some of those diuretics may have been hydroflorothiazide?
		DR. YUSUF:  Yes.
		DR. PINA:  There was also a very significant increase in HMG co-reductase use, almost half of the patients.  Was there a region, a geographical region difference in that where people encouraged to do secondary risk modification factors during the trial?
		DR. YUSUF:  At the very beginning of the trial we encouraged people to use the best possible therapies in their opinion, and as you can see, it was pretty good given we started in '93.  That's when we started.
		The increase in HMG co -- in lipid lowering therapies was worldwide.  We saw that increase in every region.  I don't remember the absolute numbers by region, Ileana, but I remember at one of our meetings discussing a worldwide increase and showing it by region.
		DR. PINA:  I have no more questions.
		ACTING CHAIRMAN CALIFF:  Dr. Graboys.
		DR. GRABOYS:  I have no questions at this time.
		ACTING CHAIRMAN CALIFF:  We're moving along nicely here.
		DR. MOLITCH:  I don't know whether you would like to bring up the issues of the development of diabetes in this group in people who did not have diabetes.
		ACTING CHAIRMAN CALIFF:  I think it would be better to hold on that until we have the diabetes presentation.
		DR. YUSUF:  If you want, I could deal with that because that's not going to be dealt with by Hertzel, if you want.
		ACTING CHAIRMAN CALIFF:  I'd still rather handle diabetes all at one and you can come to the microphone when needed during that section.
		DR. YUSUF:  Okay.  Happy to do that then.
		DR. MOLITCH:  I'll pass then.
		DR. BAKRIS:  I just have a quick question.  Looking through all of the data here, this is more of a curiosity, but did you look at heart rate differences between the groups and look at the impact of heart rate?  Was there even a difference?
		I didn't see that data, and there are certainly some small studies that suggest ACE inhibitors do affect that, but I'm just curious.
		DR. YUSUF:  No.  As you know, heart rate was balanced at entry, which I showed you, and I know in the secure study we looked at heart rate and there was no impact of treatment.  I don't know if we looked at it in the whole population, but in the 700 we did.
		ACTING CHAIRMAN CALIFF:  Okay.  I have a couple of questions, and actually I'm hoping to engender a little interaction here with Bob and Ray on these issues because I think everything at least that I thought was important has been brought up, and I think it would be useful to have a little bit of FDA questioning on a couple of these.
		The first is the race issue, and I think it seems like we're in a bit of a dilemma here because, on the one hand, we can say there aren't enough black people in the trial or any of the trials to say anything meaningful.  On the other hand, it's 14 percent of the U.S. population and even more than 14 percent of the population at risk for the problem that we're discussing.
		And so it brings up a fundamental question of what is the FDA position on studies that come in without an adequate representation of minorities, and how is the FDA looking at this.
		DR. LIPICKY:  Okay.  I don't have a good answer for you.  In general, I guess, I would be entirely in tune with the notion that in this study, it doesn't appear as though there is a signal that is worth worrying about, which is the usual kind of thing that happens. and we kind of take the point of view that if things are consistent across most subgroups and you don't have anything to worry about in one subgroup that doesn't look consistent, then you shouldn't worry.  So that's my answer, number one.
		And I guess my answer, number two, is that the question of blacks and their responsiveness to ACE inhibitors irrespective of what it is that you look at is really pretty muddy, and I suppose the nicest or the one area where people would be most in agreement is that blacks don't respond as well in terms of decreasing blood pressure, and there, indeed, those are subgroup analysis that if you look at any one study or any one development program, I think you should hardly believe that conclusion from the one development program where it seem to be there in more than one.
		And to give you an example of how FDA thinks, in spite of one development program which clearly show in that development program that there was no blood pressure difference in the blacks, that drug is labeled it doesn't work as well in blacks.
		So I don't think we have the answer to these questions or know how to address them or actually be able to do a good job of doing that, and I think it's a topic that might be worthy of more general discussion when, indeed, there is a larger group of data to look at because I don't know how you tell when there's a signal you should pay attention to.
		ACTING CHAIRMAN CALIFF:  Well, this will certainly be a topic of discussion during the panel portion this afternoon.
		I wanted to give Salim a chance to make a statement in relation to the trial after hearing the FDA position.
		Bob, I don't know if you have anything further.
		DR. TEMPLE:  Well, there isn't any doubt that the description of the study results will point out that there is a dearth of black patients in it.  It's worth thinking about history.  There aren't a lot of blacks in the 4F study.  There weren't any blacks in the Scandinavian timilof (phonetic) study.  
		To the extent that a large trial becomes difficult to repeat is carried out in parts of the world that don't have an appropriate distribution, a distribution relevant to the United States, we are to a degree stuck.
		We have one experience that we feel funny about.  When the first Canadian trials, mostly Canadian, partly Texas, supported the use of aspirin in patients with TIA, there were very few women in the trials, and to the extent that there were any women, they didn't seem to be showing any benefit.  So for many years the drug was labeled as for use in males.
		And I think a lot of people questioned whether that was the right thing to do, whether the absence of data should have led to that conclusion, and you have something of the same question here, and there is obviously no perfect answer.
		But one of the things I'd be interested in throwing out is whether people believe that you could mount a trial of this kind in a black population since there are no data.  It really brings to a head the question of data versus likelihood and a wide variety of other things.
		Can I ask a question, too?
		ACTING CHAIRMAN CALIFF:  Sure.
		DR. TEMPLE:  This may not matter a great deal, but were the individual components of the combined endpoint explicitly said to be secondary endpoint or co-primaries or something?
		DR. YUSUF:  Yes, they were.
		DR. TEMPLE:  Okay.  My presumption -- maybe other people will talk about this -- the labeling is not perfectly clear as to whether the proposed claim is that it treats each component of the combined endpoint or the combined endpoint itself.  Which did you have in mind, you and the company?
		DR. YUSUF:  You're asking me?
		DR. TEMPLE:  I'm asking anybody who will ‑- you're at the mic.  So yeah.
		DR. YUSUF:  I must confess lack of high level of intelligence on labeling issues.  I think I can tell you how I would interpret the data.  I'd interpret the data we have clear evidence in each component, you know, and so I would see when I give a talk I would tell people.  I'd show the data exactly like this.
		Now, how that affects labeling, Bob, you know better than I do, but clearly we have each component significantly different.
		DR. TEMPLE:  Okay.  Well, we'll need to make sure the labeling conveys what people want it to convey.
		Do I understand there was one case of fatal angioedema?
		DR. YUSUF:  Let me tell you what happened.  The first thing was this was a patient that the center did not report his angioedema, just reported it as a sudden death or something like that.  
		When you had concerns about another product and we were preparing for this, we got a call from the medical reviewer, I think, saying were there any fatal cases or ventilated cases of angioedema, and we went through all of them.
		And Janice then came up with one death where she did not tell me what the allocation was and said, "This is the description," and the description was an individual in a given remote hospital who had a short history of shortness of breath and a 24 hour history of -- right, right -- so that case, shortness of breath of only 24 hours, the clinicians did not report heart failure, and this is the report from the wife, not even from the family, and we said we think there may be one case.  So that's the history of that case.
		DR. TEMPLE:  How far into treatment was that patient?
		DR. YUSUF:  That's interesting.  It was at 30 days, and it happened when we went from the five milligram dose to the ten milligram dose.  It did not happen early.
		The other thing is, you know, because of these issues I looked median time to angioneurotic edema in our eight, and it was something like 48 days or 48 or 50 days.  It wasn't clustering early, which was what I hoped we would see.
		DR. TEMPLE:  Two more short questions.  One just relating to the comment Dr. Di Marco made.  There may be debate about whether a death was caused by an MI, but I believe you would say that the definition of MI that you used for non-fatal MIs was fairly rigorous, and that's what the claim is.
		The claim is not for fatal MIs.  It's cardiovascular deaths.  It's for MIs, presumably non-fatal, over all cardiovascular deaths and stroke.
		I guess finally I just want to make the observation that this is the first trial I know where a robot was responsible for the conduct of the study.  Now, do you know what I mean?
		DR. YUSUF:  Yeah, I've never been called ‑-
		DR. TEMPLE:  C3PO is the managing --
		DR. YUSUF:  I know.
		DR. TEMPLE:  I thought that was cute.
		DR. YUSUF:  It's an honor to be called a robot.
		The second thing that you don't know --
		DR. TEMPLE:  Do you know my reference?
		DR. YUSUF:  I know the C3PO.
		DR. TEMPLE:  I don't want to be --
		DR. YUSUF:  It was deliberate.
		DR. TEMPLE:  I don't want to be obscure.  Right.  I figured it was.
		DR. YUSUF:  The other thing that you don't know is that we tried to get a randomization number, 1-800-dot, dot, R2D2, but they wouldn't give it to us.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  Dr. Lipicky, you have questions?
		DR. LIPICKY:  Just a couple of questions.  One is do you think the angioedema results rebut the notion that angioedema is more common in blacks?
		DR. YUSUF:  Oh, our numbers are so small, just like on the efficacy subgroup, I would say --
		DR. LIPICKY:  Yeah, okay.
		DR. YUSUF:  -- we have -- they're so small that --
		DR. LIPICKY:  So it's just really a testament for the few numbers of blacks --
		DR. YUSUF:  That's right.
		DR. LIPICKY:  -- that exist and not to say that blacks are not more sensitive than whites.
		DR. YUSUF:  I mean, if I did a subgroup on the angioedema and I -- of which we did -- and there was, say, two cases in the placebo and zero in the active, it still is not helpful in telling us -- I know where you're going -- you know, about the blacks having more angioedema.  I don't think we can say anything from 144.
		DR. LIPICKY:  Right, and then the next question is:  do you think or is it true that I should believe that none of the patients enrolled in the trial were symptomatic?
		DR. YUSUF:  It is true that you should believe that their physicians told us they weren't symptomatic.
		DR. LIPICKY:  Okay, fine.
		(Laughter.)
		DR. YUSUF:  Right.
		DR. LIPICKY:  Then the last question.  The last question is this sort of large, simple trial, do you think that any of the questions that you've been asked to respond to are a reflection of that or the ability to answer any of the questions that were asked just now are a reflection of that?
		DR. YUSUF:  I don't think so.
		DR. LIPICKY:  Nor do I.  I just wanted to know what your interpretation was.
		DR. YUSUF:  Yeah.
		DR. LIPICKY:  And I suppose this study cost around 200 million?
		DR. YUSUF:  I wish it did, but it didn't.  It cost about less than ten percent of that.
		DR. LIPICKY:  Okay.
		ACTING CHAIRMAN CALIFF:  Well, let me ask the remainder of my questions then, which are oriented towards these general issues.  The first one,  and Ray may want to make a comment on this, too, you used words like "compelling," "convincing," et cetera, to describe your P value from a single trial.
		We've had some recent experiences in cardiovascular disease where apparently compelling, convincing results from smaller studies have been overruled by follow-up studies that tried to replicate the Elite 1 and 2, for example, or Praise 1 and 2.
		As a general comment, what is it about this P value or this result?  What's your mathematical threshold?
		DR. YUSUF:  Do you want me to?
		ACTING CHAIRMAN CALIFF:  This is your chance to address it because we'll certainly need to address it as a panel when you're excluded from the discussion.
		DR. YUSUF:  First, the Praise examples you give, the main results were no value of significant -- it wasn't significant.  So it's really not analogous.
		But let's think of Westner (phonetic), you know, because that might -- you know, the first set of Westner neuron (phonetic) studies.  It was the first trial.  It was on a composite endpoint, which is heart failure.  That's true, but there were too many inconsistencies within the trial, you know,  that those relationships within the trial were not what you'd expect.
		Plus, as a plus the PDE inhibitors we were all concerned about at that stage because we had data with Milrinault (phonetic) that was harmful, and of course, you can spin a story, but this is different.
		The thing with the HOPE data are two or three things.  Coming into this there was already evidence that MI was prevented based on SOLVD and SAVE.  Of course, it didn't meet regulated criteria, and there was still some debate.
		We had data from other studies that lives were being saved.  We knew its safety profile.  So there's a body of evidence on which HOPE is built.  So HOPE Is not in isolation.
		And then we get the meta analysis that's coming out of the Lancet in two weeks' time.  The relative risk reduction and MI reduction is identical to what you get from the previous trials from a meta analysis.  So there is external data backing it.
		The second thing is internally there is a consistent story, say, between two halves of the study, the Y2ME and the non-Y2ME part.  It's like two random halves are over three standard deviations.  So the whole thing is five standard deviations on the primary.
		Then when you take other endpoints, which are not part of the primary, like revascularization, it fits in with it.  So you get a nice, warm, fuzzy feeling that something good is happening overall.
		So I think it's the external supporting data, the overwhelming nature of the zed value, which is five standard -- nearly five, 4.89 to 4.9 in the primary, clear results of some of the secondary.  All of that put together, I think, make a compelling case.
		ACTING CHAIRMAN CALIFF:  So, I mean, all of that is warm and fuzzy, but if fundamentally you have a trial with a P value, it's been said if it's mortality, less than .05 is okay in previous cardiorenal meetings, but now we have some examples of a few that are less than .05 in the first trial and nothing in the second trial.
		Is .001 something that we should think about or --
		DR. YUSUF:  I think you and I may be in the same camp on this issue.  I really believe we shouldn't interpret P values in  isolation.  We should interpret the totality of the evidence, look at the internal coherence of the data, the external coherence of the data.
		Let me give you an example.  Let us say that we had a P value of 0.045 in a given trial, and that one total, total mortality, and that was a primary endpoint.
		That would not be enough for me.  I would try to say, like if it was an anti-platelet agent, I would expect to see all of the effect on cardiovascular.
		But suppose we see there is very little effect on cardiovascular, but that P of 0.045 is coming from non-cardiovascular.  To me that's not plausible.  The second thing I'd like is at external data, like are there supportive trials.
		For instance, I would disbelieve a trial of an 0.04 if there are no external trial data, if internally it's not coherent, and there aren't supportive data on related endpoint.
		So to me the P value is only one part of the equation, and I know you think that way, too.  At least I think so, and so I think any given P value at some stage we'll make a mistake if you only use the P value.  I don't know what others fee.
		ACTING CHAIRMAN CALIFF:  Right.  Ray?
		DR. LIPICKY:  Let's say that HOPE for the combined primary endpoint had a P value of .035, not less than .001, and all of the things that you say are still true.  That is, there's external data, and all of the internal data would have lined up the same way as they do now with one or two exceptions.
		Would you consider that to have been compelling?
		DR. YUSUF:  I wouldn't certainly use the word "compelling," but I would say the HOPE results indicate a significant reduction in mortality which is totally supported by external data, and therefore, i believe the concept that these agents reduce events --
		DR. LIPICKY:  Except that it is an advocacy for treating asymptomatic people who doctors think are bad.
		DR. YUSUF:  But that's where, you know, we make other judgments.  It's not just the P value that helps you with your judgment.  If you prevented a major event, then it's worth -- that is important enough, then it's worthwhile.
		If there are side effects, that may detract from it.  If there is a beneficial effect on a lesser -- on something that's not stated on your primary, but is a secondary endpoint, less severe or maybe even more severe but less frequent, a similar effect?
		Look at the totality of the data.
		DR. LIPICKY:  I agree, and it's sort of hard to dissociate oneself from what you saw, but let's say you had only studied $1,500 patients.  You know, you had a P value of .035 for your parameter endpoint.  I think that I would say, "Very interesting," but not believe it.
		DR. YUSUF:  If that --
		DR. LIPICKY:  Even with all of the other things that are true, you know, all of the other external data and everything else.
		DR. YUSUF:  Well, it all depends on how much that external data are.  If the external data using the same drug or very similar drugs is three zeros on the P value and the same endpoint, I would say I could probably over a drink persuade you to believe it, but to approve it, I don't know.
		DR. LIPICKY:  Two drinks.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  Speaking of external data, you know that there are several other trials that are ongoing looking at --
		DR. YUSUF:  Sure.
		ACTING CHAIRMAN CALIFF:  And this is a big change in indication when we're talking now about people with normal left ventricular function who are at risk of coronary disease, as I'm sure we'll get into with Dr. Furberg's presentation.  How should the committee consider the fact that those other trials have not been stopped?
		You used words like "compelling" to describe this one trial, and yet there are obviously safety committees of other trials that are saying maybe it's not quite so compelling.
		DR. YUSUF:  Well, I think we'd be foolish to guess what data they've seen.  You know, I just don't know, and I think that would be really hazardous to try to make the decision based on data none of us have seen.  I don't know, and I think we can only make decisions based on what we have, Rob.  We can't make even educated guesses based on --
		ACTING CHAIRMAN CALIFF:  Udho, do you have a comment on this?
		DR. THADANI:  Yeah.  I think you mentioned the consistency of data.  I think you're right to a certain point, but it's driven by the MI consistent with cardiovascular death in the HOPE trial because I'm really surprised -- no, and stroke, heart endpoints -- I'm really surprised that unstable angina -- because most of the patients with MI, we are doing unstable angina, non-Q MIs, as you see so hard to differentiate.  The hospitalizations are really driven by those more than (unintelligible) infarcts now, and I'm really surprised that in a plaque rupture hypothesis of the ASS-2, according to Victor it's not holding here; there were 10,000 patients and there's no difference within placebo either in unstable angina or need for hospitalization for unstable angina.
		So you're driven by heart endpoints I'm not arguing.  I think you showed great data.  Revascularization, I think you could argue the threshold is different.  Somebody got chest pain.  He gets angioplasty.  It's more biased than other endpoints.
		So why do you think there's a dilemma here?
		DR. YUSUF:  I think this is an interesting issue.  First, it could be that unstable angina is a pretty nonspecific endpoint, especially in the North American context where anybody with any chest pain comes in.
		And when we said new ECV pic. changes (phonetic), a little squiggle on the T wave is considered that.
		The second thing is there is another good example of this apparent paradox, and that's aspirin.  We have no doubt that aspirin prevents MI.  We all agree, but if you pulled the same data where you can get it for unstable angina, we did this because of a trial we were designing.  There is absolutely no effect on refractory angina or rehospitalization with angina.
		DR. THADANI:  So I think you can't say it's very nonspecific because if you look at outcomes in unstable angina, all the trials, including your doing the CURE trial and every basis based on the assumption the prognosis is not as good as people have believed, and I think clinicians can tell obviously are wrong.  Sometimes patients don't have coronary disease because they have unstable angina.
		But I think it would be nice if the hospitalization for unstable angina went in the right direction.  It would be great.
		DR. YUSUF:  I agree.
		DR. THADANI:  I'm just very confused with that.
		ACTING CHAIRMAN CALIFF:  But, you know, we've all agreed to that.
		DR. THADANI:  But the question is is MI is really determined by your changes on annual visit because only two ECGs were done, one at baseline --
		DR. YUSUF:  No, no, no.
		DR. THADANI:  -- one at two years, and one at endpoint.  That's what the protocol says.
		DR. YUSUF:  Wait a minute, wait a minute, wait a minute.  MIs were based on clinical MIs.  That's the MIs.
		DR. THADANI:  But also silent MIs are on it.
		DR. YUSUF:  No, silent MI is not part of the data.  We have data on silent MIs, and --
		DR. THADANI:  It says in there --
		DR. YUSUF:  Sorry.  We have data on silent MIs, and I can show a slide, and there is a numerical trend identical to the clinical MIs, but it's not part of the primary endpoint.
		DR. THADANI:  So in the patient who is not hospitalized, he has Q wave if he's countered, right?
		DR. YUSUF:  Not in this, but that's a separate set of MIs which you haven't seen.
		DR. THADANI:  So you could have missed several MIs in patients in diabetics who have no symptoms because they got short of breath and they got ‑-
		ACTING CHAIRMAN CALIFF:  All right, Udho.  He said -- he said he has the silent MIs.  Would you like to see the data?
		DR. THADANI:  I think so because I think the whole --
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. THADANI:  The definition is that cardiovascular and then MIs and he says MIs have to be symptomatic, and we know diabetic patients don't have symptoms, and the way you do it here, (unintelligible) of MI doing by the FDA, it says silent MIs is a composite MI endpoint.
		So why is there difference here?  That means you're dissecting the data here.
		DR. YUSUF:  I can't control everything the FDA does.
		DR. THADANI:  No.
		DR. YUSUF:  But when we have --
		DR. THADANI:  -- your protocol.
		DR. YUSUF:  Slide 35, please.
		DR. THADANI:  I'm looking on page --
		DR. YUSUF:  Would you like to look at this?
		DR. THADANI:  Yeah, sure.  -- page 1351 in your MI definition.  "Silent QAMI is composite of the A, B, C, D criteria," which is new QAs.  That I would presume you have to do ECGs often enough to account for it.
		DR. YUSUF:  But it's not, Udho, in what I showed you.
		ACTING CHAIRMAN CALIFF:  Right.  I think you've been clear.  I mean the slide here shows that there's a trend for silent MIs and you add them all together.
		DR. YUSUF:  Could I just show you?  If you add silent MIs, it becomes stronger.
		DR. THADANI:  Okay.
		DR. YUSUF:  These are the data on clinical MIs, which is what we've, you know -- which is what is in our main papers.  This is silent MIs, and you will see it's the same directional effect.
		ACTING CHAIRMAN CALIFF:  I might parenthetically add there's several other large studies now showing very little contribution of silent MI in clinical trial populations, the HERS (phonetic) trial, in particular.
		DR. YUSUF:  And that's why we did not --
		DR. THADANI:  And this is by CK, CKMP, or triple MIs now?
		DR. YUSUF:  Which one?  Silent MIs?
		DR. THADANI:  Any MIs, whether enzymes.
		DR. YUSUF:  Oh, there is about two pages of criteria.
		DR. THADANI:  So you have that.
		DR. YUSUF:  Yeah, we needed two out of three criteria.
		DR. THADANI:  And sine I had a chance to ask, I would come back to your question now for cancer.  I think the cancer rate was a bit higher.  I know this didn't come out, but the cancer rate is higher in the active treatment on the placebo number-wise, and yet you say you did not ask the physicians to report cancer.  Is this --
		DR. YUSUF:  Wait a minute.  What you're seeing from the FDA is not a reliable analysis I'm sorry to say.
		DR. THADANI:  What is reliable then?
		DR. YUSUF:  Okay.  What I --
		(Laughter.)
		DR. YUSUF:  Let's come to this.  What the FDA has done --
		ACTING CHAIRMAN CALIFF:  Salim, I think it's important to go through this carefully because actually it was going to be my last question.  The adverse events versus what you collected on the case report form.
		DR. YUSUF:  That's right.  I think Rob hit it on the head.  Cancers that the FDA reported is from the AE database.  The AE database does not include all cancers because we only asked people to report SAEs if they met certain criteria, and if something was part of the natural history of the disease and occurs in a 60 or 70 year old, it's not counted.
		Now, I'll tell you what the total number of cancers were.  There were 401 in the placebo group, and there was 383 in the ramipril group, and since, Paul, you were interested in GI, Paul, there were 72 in the placebo group, and there were 69 in the ramipril group.  So that's the total cancers.
		ACTING CHAIRMAN CALIFF:  And, Salim, again to clarify, the reason you know those are the right number of cancers is that you had a page on the case report form that asked about cancer?
		DR. YUSUF:  No, we didn't.  I'll tell you what happened.
		ACTING CHAIRMAN CALIFF:  How did you collect the cancer data if it was not on the adverse events?
		DR. YUSUF:  Yes, we did at the end, but not to start with for a certain reason which I cannot disclose because one part of the trial is going on.  Okay?
		We decided we'd better get a better handle on the cancers, and when we started to look at it, we realized cancers were being reported haphazardly because we didn't have a cancer form.
		So at the last visit we had a specific form where we asked them to fill it out on every patient.  So we capture it because they could go back to the notes and get any cancers, and that's how the numbers I've told you are from.
		So the SAE report, to be fair to the FDA, they took it out of that component which doesn't capture everything.
		ACTING CHAIRMAN CALIFF:  Okay.  I just had two more points, and then we can -- if we're going to finish today, we're going to have to move along, I think, and my hope would be we're scheduled for lunch at one.  My hope would be that we can get through the renal protection presentation and most of the questions by one, then take a lunch break, come back and do the diabetes, and then move into the panel discussion.
		So anyway, just a clear statement from you on this because it's very -- we're going to discuss in this trial, and I think you've been clear about it already.  
		You don't think that trials that are internationally done should routinely look for interactions according to region of enrollment?
		DR. YUSUF:  I actually think if there is no prestated hypothesis before you start off with, then you shouldn't look, and if you look, you should generally place more emphasis on the overall analysis because that has been a data derived analysis, and just like any data derived subgroup analysis, it's fraught with all kinds of problems.  A data derived regional analysis is fraught with the same methodological problems.
		On the other hand, if we have good reason to believe there may be different reasons, and we've stated in the protocol, then we are obliged to do two things.  One is to insure we have reasonable power to pick up those interactions, and then to test for heterogeneity at the end of it.
		In most trials that I've been involved with and most people do, these are not issues.  So I think in such circumstances really one should base the results on the totality of the data and not by any subgroup analysis.
		DR. FLEMING:  On that issue, Salim, do you think you've consistently followed that guideline in your reporting of results, i.e., that you have recognized that if it wasn't prestated or if there wasn't a biological rationale to in advance justify that you essentially have given little credence to results?
		DR. YUSUF:  I know I'm walking into a trap here, Tom.
		(Laughter.)
		DR. FLEMING:  Okay.  Then let me tell you what the trap is.
		DR. YUSUF:  Let me answer your question.  On subgroups, there are different things that we are looking at.  I'm talking about subgroups, and regarding subgroups the answer is yes.  That's the way I have consistently looked at the data on subgroups.
		DR. FLEMING:  Well, certainly subgroups are one type of analysis that presents substantial risk of being misled because of multiplicity of testing, but it's certainly not the only one, and, yes, the trap was just to pull out one example, new diagnosis of diabetes.
		DR. YUSUF:  I knew what you were going to put up.
		DR. FLEMING:  You know, it's of interest to me that those results are being presented, and in your formal presentation there was nothing stated about subgroup analyses by aspirin, subgroup analyses by country, subgroup analyses by race.  So it's just ‑- it's trying to get a sense of what is, in fact, that --
		DR. YUSUF:  Can I just explain to you what our position on the -- or my position at least is -- on the development of new diabetes?
		I think it is an interesting hypothesis that requires testing, and we've designed a trial to test that.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. YUSUF:  So I hope that's consistent with fair methodological thinking.
		ACTING CHAIRMAN CALIFF:  We'll come back to this, I'm sure.
		I just had two more questions.  The factorial design, and again, I'm interested here in whether there's any interaction between you and Bob and Ray in this regard.
		It's commonly believed and stated that when you're doing studies for an indication with the FDA that you can't do a factorial design because it's two experimental therapies being given together, obviously you've done it here.  But one is a vitamin which is not regulated by the FDA, and the other is a drug.
		Would you say the factorial design is a better way to do things, given the number of potential treatments that we have today?  And is there a down side to it that you've seen?
		DR. YUSUF:  Asking me or --
		ACTING CHAIRMAN CALIFF:  Yeah.
		DR. YUSUF:  Who, me?
		ACTING CHAIRMAN CALIFF:  Why don't you start?  I'd just be interested in hearing from Drs. Temple and Lipicky.
		DR. YUSUF:  Well, I tend to be a big believer in factual design for several reasons.  One is doing these trials is really tough and expensive, and if you can evaluate more than one treatment in that trial effectively, one should do it as long as there is no postulate for a negative interaction or bad side effects or anything or the fact that the mechanisms may overlap.  You know, you've got to choose your questions carefully.
		So I tend to say -- in my writings I always say -- do a factorial design unless you have good reasons not to do so.  That's the way I believe, and I think 75 percent of the trials I've been involved with have been factorial designs.
		Now, there are obviously certain issues with factorial designs, but in one way you can think of your second factor as background therapy.  For instance, let us assume in this population aspirin was not indicated or capitobril (phonetic) was not indicated, and we have two options.  We could let aspirin float in as background therapy.  If there is an interaction, you'll still get the interaction.  If there's no interaction, you've lost nothing.  If there is, you learn about aspirin, and you learn about the interaction.
		So I think unless there is a strong a priori reason not to do a factorial design, the starting point should be let's consider a factorial design.
		ACTING CHAIRMAN CALIFF:  Rob or Ray, do you have guidance on factorial design?
		DR. TEMPLE:  Well, we've  certainly never given to my best knowledge advice that they should not be carried out.  This factorial design is where both components were directed at the same endpoint.
		For what it's worth, the approval of aspirin and thrombolysis was -- the use of those two together and the knowledge of how they interact was a very important outcome of one of the ISO studies.  So, I mean, there's a time honored tradition.
		We've occasionally been asked what about throwing in a completely separate randomization not even for the main endpoints, something completely different, and when we've been asked, we've said that's a really good idea, but companies have been nervous that there might be some odd interaction that would bite them and have been reluctant to do it, but it's not because we've advised against it, although it's perhaps true that an unwelcomed interaction could be troublesome.
		Personally I'd like to see a wide variety of alternative medicines tested in the context of, you know, good studies where the resources to study those interventions would not be available.  So I think we think they're good.
		ACTING CHAIRMAN CALIFF:  Isn't it true that such an interaction could still wreck a study even if it wasn't part of the randomization?
		DR. TEMPLE:  You can imagine outcomes -- oh, I see.  Sure.  Look at the discussion we just had of aspirin.  That's interaction.
		ACTING CHAIRMAN CALIFF:  Right.  Okay.  Ray.
		DR. LIPICKY:  Not to let the opportunity go, we like factorial trials and try to talk people into studying more than one dose that way frequently, not because marketing thinks it's a good idea, but because it makes sense medically.
		ACTING CHAIRMAN CALIFF:  Okay.  My last question has to do with the monitoring, auditing of this trial, and you obviously didn't reconcile your adverse events database with the main database because you have different numbers.  At least from my experience about half of the cost of a trial is spent on chasing down details and adverse events databases, and I just wanted to get a sense from you and from Bob and Ray about what the advantages might have been of spending more time on the details of the adverse events.
		There appears to be a consultation going on here.
		DR. LIPICKY:  I can give you my answer to that, and that would be none.
		DR. TEMPLE:  There have been a lot of discussions about what necessary monitoring is, as Rob is undoubtedly familiar with.  The good clinical practice document that came out of ICH and is now our guidance also says that monitoring, the amount of monitoring and, indeed, the presence of any on site monitoring at all is something you have to figure out depending on the circumstances of the trial.
		So in the present case with the mortality endpoint being at least part of it and some of the other endpoints fairly hard, you might conclude that not a great deal of on site monitoring is necessary because you can check centrally whether the rules are being followed, and we take an open minded attitude toward that.
		It certainly is true that the cost of trials go up enormously if you do what would be called conventional drug company on site monitoring.  So I think we're open minded about it.
		If all of the elements are subjective and you're worried about blind breaking, things like that, there might be reasons to be on site and find out more about it, but you can make a case that it's less necessary when the endpoints are hard, easily verifiable, and which at least some of these are.
		ACTING CHAIRMAN CALIFF:  So what was done in this trial?  What was the auditing procedure?
		DR. YUSUF:  It was modest and sensible, and what we did was randomization was central and we controlled it.  So we knew that was integral.  All primary and prestated secondary endpoints, they had to fax in supporting data.  So we knew it actually happened.
		So those were the two things that were 100 percent audited.
		The second thing is a random ten percent of the patients were reviewed.  The charts were reviewed by the company's staff, and at the end of the study every center was visited once at least by the monitors.
		So compared to some trials it was much more minimal, and I think there were three factors that were driving this minimalistic approach.  One is it was a low cost trial.  Second is there were at least some enlightened people in the company who backed us, which was very important.  Otherwise we could not have done this trial.
		And the third one is I believed methodologically all along monitoring was a waste of money at least to the extreme that it went.  But what we also did was what Bob said.  We monitored for cause.
		When we looked at data and we found sloppy data or lots of missing data or suddenly in a given region or center the event rates are markedly different, we then got people to go out and check those.
		So we did central monitoring very carefully, and then when we had a suspicion something was wrong, we sent people out, and in fact, in all those cases all we found was sloppiness, not fraud or anything like that.
		ACTING CHAIRMAN CALIFF:  So to be clear, it's frequently said that 100 percent monitoring has to be done because the FDA requires it, but in this case, there's ten percent, and it's okay with the FDA?
		DR. LIPICKY:  Yes.
		DR. TEMPLE:  Well, a lot of what Salim described wouldn't even be called monitoring.  It's auditing, which is not the same thing at all.  The issue is on site monitoring.
		We had a workshop under the auspices of the Institute of Medicine on this, and you know, as everybody knows, typical drug trials, you visit every four weeks and go over and do stuff, and we had a lot of the discussions of this while writing the international guideline, and there was an initial inclination to say that that's what monitoring means.
You go every four weeks out to the site and visit every site.  
		What I said and what Jay Siegel, who was there with us, is that not trial that's ever shown anything really important has ever been monitored like that, so that it didn't really seem like it could be an absolute necessity.
		Most NIH trials aren't monitored that way.  Most cancer cooperative group trials, you know, the typical study, none of those trials get that kind of monitoring.  So the guidance is quite flexible, and for a large outcome trial it's virtually inconceivable that you can go to every site every four weeks.  So it's written quite flexibly.
		I think the idea is that it should be part of the plan.  There should be a reason for choosing the monitoring and follow-up and auditing arrangements that you have and that we're prepared to look at anything reasonable.  It's a good idea to think about it ahead of time, however.
		ACTING CHAIRMAN CALIFF:  Great.  Okay.  Well, Tom, last comment.
		DR. FLEMING:  Very brief.  I just wanted to concur with Salim's advocacy for factorial designs, particularly in those settings as you point out where it's not anticipated that there will be negative synergy and the interactions that would, in particular, cause you to have to reduce the dose in the cell in which both interventions are delivered.
		Point of information.  You had referred to an upcoming Lancet publication that was a meta analysis.  What are the other -- in fact, is this a meta analysis in a setting that is specific to HOPE?
		DR. YUSUF:  No, no, no.  It's really the pre-HOPE trials.  It just took one and a half years to get reviewed and published.
		DR. FLEMING:  And which of the studies are included in that?
		DR. YUSUF:  It is the two SOLVD trials, SAVE, TRACE, and AIRE, and it's about what level, 12,000 or so patients, and it's got about two, 3,000 deaths, another four, 5,000 non-fatal events.
		I'd be happy to send you a copy.
		DR. FLEMING:  Could this be a source of the types of studies to look at, for example, the race issue in larger numbers?
		DR. YUSUF:  It's not in the paper.  We tried to do it, Tom, but what we found was there was so few people who were non-white in these trials.  That would have been the best place to look at it, and you're absolutely right in your instincts.
		DR. THADANI:  Salim, if I may ask you the last question here, given the constant different practices of medicine, especially cardiovascular coronary disease in the States, Europe, Canada -- if you work in three places it's different -- and given some concern regarding that most of the population is coming from Canada, there might be differences in race and also numbers are small in U.S. and elsewhere.
		Why don't you when you design the trial -- I realize there are difficulties -- limit the number of patients who can go from each country?  So you reach 1,200 patients, 1,400.  I know trials are difficult, but then we won't be arguing with what you're doing today because then we'd be more sure that when you analyze the data for the variability, either its race or region will be more consistent.
		Why don't we do that?  I know in small trials, say, if you're doing a stable angina exercise, we won't let a center -- it reaches 12 patients and they cut off.  Otherwise in the end his results are biased just from that sample.
		I'd like your comment on that.
		DR. YUSUF:  I think it is impractical because you can never predict exactly what the recruitment is going to be in different parts of the world, and then what will happen is your slowest recruiting region will delay your entire program.
		The other part is the cost of doing the trial varies by regions, and in the end you have only so much money, and the main thing you're interested in is getting a clear overall result.  So you want that money to go really far and Ray made the point this is for the size of the study and the duration of the study not a generously funded study.
		The third point is let me take a methodological issue here with you on the variations in treatment.  Let us say --
		ACTING CHAIRMAN CALIFF:  Be brief.
		DR. YUSUF:  Very brief.
		Let us -- the thing that you raised earlier on, Udho, was perhaps revascularization rates differ in different parts of the world.  Well, the best way then to do is to take the patients who had revascularization and then look at the treatment effect in them, and in those who didn't have revascularization and look at the treatment effect in them, and then if you see an interaction, your hypothesis would be supported, but if you didn't see an interaction by previous CABG surgery or PTCA, then you'd say, "Well, that's not supported."
		And, in fact, in HOPE we've done that analysis.  I haven't brought it here, but there's about 35 percent of the people have previous revascularization.  Get them into the trial, and the relative risk reductions are identical.
		So when you say, yes, practice patterns may vary by region, then you take each of those practice patterns and do the subgroup analysis by those practice patterns to understand it, and we've done it, and there is no heterogeneity.
		ACTING CHAIRMAN CALIFF:  Okay.  Let's move along now to the renal protective issue.
		DR. YUSUF:  I'm also standing as the moderator.  So if you don't mind, I'll introduce the next speaker.
		ACTING CHAIRMAN CALIFF:  That will be fine.
		DR. YUSUF:  The next speaker is Dr. Hertzel Gerstein -- no, it's Dr. Barry Brenner from Harvard, who will give us a perspective on renal disease that will assist us in interpreting the next speaker's presentations.
		DR. BRENNER:  Thank you, Dr. Yusuf.
		Ladies and gentlemen, I feel a little bit as you do when you attend an elegant banquet.  There's usually a separation at the beginning of the meal and the main course by some sorbet, and I think I've been asked to provide the sorbet this morning or this afternoon after this lengthy discussion and simply to introduce the subject of chronic renal disease.
		Now, as many of you know, chronic renal disease is a category of many etiologies, but they all have in common one feature, and that is that renal disease of a chronic nature is inexorably progressive.  Nobody gets better on their own with chronic renal disease.  They only get worse.  
		There is a progressive march from mild to advanced renal disease that is true whether the renal disease is congenital, hereditary, metabolic as in diabetes, inflammatory as in arthritis, or due to any other etiology.
		My first slide shows you the multiplicity of causes of end stage renal disease.  At one point in time, 1992, the United States renal data registry provided this information, and what you see is that in 1992 there were roughly three populations making up the whole of end stage renal disease.  This is renal disease that has advanced to the point where for life to continue the patient requires either renal replacement therapy in the form of hemodialysis or rental transplant patient.
		In these patients, a third have their renal failure due to diabetes, roughly a third due to hypertension, and a roughly a third due to all other causes.
		In 1972, when the United States Congress took the bold step of insuring totally the cost of care for patients with end stage renal disease, roughly 20,000 Americans qualified in the first year, and the cost in that first year was $270 million.
		Now, in 1992, 20-some years later, 300,000 Americans are being maintained on chronic renal replacement therapy, and the cost was $15 billion.
		The latest figures we have are for 1998, and now we learn that there are nearly 500,000 Americans on renal replacement therapy, and the cost at least in 1999 from the most recent estimate is crossing the $20 billion mark.
		So the problem with chronic renal disease, even though we have a life support system called dialysis, is not being met because the growth of this population and the cost of incurring this kind of care is so great that there has to be an emphasis on providing some regard to the chronic renal disease paradigm.
		Now, another element that's shown here is that in 1992 the number of diabetics who made up the whole of end stage renal disease was roughly a third of the total.  In 1972, it was less than ten percent, and in 1999, again where we have the latest figures, 44 percent of the total are diabetics, and of course, Type 2 adult onset diabetics are the dominant population here, more than 90 percent being Type 2.
		Now, in the year 2015 what should this pie chart look like?  By everyone's best guess, diabetes will represent 80 or 90 percent of the total, and that's because our population is aging, and our population is growing in size.  I'm talking about this.  And more and more people are living to the development of Type 2 diabetes, and equally importantly, are living 20 years with their disease.
		So that the complications of advanced microvascular disease, including end stage renal disease, are beginning to accumulate.
		The time line for progressive nephropathy in diabetes is very well described.  It is well recognized from many natural history studies that it takes approximately 25 to 30 years for the kidney to fail.  So a fatal myocardial infarction three years after the onset of Type 2 diabetes will occur in an individual who has relatively normal renal function.
		On the other hand, postponing fatal stroke or fatal MI will allow roughly 40 percent of the diabetic population to travel this road toward end stage rental therapy.
		In the initial years, there is already abnormalities of the kidney if one looks histologically, but by usual function tests very little abnormality is detected.  There's not protein in the urine, not even scanned quantities of protein, the so-called micro albuminuria, and function studies are, by and large, normal.
		In a five to 15 year interval there is now evidence that blood vessels everywhere in the body are beginning to leak plasma proteins.  The leak is relatively small at first, but can be measured, and any number of compartments have been measured.
		For example, the leak of albumin occurs into the retinal field and can be detected with fluorescein labeled albumin.
		The leak of albumin also occurs across capillaries into interstitial fluid around muscle capillaries, for example, but it's difficult to sample.
		The largest volume of interstitial fluid is urine.  Urine is the interstitial fluid that surrounds the glomerular capillary bed.  The glomerular bed, like all other beds in the diabetic, are under higher pressures from the very start of the hyperglycemic state, in part, because of the overload of volume and the increase in flow through the microvascular bed in diabetes, Type 1 and Type 2.
		The leak of albumin, this transcapillary escape of albumin, occurs into the fluid surrounding the glomerular capillaries as it does across all capillaries, but recall that the fluid that crosses the glomerular capillary eventuates as final urine and is an easy and readily available fluid source in which to measure this escape phenomenon.
		This process is already evident early in the course of diabetes.  After five or so years, many patients with diabetes will develop micro albuminuria, and as it turns out, those individuals who develop micro albuminuria are the ones who will, if left unchecked and live long enough, develop end stage renal failure.
		Micro albuminuria in many, many studies has been shown to predict all of the bad events that fall on patients with diabetes with respect to the kidney, but also with respect to other risks.
		So the more protein in the urine, the shorter the life span.  In diabetics, the more protein in the urine, the greater the cardiovascular event rates.  That means myocardial event rate, coronary artery disease event rate, peripheral vascular disease event rates, retinopathy, neuropathy, the entire gamut of microvascular complications increases in risk as the expression of the proteinuria rises.
		The proteinuria is not just a renal problem.  It is a hallmark of a larger syndrome of microvascular leakage which is taking place everywhere, and these other organs that I just enunciated are affected by that abnormality.
		This diagram indicates something about how clinical trials are done.  When it is recognized that in order to convince people about the protective effect of a particular drug, you will expect to have studies that are done near the end stage of renal failure because within a five or ten year interval and as short as a three year interval, the number of events like loss of renal function totally or fatal MIs, all cause mortality will accumulate in this later interval.
		Very different would be a trial where the initial enrollment is in HOPE, and you'll hear the data include data of patients with diabetes who have not had any detectable abnormality of renal function.  They have not yet proteinuria, micro albuminuria, and they include some patients who do have micro albuminuria.
		To wait until those patients develop end stage renal failure would require a study of some 20 years, not a popular study for most of the fellows who come to my laboratory to want to undertake nor the investigators who want to undertake nor the funding sources want to take on.
		Very different are the endpoints that accumulate along this line for cardiovascular events.  Myocardial infarction is occurring everywhere along this window, and of course, the patients enrolled in HOPE are showing the myocardial infarctions and other all causes of primary outcome event that were documented by Dr. Yusuf.  But renal failure won't occur for another 20 years.
		The challenge to people working on the kidney has been to try and identify which other factors might serve as risk for mortality and for cardiovascular complications.  In diabetics, in particular, glycemic control has been proven, and those studies of glycemic control have been done primarily at the very early stages of diabetes.
		And going back again to that line diagram, the DCCT trial was done in here.  Some of the patients were normal albuminuric, and some were micro albuminuric, and the endpoints were to cross the next milestone.  For the normal albuminuric did they become micro albuminuric?  For the micro albuminuric, did they develop overt nephropathy, which is simply defined as reaching a level of protein in the urine of dip stick positive sensitivity, a half a gram a day or more?
		So the milestones here are short in DCCT, short of an endpoint of renal failure.  Yet the glycemic control story is now universally accepted.  The better the control, the less likelihood the normal albuminuric will develop micro or the micro albuminuric will develop overt nephropathy.
		So this time line governs a great deal of what we think about when we try and identify these early events that might predict delayed renal failure.
		In addition to glycemic control in the diabetic, we include proteinuria, and we include hypertension as the hallmark risk factor.  Control of their of these delays progression to the next milestone, but no study has taken the control of blood pressure, the control of blood glucose or the control or proteinuria at the earliest stages and followed the patient all the way through because, as I said, the demand of time of 20 years.
		You heard from Dr. Yusuf today, and you know from your own experience that the initial studies of cardio protection with ACE inhibitors congregated in patients who had the most advanced heart disease, and then only over time with demonstration of efficacy in the most advanced populations did trials begin working at earlier and earlier stages in the evolution of heart disease, now to the point not only of not asymptomatic left ventricular dysfunction, but now with no left ventricular dysfunction as you heard in HOPE.
		The same pattern is emerging in the nephropathy field.  The initial renal protective studies in insulin dependent diabetes were done at the late stage where you could affect mortality, expect mortality and renal death to occur, and in both studies, the insulin dependent diabetic, efficacy of ACE inhibition was established, was demonstrated.  And the Lewis trial received an FDA approval.
		Currently three trials are in progress, not with ACE inhibitors, but with angiotensin receptor antagonists, and they are in the population that had never been studied in detail in this late phase, the non-insulin dependent population, and no data are expected from these trials for another year or two.
		We see small trials accumulating in the incipient phase and three published trials completed in the preclinical stage.  In the aggregate, eight trials in non-insulin dependent diabetes with micro albuminuria, and five in insulin dependent diabetics where the enrollment criteria in this micro albuminuria and the event is protection of protein in the urine at an overt level, that is, more than a half a gram a day.
		These trials have been published, have not received FDA attention, to my knowledge, and now we have data that you will hear again in non-insulin dependent diabetes from the HOPE study with more patients in this HOPE database than in the aggregate of this A trial population already studied.
		And HOPE also addresses the earliest phase of all, patients who are normal albuminuric at enrollment and where the endpoint is the detection of micro albuminuria.  Does ramipril protect or not?
		And, again, the number of patients in HOPE in this NIDDM trial -- it's primarily NIDDM.  There are only a few IDDMs in the database -- exceed those already studied.
		So I think what we have from HOPE, and I was not an investigator included in the study, is an opportunity to have more aggregate information looking at trends of protection that are possible with ACE inhibition, and to see whether the accumulation of experience warrants recommendations for general acceptance by the physicians in our communities.
		Thank you very much.
		ACTING CHAIRMAN CALIFF:  Are there questions for Dr. Brenner?
		DR. THADANI:  In the progression of disease, is there a difference between insulin dependent and non-insulin?  You know, you showed the chart from zero to five, five to ten, or is that data really driven from insulin dependent diabetics?
		DR. BRENNER:  The natural history of Type 1 and Type 2 diabetes by most experts today is considered the same.  There was a time when it was thought that insulin dependent diabetics had a greater risk of nephropathy than non-insulin dependent diabetics, but that has been shown clearly not to be the case when young, non-insulin dependent diabetics are now included and have the likelihood of living 20 years with their disease.
		Before, it was a 50 year old with NIDDM who died three, five, seven years later with an MI, didn't have renal disease, and was, therefore, leading people to think no nephropathy.  But now we know that if you study, for example, the American indigenous population around the Hela Reservation or the Canadian Inuit population or the aboriginals in Australia, and in some other populations of young, relatively young onset, maturity onset diabetes with that 20 years of life the time line for the development of nephropathy superimposes exactly on Type 2 or Type 1.
		DR. THADANI:  What about the question of it won't come in this HOPE trial, but glycemic controls, especially with the hemoglobin glycemic --
		DR. BRENNER:  I think there --
		DR. THADANI:  Were there a difference in the progression if you control it better or you don't?
		DR. BRENNER:  There are fewer NIDDM  glycemia trials, and nothing as rigorous as DCCT, which was done in IDDM.  IDDM carried out at the earliest stages of nephropathy clearly influenced recommendations about renal protection, but it's largely been extrapolation from the IDDM study to the NIDDM population.  There's no clear, rigorous trial, to my knowledge.
		ACTING CHAIRMAN CALIFF:  Other questions for Dr. Brenner?  Yes, Dr. Fleming.
		DR. FLEMING:  This issue of  valid surrogates for diabetic nephropathy, albumen excretion rates and albumen creatinine rations, and you did show us this plot that looked at the relationship of proteinuria and mortality showing quite a thinning out in survival differences by five years.  The question:  how much is this the causal agent?  How much is this a marker for other differences that are, in fact, causal?
		Was there any expiration in those data to try to understand --
		DR. BRENNER:  Not in that study.
		DR. FLEMING:  -- imbalances?
		DR. BRENNER:  Not in that study.  That study in insulin dependent diabetics is one of about eight that shows a similar pattern, that the more the proteinuria, the greater the mortality.
		DR. FLEMING:  The correlation is undoubtedly real.  What's the strength of evidence for this being a causal factor?
		DR. BRENNER:  I don't think the proteinuria is a cause.  The proteinuria tells you that the patient has a transcapillary leak.  It's easy to find when you measure urine.  It's hard to find when you look at that leak in the organ because you're not accessing the interstitial.
		So the question is:  what's wrong with the blood vessel wall?
		It turns out in diabetes to be, from my viewpoint, rather simple.  The pressures in all capillaries are higher than normal within three days of the onset of diabetes.  As soon as you have hyperglycemia, you retain salt and water because in order to reabsorb glucose, the renal tubule does the reabsorption of the glucose in co-transport with sodium.  So there is extracellular volume expansion.
		And within a few days, you can measure a 30 percent increase in cardiac output.  I think Dr. Borer did that study.  You can find an increase in retinal flow, muscle forearm flows, and renal blood flow.  All of these organs are over profused, and when the pressures are measured in peripheral capillaries, they double.
		And when we measured them for the first time in the glomerular capillaries in diabetes, they went up like 35, 40 percent.
		The singular benefit of ACE inhibition was to restore those glomerular pressures to normal, more so than any other class of drugs at the time that the studies were done.  And that motivated the Lewis trial and what have you.
		ACTING CHAIRMAN CALIFF:  You seem to be making the case that albumen in the urine is a valid surrogate for the ultimate permanent loss of renal function.  I think that's what Dr. Fleming was getting at, and I'm just wondering whether there's adequate evidence by the criteria that have been developed for validating surrogates that we can really accept.
		DR. FLEMING:  And just because that's leading into where I'm headed with the next question, which is if you have a patient with pre-clinical nephropathy or incipient, early incipient nephropathy, which as you've noted is patients in the HOPE trial, how do we know what level of change you need to see in proteinuria for as long a period of time as we're following for you to have even a moderately reliable sense that that, in fact, is going to influence long term occurrence of --
		DR. BRENNER:  Long term recurrence?
		DR. FLEMING:  Well, the long term clinical course of renal failure.
		DR. BRENNER:  The renal outlook, the prognosis for the kidney.
		DR. FLEMING:  Right.
		DR. BRENNER:  What we have is clear evidence in patients who have macro proteinuria and where the macro proteinuria has been reduced.  Studies in diabetic and in non-diabetic alike, the more you reduce the level of albumen in the first year of ACE inhibitor therapy, the greater is the slowing of the rate of loss of GFR in the subsequent three year period.
		In other words, the more the proteinuria are based with the therapy, the more the trend down in renal function is stopped.
		DR. FLEMING:  But that's still not evidence to validate a surrogate, and secondly, that's a more proximal event to the actual occurrence of renal failure than where we are here, and it's much more of a reach.
		DR. BRENNER:  But it's a look at a later stage, and --
		DR. FLEMING:  But still it --
		DR. BRENNER:  But the answer to your question is we don't have the data.
		ACTING CHAIRMAN CALIFF:  Dr. Lipicky.
		DR. LIPICKY:  In the slide that you showed with the time line and the Lewis paper --
		DR. BRENNER:  Yes.
		DR. LIPICKY:  -- of those studies that are in the late stages of development, the Lewis study certainly did measure clinical endpoints, such as the need for dialysis,a nd things on that order --
		DR. BRENNER:  Yes.
		DR. LIPICKY:  -- which were affected by treatment significantly.  How many -- where does the REAM (phonetic) study --
		DR. BRENNER:  The RAIN (phonetic) trial is a study in non-diabetic patients.
		DR. LIPICKY:  I see.  Okay.  So --
		DR. BRENNER:  And it has the same endpoints as Lewis.
		DR. LIPICKY:  So much of these other studies that are in this --
		DR. BRENNER:  No, everything here is for diabetes.  I didn't --
		DR. LIPICKY:  Right.
		DR. BRENNER:  -- address the non-diabetic study.
		DR. LIPICKY:  So which of these studies, in fact, have clinically relevant endpoints in addition to Lewis?
		DR. BRENNER:  Only Lewis.
		DR. LIPICKY:  Only Lewis.
		DR. BRENNER:  In what has been reported to date.
		DR. LIPICKY:  Right.  So that --
		DR. BRENNER:  In all of these other trials that you see where they are used with angiotensin suscepta (phonetic) blockers, I believe -- I know for sure RENALE (phonetic) because I chair it -- IDNT, which is the abisarten (phonetic) diabetic nephropathy trial, has the same hard endpoints that was in Lewis.  In fact, Lewis is the director of that trial.
		And I believe ABCD-V2 has the same hard endpoints.
		DR. LIPICKY:  So at the moment with respect to the story that you're evolving, there is one trial in diabetics that actually --
		DR. BRENNER:  One trial.
		DR. LIPICKY:  -- would lend support to the notion that seems to be the notion that most nephrologists have.
		DR. BRENNER:  I don't know what you mean by that.  Let me -- let me, I think, say what you were thinking.  Lewis is the only study in diabetes, published study in diabetes, that has the hard endpoints of renal death and all cause morality, in addition to having doubling of serum creatinine or changes in proteinuria or less -- let's say less rigorous measures of renal function.
		DR. LIPICKY:  Right.
		DR. BRENNER:  Okay, and the only other trial that has that in all of nephrology is the RAIN trial with Altace in non-diabetic patients.
		DR. LIPICKY:  And those endpoints were --
		DR. BRENNER:  The same.
		DR. LIPICKY:  -- thought of afterwards, right?  They weren't part of the prospective trial.
		DR. BRENNER:  I think they are part of the prospective trial.
		DR. LIPICKY:  Were they?
		DR. BRENNER:  To my knowledge.
		DR. LIPICKY:  But they weren't part of the original publication, were they?
		DR. BRENNER:  They were.
		DR. LIPICKY:  They were.  Okay.
		DR. BRENNER:  It was composite endpoint of the things I --
		DR. LIPICKY:  Okay, fine.  So then there are two trials in all of kidney disease --
		DR. BRENNER:  Yes.
		DR. LIPICKY:  -- that might support the notion that you're forwarding.
		DR. BRENNER:  Yes.
		DR. LIPICKY:  Okay.
		DR. BRENNER:  There are also some other experiences that are worth mentioning.  There are some repeat biopsy trials which show that the reduction in proteinuria is matched by some lessening of the histologic changes.  In some cases, in the kidney transplant, for example, where the biopsy is often carried out quite frequently to monitor so-called rejection episodes, there is clear regression of lesion with these kinds of therapies.
		So that adds to the sense of confidence we have that early studies on that time line are pertinent to predicting late events, late being loss of renal function or all cause mortality.
		DR. THADANI:  If I may ask on two minor points.
		DR. BRENNER:  Yes.
		DR. THADANI:  When you're assessing proteinuria or micro albuminuria, protein intake has got a lot of influence.  If you eat more protein, do you leave more protein?
		DR. BRENNER:  Not in a normal subject.
		DR. THADANI:  In the patients with diuretics?
		DR. BRENNER:  Insofar as their eating more protein will raise their renal blood flow.
		DR. THADANI:  So it will increase the micro proteinuria, right?
		DR. BRENNER:  It may provoke a slight --
		DR. THADANI:  So if you don't control the dietary intake, how confident could you be that on a given day or one year later your variation in the total 24 hour urinary --
		DR. BRENNER:  Well, to the extent that you have a randomization --
		DR. THADANI:  I realize, but with the sample size you get away, but if you don't have the samples, that would be one issue possible.  You have a heavy meal with a lot of -- you know.
		DR. BRENNER:  These protein measurements are typically made on first morning specimens.
		DR. THADANI:  I suppose --
		DR. BRENNER:  And whatever meal effect you're contemplating is largely dissipated.
		DR. THADANI:  Even if you have a heavy meal the night before?
		DR. BRENNER:  Even if you had dinner the way I did last night.
		DR. THADANI:  Okay.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  All right, Udho.  Last question.  We have a hungry audience here.
		DR. THADANI:  The last question is in the Lancet article they define three different -- one is the micro endoneuria.  The other one is the ratio of the creatinine --
		DR. BRENNER:  Which article?
		DR. THADANI:  I think the renal --
		DR. BRENNER:  The HOPE study?
		DR. THADANI:  Yeah.
		DR. BRENNER:  I don't want to get into that.
		DR. THADANI:  No, no.
		DR. BRENNER:  Somebody else will.
		DR. THADANI:  I just want to say what's your idea of measuring just the albumen.  Was it the ratio of albumen to creatinine?  Which is more relevant in your judgment to assess the significance of progression?
		DR. BRENNER:  I would say a change in any of them as long as you try and stay with the same --
		DR. THADANI:  So you define it for?
		DR. BRENNER:  Yes.
		ACTING CHAIRMAN CALIFF:  Okay.  Thank you.
		And with what we'll take a 45 minute break for lunch and try to start at about ten till two.
		(Whereupon, at 1:08 p.m., the meeting was recessed for lunch, to reconvene at 1:50 p.m., the same day.)

A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
(2:00 p.m.)
		ACTING CHAIRMAN CALIFF:  If everyone could take their seat, we'd like to get started.
		I think we had a good morning covering the general issues in the trial and the cardiovascular outcomes, and we've now had the introduction to the renal outcomes.  It's time now to turn to the diabetes sub-study.
		Our goal will be to try to get through the sponsor portion in the next hour, and then that will leave us two hours for deliberations.
		DR. YUSUF:  Sure.  Our next speaker is Dr. Hertzel Gerstein, who was the principal investigator of the diabetes component of the HOPE study.  He will be discussing the results on the main endpoints amongst diabetics, and also on the nephropathy issue.
		DR. GERSTEIN:  Mr. Chairman, ladies and gentlemen, it is my pleasure to present the results of the HOPE study as they pertain to individuals in the study who had diabetes.
		I will first discuss the cardiovascular outcomes in the diabetic subgroup in the first half of my presentation.  In the second half of the presentation, I will discuss the nephropathy, the renal outcomes in the diabetic subgroup.
		Diabetes is well known to be a strong risk factor for cardiovascular disease.  Individuals with diabetes are two to four times more likely to die of cardiovascular causes than those without diabetes.
		Middle aged individuals with diabetes and other risk factors have an annual risk of a cardiovascular event of four to five percent.
		Evidence from other studies show that ACE inhibitors reduce end stage renal disease in people who have Type 1 diabetes, as well as diabetic nephropathy, and it is clear that this reduction may also be due to a cardiovascular benefit in addition to the renal benefit, and there's also evidence that ACE inhibitors may have favorable metabolic effects.
		It is important to state that the HOPE study prespecified diabetes as a separate subgroup for separate analysis of the primary outcome, and in fact, at the time that this study was planned, there was a plan to recruit up to 4,000 individuals with diabetes in the study, which would have given us, assuming an event rate of five percent per year, 90 percent power to detect an 18 percent reduction in the cardiovascular primary outcome.
		We were very successful, and as I'll show you, we recruited at least one in three participants with diabetes.  So this was a prespecified subgroup.
		You've already seen this slide, and this is the same inclusion and exclusion criteria for those with diabetes as those without, with the exception that individuals with diabetes could have been recruited to the study if they'd had a previous cardiovascular disease as in the other individuals or if they had at least one other cardiovascular risk factor, and that would be a systolic greater than 160 or a diastolic greater than 90 or on therapy; cholesterol greater than 5.2 millimeters per liter; HDL less than 0.9; smoker; or micro albuminuria, and I'll show you that micro albuminuria or small amount os albumen in the urine at the time was felt to be a strong cardiovascular risk factor and now clearly is a very strong cardiovascular risk factor, and we'll discuss that later on.
		Just to remind you that individuals with diabetes and, indeed, individuals in the whole study were excluded if they also had dipstick positive proteinuria.  So in light of the previous presentation before lunch, we excluded anybody who would have been called overt nephropathy or well on their way to end stage renal disease, and for the diabetes group and, again, for the group as a whole, this was a study of those with either no proteinuria or just micro albuminuria, and I'll come back to that in the second part of the presentation.
		The same outcomes apply to the diabetic subgroup as they apply to the group as a whole.  Clearly, the exact same primary outcome and the exact same secondary outcomes.  I'm just going to highlight for the second part of the presentation that one of the secondary outcomes was overt nephropathy, and this was an outcome that we had discussed fully in a previous sub-study which was funded in 1994, and I'll talk about that later on, the micro HOPE sub-study.
		Okay.  Now I'm going to present the baseline characteristics for the individuals in the study with diabetes, and this just applies to those with diabetes.  As you can see, about 36 to 37 percent of all the diabetic subjects in the study were women, which is one of the largest studies of women with diabetes for cardiovascular outcomes, and the average age was 65.
		The duration of diabetes was about 11 years in the study, and it's important to note that the diabetes therapy were balanced across groups as were the other baseline characteristics.
		These are the baseline risk factors.  Approximately 56 percent of the individuals with diabetes had a history of hypertension at the time of randomization.  The other important thing to note on this slide in addition to the balance across groups is the fact that one third, 1,119 individuals with diabetes were enrolled in the study because they had at least one other risk factor, but did not have a previous cardiovascular disease as defined in the protocol.  So that was one third of the total group of individuals with diabetes.
		The blood pressure at the time of randomization was about 142 over 80 for the individuals with diabetes, and as you can see, there was a fair bit of abdominal obesity, about 100 centimeters for the waist circumference, and the ankle/brachial index was about .97.
		With regards to concomitant drug use, these were balanced across the two groups.  Approximately 20 percent of the individuals with diabetes were taking diuretics, 28 percent on beta blockers, and slightly greater than 40 percent on calcium channel blockers, 20 percent on cholesterol lowering drugs.
		Finally, with regards to baseline biochemistry, you can see that the glycated hemoglobin in the study was about 7.4 percent, which is typical of what glycemic control would have been in the United States at around the time the study was being conducted.  These people had essentially normal renal function at the time that they were recruited into the study, again, emphasizing the fact for later on that these were very early in any course towards later renal disease.  They had normal function at the time of randomization.
		One third of the people with diabetes in the study, 1,140 individuals had micro albuminuria, defined as an albumen to creatinine ratio greater than or equal to two in a dipstick negative population.
		These are the results for the individuals with diabetes, randomized to ramipril or placebo.  This is the slide showing the primary outcome of cardiovascular death, myocardial infarction, or stroke, and as you can see, ramipril reduced the risk of this primary outcome by 25 percent, and the result was fairly clear at the beginning and continued as the study progressed over the four and a half years.
		In addition to reducing the primary outcome, ramipril effectively reduced each component of the primary outcome.  This is the data for cardiovascular death.  There was a 37 percent reduction in the cardiovascular death on ramipril compared to placebo.  There was a 22 percent reduction in myocardial infarction on ramipril compared to placebo, and there was a 33 percent reduction in stroke in individuals randomized to ramipril compared to placebo in just the diabetic subgroup of the study.
		We then looked to insure that the results were consistent across various subgroups of the diabetes subgroup, and the next slide will show these subgroups, and I'll go through this a little bit slower since the slide may be a little difficult to read.
		These are those with micro albuminuria at baseline and those without micro albuminuria at baseline, and as you can see, there was a very consistent relative risk reduction for both groups.  The interaction P value was 0.34 showing no reason to suspect any heterogeneity.
		These next two lines are those individuals with a history of a previous cardiovascular event, and these were those 1,119 individuals without previous cardiovascular disease, and as you can see, one thing that we did find was that those without previous cardiovascular disease had a lower event rate than we expected.
		We had planned that this group would have an event rate about 18 to 20 percent, and we were somewhat surprised to that it was lower than we expected at 9.9 percent.  So we had much less ability to detect a difference.  The group with diabetes and a cardiovascular event in the past had a 24 percent placebo rate.
		There was no evidence whatsoever of a difference between the results for the two groups.  The interaction P value was close to unity at 0.65, showing the results were consistent whether or not there was a history of cardiovascular disease as defined in the protocol.
		The next four lines relate to the anti-hyperglycemic agents used by the individuals with diabetes in the study, and regardless of whether they were taking dietary therapy alone, oral agents, insulin or combinations, the results were consistent with an interaction P value of 0.51.
		As has already been mentioned, we had very few individuals with Type 2 diabetes, about 2.3 percent of the total -- pardon me -- Type 1 diabetes.  Two, point, three percent of the total had Type 1.  Ninety-seven, point, seven percent had Type 2 diabetes.  However, the results were again consistent.  There's a point estimate for Type 1, the point estimate for Type 2.  Large confidence intervals because of a few numbers.  No evidence of interaction.
		The next slide shows the results in the diabetes subgroup for a total mortality.  As in the group as a whole, there was a clear benefit of ramipril on total mortality showing a 24 percent risk reduction with ramipril compared to placebo.
		I don't have a slide showing the revascularization benefit, but there was also in the diabetic subgroup a 17 percent relative risk reduction in revascularization with a P value of 0.031.
		Finally, as in the group as a whole, the question arises as to whether or not the effect of ramipril in the study was due to its blood pressure lowering effect or whether it was due to another effect, and we tried to analyze that by that have been described for the group as a whole, but we did a simple, multivariate regression, Cox regression analysis in which we asked the question:  after controlling for the mean change in blood pressure during the course of the study, to what degree does ramipril prevent the composite outcome of myocardial infarction, stroke, or cardiovascular death.  And you see that there's the exact same relative risk reduction, same relative risk with essentially the same confidence interval even after controlling for the mean change in systolic and diastolic blood pressure.
		And if there's questions later, I have time dependent changes on another slide which I can show, suggesting that the effect was over and above that related to blood pressure lowering.
		Now, that is the first part of the presentation related to the effect of ramipril on the cardiovascular endpoints that were in the HOPE study.
		The second part of the presentation, I will discuss the renal outcomes, and that will be what we're talking about now.
		As many of you know, there is evidence that ACE inhibitors may reduce progression of early renal disease in individuals with diabetes, and indeed, even late renal disease individuals with diabetes.  Dr. Brenner has already shown some studies that show that ACE inhibitors work in the late stages of renal disease.
		At the time that the study, that the HOPE study began, as I mentioned, we also submitted and received approval for a sub-study called the micro HOPE sub-study, which stands for micro albuminuria, cardiovascular, and renal outcomes in the HOPE study, and the purpose of the micro HOPE sub-study was to assess the effect of ramipril on albuminuria in HOPE study participants.
		The methods of the micro HOPE study were subsequently published in a paper in 1996.
		I want to remind the committee at this time that in the HOPE study participants with high degrees of proteinuria at baseline were excluded on the basis of a simple urine protein dipstick.  So, again, this is a group of individuals that were early in that line of progression of renal disease that was described earlier on.
		In this substudy and in the protocol and in the diabetes care paper, we prospectively defined micro albuminuria as a urinary albumen excretion rate of 20 to 200 micrograms per minute, and if you do the urine collection for 24 hours, this is exactly equivalent to a 24 hour urine collection of 30 to 300 milligrams of albumen per day.
		We also prospectively defined micro albuminuria to be present if the albumen to creatinine ratio was greater than two milligrams per millimole in a first morning urine collection, and you divide by creatinine in these because you need to control for the volume of the urine.
		Now, in the sub-study, we stated that we would define diabetic nephropathy on the basis of the gold standard test for diabetic nephropathy, and I'll show that in the next slide, the gold standard being a 24 hour urine collection for either albumen or protein.
		We also stated, however, and we published that, that we would screen using two possible ways of screening for this gold standard.  We would screen centrally at baseline, one year, and study end, and in fact, we did, using a central measurement of first warning albumen to creatinine ratio, and this was done in four different laboratories around the world.  Most of them in Europe and North America were all done in Canada and the U.K.
		We stratified the results for the lab in which it was measured, and there was no evidence of heterogeneity across the different labs.
		At the other visits, those that were not at baseline, one year, and study end, we stated that we would do a less accurate screen for diabetic nephropathy with a urine dipstick, and just to remind the committee, this is a qualitative test where a nurse research assistant dips the color reagent into urine and compares the color on the bottom to see if it's one plus or two plus or trace, et cetera.
		And for the purposes of triggering a 24 hour urine collection, we stated that either a first warning albumen to creatinine ratio at baseline, one year, and study end or at the other visits, a urine dipstick being greater than or equal to one plus would trigger the 24 hour urine gold standard measurement.
		And these are the diagnostic characteristics of those two tests.  You see the albumen to creatinine ration measured centrally is by far much more accurate with the sensitivity and the specificity of 93 and 98 percent, whereas because of the qualitative nature and other problems with it, the dip stick has only got about 70 percent sensitivity and about 90 percent specificity.
		We defined diabetic nephropathy prospectively in the study as a 24 hour urine collection for albumen which was greater than 300 milligrams in 24 hours or if it was an excretion rate, greater than 200 micrograms per minute, and as I've said, those are exactly equivalent.
		We also said because the urines were actually measured locally, the 24 hour urines were measured locally, that if the local lab couldn't measure an albumen, we would also accept a 24 hour urine total protein, which includes albumen as well as some other proteins, of greater than 500 milligrams per day, and these are the currently accepted definitions of diabetic nephropathy today, and they were also in 1993, 1994, and we published this in the methods paper.
		So that was the prospectively defined gold standard for diabetic nephropathy that we used.  Now, as has already been presented, this study was ended early, and because it was ended early, we were not able to collect all of the 24 hour urines that we needed to collect because -- for two reasons.
		One, people were coming in quicker, and also a lot of the local labs were not able or did not go and collect the 24 hour urine collections.
		Therefore, prior to analyzing the results for nephropathy and prior to doing the analysis, we thought that we would be very appropriate to include the most sensitive and the most specific screening test that we used as well, and so the final definition that was reported in the Lancet paper was as follows.
		The exact same gold standard, but we said if there was no gold standard available, but it should have been done because the albumen to creatinine ratio said it should have been done, that we included an albumen to creatinine ratio greater than 36 as well.  So what was used in the Lancet paper was a 24 hour urine collection being positive, and only if one is not available, an albumen to creatinine ratio greater than 36 in the first morning urine.
		Before I show the results of the effect of ramipril on the renal outcome, I just would like to emphasize the point that was made by Dr. Brenner earlier regarding the importance of micro albuminuria as a risk factor for cardiovascular disease and for cardiovascular outcomes.
		This is epidemiologic data drawn directly from the HOPE study, and this is just the subgroup of individuals with diabetes who are on placebo throughout the study.  This is the primary outcome of MI, stroke, or cardiovascular death.
		And as you can see -- and remember only a third of the patients with diabetes and micro albuminuria, two thirds did not have micro albuminuria.  As you can see, and I'll walk you through this, close to 30 percent of those with micro albuminuria at baseline had the primary outcome, and about half of the, 15.3 percent of those with no micro albuminuria at baseline had the primary outcome.
		The relative risk for an MI or stroke or cardiovascular death, if you just have micro albuminuria, after adjusting for age and gender and smoking and hypertension and hyperlipidemia and waist to hip ratio and creatinine and the duration of diabetes, the use of diabetes agents and the glycated hemoglobin, even after adjusting for all of those things in a Cox analysis was 1.84.
		Very similar thing seen for all cause mortality.  The adjusted relative risk was 1.85.  For diabetic nephropathy, as you find in the Lancet paper, which as you know is a progression from micro albuminuria to nephropathy or normal albuminuria to diabetic nephropathy, for those with micro albuminuria at baseline, they were 17 times more likely to develop diabetic nephropathy than those without micro albuminuria at baseline.
		Now, I'm going to show you the effect of ramipril on the renal outcome of diabetic nephropathy.  I will first show you the first line are the results according to the previously specified and defined definition that was published.  Just using the 24 hour urine measurement alone, just using the 24 hours urine measurement alone, there was a 20 percent relative risk reduction that just did not make the nominal P value of 0.05.
		When we included the 24 hour urine collection, plus in the absence of a 24 hour urine collection, an albumen to creatinine ratio greater than 36, it's important to note that there were a lot more events, 48 more events in both groups, and clearly we see that there's a 22 percent reduction in the development of overt nephropathy.
		If one broadens it further and explores the data by including in the absence of a 24 hour urine collect an albumen to creatinine ratio, and in the absence of that, dipstick positive proteinuria, that less accurate test that I described, you still have a very consistent result of a 20 percent reduction.
		And the point to note in this slide is regardless of how you define overt nephropathy, we see the same result essentially, but a 20 to 22 percent risk reduction in the development of overt nephropathy as the study progresses.
		When one measures -- when one analyzes albuminuria as a continuous variable, this is a centrally measured, first morning, albumen to creatinine ratio.  We measured it centrally at baseline, one year, and study end, as I've already described.
		You can see that the effect of ramipril is apparent immediately within a year's time and continues as the study progresses.
		With the last few slides, we thought it would be useful for the committee to see what the effect of ramipril was in those both with and without diabetes.  In other words, the whole HOPE study population as a whole.  We haven't made a big point of it, but I want to remind the committee that 30 percent of individuals with diabetes had micro albuminuria at baseline, but 15 percent of those without diabetes also had micro albuminuria at baseline.
		So when we looked at what the effect of ramipril is in the group as a whole, what we see is that all patients, 20 percent of individuals who had no micro albuminuria, who were normal albuminuric at baseline went on to develop micro albuminuria, and 23 percent of those on placebo went on to develop micro albuminuria with a relative risk reduction of about nine percent, and this was consistent in those with diabetes and those without diabetes.
		The next slide shows the progression from no albuminuria to either micro albuminuria or overt nephropathy for the group as a whole, and that is the same type of finding.  Twenty-one percent went from no micro albuminuria at all to any albuminuria compared to 24 percent on placebo with a relative risk reduction of about ten percent, again, consistent across the groups with no heterogeneity.
		Finally, another way to look at that is the progression from either no micro albuminuria to any albuminuria or from micro albuminuria to nephropathy, which is the last slide.  So this is the progression from one stage to the next stage, and you see that there is 20 percent progressed on ramipril compared to 22 percent on placebo, with a reduction of 12 percent, again, consistent across the groups.
		In summary, ladies and gentlemen, I believe that in the diabetes subgroup of the HOPE study we've shown that in people with diabetes who are at risk for cardiovascular disease, the addition of ramipril to other effective therapies reduces cardiovascular death, strokes, and myocardial infarction, total mortality, revascularization, and diabetic nephropathy.  
		The effect was independent of the effect on blood pressure of ramipril, and the only substantial adverse effect is as has been described in the group as a whole, was a five percent excess of cough.
		Thanks for your attention
		ACTING CHAIRMAN CALIFF:  Okay.  So what we want to do here would be to address questions related to diabetes, renal function, in particular, and maybe we'll reverse direction and start on the far right-hand side with questions or comments.
		DR. BAKRIS:  A very nice presentation.  You know, I just wanted to ask your opinion about something.  
		The next to last slide, just before the summary slide, I was looking at the impact on the diabetic and the non-diabetic, and one could make the argument looking at that data that, in fact, you had more of an effect if you didn't have diabetes than if you had diabetes, and I just wanted to get your thoughts on that.
		DR. GERSTEIN:  I think it's essentially a subgroup analysis.  The results were heterogeneous or -- pardon me -- there was no heterogeneity with the result.  I don't really think that it means much other than just the play of chance.  I think the result were consistent across the groups.  It's clearly something that has not been explored in the literature.  The whole role of micro albuminuria and the benefits or risks, et cetera, in nondiabetic people is a relatively new area of investigation.
		DR. BAKRIS:  Right.  The other related question, and I didn't see this, and I know you excluded people with frank proteinuria de novo, but was there anybody or was there even a percentage of patients in the ramipril group that even developed proteinuria?
		In other words, maybe they had micro albuminuria and paradoxically went on, which is not something that I would have predicted, but you never know, and I'm just asking.  I didn't really see that, and I don't even know if that existed.  So there may not have been a reason to see it.
		DR. GERSTEIN:  Well, clearly individuals who are on ramipril, 5.6 percent or actually 6.8 percent according to the lancet definition of individuals on ramipril went on to develop proteinuria or diabetic nephropathy.
		DR. BAKRIS:  Right.
		DR. GERSTEIN:  Compared to a higher percentage in those on placebo.  I'm not sure if that's ‑-
		DR. BAKRIS:  Okay.  Well, then given that, and I know the numbers will be small, but is there any explanation for that since that really kind of flies in the face of a lot of other literature?
		DR. GERSTEIN:  Well, I guess the first thing is that it doesn't appear that ramipril totally prevents it from happening at all, individuals.  I mean it reduces the risk of progression of the problem, but there are other studies in which individuals on ACE inhibitors do go on and --
		DR. BAKRIS:  No question about it.  Let me ask it a different way.  Was there a difference in -- okay, Salim.  Go ahead.
		DR. GERSTEIN:  Which data are you?
		Okay.  I may have heard the question differently.  Maybe it might help if I have Slide 27.  Perhaps that might explain that.
		DR. BAKRIS:  Okay.
		DR. GERSTEIN:  I think maybe that's what you're asking.
		DR. BAKRIS:  All right.
		DR. GERSTEIN:  Okay.  These are the  results showing the development of overt nephropathy in those with diabetes, those without diabetes according to micro albuminuria status.  I'm not sure, George, but maybe that's what you're asking.
		DR. BAKRIS:  Yeah.
		DR. GERSTEIN:  So as you can see, for those with diabetes who had micro albuminuria, 18, eight percent on ramipril and 21.6 percent on placebo developed overt nephropathy for a risk reduction of 15 percent.  Those without micro albuminuria at baseline, clearly there were much less numbers that went on to go to get nephropathy, but there was a consistent relative risk reduction of 30 percent.
		Those without diabetes, you see that there were 823 with micro albuminuria and four, eight, nine, seven without micro albuminuria.  There is a reduction in the development of overt nephropathy in both groups, 30 percent reduction with micro albuminuria, and again it's small numbers, but a like reduction.
		DR. BAKRIS:  Sure.
		DR. GERSTEIN:  So it's consistent.
		DR. BAKRIS:  Right.  No, that's fine.  Let me just ask a quick question regarding that.  I know for the whole group, you know, the blood pressures were not significantly different, but  in this subgroup, did you look at the differences in blood pressure to see if that may have accounted for why this percentage went on and the others didn't?
		DR. GERSTEIN:  We didn't really look at that.  The subgroup of those for nephropathy, no.
		DR. BAKRIS:  Okay.
		ACTING CHAIRMAN CALIFF:  Dr. Molitch.
		DR. LIPICKY:  Excuse me.  Before you leave this slide, that slide really said that the largest drug effect was in people who had no diabetes and had no micro albuminuria.  Is that not correct?
		DR. GERSTEIN:  Well --
		DR. LIPICKY:  Relative risk went down to .34.
		DR. GERSTEIN:  I'm going to make the same argument that was made --
		DR. LIPICKY:  Just looking -- just looking at point estimates.  So --
		DR. GERSTEIN:  Looking at the point estimates, you're right.  The point estimates --
		DR. LIPICKY:  That's what George saw in the previous slides.
		DR. GERSTEIN:  Yes.
		DR. LIPICKY:  And the point estimate -- you know, the question is:  is that a fact?
		DR. GERSTEIN:  Yes.
		DR. LIPICKY:  And I agree it's not a fact, but in fact, the two slides are consistent with one --
		DR. GERSTEIN:  Yes.  No, this is consistent with the other slides, and it's something that needs to be looked at in other studies.
		ACTING CHAIRMAN CALIFF:  Okay.  Dr. Molitch.
		DR. MOLITCH:  I have several questions.  One, I wasn't quite sure why the number 36 was priced for the albumen and creatinine ratio.
		DR. GERSTEIN:  Yes.
		DR. MOLITCH:  If two is equal to 30, then 20 would be equal to 300; is that correct?
		DR. GERSTEIN:  No.
		DR. MOLITCH:  Of milligrams per 24 hours?
		DR. GERSTEIN:  Maybe I can just go through that a little bit more carefully.  Micro albuminuria, the albumen-creatinine ratio for micro albuminuria was chosen.  The cutoff was chosen as greater than or equal to two in dipstick negative individuals at the time of recruitment to this study.  And that was because at the time in 1993 and 1994, albumen to creatinine ratio was relatively new metric.  It was not yet clearly described as to what would be the one that would correlate or the number that correlates best with a 24 hour urine collection of 20 to 200 micrograms per minute.  That's why albumen-creatinine ratio greater than two was chosen for micro albuminuria.
		DR. MOLITCH:  So where would an equivalent of that be in milligrams per gram of creatinine?
		DR. GERSTEIN:  Well, that's actually --
		DR. MOLITCH:  Does that use millimoles?
		DR. GERSTEIN:  About 30, 30 milligrams per gram.
		DR. MOLITCH:  Which is pretty close to --
		DR. GERSTEIN:  Micro albuminuria cutoff.
		DR. MOLITCH:  Which is pretty close to 30 milligrams per 24 hours for most studies that have looked at it.
		DR. GERSTEIN:  Yeah, the lower limit of the albuminuria definition, the 24 hour definition, correct.
		DR. MOLITCH:  Okay.  And so the upper limit?
		DR. GERSTEIN:  Then for 36, there was -- in 1994 and even today actually there's not a lot of data about what albumen to creatinine ratio to choose which might screen for diabetic nephropathy, which is clinical proteinuria.
		So at the time we chose the number of 36 because there was some regression curves that have been published in the literature that suggested that numbers greater than 30 were very highly sensitive and specific, and using those curves and using some data, we chose 36 as being a very conservative estimate, and we knew that using 36 we would miss some clear nephropathies.
		DR. MOLITCH:  Because if you used 20, we should be closed to 300 milligrams per gram of creatinine.
		DR. GERSTEIN:  Well, 20 is probably a little bit too low.  I mean maybe 30 might have been okay, but we chose prospectively 36, and we published that in the Diabetes Care paper.
		DR. MOLITCH:  Okay.  A few other things.  One is I presume a lot of these patients were developing congestive heart failure, which is one of the outcomes that I presume that urine protein was not collected when the patients were in heart failure or in patients who were exercising?
		DR. GERSTEIN:  Urine protein was -- individuals who had heart failure -- we only collected the urine protein at baseline one year at the routine study visits and at study end.
		DR. MOLITCH:  Right.
		DR. GERSTEIN:  So that would have been essentially no patients who would have been given a urine protein at the time that they were in heart failure.
		You're alluding to the fact that heart failure may increase proteinuria, I think.
		DR. MOLITCH:  Yeah.  So we know that they weren't; is that correct?
		DR. GERSTEIN:  I don't think that we were collecting them in heart failure.  We don't have any data.
		DR. MOLITCH:  Do we know that?
		DR. GERSTEIN:  We don't know that for an actual fact, but these were at the routine study visits when they were sent centrally, and if they came to a routine study visit in heart failure, I don't think we know whether there may have been one or two people.
		Do we have any?
		DR. YUSUF:  Collected it from everybody?
		DR. GERSTEIN:  Yeah, in everybody in the study.
		DR. YUSUF:  But just for what it's worth ‑-
		ACTING CHAIRMAN CALIFF:  If you could, go to the microphone.  You might want to position yourself up there for further questions.
		DR. YUSUF:  -- 11 percent in the ramipril group and 13.3.  So the difference is 2.3 percent.  It'll be a little hard to believe that that's what made the difference.
		DR. MOLITCH:  Does anyone know with what vigor these were collected?  I presume also that people with heart disease were put into exercise programs and exercise was not done the same day as their urine protein collection and this type of thing?
		DR. GERSTEIN:  People were asked to be in a first morning urine collection.  In fact, they were given a bottle the previous visit and told to bring in the first morning collection even when the visit was later in the day.
		DR. YUSUF:  Yeah, we didn't use standardization for that.  You just let it happen, you know, because there was a visit scheduled, and at every visit for that one year and four year visit, at that visit it was collected, and it wasn't based on whether they were exercising or not.
		DR. MOLITCH:  The patients weren't asked to not exercise --
		DR. YUSUF:  No.
		DR. MOLITCH:  -- before they came in?
		DR. YUSUF:  No, no, and that would have randomized out.
		DR. MOLITCH:  Okay, and these are all on the 24 hour urines when they were done as a second test after the first treating.
		DR. GERSTEIN:  Twenty-four hour, yes.
		DR. MOLITCH:  What percentage of patients had, in fact, an elevated 24 hour urine that had the elevated screen? 
		Do you understand my question?
		DR. GERSTEIN:  Everybody that had a positive albumen to creatinine ration of 36 or higher or dipstick positive proteinuria, we sent them a message that they were to obtain a local 24 hour urine collection for either albumen or total protein.
		DR. MOLITCH:  And what percentage of that group that had elevated levels on that initial value then had a subsequent 24 hour urine that showed an elevated level?
		DR. GERSTEIN:  Well, of all the individuals that we reported, there were 48 individuals that should have had an albumen -- a 24 hour urine collection, who didn't have the 24 hour urine collection.  So let me just -- that was 48 --
		DR. MOLITCH:  How many had an elevated level on the subsequent 24 hour urine collection?
		DR. GERSTEIN:  I don't think we know the answer to that question.  We know that -- well, I can just review the numbers one more time.  We know that 373 individuals -- pardon me -- 273 individuals had an albumen-creatinine ratio positive over the 24 hour urine collection, but 225 individuals had just the 24 hour urine collection, which is the 48 individuals who didn't have one or the other.
		I'm not sure that answers your question.  I don't think we have any other data to answer that.
		DR. MOLITCH:  You probably have the data.  You just haven't looked at it in that fashion.
		DR. GERSTEIN:  Yeah, that's right.
		DR. MOLITCH:  Of the oral agents that people were using, did they stratify it across the two groups that were the, for example, thiazoline diones (phonetic) or Metforman.  Was there more in the ramipril group?
		I presume since it was randomized they should be possibly equal, but that should have been looked at since they were lower in the urinary protein as well.
		DR. GERSTEIN:  We did not collect data on which oral agent people were taking.  We collected whether they were on oral agents or whether they were on insulin.  So we did not collect whether on TZDs or whether they were on Metforman, et cetera.
		DR. MOLITCH:  Okay.  I think with respect to the prevention of micro albuminuria to begin with, whether we really have shown that here, I think, is certainly open to question in the diabetic group, and also I know the Euclid study had difficulties trying to show that also for Type 1 diabetes.  So I'm not sure that that case certainly has been proved at this point.
		I have a question also about the development of diabetes, and I guess I don't know whether you're going to answer that or --
		DR. GERSTEIN:  That's a question either me or Salim or both.
		DR. MOLITCH:  Okay.  When we looked at the curves of development of diabetes, and that went by pretty quickly, it looked like most of the effect was within the first year or so; is that correct?  It didn't look --
		DR. GERSTEIN:  Well --
		DR. MOLITCH: -- like there was continued divergence, like we saw with some of these other effects.
		DR. GERSTEIN:  Well, okay.  Go ahead.  Why don't you answer?
		DR. YUSUF:  Can we go back to my tray, that is, Yusuf's tray, and get Slide 48 and then we'll look at 49 as well?  Not that one, 48.  Of the main presentation, not the back-up; the main presentation.
		DR. GERSTEIN:  While they're getting that, I mean, you'll see that the results were apparent at the beginning and continued throughout the whole length --
		DR. YUSUF:  Of the one year, not the --
		DR. GERSTEIN:  Yeah, after the first visit.
		DR. YUSUF:  Yeah.  Forty-eight.  Can we go on?  Yes, that's the slide.
		So this is essentially the first visit.  The curves are already diverging, and then at the next visit they're further apart, and they're further apart, and they're further apart.
		DR. MOLITCH:  Is there really a further difference after the second year?
		DR. YUSUF:  Well, just look at the first one there and then look at out here.  It's hard to know exactly whether it's, you know --
		DR. MOLITCH:  It looks like there's at least 50 percent of the curve within the first year and maybe another 45 percent, 35 percent after that.  Does your trend analysis clearly show a clear trend to further divergence under --
		DR. YUSUF:  We haven't done that analysis.  All we've done is this curve, and we have the overall numbers, which was reduced, and we have a few other slides that could clarify some of issues on this if you'd like me to show them.  I don't know.
		DR. MOLITCH:  On this particular aspect?
		DR. YUSUF:  On this particular aspect.
		DR. MOLITCH:  Please.
		DR. YUSUF:  The next one, you have already seen this on, you know, 155 versus 102 difference, and the difference was there mainly in the use of oral agents, but also a trend here.
		But I also want to go to my back-up slide, if I could, and go to back-up slide number 42.  In a sub-study in one center, not one center, five centers, on the secure sub-study on 730 patients we had fasting glucoses at baseline and at two years.  We haven't yet analyzed the four year data, but these are the data on fasting glucoses in everybody in that site, and this is the increase in glucose level from baseline, is .42 in the placebo group, and it also increased in the ramipril group, and that was different.
		So these are the only data we have on diabetes that overall the new diagnosis was different, the use of drugs was different, and the glucose levels in a subset of 700 patients were different.
		You could switch that off.  Thank you.
		DR. FLEMING:  Can you go back, Salim, to your slide one or two back that was looking at time to diabetes?
		DR. YUSUF:  Sure.  So could we go back to 48 of my main presentation again, please?  Thank you.
		DR. FLEMING:  While they're going back, was your point to try to establish that there was a constancy in the relative risk?  Is that what you were trying to get at?
		DR. YUSUF:  We weren't trying to do that, no.  We haven't done an analysis for that.
		DR. FLEMING:  It's very apparent that the relative risk in that first year is in the neighborhood of .5.  The incremental relative risk after that first year is pretty close to one.  So the excess is predominantly derived in that first year.
		DR. YUSUF:  I see, and at the end it's .66, isn't it?  So that there has to be something in favor.
		DR. FLEMING:  Well, it's -- it's cumulative as .6, and so the incremental, which in the hazard ratio is, in fact, the incremental hazard, and that is close to --
		DR. YUSUF:  The only way we can really do is to put the numbers against each other, and we could put it --
		DR. FLEMING:  Okay, but if you've eyeballed these enough, it's pretty clear that the relative risk is converging toward one in the incremental hazard.  I don't know how compelling that is, but the point is most of the excess is occurring in that first year.
		DR. YUSUF:  I think -- how about the second year, Tom?  Don't you think there is a further absolute difference?
		DR. FLEMING:  No.
		DR. YUSUF:  No?  Well, we'll have to look at the --
		DR. FLEMING:  At least in terms of you have to look at how much the blue goes up versus how much the yellow goes up.
		DR. YUSUF:  I'm just looking at the difference between the yellow and the blue.  In the first year it seems to be --
		ACTING CHAIRMAN CALIFF:  Is this hard, quantitative science here?
		DR. FLEMING:  Yeah.  Well, what it gets at is whether or not the effect is continuing to grow, and my point was just if that was what you were trying to get at, it's apparent that most of the effects are in the first year.
		DR. YUSUF:  Yeah, I'm not trying to get at that.  I agree with Rob.  This is an eyeball P value.
		ACTING CHAIRMAN CALIFF:  I think you have to be in the third year of your Ph.D. in statistics to be able to do this.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  Dr. Molitch.
		DR. MOLITCH:  Yes.  Were there any supporting data at all for the diagnosis of diabetes or this is simply a check-off on a box?
		DR. GERSTEIN:  Self-reported history of diabetes, in addition to whoever the fact that that Dr. Yusuf just showed the slides.  Dr. Yusuf just showed the slide showing that they were on  agents.  In other words, the doctors were substantiating diagnoses essentially by putting them on drugs or therapy for diabetes, but essentially they were asked at each visit do you have diabetes, yes or no.
		DR. YUSUF:  I think just to give you an overall picture of the thing, it's fair to say we did not pre-specify this as something we were looking for.  It's also fair to say in the rationale part of the protocol we did not write any rationale for this.  We didn't expect this.
		So we then saw the result.  It's a striking P value.  So in a sense that first slide is data derived.  Then we said, "Is this real or is this a fluke?"
		And in order to get whether this was real or a fluke, we looked at what do the doctors do, and, well, they followed their diagnosis by differences in treatment, and then we said do we have some objective data in everybody, and that's where we went to the 700 people, and we found a difference.
		So I've just given you the whole story.
		DR. MOLITCH:  Just to try to get at why this might be the case, obviously there's a number of potential mechanisms.  One of them is improvement in insulin resistance essentially by the ACE inhibitor itself.
		Second, there was also -- it looked like there was a reduction in the total number of people who were on thiozides and beta blockers when they were on manipril is that correct?
		And did you look to see whether that could potentially account for this?
		DR. YUSUF:  Yeah.
		DR. MOLITCH:  And number third is was there any change in body weight for the two groups?
		DR. GERSTEIN:  The answer to your question, you saw the slide in Dr. Yusuf's presentation that there was a difference in the use of thiazides and beta blockers, and that clearly is one methodologic explanation that may account for the difference.
		I think that -- have we done body weight changes?  We haven't done that analysis.  We haven't analyzed that, but I think that what you're saying, Dr. Molitch, is that this needs to be tested prospectively, and as Dr. Yusuf has said, we think it's a good idea and we're doing it.
		DR. GRABOYS:  Just to pick up on the issue of diuretics, any obvious explanation why the use of beta blockers in the diabetic group was so low, 28 percent versus about 40 percent for the group?
		DR. GERSTEIN:  Sure.  There has been a long and old literature sort of scaring doctors away from using beta blockers in individuals with diabetes.  Based on early studies with the early nonselective beta blockers that in Type 1 diabetes, that they may impair the detection of hypoglycemia, so most physicians in medical school were taught to beware of beta blockers, individuals with diabetes, and that's probably why we were seeing that.
		Do you want to come up and make the point?
		DR. YUSUF:  See, the non-diabetics are all people with vascular disease, and so they -- a very high proportion had an MI or other coronary disease, but as the diabetics include people about 50 percent or more who didn't have an MI, so there's a difference in the reasons why you would use a beta blocker, too?
		DR. GRABOYS:  Yeah, and any data on the potassium levels in the diabetic group.
		DR. GERSTEIN:  Potassium levels in the diabetic group were not elevated.  In fact, the potassium levels went high.  In the run-in period they were excluded from participation in the study, and so there was no problem with potassium in the diabetes group or the group as a whole.
		ACTING CHAIRMAN CALIFF:  Dr. Pina.
		DR. PINA:  In the FDA reviewer's comments, I see that at the visit 558 patients have self-ramipril.  Was there a difference in rates for the drug in diabetics and the group as a whole?  And were reasons for this situation similar in diabetics  as the group as a whole?
		DR. GERSTEIN:  Okay.  Could I have the reserve slides, number three?  Right.
		So I think this may address the question.  The adherence to ramipril was similar to what it was in the group as a whole.  So at the end of four years, 61 percent were still taking study ramipril, and 12 percent on ramipril were taking open label ramipril, whereas the placebo, 52.7 percent, were on study drug, and 15.4 percent were on open label use.
		So at the end of the study 61 plus 12 is about 73 percent were taking an ACE inhibitor compared to 15 percent on placebo.
		DR. PINA:  Were the reasons for discontinuation of ramipril in diabetics different than --
		DR. GERSTEIN:  These are for stopping therapy.  If you go to the next slide actually, Slide 4, these are the reasons for stopping therapy in the individuals with diabetes, and you can see that these reasons are, in fact, the same as they were in the group as a whole.
		So cough, which I've already alluded to and very low rates of angioedema, et cetera.  So essentially there was no different reason for stopping study ramipril in the diabetic subgroup than there was in the group as a whole.
		ACTING CHAIRMAN CALIFF:  Why did you ask that question?
		DR. PINA:  Because it looked like the numbers that stopped the trial, well, it does seem to be high.
		DR. Di MARCO:  Looking at the numbers, how certain are you that this is or are you certain that this is an effect on the kidney itself or do you think that this is all secondary to the effects on cardiovascular disease?  I mean you have more heart failure in the placebo group, more myocardial infarction, more limb ischemia.
		I would guess they had more interventions and more diagnostic procedures.  Could the changes you see in the kidney be secondary to that rather than a primary effect of the drug?
		DR. GERSTEIN:  Well, actually, I think that's a very difficult question because the kidney is essentially part of the vascular system, and things that happen to the vasculature also affect the kidney.  So it becomes a very difficult mechanistic question to sort out.
		I think if we're reducing atherosclerosis or reducing cardiovascular related intermediate things, then it's certainly reducing them in the kidney, and the kidney may very well do better over time.
		So I don't know that one can give a mechanistic.  We don't have obviously sort of a --
		DR. Di MARCO:  Well, could you look at your population and look at people who didn't have events, didn't have heart failure, didn't have an angiogram, didn't have other things, and see if they also had these same changes in kidney function?
		DR. GERSTEIN:  I don't believe we've done that analysis, in other words, looked at those who sort of got through the whole study without anything and looked at their change in function.  That's actually another analysis that we can do.
		ACTING CHAIRMAN CALIFF:  Dr. Borer.
		DR. BORER:  I need to preface my comment and question by admitting that the subgroup hazard rate analysis is hazardous, but, you know, we've been shown a lot of analyses that generally sort of go the same way and occasionally reach nominal statistical significance, and that's very nice, but there are clearly important public health implications if we accept the concept that there are biologically important prophylactic effects on the kidney in diabetics as opposed to the more conservative accepting that there's a possibly associated goodness when you treat patients for the primary endpoint who have diabetes or don't have diabetes.
		With that in mind, I'm going to ask for one more subgroup analysis if you have it because I'm trying to isolate a group with diabetes for which there may not be very good evidence that the drug is useful for the kidneys or importantly useful, and I think it's really a follow-on to John's question a minute ago.
		Have you looked at that subgroup of diabetics that didn't have evidence of cardiovascular disease to see what the effects of ramipril is on the kidneys?
		DR. GERSTEIN:  Are you asking me about the CBD negative group of people?
		DR. BORER:  Right.
		DR. GERSTEIN:  And that's Slide 8, reserve Slide 8.
		So this is expanding some of the stuff that I've already showed you.  In those who did not have cardiovascular disease and those with cardiovascular disease, I'm going to show you these are the primary outcome, the primary and secondary outcome.  This is all heart failure, and this is overt nephropathy.
		And as you can see, first of all, is that the results are consistent so when those -- when the primary outcome -- those with cardiovascular disease, there was a 24 percent reduction with ramipril.  Those without cardiovascular disease, there was a 16 percent reduction with ramipril.  I already pointed out the much higher placebo event rate in this group than in this group.  There was no interaction.  So they were not statistically heterogeneous, and I just want to take a moment to point out that this was a much lower rate than we'd expected.
		In order to detect a 25 percent reduction from 9.9 percent, we would have needed well more than the 3,577 patients that we had had in the study.  We would have needed in excess of 10,000 diabetics with no previous cardiovascular disease in order to detect the same type of event rate in the study.  So that's the primary outcome.
		As for the primary and secondary outcome, the same thing for overt nephropathy, which again those with CVD positive versus those with CVD negative, there was an 18 percent reduction in those CVD positive, an eight percent reduction -- pardon me -- an 18 percent -- excuse me -- a 26 percent reduction there, an 18 percent reduction there, no evidence of heterogeneity.  The results were consistent across subgroups regardless of how you cut the data in those with or without a history of cardiovascular disease in the past.
		And I think that the results say the same thing for both groups.
		DR. BORER:  And just staying on that last line there, overt nephropathy defined as you've defined it is one possibly interesting endpoint, but, you know, extrapolating from Dr. Brenner's presentation, what about the development of micro albuminuria and other renally related or vascular related or diabetic vascularpathic changes like eye changes requiring laser therapy or what have you?
		DR. GERSTEIN:  I showed the data earlier on about developing -- do you mean micro albuminuria in those according to CVD positive or CVD negative?
		DR. BORER:  Right, right.
		DR. GERSTEIN:  We haven't cut the data that fine to look at micro albuminuria in that group.  As far as eye disease is concerned, we assessed diabetic eye disease using a very simple question.  We just ask people at every visit since the last visit if they'd have laser therapy for diabetic eye disease, and so we did not do retinal photographs.  We did not do seven field stereoscopic, et cetera, type assessment.  So it was just a history of laser therapy for diabetes in the eyes, which is what we used.  So we didn't do any -- we did not analyze it according to CVD positive or CVD negative for micro albuminuria development or progression.
		ACTING CHAIRMAN CALIFF:  Dr. Lindenfeld.
		DR. LINDENFELD:  To clarify once again, according to our briefing document from the FDA the protocol definition for overt nephropathy was to be greater than one plus proteinuria and/or the albumen excretion rate of greater than 200 and/or the albumen to creatinine ratio.
		And when one analyzes that, the hazard ratio is 1.07, and so again, I'm wondering.  That's not the definition that was published, but according to our documents that was the original protocol definition.
		Can you clarify how that change was --
		DR. GERSTEIN:  Yeah, I'd be happy to.
		Could I have my main presentation Slide 20, please, my main presentation Slide 20?
		Okay.  I can't account for the exact numbers that you just said.  However, I can tell you that this was the protocol definition for diabetic nephropathy that was published in Diabetes Care, which was a methods paper of the micro HOPE protocol, and the micro HOPE protocol was submitted in 1994 and funded in 1994, and this was the methods paper published in 1996.
		So the definition of diabetic nephropathy stated in Table 2, I think, in that paper was exactly as we see above.
		As I've already described, for the Lancet paper we included with that definition the most sensitive and specific first morning albumen to creatinine ration, which was the only -- which was the best screening test that we had for it because we didn't have all of the 24 hour urine collections that we wanted to have.
		At no time in the micro HOPE paper or in the subsequent, you know, methods -- micro HOPE protocol or the methods paper in Diabetes Care did we state that one plus proteinuria was going to be a definition for diabetic nephropathy as an outcome.
		ACTING CHAIRMAN CALIFF:  Could we hear from the FDA about this?  Because there is a discrepancy between what you say and what we have in our briefing document.
		DR. GERSTEIN:  We recognize that there's a discrepancy, and there was -- I should make one comment, that in the original HOPE paper, the original HOPE protocol that was originally funded, which was before the micro HOPE protocol was funded, there was a much less specific and a very general discussion of albuminuria, but the micro HOPE protocol clearly defined what we would be talking about in terms of diabetic nephropathy.
		DR. LIPICKY:  I'm not sure that we need to comment.  There are two definitions that are applicable here, and after the primary -- after the review that you received, there was an addendum to the review, and I guess that was not transmitted so that there FDA agrees with the numbers that were shown when it is defined this way.
		So the problem is there are two definitions, one that was the protocol and the second which was the publication.
		Did I say that correctly?
		DR. MOLITCH:  You're saying this is a case where the protocol is not amended to reflect the publication.
		DR. LIPICKY:  Right.
		DR. MOLITCH:  But they both occurred well before the study with --
		DR. LIPICKY:  Yeah, let Dr. Hung say what I've say.  I may have been --
		DR. HUNG:  Jim Hung, FDA statistician.
		These two actually we analyzed, and so we have that addendum dated April 17th, so agree with the sponsor's numbers.  So I don't know whether you got that addendum or not.
		ACTING CHAIRMAN CALIFF:  Okay.  Thank you.
		DR. FLEMING:  Rob, this was the issue I wanted to raise as well.  So I'd like to at least pursue it until I understand it.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. FLEMING:  Are we saying that the -- if we look in Table 23 where we see a striking difference in these two definitions, which I guess no matter what the history of this evolution of definition, it's bothersome to me when you see such a strikingly different result, a relative risk of 1.07 versus a relative risk of .81.
		DR. GERSTEIN:  I must -- I have to just show, I mean, the next slide, and I have to make the point.  The 1.07 was -- I'm not sure where that comes from actually, but regardless, the next one after that ‑-
		DR. FLEMING:  According to this, it comes from what was the protocol definition.
		DR. GERSTEIN:  No, but the -- it's incorrect.  The protocol definition is this one, the 24 hour test only.  That is the protocol definition published in 1996.  It said in the protocol in 1994, that the micro  HOPE protocol -- and this was the one that we used in the Lancet paper.
		DR. FLEMING:  We understand what the published paper showed, but what we're interested in is what was in the protocol and was the protocol amended formally.
		ACTING CHAIRMAN CALIFF:  Dr. Hung.
		DR. LIPICKY:  We have to ask you whether that 1.07 relative risk was the protocol defined definition or an error on your part.
		DR. HUNG:  That 1.07, that actually is the definition I thought originally according to the protocol, but then you must clarify that that is not the case.  So 1.07 hazard ratio, that one is much more restricted definition than the first one, which is -- I don't know.  It doesn't show up here.
		DR. LIPICKY:  Shari Targum is going to the microphone.
		DR. TARGUM:  I'm just going to read the definition from the protocol, and the definition of overt nephropathy in the protocol is greater or equal to one plus proteinuria on dipstick or urinary albumen excretion greater than 200 micrograms per minute or 300 milligrams per 24 hours.
		That is in the protocol.  That is not the same as the published --
		DR. LIPICKY:  And that is the analysis that the 1.07 comes from?  Well, Jim says no.
		DR. HUNG:  According to the definitions read by Shari, we have addendum saying that the hazard ratio is .86.  (Unintelligible) was .72, 1.02.
		DR. LIPICKY:  Well --
		DR. HUNG:  The P value is --
		DR. LIPICKY:  I'm sorry.
		DR. HUNG:  According to the definition just read by Shari we call it the protocol definition.
		DR. TEMPLE:  So the 1.07 is incorrect?
		DR. HUNG:  No, no, no, no.  The 1.07 is not.  One, point, oh, seven is much restricted definition than the protocol definition just read.
		DR. LIPICKY:  Well, it's an analysis that only Jim did.
		DR. HUNG:  Right.  I'm trying to entertain ‑-
		DR. LIPICKY:  The sponsor has not represented that same data in any way.
		DR. HUNG:  Yeah, I'm trying to entertain ‑- I'm trying to, you know, entertain the sensitivity of the results.
		DR. LIPICKY:  -- the sponsor define nephropathy according to the rules that Jim did the analysis by.
		DR. HUNG:  Okay.  Let me read again.  Okay?  According to definition just described by Shari, that the P value for that endpoint is .075, and I think sponsor agree with that and -- I'm sorry -- not sponsor; the HOPE study group, and the hazard ration is .86.  (Unintelligible) single is .72, 1.02.  That is in the April 17th addendum.  
		In fact, the Lancet article has three more definitions, you know, more restrictive definitions, and I can verify that.  I was trying to entertain the sensitivity and robustness of the results.
		DR. GERSTEIN:  Can I just address a couple of issues related to that?
		The first one is that the definition that was published and was in the literature is the first one that's on the line here, the 25 urine collection.  It's also universally accepted around the world as the definition of diabetic nephropathy, and I see Dr. Bakris nodding his head, which is the top line on the thing, and this was published, and they said many years before the study ended, and so that's the first point.
		The second point is I want it to be clear that we used this second definition in the paper for the reasons I mentioned above.  However, we also wanted to make sure that this was a real number.  So we explored the definition of diabetic nephropathy in the paper, and I'd like to have reserve Slide, if I could, No. 21, please.
		Many people -- Number 21, reserve slide -- many people have stated that in order to be really sure that somebody with diabetes has diabetic nephropathy, you want to see that they've also had evidence of eye disease.  
		I've already stated that we didn't do eye photographs in patients, but in the Lancet paper, we said, "Well, let's explore this diabetic nephropathy finding.  Let's use" -- because, you know, we didn't do kidney biopsies in these people -- "so let's use the most specific definition that the literature would accept on clinical data for diabetic nephropathy," which means a urine collection that shows nephropathy, plus eye disease.
		And so, of course, we have very few numbers, but we see that exact same trend showing, that there's a 38 percent relative risk reduction.  So it was not that the Lancet paper was making a whole bunch of definitions.  We were saying let's be more specific.  Let's be even more specific, and let's see what happens to the results.
		So this even further emphasizes the point.  No matter how you define diabetic nephropathy in the HOPE data set, we get the same consistent results, and that was the only reason that we did explore it in the Lancet publication.
		ACTING CHAIRMAN CALIFF:  Tom, are you satisfied now?
		DR. LIPICKY:  Let me see if I can explain again because this is now confusing, and it's confusing to me.
		In the blue books there that you have that came at the conference, there is an addendum.  A lawyer in committee management decided that you all didn't need to see that until today, not us.  We wanted to get it to you two weeks ago.
		So one part of the thing that would have been -- one part of the discussion would have been avoided in the sense that that is the same data in the same analyses that were shown at the meeting now.
		We received the HOPE protocol set of case report forms that had sacks with variable names in every block in the original data so that we saw no written material from HOPE or the sponsor for purposes of the reuse that were written.  In fact, it was rather difficult from the protocol and from the publication to figure out how things were defined.  That's why there are a bunch of different analyses that you have seen.
		There is no discrepancy at all with respect to how the sponsor is represented or how HOPE is representing the data as they defined it, and what you're seeing is that you can take some trips when you interpret how things should be defined a little differently.
		ACTING CHAIRMAN CALIFF:  Okay.  Tom, are you --
		DR. FLEMING:  All right.  I'm now following along on Table 23(r) from the blue book that we were just presented today, and if I understand, then we are to discard the 122, 110, the 1.07 relative risk, as not having been correct.  The correct, I understand, per protocol is the .86.
		DR. HUNG:  Yes.  Just ignore the second line because second line seems to entertain the robustness.
		DR. FLEMING:  You're tell us that is, in fact, the protocol definition, and the protocol in spite of these more recent developments and publications in '96, et cetera, et cetera, the protocol was never formally amended?
		DR. LIPICKY:  That's correct.
		DR. GERSTEIN:  The protocol was never formally amended.
		DR. FLEMING:  And so essentially what we're seeing here are results showing that they're about 270 events according to the definitions used in Lancet, which are about half the number of events that fit the protocol definition.
		The good news is they both now trend in the right direction, relative risk of .86 versus relative risk of .78, if you use the original.  If our interpretation is correct in Table 23(r), it continues though to suggest that micro albuminuria is actually only marginally affected, and renal dialysis is slightly in the wrong direction of only 18 cases.
		And doubling in creatinine from baseline is slightly in the wrong direction.  Are those, in fact, accepted as correct analyses per protocol?
		DR. GERSTEIN:  The doubling of creatinine, yes.  That is what we found, very few numbers of individuals, and as Dr. Brenner said, we're way back in the course of renal failure.
		DR. FLEMING:  Right, right.
		DR. GERSTEIN:  So we would not expect this to have any effect on doubling the creatinine or end stage renal disease.
		DR. FLEMING:  Or micro albuminuria.  That shows almost a relative risk of .94.  Is that also correct?
		DR. GERSTEIN:  Well, I showed the micro albuminuria data already for the diabetes and the non-diabetes group.  I can show them again if you like, but ‑-
		ACTING CHAIRMAN CALIFF:  No, no, no.
		DR. FLEMING:  Don't have to.  I'm just asking if this is, in fact, essentially consistent with what you understand the protocol definition.
		ACTING CHAIRMAN CALIFF:  It's one, two, three, four --
		DR. GERSTEIN:  I don't have those numbers, your numbers right in front of me.  I can --
		DR. YUSUF:  Actually while Hertzel is trying to look at that, Tom, can I deal with that first thing?
		You know, when FDA did the initial review, they did not have the design paper that we published about four years ago.  So we superseded the definition.
		Now, it is fair we didn't file an amendment, but you've got to understand there's an investigator driven study, and we don't file amendments every time a slight definition protocol occurred.
		However, the key point is:  did we define what the outcome was before we looked at the data?  And whether our definitions are data derived or not, and the point is three years before the study was completed, we made that definition which is there in the Diabetes Care literature.  It's published, and those are the two things that Hertzel showed you.  The first one was 24(r) urine where the P values are .08 and the relative risk is .78, and the second one was, because of the early closure, we did not have -- it wasn't possible to get 24 urines in everybody.
		So without him knowing the data, he said, "Let's take the next best thing we have, and that is the albumen creatinine ratio," and he has reported that.
		Now, to be fair, they all show a relative risk from .78 to .8, with P values just below or just above PO .05.  So it's consistent, and I think it will be fair to say they're borderline P value.  Nothing is three zeros, one.
		ACTING CHAIRMAN CALIFF:  I think we're all in agreement on those points.  Now we've moved on to the issue that some of the other renal endpoints tending even in the wrong direction or show no effect, and the one that we were most concerned about, I think, that you were just going to look at was micro albuminuria.
		DR. LIPICKY:  Yeah, that was confirmed to be the correct number.
		DR. GERSTEIN:  That is the correct number.
		ACTING CHAIRMAN CALIFF:  So that has a ratio of .94?
		DR. GERSTEIN:  Point, nine, four.
		ACTING CHAIRMAN CALIFF:  With a P value of 0.34.
		DR. GERSTEIN:  Yes, .33.
		ACTING CHAIRMAN CALIFF:  Okay.  Joann, did you have any further questions?
		DR. LINDENFELD:;  Well, I have one other question, and I had asked earlier.  In the diabetic patients without cardiovascular disease who were entered because they had diabetes in one respect, can you show us those patients and their risk factors?
		In other words, what I want to know is how many of those --
		DR. GERSTEIN:  No.  You're asking which of the risk factors those diabetic individuals had?  Regarding if they had at least one risk factor, most of them had greater than one.  Janice, I don't think we have an analysis broken down according to each risk factors.  You can do it, but we haven't cut the data that way.
		DR. LINDENFELD:  The reason I'm asking just for clarification is when you look at your patients with diabetes and one risk factor, we know that there are some we would treat anyway, but how does this data apply to those, a diabetic?
		DR. GERSTEIN:  Well, I should say, I mean, we defined what risk factors they could have.  So it's not that any risk factor got them in.  They had to have one of those five that we said:  hypertension or smoking or micro albuminuria or lipid abnormalities.  So they're very carefully defined risk factors based on epidemiologic data showing that those substantially increased the risk of a person with diabetes.
		DR. LINDENFELD:  I'm asking this mostly for the physician who looks at their patient and say, "Does this study apply to this specific?"
		DR. GERSTEIN:  Yeah.  We haven't cut it that way.
		DR. THADANI:  Before you go on to the next, although you're showing there might be some subtle changes in micro albuminuria, but the hard endpoints of dialysis, others are not in your favor; is that correct?
		DR. GERSTEIN:  We have no reason to expect that dialysis or creatinine change would be in our favor because of the fact that Dr. Brenner was just saying earlier on that the way -- early on in the course of the development of renal disease I think we're seeing just random play of chance.
		DR. THADANI:  I realize that, but in what you showed, the data, one of the studies was positive, and it's nice to know the endpoint is going in the right direction.  So we may not have enough data.
		Now, also you've made a comment that your P value went down from .04 to .07 because you say we don't rely too much on one plus dipstick, and yet you excluded all of those patients at baseline.  How can you just contradict your own statement?  If I had a new patient --
		DR. GERSTEIN:  It's different --
		DR. THADANI:  -- if it is one plus, you said those patients could be treated.  Forget about that.  Now you're saying that's not a good test.  So I think I've got a problem with that because your entry criteria -- you're violating all of the entry criteria by doing that.
		DR. GERSTEIN:  I'd like to address that question.  We excluded people with one plus proteinuria at entry for two reasons.  One, the main reason is -- there's two points.  The first one is it's a difference between an exclusion criteria and an outcome.  So that's number one.  So we defined an outcome more rigorously than an exclusion criteria.
		The second point is that there was even in 1993 a very strong bias in the diabetes community based on the Lewis study and other studies, that anybody with diabetes, regardless of whether they had Type 1 or Type 2 diabetes, should be in an ACE inhibitor, and we felt at the time that if we had included people with one plus or more dipstick proteinuria that we would have had (a) a very hard time recruiting and (b) a lot of violation of recruitment and a lot of use of unblinded ACE inhibitor.
		So we thought for methodologic reasons that we should include anybody that's got clinical proteinuria at the time, but that is not the same as an outcome.
		DR. THADANI:  No, I buy that, but, on the other hand, if you are one plus, the chance are your proteinuria has increased.
		ACTING CHAIRMAN CALIFF:  Udho, let's maintain the order of questioning here.  I think you'll be cleaning up at the end here if we could move on to Dr. Armstrong.
		DR. ARMSTRONG:  Following this discussion it would help me if we could start first with the methodology and the threshold for this dipstick, how symmetrical the methodology was across the centers.
		And you mentioned it had a 70 percent sensitivity, and I wondered if you'd comment on the intra individual variation.  Could you tell me something about the methodology and then I could ask my second question?
		DR. GERSTEIN:  Sure.
		DR. ARMSTRONG:  I only have two questions.
		DR. GERSTEIN:  Okay.  The sensitivity and specificity data that I showed is not from the HOPE study.  It's from the literature at the time.  That's the first thing.
		There's actually very little good sensitivity and specificity data on a year end dipstick, but just for the committee, again, it's like an Ames dipstick which has got a strip on it and different reagent pads on the strip.  You dip it in the urine.  It turns a color.  You compare it to a reference color on the side of the bottle.  If it's a certain color, you call it trace.  If it's a darker color, it's one plus.  If it's a darker color, it's two plus.  It's a qualitative test, and it was simply used in the inter central measurements visits as a screening test.
		That figure for sensitivity and specificity actually came from one paper many years ago which tried to look at it compared to 24 urine collections.  I'm not aware of any other paper that's looked at it since that time, and which is why we never included that as a definition of nephropathy.
		DR. ARMSTRONG:  Did all of the centers in HOPE use the same dipstick?
		DR. GERSTEIN:  No, it would be different.  There aren't -- I don't know all of the companies that make dipsticks, but it's a similar technology.  It's an old, you know, technology, and I'm assuming that someone in France may have used a different company's dipstick than somebody in the United States.
		DR. ARMSTRONG:  To what extent were the quantitative measurements that were driven by a positive dipstick similar or different?
		DR. GERSTEIN:  Oh, I see.  I don't think we've cut the data showing the 24 hour urines driven by a positive dipstick compared to 24 hour urines by a positive central screen.
		DR. ARMSTRONG:  So finally, could you construct for me some kind of flow diagram so I could understand the patients in your study who had a positive and negative dipstick during the course of the study and then sort of how they came down the hopper to the end?
		I'm confused as to how this study unfolded and how many patients actually ended up with a positive versus a negative dipstick and went on to quantitative measurements.  I'm really having trouble following this discussion.
		If someone could provide a flow diagram, it would facilitate my understanding.
		DR. GERSTEIN:  We could certainly do that with the data.  We haven't done that type of flow diagram with the data to now.
		DR. YUSUF:  What we did was we collected urines for the albumen-creatinine ratio, and everybody at baseline one year and at the end of the study irrespective of anything else.  So that way the mean ACR changes are really good data.  Plus they're central labs, all that stuff, and that's audit.
		Now, the dipstick at the beginning excluded people.  They were out.  Then every year they had a dipstick, and if they had a dipstick, then two things happened.  They were asked to provide the morning urine because it was the urine they brought anyway that was done.  That was sent to a central lab.
		So two things, two events could trigger a 24 hour urine.  One is a positive dipstick.  Another thing is if any urine that we collected at one year and four years went over that threshold, then we again asked for that.
		So that in a sense the ACR is an objective measure, and it's a standardized measure.  The dipstick is a qualitative measure, and the mean ACRs at one year and at four years are unbiased by anything, and it's standardized and it's complete.  So that's all I can tell you.
		ACTING CHAIRMAN CALIFF:  Okay.  Dr. Fleming, are you finished?
		DR. FLEMING:  I'm done.
		ACTING CHAIRMAN CALIFF:  Dr. Thadani.
		DR. THADANI:  On that question, why didn't you show if you -- Salim says that ACR is the most sensitive.  Why did you not show ACR alone?  Because you never --
		DR. GERSTEIN:  Well, we had the gold standard.  I mean --
		DR. THADANI:  No, I realize that, but you are saying that the most sensitive method of estimating, that's the definition.  I know you showed a composite of three.
		DR. GERSTEIN:  Yes.
		DR. THADANI:  You must have analyzed ACR alone because you've written papers.  Somebody in the review must have asked you that.
		DR. GERSTEIN:  No, I think that would have been almost a little bit disingenuous.  I mean what we said is we have the gold standard.  We wouldn't go to the ACR alone, and in fact, you know, if there was a patient who had an CAR who was less than 36, but they did have a 24 hour urine collection, we believed the 24 hour urine collection because that is the gold standard.
		The ACR is only 93 percent sensitive and 98 percent specific compared to that gold standard.
		DR. THADANI:  I realize that.  Give the problems with the dipstick, missing it on some patients, you must have data on the issue on everybody, right?
		So you --
		DR. GERSTEIN:  We have ACR on most --
		DR. THADANI:  Why don't you who us what happened with ACR?
		DR. GERSTEIN:  We analyzed the data just with the ACR without looking --
		DR. THADANI:  What's the significance on that?
		DR. GERSTEIN:  -- at the 24 hour urine collection.  I don't think we have done the cut yet, yet.  We haven't done that cut yet.
		DR. THADANI:  And what happens if there's no trend or anything on that?
		DR. GERSTEIN:  There's no reason to believe that -- sorry.
		DR. YUSUF:  It's unlikely, given the (inaudible).
		DR. THADANI:  All right.  The other point is that you talked about micro angiopathy in the diabetes.  It's a tough issue unless you do photographs, as you said.
		DR. GERSTEIN:  Yes.
		DR. THADANI:  And my ophthalmologist colleagues tell me that you really can't even diagnose it.  You know, they're talking about the micro angiopathy, especially the retinal one, unless you're doing routine photographs, which you said you did not do.
		DR. GERSTEIN:  We did not do.
		DR. YUSUF:  What is the confidence level?  Because if you take diabetes, a lot of them will have small, you know, aneurysms which you pick up on the regular limits.  So how much confidence we have, these are really bad eyesight with a laser or in order to address that issue, really a prospective study on that?
		DR. GERSTEIN:  Well, clearly one could take the same model that  Dr. Brenner showed for diabetic renal disease progression and apply it to diabetic eye disease progression.  You have people that have no diabetic eye disease.  They then get a couple of micro albuminuria -- micro aneurysms.  We then get a couple of hard extrudates and soft extrudates, and et cetera, et cetera.
		So for the eye disease we just asked people about the very, very end of the spectrum, and that's why we have two events, and it's one that most people who say they have laser therapy for diabetic eye disease do have laser therapy for diabetic eye disease, but we don't miss those who don't --
		ACTING CHAIRMAN CALIFF:  Udho.
		DR. THADANI:  But be sure that --
		ACTING CHAIRMAN CALIFF:  Udho.
		DR. THADANI:  -- the biopsy is --
		ACTING CHAIRMAN CALIFF:  Udho.
		DR. THADANI:  Yeah?
		ACTING CHAIRMAN CALIFF:  Your co-panelists are urging just one more question.
		DR. THADANI:  The last question is if the (inaudible) retinopathy is in the same direction, then why there's no difference.  Actually there are 170 patients in ramipril group and 186 in placebo.  It's going in the wrong direction.
		DR. GERSTEIN:  Sure.  Could I have reserve slide, just to maybe answer that, number -- give me a moment -- yeah, Number 24.  Reserve Slide 24, please.
		Okay.  We included this in the paper, and I'll show you the results.  We did then come up with a post hoc, post hoc definition, composite outcome of microvascular disease defined as either diabetic nephropathy or laser therapy or dialysis.
		So in direct answer to your question, you see that 9.4 percent of people on ramipril compared to 10.5 percent of people on placebo did report a history of laser therapy for their eyes with a 12 percent relative risk reduction.  I've already showed you the nephropathy.  We threw in dialysis as a fair measure of part of the microvascular outcome, .6 versus .5, going in the wrong direction.
		When you combine all three as a composite measure of microvascular complications, 15.4 percent versus 17.8 with a relative risk reduction of 15 percent of the nominal P value of .05.  So I think that answers your question directly.
		Slide off.
		ACTING CHAIRMAN CALIFF:  Okay.  I have two questions to which I would like a brief answer, which I know you can do after having been through the grilling you've already been through.
		There are two things here that at least for this committee we've had kind of a standard that to recommend an indication it has to either cause the patient to live longer, feel better, or avoid an unpleasant experience of some kind.
		And you've got two things here:  the delayed onset of diabetes and albumen in the urine as measures that you're considering important.  Could you make a case for each as briefly about -- and obviously the implications to the public health, as Dr. Furberg is going into, I guess, in terms of cost, on the other hand, could be substantial if this was seen as a very important surrogate or way to interrupt a disease pathway.
		Could you just speak briefly to each?
		DR. GERSTEIN:  All right.
		ACTING CHAIRMAN CALIFF:  As to how we should view this as a panel?
		DR. GERSTEIN:  I'll first address the diabetes and then the micro albuminuria.
		From a diabetes perspective, the most important thing about diabetes is that it's a really bad risk factor for really bad outcomes.  So people with diabetes are at high risk for many bad things down the line, including microvascular and macrovascular disease and things like erectile dysfunction and everything else.
		If you can have a therapy which even on average delays that development by two to three years, then you can make a substantial differences in diabetes.  After all, in 1992, diabetes cost the American taxpayer $100 billion a year just in that year alone.  Anything that delays the development of that disease obviously is going to be cost savings and a difference to the individual's health.
		Micro albuminuria can be viewed in a very similar way.  You've got end stage renal disease, which is a serious outcome.  Dr. Brenner has alluded to the cost and the numbers of people with end stage renal disease.  Clearly if you can slow down the progression of renal disease even with an ACE inhibitor, then you can make a big impact on the serious outcomes down the line.
		And so that's I think the best answer I can give.
		ACTING CHAIRMAN CALIFF:  Great.  All right.  Thank you.
		Now, Dr. Furberg, if we can ask you to briefly summarize, perhaps even more briefly than you had planned.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  Like in about three minutes, if possible.
		(Laughter.)
		DR. FURBERG:  Well, I'll try to be brief.
		Members of the panel, ladies and gentlemen, let me just skip the slides.  I was going to cover the composition of the experience board, going to comment on the prespecified outcomes and how we focused on the primary outcome, but also on all cause mortality and on safety.
		I was going to say that we have adequate power to see meaningful differences in the various subgroups, those with various stages of disease and diabetes ranging from 11 to 16 percent, that before we looked at the data established monitoring boundaries that were really restricted during the first half of the trial, and strictly for benefit than for harm, and that we had planned annual visits.
		And here is the experience I ant to spend a little bit of time on.  At our first look when we had less than one year of data, the Z score was 1.1.  So nothing too exciting.  Almost a year later we had tests, the nominal P value of .05, which was well below the boundary of four.  So we decided to take another look a year later, and at that time the Z score was 2.75.  We dropped the boundary well below at that time.
		And we made some projections.  We decided on the next meeting and projected that maybe by a year later it would cross the boundary and be able to stop the study.  To our surprise, I mean, in November the Z score had jumped up and reached 4.3, but at that time it was clear that we needed to take some action and stop the study, and that was in November.
		The problem we had at that time was that 40 percent of all of the primary events had not been duplicated, and we didn't know how many events were in the pipeline.  So we wanted to give the investigator some time to clean up the data, get complete data, do the classification so that the data would generate discussion like you've had today, very clear.
		And that's why we gave them a few more months, and we also asked for some specific analyses and stratified analysis looking at MI by type, stroke by type, et cetera.
		Here are the Z scores over time just so that you can see what you lived through for the primary, and the pattern is very consistent.  It started off with lower -- low values in the increase.  You accumulated more events.  The typical pattern for basically all of it, and it's interesting to note that in November '97 for some of these  maybe we're around two and a half.  All cause mortality was just one and a half.
		So I don't think we had any problem saying let's go for another year, and that's when we got these fairly striking results and took the action that I had talked about, but the subgroup -- I think this is important -- has not maybe -- should even receive more attention.  The two major subgroups, patients with vascular disease of various kinds and the diabetics, and again, the pattern is fairly striking here, the marked increase over time and with Z scores well over four for the larger group with vascular disease and three and a half for the diabetics.
		We noted at that time while it didn't affect the monitoring that the benefit was primarily in the older people in men, and the fact that we extended -- the study went to March mean that a few of these now reached nominal significance.
		We were not concerned about safety at all.  ACE inhibitor is well established, and we saw a fourfold increase in cough, and it led to discontinuation of treatment, and as you've talked about earlier, some cases of angioedema, nothing beyond what we expected.  So safety was never an issue.
		I think it's important to get back to the bigger picture.  We had a good discussion today and really considered the primary outcome, and I would like to sort in closing to make some comments as a person who had no involvement in the conduct and analyses  of the data.
		The public health implications are substantial.  The reduction we see here and for the major outcome of 22 percent with a remarkable P value is similar to that we've seen with other important interventions, beta blockers, similastaten (phonetic) and pravostaten (phonetic), the statens, and also with aspirin.  So they're adding important information from that point of view.
		But what's so remarkable about the study is that ramipril was shown to be effective on top of these proven interventions, making, I think, the findings particularly important.
		The documented benefit in patients with the various manifestations, the important subgroups, those with vascular manifestations of atherosclerosis in the heart, brain and peripherally, and the diabetics, they all had significant benefits, and I think that's where the importance of the trial lies, is because they extend the potential indications of ramipril to maybe as many as 15 to 20 million Americans, and the absolute benefit, again, as has been pointed out is also substantial.
		A reduction of 43 events per 1,000 patients treated for four and a half years is important in the area of prevention, and that translates as you heard to a number needed to treat of 23, and that number is obviously higher if you include some of the secondary outcomes.
		So in summary, and Mr. Chairman, I think HOPE was a very well designed trial with important scientific findings that also had substantial public health importance.
		Thank you.
		ACTING CHAIRMAN CALIFF:  All right.  Thank you.
		I think it's time now to move to the questions.
		DR. TEMPLE:  Rob, can I ask one?
		ACTING CHAIRMAN CALIFF:  Sure.
		DR. TEMPLE:  I just wanted to ask Curt something.
		I mean in some ways the robustness of the findings was something of an accident because instead of stopping it earlier, you didn't really have the overwhelming finding early and then the curve went up.
		One of the things we've been suggesting to people is that the monitoring committee only count mortality, perhaps even total mortality, a more conservative endpoint which means more trials will go longer.
		Do you have any thoughts about that?  Would you all have felt comfortable operating under that termination rule or wouldn't it have made any difference or did you sort of do that anyway?
		DR. FURBERG:  I think we do it anyway.  As you know, I'm sure we agree on this point.  I mean, with my NIH background, total mortality is often the primary outcome.  That is always the yardstick, the comparison, and we kept an eye on that, and mortality was lagging a little bit behind the other outcomes.
		So by going the other year, I think we got important results on all cause mortality, and it makes me feel much better both in terms of efficacy and safety about the time.
		DR. TEMPLE:  But your official stopping rules were based on the combined endpoint.
		DR. FURBERG:  That's correct.
		DR. TEMPLE:  So it could have been that you would have been confronted with a consideration to stop it much earlier.
		DR. FURBERG:  I think that typically you use the primary outcome for your stopping guidelines.  These are guidelines only, but we always kept an eye on all cause mortality.
		ACTING CHAIRMAN CALIFF:  So, Bob, if I interpret your question right, you're saying that you would recommend from the FDA perspective that people not stop for non-fatal endpoints if mortality is not ‑-
		DR. TEMPLE:  Yeah.  Look.  Obviously we have no rule or official guidance on this, but you know, endpoints are evanescent.  Death is not.  You know, you don't have to really worry it's going to go away, and you don't stop a major endeavor prematurely.
		But in addition, I have to say having studies go longer has some appeal.  First of all, we like easy regulatory decisions than more difficult ones, but I don't want to advertise that.
		But you do get to look at subsets.  You get to look at all of the people under -- you get tons more information if you can go a little longer.  Obviously there's the ethical difficulty of continuing when you know the answer, and I was just fresh from this recent experience.  I was wondering what Curt thought.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. FURBERG:  Well, it was made easy when we had that jump in Z score.  If we at the November '98 meeting had a Z score just about three, I think we would have had a lengthy discussion, but it was made easy, and then when mortality passed the -- reached .01, I think it was very clear.
		ACTING CHAIRMAN CALIFF:  All right.  Now, we move into the panel session.  As I understand it, everyone who's here on the panel can vote except Dr. Bakris, who is not a special government employee.  So you're welcome to participate in the discussion though as we go through the questions.
		And I'm going to ask Dr. Lindenfeld to lead the discussion.  The first question is:  does the HOPE study adequately establish the beneficial effect of ramipril compared to placebo on the combined endpoint of MI, stroke, and death and cardiovascular causes?
		DR. LINDENFELD:  Yes, I would say absolutely it does.
		ACTING CHAIRMAN CALIFF:  Is there any disagreement?
		(No response.)
		ACTING CHAIRMAN CALIFF:  Okay.  Well, then we move to 1.1.  Does the proposed labeling adequately describe the risk factors of the HOPE study population?
		DR. LINDENFELD:  Well, I think in general it does.  The one concern I still have is as written at least to me this implies that diabetics with a single risk factor, not necessarily with coronary disease, and with any single risk factor the study applies to them, and I'm a little bit concerned that that's not the case here.
		Although the trends were suggestive that diabetics without coronary disease had a benefit, many of those probably would be treated anyway.  Many of them probably had micro albuminuria as a single risk factor and some with hypertension.  So I'm a little bit more hesitant about the wording of this.
		ACTING CHAIRMAN CALIFF:  Are there other opinions on this issue?
		DR. THADANI:  Just one minor point on that with the low exterior levels and divudex (phonetic) because now you've got Jim Fabrils (phonetic) who study very positive in that group, too.  I think just a bit of concern, but given the data, it's positive, but perhaps more questions than answers from the studies.
		ACTING CHAIRMAN CALIFF:  Would you propose a change in the wording of the label, Joann?
		DR. LINDENFELD:  Well, I might say in patients both diabetic and non-diabetic 55 years or older, and then stop it at coronary disease, stroke, peripheral vascular disease, period.
		ACTING CHAIRMAN CALIFF:  Would it be safe to say based on the questions that if the HOPE group or the sponsor came up with more analyses that justified the statement about diabetics with one risk factor, I mean, you have some questions, I think.  They just hadn't looked at the data now.
		DR. LINDENFELD:  Yeah, right.  I think if we saw the data there where there was significant, sure, we'd add that.
		ACTING CHAIRMAN CALIFF:  Does anyone else on the panel feel that there's any change needed in the label?
		DR. Di MARCO:  I don't.  I agree completely with Joann.  I think one issue one might raise if one were to do the analysis that Joann is suggesting, since the numbers would be relatively small, you know, we've got to consider what the level of significance, of statistical significance would need to be to accept the implications of the diabetics with one risk factor clause.
		I mean I don't want to make a concrete suggestion here, but I think that's something that's going to have to be considered in the discussion about the labeling.  Small numbers.  How compelling do the results have to be to accept the mandate that would be implicit in this label?
		DR. PINA:  It might be difficult -- correct me if I misinterpret it -- but that it was not -- the P value was greater than .05 in diabetics without cardiovascular disease.  So it wouldn't even meet the .05 criteria.
		ACTING CHAIRMAN CALIFF:  But it is a subgroup with trending in the same direction as the overall study.
		DR. PINA:  Right, right.
		ACTING CHAIRMAN CALIFF:  Well, maybe at this point, the question 1.2 actually raised looks a little bit tricky to me.  Does the proposed label have what we describe the characteristics of the population that should be treated -- underline the word "should."  So maybe we could go ahead and vote on the main Question 1.
		I'm assuming this will be quick based on the fact that no one had discussion.
		DR. TEMPLE:  Yeah, Rob, I have a question.  The wording in the indication section is written the way we usually write combined endpoint wording, and it says "or."  That is, myocardial infarction, stroke, or death.  Is that what people mean, or do they believe as Salim did that it, in fact, has shown an effect on each of those, in which case you would write it differently?
		You might start with "and."  I would put an "of" in front of each one to make it clear if I wanted to convey that impression.  Do you see what I mean?
		ACTING CHAIRMAN CALIFF:  Yes.  I think that's a good question.  
		Joann, the question is:  are you convinced that an individual effect was shown on each component?
		DR. LINDENFELD:  Yes.
		DR. LIPICKY:  That's sort of part of 1.3.
		ACTING CHAIRMAN CALIFF:  Well, I interpreted 1.3 to be a different question.
		DR. LIPICKY:  Well, okay.  Then it was poorly written.
		(Laughter.)
		DR. LIPICKY:  But, in fact, that discussion would appear if one started to add things that were not part of the combined endpoint.  Okay?  So that really is part of 1.3, and right now I think all one is talking about is if one defines the population the way in which it was defined in the protocol, is that sufficient, and that's one to describe it in the indications, and secondly, if that's how it's described in the indications, you'd think people like that should be treated.
		So those are the questions that are being discussed now.
		DR. TEMPLE:  Ray, I was asking about the endpoint, not the population.
		DR. LIPICKY:  Well, but we're talking about the population now.
		DR. TEMPLE:  I know.  I was trying to go back to the first question.
		ACTING CHAIRMAN CALIFF:  Well, let me try -- well, all right.  So let's go back to the main Question 1, and the question there is for the components of the composite, MI, stroke, and death from cardiovascular causes.
		Are we convinced there is an effect on each of those endpoints?
		DR. LINDENFELD:  I was convinced there was an effect on each one.
		ACTING CHAIRMAN CALIFF:  Tom?  As the panel statistician, do you have a comment on that?
		DR. FLEMING:  The much easier question to answer is the one that have answered all unanimously positively, and that was what was the study designed to address as its primary goal, and that was the composite endpoint, and did it achieve that, and the answer is, yes, it did, and in fact, as Curt showed, with one chance in a half a million.  Five hundred thousand to one is the P value.
		We have also, because of the robustness of that result, seen that when you split this in innumerable ways you get, because of the compellingness of the result, which is what Bob Temple was saying, it's nice when your study can go that long so that you can get such a compelling result, so that when you split it in so many different ways, it's still convincing.
		We never gave the same level of rigorous inquiry to the individual components.  I don't know the answer.  I certainly am more inclined to think that those individual components have been established than I am for mortality, which is an 05, which is a 200 to one or 2,500-fold more convincing is the composite endpoint than mortality, and mortality is secondary and the composite was primary.
		And I haven't looked in subgroups, and I don't know what happens when we look in the U.S. or in the non-Canadian setting, and is at least the point estimate consistent for mortality?
		Now, you're asking, and I see some were in between my reluctance to say mortality has been shown and my complete acceptance at the composite endpoint has been shown.  Somewhat in between you're asking Rob  has the individual components of the composite been shown.
		Is this a question that we have to answer?  Can the labeling essentially reflect that the study established compelling evidence of benefit on this composite with these three components?
		ACTING CHAIRMAN CALIFF:  Well, I think, Bob, if I --
		DR. TEMPLE:  It could, but that's not nearly as good as telling people who happened if that's not the only thing you can conclude.  That's why -- I mean you're right.  The other question is easier.  The P value is as long as your arm, but this is still a relevant question.  Was there a mortality effect or was there a stroke factor?
		DR. FLEMING:  Yeah.  The mortality question I'm more concerned about than the individual component question.  The mortality question, because of the incredible importance of mortality and the fact that it is the least compelling of the five things, the composite, the three components of the composite, and mortality; mortality is the least compelling, and data has not been presented to us to look at how robust the mortality result is.
		We don't even know what the result point estimate is in the U.S. or in the non-Canadian setting.  So it seems to me we have focused, as makes sense, on, as Salim keeps telling us to:  focus on what you said you would do as the primary endpoint, and that has been compelling.
		DR. TEMPLE:  No matter what the results, once you've set up --
		DR. FLEMING:  No, not true, not true, but what I'm saying is at least as so far as mortality is concerned, if we wanted to conclude that we have established with this one study on a secondary measure mortality as having been convincing, I would have wanted to have had more insight presented to us today about what the mortality results show, in the same way that we spent an enormous time spending -- looking at what the composite results show.
		DR. TEMPLE:  Tom, let me be clear.  The cardiovascular death significance level is .0002, and overall mortality, which is obviously a compromise measure since half of the deaths aren't affectable, was significant nominally at .005.
		DR. FLEMING:  Right, right.  Twenty-five times less convincing.
		DR. TEMPLE:  I guess to me I contrast this with our usual use of combined endpoints where we just throw the three out together and somewhere in clinical pharmacology can find out what actually happened to each of them, but in some ways that doesn't seem as satisfactory if you don't have to do it.
		So I'm pressing you on this because it seems to me if there were a good basis for it, you'd like the label to give all of the things that were reasonably likely to have been found.
		ACTING CHAIRMAN CALIFF:  Tom, I want to press on you a little bit, too, on this because, you know, I'm consistently finding as I'm a guest panelists on other groups that 90 percent of clinicians can't deal with saying the composite was different.  They always want to know the individual.
		And most patients, if you say this prevents death, stroke or heart attack, may say, "Well, what does it do to stroke?" and you say, "Well, we can't say," that's a problem.
		And this is a trial that's, I think, so robust.  I mean we rarely get a .005 for cardiovascular death, and here we have it for all cause mortality.
		DR. FLEMING:  I understand, and your question is?
		ACTING CHAIRMAN CALIFF:  Why is .005 not persuasive to you?  You say you want to know the North American or U.S. results.  I'm surprised.
		DR. FLEMING:  Well, .005, this is very important, but nevertheless a secondary endpoint, a single study.  Traditionally we would have assumed if this was the primary endpoint in a single study the general guideline, and it's only a guideline, would be .025, and is how many -- I mean, one of the reasons that to me this single study carries the day is the overwhelming evidence that it provides on the composite endpoint, which was the primary endpoint.
		And yet we still spent a considerable amount of time dissecting this in many different ways to understand strength of evidence, and I'm suggesting that on a secondary measure whose strength of measure is 2,500-fold less, that we haven't even been shown what these patterns are for consistency of effects on mortality over various subgroups.
		If we wanted to answer this question, shouldn't we have seen more of the evidence on mortality, which would have been a much less obvious answer than the composite endpoint.  My sense is the composite endpoint is absolutely shown, and there is potentially enough evidence to even say that the individual components have been shown.  I'm not sure that the distinction between those two is so important, but the distinction with overall mortality is important.
		And we've understood that we didn't expect to have effects on non-cardiovascular mortality, and the study properly showed us, the investigators properly showed us that we didn't have an adverse effect, but in fact, it certainly did, as you would expect, dilute the overall strength of evidence, and that strength of evidence is on the margin I'm saying for what I would have typically expected we would have looked at even if it was a single study as the primary endpoint.  This is a secondary endpoint.
		ACTING CHAIRMAN CALIFF:  Ray, you had your hand raised?
		DR. LIPICKY:  Well, no.  I can't say it better than Tom.  I just want to support him.
		ACTING CHAIRMAN CALIFF:  Are there other views?
		DR. THADANI:  I think it's important.  You know, the composite endpoint is positive, and as Tom has said, why we have to say that mortality went down with the composite endpoint is clear.  They're all hard endpoints.  There's no ischemia driven endpoint here.
		So I think directing that, myocardial infarction and stroke, which matter a lot, so why do you want -- perhaps one important area, you could give a table how each contribution was rather than mentioning in words, just give the numbers.  What were the mortality, the morality at each point?  Could you add that?
		DR. FLEMING:  The three components were not overall mortality, stroke, and myocardial infarction.  They were cardiovascular mortality, stroke, and myocardial infarction.  Cardiovascular mortality is significant at, you know, .0001, which makes most people's test for robustness, at least compared to anything else we've ever seen.
		I guess I want to throw something out because this comes up a lot.  I think in a trial where there are a lot of noncardiovascular deaths, total mortality is a robustness test.  It may or may not, however, be the best description of what the drug did.
		The fact that a total mortality still comes out favorable makes you feel you haven't lost any -- there's nothing weird going on, and that's all to the good, but we already know this drug isn't going to interfere with death due to cancer.  We don't expect it to.
		So I would argue that at least in some of these cases, the best measure of what the drug did is, in fact, cardiovascular mortality.
		In any case, this seems the one thing I do think is that you want to tell people as much as you responsibly can and not let them guess about what the combined endpoint means.  We use combined endpoints as something we have to do to get enough endpoints, but it's quite undesirable.  You'd rather know the answer for each of them.  That's a second best approach which you usually have to take because there aren't enough endpoints.
		Here, for better or worse, there were lots of endpoints.
		ACTING CHAIRMAN CALIFF:  John, you had a comment?
		DR. GRABOYS:  Just a comment.  The nice thing about total mortality though is that you don't have to worry about adjudication then, and I think of reasons why, you know, people with pneumonia, if they've had a prior infarct or if they've had renal failure might do less well, and so the fact that total mortality doesn't move in the wrong direction takes away a lot of the uncertainty, and so I like that.
		And the cardiovascular mortality is very strong.  So I think that those very hard endpoints are good.
		I'm a little uncomfortable about the myocardial infarction because of the way it was -- in the fatal events at least it covered a lot of things.
		DR. TEMPLE:  But that finding is not the fatal events.  It's the non-fatal events.
		DR. GRABOYS:  Yeah.
		DR. TEMPLE:  The fatal ones are already in the test.
		ACTING CHAIRMAN CALIFF:  Are there more comments on --
		DR. THADANI:  Yeah.  Even on the cardiovascular mortality, there are patients who died off a pulmonary embolism, which one presumes had nothing to do with it.  I've got some patients have died.
		PARTICIPANT:  (Inaudible.)
		DR. THADANI:  I realize that.  So, again, that's the trouble with the cardiovascular mortality.  They're encountered in that.  So I think total mortality is a better endpoint than dissecting everything else out.
		DR. PINA:  Rob, are you asking for comments beyond the mortality issue or are you back into the statement here toward the bottom?
		ACTING CHAIRMAN CALIFF:  I'll entertain anything on Question 1 now you want to comment on because we're about to close it out.
		DR. PINA:  Right.  I have a problem in the last sentence with the secondary endpoint of heart failure because that was not a prespecified secondary endpoint.
		ACTING CHAIRMAN CALIFF:  Oh, we're going to get to that.  That's Question 9.
		By the way, Question 9 is the last one in case you don't have it in front of you.
		DR. PINA:  Right.
		ACTING CHAIRMAN CALIFF:  We need to discuss 1.2 just for a minute.  Does the proposed labeling adequately describe the characteristics of the population that should be treated?
		Now, Ray, I thought that our job was not to define who should be treated.  That's the doctor's job.
		DR. LIPICKY:  Yeah, that's okay, and that's a perfectly good answer.  That means that then the people who are described as having been enrolled in the trial will sound like they should be treated, and the question was meant to just see whether you had any problem with that, and if you don't that's okay.
		ACTING CHAIRMAN CALIFF:  Okay.  So that would roughly be the same as Question 1.1 then.
		DR. THADANI:  Rob, on that issue, a patient who was diabetic in one respect or hypertension, the new guidelines would suggest that one should lower the blood pressure to below 130 or 120, and one of the difficulties you might run into, I don't know what this drug will do if you follow that correctly here, too.
		So are you concerned at all or are the panel concerned that that -- you find the therapy?  Because one possibility, you would just stop with this, but I understand the recommendation now is to lower the pressure to 120 or 130 in those patients.  And would this probably still hold?
		DR. TEMPLE:  The way it's written now, it lists as the people who should be treated -- and make no mistake.  Labeling does suggest who should be treated.  It doesn't command it, but it suggest is -- is the exact people who were in the study.  That's what all those listings of factors are.
		That isn't the only thing one could do.  One could say it's for people at high risk of coronary artery disease and here's what we mean, or of these events, and here's what we mean by that, which is a somewhat more flexible definition, and I think one has some choice there.
		ACTING CHAIRMAN CALIFF:  Okay.  
		DR. LIPICKY:  Maybe the right way to think about the answer to these questions, the 1.1 and 1.2, is that if one thinks one needs a lot of words written in parentheses or two or three more sentences that describe the patients, if that would help any, or if the few words or the one sentence that reasonably reflects the population randomized is sufficient, I think that maybe is what those were getting at.
		ACTING CHAIRMAN CALIFF:  Right.
		DR. LIPICKY:  Because, clearly, we could write a textbook on, you know, what this is all about and how you tell whether there's coronary artery disease and how you know the EST segment.
		ACTING CHAIRMAN CALIFF:  Yeah, my sense of the panel is that people are pretty happy with the way it's written except for the question of the people with diabetes, and one risk factor is how robust that population is.
		And I think the concern, if I'm sensing the panel, is that that's a huge population.  This is one study and sort of the first time out of the box with it.  So --
		DR. LIPICKY:  But the primary endpoint is met.
		ACTING CHAIRMAN CALIFF:  Yeah, the primary endpoint was met.
		DR. LIPICKY:  Rather adequately, right?
		ACTING CHAIRMAN CALIFF:  Quite adequately.  No question about that.  It was met, and so what I'd like to do is just to move to a formal vote on Question 1, and then we'll quickly vote on 1.1, 1.2, and 1.3 so people can formally express their opinion on it.
		Does the HOPE study adequately establish the beneficial effect of ramipril compared to placebo in the combined endpoint of MI, stroke, and death?
		If we could just start at the right-hand side.
		DR. MOLITCH:  Yes.
		DR. GRABOYS:  Yes.
		DR. PINA:  Yes.
		DR. Di MARCO:  Yes.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  Yes.
		DR. LINDENFELD:  Yes.
		DR. ARMSTRONG:  Yes.
		DR. FLEMING:  Yes.
		DR. THADANI:  Yes.
		ACTING CHAIRMAN CALIFF:  This is a first for me, I think, on this panel, a unanimous vote.
		(Laughter.)
		PARTICIPANT:  Six zeros in front of the one will do that.
		ACTING CHAIRMAN CALIFF:  Now, I think we can combine 1.1 and 1.2, and I think the primary proposition is that the labeling, which describes the population enrolled in the trial, is adequate and the reasoning being that the primary endpoint was met for the subgroups that we've discussed.
		So if we could take a vote on that.
		Yes?
		DR. MOLITCH:  Sorry, Rob.  One question.  Is this what we have here in front of us or what was shown up on the slide, which I think included all cause morality?
		ACTING CHAIRMAN CALIFF:  This is -- until we get to 1.3, this pertains only to the primary composite endpoint.
		DR. MOLITCH:  Okay.
		ACTING CHAIRMAN CALIFF:  And you can go ahead and start with your vote.
		DR. ARMSTRONG:  Can I just ask, Rob, before?
		ACTING CHAIRMAN CALIFF:  Yes, sir.
		DR. ARMSTRONG:  On 1.2 are we talking then about the preselected secondary endpoints in the context of this question?  Is that right?
		ACTING CHAIRMAN CALIFF:  No.  We're only talking about it with regard to the primary endpoint.
		DR. ARMSTRONG:  Sorry.  Okay.
		DR. GRABOYS:  Yes.
		MR. MOLITCH:  Yes.
		DR. PINA:  Yes.
		DR. Di MARCO:  Yes.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  No.
		ACTING CHAIRMAN CALIFF:  Could I -- yeah, just comment.
		DR. BORER:  Yeah.  Before I could accept this, I would want to see the data on what appears to have been a very small group of patients who had diabetes and only one risk factor.
		DR. LINDENFELD:  No for the same reason.
		DR. ARMSTRONG:  Yes.
		DR. FLEMING:  Yes.
		DR. THADANI:  Yes.
		ACTING CHAIRMAN CALIFF:  Okay.  So I'm sure that there will be an opportunity for the sponsor to bring back more data regarding that subpopulation, although the panel vote is clearly in favor also.
		Now, 1.3, should all cause mortality be included in the indications portion of the labeling?
		DR. MOLITCH:  No.
		DR. GRABOYS:  Yes.
		DR. PINA:  No.
		DR. Di MARCO:  Yes.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  Yes.
		DR. LINDENFELD:  Yes.
		DR. ARMSTRONG:  Yes.
		DR. FLEMING:  No.
		DR. THADANI:  No.
		ACTING CHAIRMAN CALIFF:  What was the final vote there?  Six yes, four no.  So -- 
		DR. TEMPLE:  Rob, that was all cause mortality as distinct from cardiovascular mortality.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. TEMPLE:  How did we understand?  Is that right?
		ACTING CHAIRMAN CALIFF:  That was all cause mortality, correct.
		Okay.  So we now move on to Question 2.
		DR. TEMPLE:  Well, before you leave, can I ask a question?  If you had a drug that unequivocally reduced cardiovascular mortality and carried along the rest of the death, would that lead you to say there's an effect on all cause mortality or on cardiovascular mortality, or maybe that's what that vote just told us?  I don't know.
		ACTING CHAIRMAN CALIFF:  I'm not sure the vote exactly addressed that, but I would certainly feel that if all cause mortality is reduced, that trumps everything else, and for what John said.  I have -- and you're an expert in this.  I think your career in a way started with an investigation of all cause.
		DR. TEMPLE:  Oh, no, that was highly cause specific.  Cardiovascular mortality in the entry in reinfarction trial was just fine.  There was only one noncardiovascular death.  So it was not a big issue.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. TEMPLE:  Cause specific mortality is a whole different thing, I think.
		ACTING CHAIRMAN CALIFF:  You know, personally I'm not very interested in cause specific mortality except as an interesting scientific question.  I mean as a patient, I really care about whether I'm dead or alive.  So --
		(Laughter.)
		DR. TEMPLE:  Yeah.
		ACTING CHAIRMAN CALIFF:  If I'm dead, I'm not going to ask what I died from.
		DR. TEMPLE:  But my reasons for asking is that it seems somewhat misleading to me to suggest that you have an effect on all causes of death, which is one way to read that, when in fact you're only having an effect on one part.
		Certainly all cause mortality needs to be in the labeling somewhere so that people know it happened.  That's not the debate.  It's what the indication should be.
		DR. Di MARCO:  But you could just say "mortality."
		DR. TEMPLE:  You could, but it worries me as being somewhat misleading for the same reason.  All of the effects on one kind of death, it doesn't affect cancer.  There were equal numbers of cancer death.  So it sound like it sort of captures that, too, which is not what one wants.
		ACTING CHAIRMAN CALIFF:  But you appear to have a lot more faith in classification of cause of death.  I have -- I think it's rubbish for the most part, and so, you know, I would see --
		DR. TEMPLE:  Even cancer versus cardiovascular?
		ACTING CHAIRMAN CALIFF:  People with cancer have thrombogenic substrate and are more likely to have clotting related causes of death.  I mean, there are now clear data showing that if you have cancer and you have coronary disease, your risk of dying of coronary disease is higher.
		DR. TEMPLE:  The observation here that the noncardiovascular deaths tend to be equally distributed even though you've had a profound effect on cardiovascular death is a fairly consistent finding.  So I'm sure there's an error rate.  I have no doubt about that at all, but I think it's probably trumped by a substantially accurate measure.
		Okay.  Well, I just wanted to hear what you thought.
		ACTING CHAIRMAN CALIFF:  Okay.  Question 2, and this is an interesting question.  Were there differences in the primary endpoint with respect to, first the easy one, gender?
		Joann?
		DR. LINDENFELD:  No differences.
		ACTING CHAIRMAN CALIFF:  Any disagreement with that?
		(No response.)
		ACTING CHAIRMAN CALIFF:  Now we get to another easy one, age.
		DR. LINDENFELD:  Again, no differences.
		ACTING CHAIRMAN CALIFF:  Now we get to a not so easy one, race.
		DR. LINDENFELD:  Well, race is very difficult because, again, the numbers were so small I don't think that we can tell if there's a difference or not.
		ACTING CHAIRMAN CALIFF:  Any further comments on the race issue?
		DR. THADANI:  The race issue is worrisome.  I realize the sample size is very small.  Given the ACE inhibitor data and hypertension, I realize there's no uniformity, but all our response, that might be lower.  It would be nice to be sure that it works in all across.  It's not the problem with the investigator.  I think they're separately very small, but especially in blacks and Asians there might be concern.  We might be giving a therapy which may not benefit, and one may forget about therapies which by reflector say take a patient with diabetes who also has hypertension.  Maybe diuretics might save their lives, and we might be giving the wrong drug which may have no impact.
		So I think I have big concerns on that.
		ACTING CHAIRMAN CALIFF:  Dr. Borer?
		DR. BORER:  Yeah.  I have concerns about this not because the populations are so small, because a lot of the other subpopulations are small, too, but because the apparent discrepancy that we see, small subpopulations notwithstanding, intuitively has potential biological basis, and therefore, I think that it would be important at least somewhere in the label to reflect the fact that this discrepancy exits.
		I don't know that you can make anything more of it than that, but certainly prescribers ought to be aware that this is an unresolved discrepancy because it's not -- and the reason I'm concerned about it, again, is not just small numbers so that we can't make a statement, but rather because there is a discrepancy that's consistent with what one might intuitively expect the discrepancy to be.
		ACTING CHAIRMAN CALIFF:  Dr. Armstrong.
		DR. ARMSTRONG:  Taken on its own, I mean, one would be inclined to stay silent, but because there's a comment in the label as it currently exists in hypertension and because of the biology that we've discussed earlier and because of the trends in Table 10 in our FDA document both for blacks and for Asians, it seems to me the right decision is not to stay silent on this issue.
		So I'm just troubled with what the right thing to say is because something already has been said, and it seems to me it needs to extend to the disease of interest which we're discussing.
		ACTING CHAIRMAN CALIFF:  Well, I think there are two points of discussion here.  One is what shall we do with the label, and then the second is I think it's important at this juncture to have some discussion and comment on how to proactively prevent this problem from continuing to occur.
		I mean I've been involved in three panels in different diseases in the last year where sponsors have brought in data that had no black people, and you're left sort of saying, "Well, we have no data.  So what can we say?"
		And yet, as I say, it's 14 percent of the U.S. population.  So Ileana.
		DR. PINA:  (Inaudible.)  I would suggest that the number of black patients were small and that something like (inaudible).
		ACTING CHAIRMAN CALIFF:  By the way, while we're on the general issue, the nomenclature for Hispanic outside of the United States is quite difficult, as you know, and for sponsors out there, I would urge that before you get into this field that you spend some time on how people are classified in South America, for example.  It's different than in the United States.
		But, Bob, what is the FDA doing to prevent this from happening.  It's a pretty important national concern.
		DR. TEMPLE:  Well, the first thing is we're blaming Canada.
		(Laughter.)
		DR. TEMPLE:  The second thing is it's not very clear about what to do.  We've accepted large outcome studies from many parts of Europe.  You know, the Wascop (phonetic) study doesn't have a lot of blacks, Hispanics, and others in it, nor does the SSSS because of where they were conducted, and there isn't really any easy answer to that.
		I mean I suppose if we were thinking about it sooner, we'd urge Salim to try harder to be sure there's -- and maybe even set some recruitment goals and things like that, but it's very hard.  It's a different country, and it doesn't have the same population.
		So, I have to say historically the world worries tremendously about ethnic factors and how they affect outcomes mostly when the outcomes are unimportant.
		There's frantic consideration all over the world about making sure you've got a good mix for all the things that don't matter that much, like whether the blood pressure falls a little and stuff like that.
		When it comes to outcome studies, I think we've generally felt we had very little choice but to accept the one or two large outcome studies that existed, even if they were conducted in place that don't reflect our population.
		That's obviously not entirely satisfactory, and I'm not sure what the answer is, but I hope you'll address my question of does everybody feel nervous enough about this to think that it would be ethically responsible to urge the conduct of a study in a black population similarly defined.  Are we so skeptical about the results that we have so far that we think that is ethically acceptable?
		We can certainly urge people to try to do that.
		ACTING CHAIRMAN CALIFF:  Let me turn the tables on you just for a second.  We've heard from Salim that aggregating all the ACE inhibitor studies and heart failure is not even though data to make a statement.  The FDA has a very large database of data that we haven't seen for the most part from which one ‑-
		DR. TEMPLE:  That may or may not be true, Rob.  Many of those studies are done outside.  Many of the large outcome studies with ACE inhibitors are done outside the U.S.  We can tell you with considerable assurance that blood pressure effects are small, much smaller in blacks with ACE inhibitors.  That's not in doubt.
		What we don't have, and it's not clear.  You'd have to ask which studies are relevant.  I don't think we've looked at the SAFE study with respect to that question, and that surely will have a reasonable black population, but many of the other outcome trials aren't U.S.  So I don't know, except for SOLVD, of course.
		So I don't know what we'll find, but we should look.  We have some reason to look actually.
		ACTING CHAIRMAN CALIFF:  Dr. Pina.
		DR. PINA:  I would have, you know, a better sense of comfort of samples in heart data population (inaudible).  And there were a very large number there.
		DR. TEMPLE:  I mean, we could go back and look at rehab., for example.  I mean, it depends on what you count.  I you're counting beta blockers, ACE inhibitors, and thinking together about all of them, that gives you a larger database to look at.
		I gather Salim couldn't replicate this, but we've been told that the favorable outcome in SOLVD is not present at all in blacks, that there is no adverse effect, but no favorable effect.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. TEMPLE:  It was like four percent versus 24 percent.  Okay?  That's just what we've been told.  I'm not --
		ACTING CHAIRMAN CALIFF:  Well, I think it's become a pressing national issue with regard to beta blockers and ACE inhibitors, now two of our most effective treatments, and at least we can publicize it at this meeting, and I'm sure people in the audience will report on this.
		DR. TEMPLE:  We can certainly try to assemble all of the available data that has both populations in it.
		DR. THADANI:  I think you have to go beyond that because this trial with the HOPE, if I treat 100 black patients and I see no benefit, I might even harm.  So I think I've got major concern.  I think you have to put in labeling we do not have enough patient population.  We have no data that it does benefit or harm, if at all.
		I could argue with you if you look at the numbers, there were 81 and 75 in blacks on the drug, 66 the other way.  I realize the sample size is small.  We can't make much issue.
		We need a study in blacks to address this issue, and I think this should go in the labeling.
		ACTING CHAIRMAN CALIFF:  I'm going to ask for a vote actually of opinion on three questions, but, Bob, I do want to make the point again that the FDA has probably the largest set of data in the world, much of which has not been published from studies of ACE inhibitors and beta blockers, and it would be helpful if that data could be made available.
		DR. LIPICKY:  I'm sorry.  I had my hand up.
		ACTING CHAIRMAN CALIFF:  Yes, sir.
		DR. LIPICKY:  I don't want to be talked into something that I don't want to do.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. LIPICKY:  Salim has looked at the ACE inhibitor heart failure trials.  I don't think we can do a better job because we don't have the data.  We'd have to ask somebody to supply us with the data.
		We could look at articles and stuff like that and do a lousier job than Salim did.  so I don't want to do that again.  That apparently again will come out soon.  So that part is done.
		ACTING CHAIRMAN CALIFF:  Well, no, Ray.  Actually I'm writing the editorial on Salim's paper.  So I can tell you he does not have that data in his paper.
		DR. LIPICKY:  Oh, well, --
		ACTING CHAIRMAN CALIFF:  So it won't be coming out soon.
		DR. LIPICKY:  -- so where are we going to get the data then?  If he didn't have it, he has all of the results.  How are we going to do it better?
		DR. TEMPLE:  Rob, it may depend on what data you consider relevant.  I think what I'm hearing is that we shouldn't consider only heart failure trials relevant, that we should look at SAVE, which is a different kind of trouble.  We should look at --
		DR. LIPICKY:  You have SAVE.
		DR. TEMPLE:  You have SAVE?
		DR. LIPICKY:  Yes.
		DR. TEMPLE:  Oh, okay.  But we could also conceivably look at --
		DR. LIPICKY:  And SAVE is a heart failure trial.  It just happens to be around MI.
		DR. TEMPLE:  Sort of.  Yeah, okay.
		ACTING CHAIRMAN CALIFF:  I would argue that you should look at all of the data you have on all kinds of patients treated with ACE inhibitors for morbid events.
		DR. LIPICKY:  We don't have the data.
		DR. TEMPLE:  Yeah, but these are trials that are all published.  Everybody has the existence of the trial.  They aren't private outcome trials.
		DR. LIPICKY:  They have the variances in there?
		DR. TEMPLE:  No, I don't know that.  I don't even know --
		ACTING CHAIRMAN CALIFF:  I've registered my point of view.  I think we ought to move on.  I think I'm getting it from both ends here.
		DR. TEMPLE:  Rob, can I just mention one other thing?  There isn't any question that the lack of information about the black population will be somewhere in this labeling.  The question you need to help us with is how strong, you know, should it be right in the indications.  We don't know, and things like that.
		ACTING CHAIRMAN CALIFF:  Well, I heard Joann basically say that the labeling should reflect the fact that there was not an adequate population to draw inferences.
		DR. TEMPLE:  Labeling or indications specifically?  Which do you mean?  There's a difference.
		DR. LINDENFELD:  Well, I'm not sure it has to be in the indications.  I think somewhere in there is adequate.
		DR. THADANI:  Why not in the indications?  We don't have any data.
		DR. LINDENFELD:  Well, we don't have any data to the other side either, I think.
		DR. THADANI:  Yeah, but it could go in the wrong direction.  You said the study was done mostly in Caucasians.  There's no data on either Asians or blacks.  I feel more comfortable with that.  I don't know.
		ACTING CHAIRMAN CALIFF:  Any other opinions on that before we vote?
		DR. TEMPLE:  There were things of both omission and commission, and you've got to decide which one you want here.
		So what do you want to vote on, Rob?
		ACTING CHAIRMAN CALIFF:  What I'd like to ask for, I don't feel we need to vote on 2.1 and 2.2 because no one disagreed with Joann's assessment.
		On the race question, should the label reflect the differences?  I would like to change that to should the label state with regard -- we could ask it either way.
		Well, I guess the question is whether it's in the indications or just in the label.  Let's say just in the label and not in the indications to start with.
		DR. LINDENFELD:  Or in the clinical trials section, describing the trial.
		ACTING CHAIRMAN CALIFF:  Right.  Should it state just in the clinical trial sections, but not in the indications section that there was not adequate data about race?  I think that's a question we can vote yes or no on.  If we could start on the right-hand side here.
		DR. FLEMING:  The direct implications of that are that basically if you do that, that blacks would be in the indication, but then later there would be a clarification of the strength of evidence.
		ACTING CHAIRMAN CALIFF:  Right.
		DR. FLEMING:  Well, the indication would be silent about race if you did it that way, and you'd find it in the indications.
		I just have to add there was more than one way to write it in the indications.  You can just say there is little information about blacks.  You could say there is no good basis for treating blacks.  I mean, there's stages of what one could say.
		ACTING CHAIRMAN CALIFF:  All right.  Let me change the question then to the indications should specifically state that we don't have adequate information about blacks.  Yes or no?
		DR. MOLITCH:  Is this what you've done in the past, Bob?
		DR. TEMPLE:  I think if we were really skeptical about something we would.  I don't have an accounting to give you.  Just all of those are possible outcomes depending on what you thought was best, but we did do it once.  I mentioned this before.
		We specifically said that aspirin -- this, of course, wasn't a prescription drug, but in the professional labeling we said that aspirin was for preventing stroke in men because we didn't have enough data in women.  I think we now believe that was probably in error, but it was what the data seemed to show at the time.
		ACTING CHAIRMAN CALIFF:  Dr. Pina.
		DR. PINA:  If the purpose of this is to get the clinicians to agree (inaudible), most of them will read the indication, and very few (inaudible).  So I think it should be somewhere in the indications about the paucity of data in other than white populations.
		ACTING CHAIRMAN CALIFF:  Before we vote, I would like to clarify whether the other ACE inhibitors have the same.  What is in --
		DR. LIPICKY:  Of course.  They have less data than this one.
		ACTING CHAIRMAN CALIFF:  But is it stated in the indications section?
		DR. LIPICKY:  No, it's not.
		DR. TEMPLE:  About the outcome studies, no.
		DR. LIPICKY:  But the same problem is there with every one.
		ACTING CHAIRMAN CALIFF:  So one issue in voting yes on this would be that we would potentially penalize this particular drug when it's a generic issue.
		DR. LINDENFELD:  It's in there for hypertension for any of the ACE inhibitors.
		DR. TEMPLE:  Is it in the indication section in hypertension?
		DR. LINDENFELD:  For hypertension, yeah.
		DR. TEMPLE:  One thing, Rob, you have to appreciate is we are getting increasingly canny about asking analyses of racial, ethnic, and other subsets.  It only became a requirement for submissions last year, maybe the year before.  Older ones are less likely to have it because we weren't as aware.
		DR. FLEMING:  Rob.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. FLEMING:  It seems to me there are two issues though that might make this unlike other examples.  One of them is unfortunately not unlike those, and that is there is a striking under representation of blacks, and strongly impressive as this study was, no study was perfect, and it may not have been designed specifically to  address issues specific to the U.S.
		But in a population here where 15 percent of the population is blacks and they undoubtedly account for more than 15 percent of the events, to have had one and a half percent or something on that order representation is unacceptable, and strong statements have to be made to that effect.
		Secondly, there is some data, and that data is of the order of 141 events.  I've been involved in many trials that in totality don't have 141 events.  So whereas I am very cautious to acknowledge that these data do not establish lack of benefit, at the same time there is a suggestion in these numbers here that there ought to be more insight about whether the effects that we see in the global group apply to blacks.
		So I think it's the two issues together that I think must be -- that lead to the need to acknowledge what we're seeing in blacks or what we're not seeing.
		ACTING CHAIRMAN CALIFF:  Jeff?
		DR. BORER:  I agree with Ileana that if we bury this information somewhere in the clinical trial section, it's unlikely to be widely disseminated, and that's not a good thing if we think it's important for people to know about it.
		I do think that, therefore, it would be appropriate for a statement to be made in the indication section, but I think the statement should be that we don't have information, not a statement with a pejorative sense to it, and then in the clinical trial section one could show the data.
		I'm not concerned with regard to your point, Rob, about penalizing a sponsor or something like that because, you know, if we made an error for one reason or another, or if we now perceive that maybe we made an error in not requiring things in the past, that's not a reason to be bound by that error for all time, if we agree that it's not right to have done that or to do it anymore.
		And the second point is that we're dealing with a drug that has an indication that's very broad, with widespread public health implications, and that indication is far broader with far greater implications than this group of drugs has been approved for in the past.
		So I don't have a real problem putting some statement in the indications, despite the fact that that's a new thing to do.
		ACTING CHAIRMAN CALIFF:  Ray.
		DR. LIPICKY:  Well, the thing that bothers me about the discussion is I must admit if it were up to me to write, I wouldn't know what to write.  I'm not sure that there has been harm shown by this data, and in fact, in some portions of the data, it looks like it leans in the right direction.
		What we're complaining about is we don't know enough, and you know, it on its face doesn't allow for a subgroup analysis to be meaningful, and we recognize that.
		So it does not say to me, this data does not say to me -- and I'll just put it out as a statement -- that blacks respond differently.  It says, what this data says is there weren't enough people for a need to be able to conclude that they respond the same.
		And I don't know how to communicate that to a doctor because I don't think it should be part of the doctor's decision making process.  It is our dilemma as regulators and researchers and as influencing studies, and so on, to encourage better definition of that stuff, but I don't think it belongs in clinical decision making.
		So I would object to putting it in labeling.
		ACTING CHAIRMAN CALIFF:  Well, your objection is duly noted.  I think we need to move to a vote, and I'd like to just vote on this approach, which was Jeff's approach, which is to put in the indication section that there's not enough information to make a statement about blacks, and then in the clinical trial section to give the specific subgroup data so that people who want to look further can do that.
		So if we could vote on that, yes or no.
		DR. MOLITCH:  In the interest of time, with 31 more questions to ask and answer, I vote that we leave it in the clinical trial session for the additional explanation, not in the indications, and I would not comment.  I would leave out geographic information.
		ACTING CHAIRMAN CALIFF:  So you vote no.
		DR. MOLITCH:  On both questions.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. MOLITCH:  And you can add another one and move it along.
		DR. GRABOYS:  Yes.
		DR. LINDENFELD:  Yes, I would agree.
		DR. Di MARCO:  I agree with the indications.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  Yes.
		DR. LINDENFELD:  No.
		DR. ARMSTRONG:  Your question had two parts.  Yes to the first part; no to the second part.
		ACTING CHAIRMAN CALIFF:  Okay.  The second part was including the specific subgroup data in the clinical trial section.
		DR. ARMSTRONG:  And, again, the first part was?
		ACTING CHAIRMAN CALIFF:  Including the statement that there's not enough data about blacks in the indications.
		DR. ARMSTRONG:  Yes to the first and no to the second.
		DR. THADANI:  Yes to the first, no to the second.
		ACTING CHAIRMAN CALIFF:  All right.  You got John all confused here.  Who do you need to hear from again here?
		DR. THADANI:  Why don't we go separately?
		MS. STANDAERT:  Well, somebody voted on two, and other people did and voted on one.
		ACTING CHAIRMAN CALIFF:  Well, those who voted yes in general voted yes on both.
		MS. STANDAERT:  What about Tom?
		ACTING CHAIRMAN CALIFF:  Tom verified that he voted yes on the first and no on the second.
		All right.  2.3.B.  Okay.  All right.  We're going to have to vote again here on both questions.  Let's just go through one more time so Joan can get it right.
		DR. TEMPLE:  Well, Rob, we can assume that there's going to be discussion of the results in the clinical trial section.  I mean, you don't particularly need to vote on that.
		DR. THADANI:  Just vote on the indication.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. TEMPLE:  It's really only the indications and then some sense of what in the indications.
		ACTING CHAIRMAN CALIFF:  All right.  So should it be in the indications?  So let's just go through it one more time to make sure Joan has it.
		DR. MOLITCH:  No.
		DR. GRABOYS:  Yes.
		DR. LINDENFELD:  Yes.
		DR. Di MARCO:  Yes.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  Yes.
		DR. LINDENFELD:  No.
		DR. ARMSTRONG:  Yes.
		DR. FLEMING:  Yes.
		DR. THADANI:  Yes.
		ACTING CHAIRMAN CALIFF:  Okay.  So over Ray's objection, we voted yes on that.
		Now we move to geographic region, and hopefully we can pick up the pace now.  No?
		DR. TEMPLE:  No.
		ACTING CHAIRMAN CALIFF:  Bob said we needed to vote on that.  So geographic region, Joann?
		DR. LINDENFELD:  I don't think there are any differences here.  I don't have a plausible reason to expect one, and I just wouldn't make any point about this at all.
		ACTING CHAIRMAN CALIFF:  Any disagreement about that?
		DR. THADANI:  I think geographic distribution, there are some issues because the race issue, geographic, could be an issue as well.  I think the population is mostly driven from Canada.  It applies to practice issues.  I'm not saying to put in the labeling, but I mean there are some concerns.
		The benefit might be lower in States, although the patient population is not large enough, and so there are some -- I have some concerns.  I think you have to say something where the patient population was driven from.
		ACTING CHAIRMAN CALIFF:  Paul?
		DR. ARMSTRONG:  Surely Dr. Thadani would accept no difference amongst Caucasians.
		DR. THADANI:  I think we accept that.  We accept that.
		DR. ARMSTRONG:  In which case the geography becomes irrelevant?
		DR. THADANI:  Well, no.  I think the problem is the practice pattern might have some influence, and that's the denominator you're going to run into because if you look at the United States, the small number is 1.5 benefit as opposed to 5.4 in Canada.
		ACTING CHAIRMAN CALIFF:  Okay.  Well, since we --
		DR. THADANI:  And the number of risk ratio reduction was far smaller at least from that to have any relevance, but very small
		ACTING CHAIRMAN CALIFF:  Okay.  So would anyone else vote yes for geographic region being mentioned?
		All right.  I would also vote no about it being mentioned, but would agree that this is an issue that needs a lot more work because there are geographic patterns emerging in a number of international clinical trials that need better understanding.
		All right.  Let's move on to Question 3.  Were the effects of ramipril on the primary endpoint of the diabetic subpopulation a new finding warranting explicit mention in the indication section?
		Joann.
		DR. LINDENFELD:  Well, I think they are, yes, and  I think it is stated explicitly in the indication.
		ACTING CHAIRMAN CALIFF:  Does anyone disagree with that?
		DR. LINDENFELD:  So it sounds like we have a unanimous vote that it should warrant explicit mention in the indication section.
		Joann, what about 3.2, a new finding warranting explicit mention in the clinical trial section?
		DR. LINDENFELD:  Well, once it's in the indications --
		ACTING CHAIRMAN CALIFF:  Show the data, huh?
		DR. LINDENFELD:  Right.
		ACTING CHAIRMAN CALIFF:  Okay.  And then ‑-
		DR. TEMPLE:  That's the answer.
		ACTING CHAIRMAN CALIFF:  All right.  That's answered.
		Question 4, were the effects of ramipril on the incidence of new diabetes a new finding warranting explicit mention in the indication section?
		DR. LINDENFELD:  I don't believe so, no.
		ACTING CHAIRMAN CALIFF:  All right.  This is one we need to discuss.
		DR. LINDENFELD:  I think that the data -- it was an interesting finding.  It was unexpected.  It wasn't prespecified.  I think that I wouldn't put it in the indications, and maybe at the clinical trials at the very end, but perhaps not even there.
		DR. TEMPLE:  No, we're trying not to put new claims into clinical trials without putting them into the indication section.
		DR. LINDENFELD:  Right.  Then just no.
		DR. TEMPLE:  It takes work to assure that, but --
		DR. LINDENFELD:  No.
		DR. THADANI:  I think it's important probably to have the implications.  As Salim said, this was a finding.  They should they should do another large trial to prove it.  I would not even mention the indications at all.
		ACTING CHAIRMAN CALIFF:  Any other comment?
		Well, I think this is one we should take a vote on.
		DR. TEMPLE:  Could you also while you're at it discuss who might do such a trial?  This would be presumably people without risk factors; is that right?
		ACTING CHAIRMAN CALIFF:  this might merit just an additional comment from our diabetologist expert.  I mean, my understanding is in the diabetes world, it's being recommended that everyone at least with nephropathy go on an ACE inhibitor.
		DR. MOLITCH:  That's correct, but the question here is on the incidence of new diabetes, and I think it is not warranted for that.  I think the data is too soft, and I would not encourage any mention of it.
		ACTING CHAIRMAN CALIFF:  Okay.  Well, let's then go ahead and vote.
		DR. MOLITCH:  I vote no for all of that.
		ACTING CHAIRMAN CALIFF:  No for all three questions.  Okay.
		DR. GRABOYS:  No.
		DR. PINA:  No.
		DR. Di MARCO:  No.
		ACTING CHAIRMAN CALIFF:  No.
		DR. BORER:  No.
		DR. LINDENFELD:  No.
		DR. ARMSTRONG:  No.
		DR. FLEMING:  No.
		DR. THADANI:  No.
		ACTING CHAIRMAN CALIFF:  Okay.  So I think the summary is people are impressed, but would like to see confirmation.  It's a good, interesting finding.
		All right.  Were the effects of ramipril on glycemic control?  The same three questions.
		DR. LINDENFELD:  These were -- I don't believe the data was enough to make any mention at all.  So I would say no, no, and no.
		DR. MOLITCH:  Agreed.
		ACTING CHAIRMAN CALIFF:  Any other comments?
		Okay.  We should take a vote for a formal measure.
		DR. MOLITCH:  No, no, no.
		DR. GRABOYS:  No.
		DR. PINA:  No.
		DR. Di MARCO:  No.
		ACTING CHAIRMAN CALIFF:  No.
		DR. BORER:  No, three times no.
		(Laughter.)
		DR. LINDENFELD:  No, again.
		DR. ARMSTRONG:  No.
		DR. FLEMING:  No.
		DR. THADANI:  No, whatsoever.  There's no adequate data.  How often do --
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  So I guess the consensus of the panel then is that with regard to diabetes and glycemic control in general this is a hypothesis generating very interesting finding that's opening up potentially a field for further work.
		And we move on to what are the effects of ramipril on diabetic nephropathy.  The same three questions.
		DR. LINDENFELD:  Now, I think we've looked at this a lot.  I think there's enough data to say, yes, there is a new finding warning explicit mention in the indications section for diabetic nephropathy.
		DR. BAKRIS:  I want to be the first before anybody says anything to congratulate a largely cardiovascularly oriented panel for appreciating the kidney, just to get it out.
		(Laughter.)
		DR. BAKRIS:  Ray and I have been talking about this for centuries, and it's important just in case anybody is even dreaming about saying no so I can sway you a different direction.  It's important to know that you're changing the natural history of disease.  This is a continuous variable.  This is not you either had it or you didn't.  This is something that you're changing natural history disease.  You're changing albuminuria.  It's a reflection, and if you look, if you actually took the time to read the papers that you have in your packet, those are all double blind placebo controlled trial, including stuff that Dr. Brenner was talking about with ACE inhibitors actually affecting renal morphology and arresting disease.
		There's no question you're having an impact here, period, end of discussion.
		DR. THADANI:  Are you trying to influence the vote or what?
		DR. BAKRIS:  I'm not trying to influence your vote at all.
		(Laughter.)
		DR. BAKRIS:  But there are people waiting outside that have vowels in their last name.  So just be careful.
		DR. THADANI:  I realize that.
		(Laughter.)
		ACTING CHAIRMAN CALIFF:  I think the key observation was that the kidney is attached to the heart.
		DR. THADANI:  You know, the trial which are, you know, backing are mostly in patients with established renal disease.  I think here we are given a different point.  The patients have their insulin dependent diabetes.  They're already at a gross proteinuria.  This is a very different population.
		So I think rather than suggesting that we all have the world cares because you believe in it --
		DR. BAKRIS:  Well, I think you have to be careful here because, in fact, if you look at the data that are there in the trial, there is data also in non-diabetic disease and there's data in patients, biopsy proven data in diabetic patients, and the data is actually very consistent, and I think you have to keep the point that, as Barry said this morning, the data that we have so far is in way established renal disease, if you want to look at time to dialysis.
		This is altering the course of the disease, and if it's one thing we do know about, it's the natural history of diabetic nephropathy, which may not represent all nephropathy.
		DR. THADANI:  But a sample size which is so small in most of the studies, I'm not sure that I buy your point.
		DR. BAKRIS:  Well, that's fine, but I'd like to see you do a trial with 1,000 biopsies.
		ACTING CHAIRMAN CALIFF:  Well, I don't want you to interpret this as not appreciating the kidney, but I have a different concern which when we talk about altering the natural course of a disease, we have many examples with a heart where altering an intermediate endpoint turns out not necessarily to be good.
		And even in a field that we took for granted, HIV, early treatment now when it leads to prolonged treatment is coming under question as being the right strategy.
		So I'm concerned about I'm sure that we've demonstrated that you can reduce the -- the demonstration has been made that the albumen and the urine is reduced.  I don't necessarily believe that we can mean that that means that this is going to benefit people in the long run.
		DR. BAKRIS:  Well, if you look at the long term trials, namely, one that is not too different from this, a normal tensive Type 2 diabetic, albeit a smaller number of patients who have now been followed up in seven years, the data you have is at seven years, but they're actually continuing to be followed.
		There is a huge difference in the people that are on ACE inhibitor not just with regard to albuminuria, but also with regard to change in serum creatinine and, for that matter, creatinine clearance.  And so, in fact, what you're doing is arresting or stopping disease.
		I mean, the data are very clear.  If you ‑- one trial that isn't in here because it just got published is the renal data from the ABCD trial, and basically at that very early stage of disease, if you aggressively intervene with the ACE inhibitor, you were able to stop disease progression.
		In all of the advance trials, in the Lewis trial or whatever trial that's out there, the best you're able to do is markedly slow disease.  You couldn't stop it, but you could markedly slow it, which may not be a bad thing, but let me remind you the number one cause of death in everybody with renal disease is cardiovascular disease, and there is a brilliant paper, stay tuned, coming out in Circulation looking at the relationship between micro albuminuria and vascular reactivity, showing a clear association with endothelial dysfunction, and it is double blind, placebo controlled.  It's a very important study that draws the link there.
		So I would argue that by reducing albuminuria, not only does that translate into altering the natural history of renal disease, diabetic renal disease and maybe even non-diabetic renal disease in specific circumstances, but you're also reducing cardiovascular events which you've already seen.
		ACTING CHAIRMAN CALIFF:  This is a very important issue, I think.  We need to hear from some other panelists.
		Tom, maybe you first.
		DR. FLEMING:  Well, there are so many things to say.  Let me just hit one issue and then let others speak and then come back with further later.
		Micro albuminuria is certainly -- from what you're saying there is evidence that it's correlated.  There are many really important issues that need to be addressed in terms of the magnitude of effect, the duration of effect that you're going to have to have for this to translate into long term clinical benefits.
		The fact that we see associations gives some plausibility that this could be the causal mechanism, but it's also entirely possible that this is a marker for many other factors that are also influencing overall rates of progression, and the data that are here are certainly at best discussing what are the shorter term effects, and to state that they have conclusively established long term clinical benefits in terms of renal disease or renal failure, renal events is not established.
		ACTING CHAIRMAN CALIFF:  Ray?
		DR. LIPICKY:  Can I just -- can everybody look at Table 23(r) in the addendum that was in that blue book and just name the line on that table that you think really establishes that something is happening?
		Before you get on to other trials, would you just look at the table on the back page and tell me what makes you say that the trial found something.  I don't see anything too convincing on that table.  We agree that the numbers are the same numbers, except for the 1.07.  Everybody calculated the same numbers from the same data.  What is it that we're talking about?
		DR. FLEMING:  The micro albuminuria result is a relative risk of .94.  So what's your point, Ray?
		DR. TEMPLE:  Only overt nephropathy has a chance at this because that's the only one that has even nominal P value.
		DR. LIPICKY:  Which role are you citing as having established that something was found?
		ACTING CHAIRMAN CALIFF:  Jeff?
		DR. BORER:  Without detracting even one iota from the importance of the kidney --
		(Laughter.)
		DR. BORER:  -- when I was in medical school, I was told by an instructor in physiology who had a grant from the American Heart Association that clearly his grant referred to research on the kidney because the only purpose of the heart was to pump blood to the kidney.  So, you know, I'm with you.
		But nonetheless, the data from the diabetic substudy, as I understand them, show really overwhelmingly that the primary endpoint is beneficially affected in diabetics if the diabetics are treated with ramipril, and I agree with that, and you've all agreed with it, and that's great.
		Now we're talking about the effect of ramipril on another problem in diabetics, which is the progression of kidney dysfunction, and you know, I found the discussion by Dr. Brenner to be very attractive and very persuasive, but nonetheless, I'm concerned by several points when I look at these data.
		One of them is the one that Ray is alluding to.  That is, the strength of evidence doesn't seem as great as what we generally would expect if we were going to approve a drug for a specific indication.  So that's number one.  You know, one would like to see these data either be stronger or be replicated somehow if we're going to look specifically at the use of ramipril for a beneficial effect on the kidneys in diabetics.  That's one point.
		The next point is one that's already been alluded to.  I'd like to see, you know, Dr. Brenner's very compelling discussion notwithstanding, I'd like to see some data linking the pharmacological effect that we think we're seeing here with the clinical benefit.
		So, you know, for those two reasons, first of all, the lack of the strength of evidence and, number two, the issue of the relation between pharmacological effect and clinical benefit.  I'm concerned about drawing strong conclusions about indication here because the implication would be not that we should be giving this drug to people with vascular disease because, in addition to reducing all the other things that it will reduce, it makes the kidneys better, but rather that people with diabetes with one risk factor ought to be treated with this drug, in part, because it's going to prevent their kidneys from deteriorating.
		And that may well be true and the data are certainly consistent with that, but I don't think the strength of evidence is what we would usually expect.  So I'm a little concerned about this.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. MOLITCH:  I think that the way the question is worded here, it is not a new finding.  We're taking a set of data that's been presented here, which taken into context with many, many other studies now fits with the other studies, we've got a whole series of studies of both Type 1 and Type 2 diabetes that look at patients who already have micro albuminuria that this class of drugs is able to retard the progression to overt nephropathy, and when you have overt nephropathy, that you have an effect on decreasing the rate of fall of GFR, and then ultimately you have a decrease in the number of patients who end up in end stage renal disease requiring dialysis and transplantation.
		This is one of a number of studies that fits into that data set, and it fits exactly into that data set.  There's no incongruity here.  There is no ‑- I don't think that there was evidence that would support the prevention of the development of micro albuminuria, although there's some suggestion that perhaps that may be true with other studies, but that's certainly not true here.
		And I think that once you have micro albuminuria that you can predict that a large majority of those patients go on and that this class of drugs is able to retard that rate of progression, and that this beta set is entirely compatible with many, many other data sets.
		DR. LIPICKY:  Would you point to the row in Table 23(r)?
		DR. MOLITCH:  Yes, Row 3.
		DR. LIPICKY:  That supports the statement that you made?
		DR. MOLITCH:  Overt nephropathy with the sign of "at," that says .045 P value.
		DR. LIPICKY:  -- .075?
		DR. MOLITCH:  Pardon me?  Twenty-three (r), with a .045  nominal P value.
		ACTING CHAIRMAN CALIFF:  I mean I think the problem a lot of us are having is we have one, two, three, four, five, six, seven different definitions, and we only have one which is less than .05, although I would --
		DR. MOLITCH:  There is insufficient data here for renal dialysis.  We certainly don't want to approve micro albuminuria.  We're not talking about laser therapies and sufficient data for doubling your fattening.
		The sponsor has looked at a definition that looks at the development of overt proteinuria as defined by 24 hour urine collection, and then in the circumstances where there weren't sufficient 24 hour urines, they added the albumen-creatinine ratio.  So that's that one.
		DR. TEMPLE:  Rob, can I ask?  Do we know that that endpoint was established prospectively and blindly?
		I've heard there was a lot of discussion of that.  It definitely didn't have an amendment to the protocol, but unequivocally written down somewhere that was the endpoint that you were going -- so there really is only one endpoint that we should be even thinking about paying any attention to, and lucky them, it's the one that comes closest.
		(Laughter.)
		DR. BAKRIS:  Let me just -- not to cut you off, I'll give it back to you -- but just to make a point, if any of you are looking at time to dialysis, as Dr. Brenner very nicely said this morning, that's fine.  When you collect your Social Security, which at the rate things are going you'll be about 85, is about the time you'd see time to dialysis in these people because that's how long it's going to take to get there.
		That's not a meaningful endpoint in this stage of the disease, in this population, and correct me so as was pointed out earlier over here on a side bar that some of the data that I've included, the double blind studies that are back here are on people with far more advanced disease, and the reason that was done to a certain extent was really to make the point that you're altering the natural history and the time to dialysis.
		So I think we at least in the renal community in this country, and I would day say the endocrine community, are to a point where we need to look at it at a much earlier point because prevention is really where it needs to be going there, and the feasibility, as Barry say very appropriately this morning, is impossible because even all of the money in the NIH-Canada and five pharmaceutical companies wouldn't be able to fund a trial meaningful enough to actually get that kind of endpoint.
		ACTING CHAIRMAN CALIFF:  But let me try to express the counter view to that as best I can.  I'm still undecided myself about how to look at this.
		It is possible to imagine that there might be a drug that would reduce the time to development of albumen in the urine that also might turn out to be bad for the body or the kidney in some other way, and so we've recently -- I don't want to divert the discussion to hypertension, but we've learned, I think, some of us think we've learned in the last few months, that it's possible to have several drugs that lower the blood pressure the same amount that have very different effects on overt clinical outcomes.
		And so if we set a standard that says lowering the albumen is good no matter what, to me that's like saying lower the blood pressure is good no matter what.
		DR. BAKRIS:  Well, Rob, let me issue a caveat there.  You're absolutely right, and I think the important point there is if you look at I would say 100 percent -- I haven't seen a meta analysis that doesn't support this -- 100 percent of all of the meta analyses that are out there, they all consistently show that agents that significantly reduce albuminuria and control blood pressure will slow renal disease progression.  I can't think of one study anywhere that doesn't say that, and moreover, there's a nice correlation with reduction of cardiovascular disease.
		Now, you could give me the argument, well, that's all blood pressure, and what you need, the ACE inhibitors about that, and that we can be here until tomorrow arguing that point, but I think the issue is in terms of what you say you're absolutely right, and we won't go to that discussion, but let me just say that I think if you know of data that suggests that reducing albuminuria has adverse effects, I'd love to be educated because I'm unaware.
		DR. TEMPLE:  Rob, there's several different things being mixed together.  One is the question of the surrogate.  The second is the question of whether there's a finding there at all, and the third is what we know from other places and how that should influence our decision.
		The first point is this is a secondary endpoint.  It was the one that they were looking at.  So that's helpful, but a P value of around .05 would be an unusual basis for reaching a conclusion on something like that.
		Counter to that argument would be we already know a lot from other sources about ACE inhibitors.  Therefore, we have a lot of priors, and we should accept a somewhat less robust finding than we would insist on if it was out of the blue, and you know, I can't contribute to that discussion, but other people could.
		The next question is the only drug we've actually -- first of all, if we take these one by one, there may be a widespread belief that ACE inhibitors are good for renal disease, but only one of them has the claim, and that's because we're waiting for data on that particular one.
		So the question is pertinent to what data there are here.  In all previous cases, we have actually had outcome data.  We've probably been kicked slightly screaming and yelling over into thinking that deterioration of creatinine is something that you can base approval on, but at least so far there hasn't been approval based on small changes in albumen status.
		That's not to say we should take that position forever, but it's a fairly big deal.  It will change the shape of all the trials that are done in this area.  You can show changes in albumen in very short order, whereas changing in creatinine clearance is much, much slower.  So it's a sort of a big deal.
		Those are my contributions.
		ACTING CHAIRMAN CALIFF:  Ray?
		DR. LIPICKY:  I just want to add to that.  It's like there aren't lots of times that this has happened.  There is one trial, placebo controlled, that in diabetes, that basically establishes that, an ACE inhibitor, in fact, improves clinically relevant endpoint.
		All of the trials that are being cited by George, I believe, are three, and they are non -- two of the others are in non-diabetics.  So it isn't like there's a wealth of data here.
		There are a lot of studies that show that indeed proteinuria is affected, and it is sort of striking to me that in this trial proteinuria was affected in the right direction in people who were non-diabetic and had no micro albuminuria to start with.
		DR. THADANI:  Also, Rob, there are a lot of concerns, patients who went into heart failure, but if you look at the outcome, creatinine is going in the wrong direction.  Renal dialysis numbers are small.  So I'm not convinced like my colleague from the right-hand party convinced me that there's adequate data.  I might be comfortable in the wrong direction, but to say that it does something to renal function, I'm not convinced.
		DR. TEMPLE:  Rob, I think Salim wants to say something that's relevant.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. YUSUF:  I'm here, Rob.
		DR. TEMPLE:  We'll see after he says it.
		DR. YUSUF:  Rob, I think today we are discussing HOPE, and to be fair to the FDA, although they have the whole database, the only part of the database they've analyzed is the diabetics, and then Hertzel showed more data on the non-diabetics which supports it, and to be fair to the FDA and to RAY, you guys need to check whether the analyses we showed you are replicated.
		So it may be permitted even on HOPE to make a decision today.
		The second thing is there are two other studies with ramipril that has been done in Europe that the company could provide to you that is at a later stage of the disease, and it's closer in concept to the Lewis study, and it may be best to defer this discussion till all of these data are brought to the FDA and you've had a chance to look at it.
		ACTING CHAIRMAN CALIFF:  Okay.  Well, that would certainly make our job easier.
		DR. TEMPLE:  Very attractive, don't you think?
		ACTING CHAIRMAN CALIFF:  But I do want to express the same concern that Bob did.  I think he was expressing a concern that if we make reducing albumen in the urine the measure, it may dissuade people from really finding out what the long term effects of future therapies are because you can show this, get a claim, get on the market, and then we may not know how to distinguish the effects on ultimate outcomes.
		I guess I need guidance, Ray or Bob.  Shall we take a vote, given Salim's last statement?
		DR. LIPICKY:  No, I think Salim told you what to do.
		ACTING CHAIRMAN CALIFF:  Okay.
		DR. LIPICKY:  Forget it.
		ACTING CHAIRMAN CALIFF:  Good.  We're moving right along then.
		Let's see.  The next one is -- yeah, we can skip seven, I guess, based on the same issue because there will be a lot more data forthcoming.
		And number eight, were the effects for ramipril and the need for coronary revascularization, the same three questions.
		Joann?
		DR. LINDENFELD:  Well, there were significant effects that were trended along with all of the other effects.  So I guess the question is not so much whether or not they were convincing, but whether or not it's enough of an indication to be in the indication section.
		I would probably say no.  I think there's enough in the indications already that would go along with this.
		ACTING CHAIRMAN CALIFF:  Any other comments?
		DR. TEMPLE:  Can you say that again?  That was no because why?
		DR. LINDENFELD:  Well, now I have to think about it.  This is a tough one.  It was definitely positive.  So I suppose -- in other words, I think when you tell everyone what this drug does that they will assume that it decreases revascularization, but ‑-
		ACTING CHAIRMAN CALIFF:  Well, it would seem to me that --
		DR. LINDENFELD:  -- I suppose it's reasonable to put it in there.  It's definitely positive.  It's positive along with everyone else.  It was a much smaller effect than the others.
		DR. GRABOYS:  If I were the pharmaceutical company folks, I'd be biting at the bit for this because I could see a series of about 100 ads coming out saying, "Here, we've got the magic pill right here.  It decreases your need for bypass."
		ACTING CHAIRMAN CALIFF:  But what do you think about it?
		DR. GRABOYS:  I don't think it should be stated.
		DR. THADANI:  No, I think you would have problems, too, though, wouldn't you, Bob?  Who decides who needs a bypass?  If a patient comes to me and I've got an exercise test, as to depression, I know he is diseased.  He gets bypass.  Other patient comes in another center.  My colleague doesn't do it.  So I think there's a softer endpoint.  Why  it has to go in the labeling I'm not sure.  You could describe it in probably the adult section, but not in the legay (phonetic).
		ACTING CHAIRMAN CALIFF:  But isn't that protected by the fact it's a blinded study?  So seeing a difference --
		DR. THADANI:  But it's not in the primary endpoint we already worded.  It does everything.  It's somewhere driven by the numbers' need for -- I don't think they even showed us why if they can need a bypass -- suppose you go in and find a triple vessel disease, and then because of your creatinine function and (unintelligible) function is below 40 percent, he goes for surgery, and it could have been just curious.  I have no idea.
		So I think all of the data is positive.  I don't think you have to label the indication.  It's probably described in the trial section.
		DR. ARMSTRONG:  My concern about this, Rob, is that there's lack of concordance with the unstable angina and the unstable angina validated with the ST segment shift.  So this is a soft indication for which we have little collaborative information, and I don't think it's concordant.
		So I would be against including this indication.
		DR. BORER:  Just to add to that, I really agree with Udho.  I don't think it's appropriate to state as an indication a reduction in a therapy that's based on a physician's judgment.  The reduction in the event that might lead to that judgment, that's fair game, but the therapy itself, it's true we have a lot of guidelines now and, you know, people tend to do things in more similar fashion around the country than might have been the case in the past, but nonetheless, there is a judgment that's involved in selecting a therapy, and I don't think that we should be providing an indication for a reduction in an event that's based on that judgment.
		DR. TEMPLE:  Jeff, we have a bunch of labels that include that as a component of a combined endpoint, urgent intervention I had, in which that's the driving force behind the indication.  Do you think we've been making a mistake here?
		DR. BORER:  Yeah, well, maybe, Bob, but I don't know that that's a discussion that we can have today, but in this case, there's a difference.  These are not --
		DR. TEMPLE:  But the implication is that it decreases whatever it was that was making clinicians think they needed to do it.
		DR. BORER:  Right.
		DR. TEMPLE:  It's not that it's trying to control what makes them make the decision.
		DR. BORER:  Well, but we've already stated or it is already stated here that many of those things that might drive a decision have been reduced.  I mean there's an indication for giving the drug to reduce the processes that might lead to the judgment.
		DR. TEMPLE:  No.  Which besides heart attacks?
		DR. BORER:  Well, heart attack is a pretty good one.  Mortality?
		DR. TEMPLE:  No, it's too late.
		DR. THADANI:  Bob, also, you know what you're alluding to, a lot of the times we've allowed revascularization, and the previous trials have been refractory angina.  Here is not that question.  I mean, as Paul said and I said before, unstable angina hospitalization is not allowed.  The patient -- you could be just influenced because --
		DR. TEMPLE:  Actually we thought that urgent revascularization is better than refractory angina because it was --
		DR. THADANI:  But this is not urgent revascularize.
		DR. TEMPLE:  Yeah, I realize that.
		DR. THADANI:  So I would not add that.  I think it's a moot point.
		DR. TEMPLE:  So you wouldn't add it even if you thought it was true, even if there was no disparity between this finding and closely related findings?
		ACTING CHAIRMAN CALIFF:  Well, I'm obviously in the minority here, but to me having a bypass operation is something you'd like to avoid if you possibly could.  I don't know many people that want it, and for example, in heart failure, hospitalization for heart failure is considered a strong part of the endpoint.  That's very dependent on physician discretion.
		DR. TEMPLE:  Absolutely.
		ACTING CHAIRMAN CALIFF:  So I find this to be persuasive.
		DR. TEMPLE:  What do you think about the lack of concordance?
		ACTING CHAIRMAN CALIFF:  What's that?
		DR. TEMPLE:  The lack of concordance that was mentioned, that is, you do not have the same thing on other closely related --
		ACTING CHAIRMAN CALIFF:  I think when a trial is almost dominantly going in one direction, you have a few things that are counter, like admission for unstable angina.  I tend to side with everything else and not try to pick because there's some small things that go the other direction, but --
		DR. THADANI:  You know, also you could argue if you're going to put this, why don't you put in there was no reduction in hospitalization for heart failure.  You always put the positive.  You don't put the negative.
		DR. TEMPLE:  Well, you can put the negative in, too.
		DR. THADANI:  No, I'm just saying how far do you want to carry it.
		DR. TEMPLE:  There's nothing that stops us and we often do put in the secondary endpoints that didn't show anything.
		ACTING CHAIRMAN CALIFF:  Well, I think everyone had expressed their point of view, and we should go ahead and take a vote.
		DR. YUSUF:  Rob, can I just make a clarification?  Is that possible?  I know it's not normal.
		ACTING CHAIRMAN CALIFF:  Quickly.
		DR. YUSUF:  Okay.  The first thing is revascularization was a prestated secondary endpoint.  It was not data dredged.  
		The second thing is the P value is quite impressive.  
		The third thing is in the meta analysis of all other trials of ACE inhibitors, there is the reduction, revascularization.
		The fourth thing is worsening angina was significantly reduced showing internal concordance.
		The fifth thing is MI is reduced showing internal concordance.  The only thing that is the outlier is the unstable angina.  So I think I'm going to put the framework --
		DR. THADANI:  Which is a very important outlier.
		DR. YUSUF:  Yeah, sure.
		ACTING CHAIRMAN CALIFF:  Okay.  Salim, you've clearly stated your point of view.  I think we ought to go ahead and vote.
		Okay.  Dr. Graboys.
		DR. GRABOYS:  What is --
		ACTING CHAIRMAN CALIFF:  We need you to vote on the question of whether the need for coronary revascularization is a new finding warranting explicit mention in the indication section.
		DR. GRABOYS:  No.
		DR. PINA:  I think it is (inaudible).
		ACTING CHAIRMAN CALIFF:  Let's see.  You vote yes.
		DR. Di MARCO:  I'd put it in the clinical trial section.
		ACTING CHAIRMAN CALIFF:  So you vote no?
		DR. Di MARCO:  No on --
		ACTING CHAIRMAN CALIFF:  Okay.  We're going to vote on the --
		DR. Di MARCO:  Okay.
		DR. TEMPLE:  I have to tell you we're not supposed to do that.  If it's an indication, it's supposed to be an indication.  If it's not, it's not.  Sticking it in a different place doesn't get us -- doesn't remove the legal responsibility to be able to say there's well controlled -- there's substantial evidence that it works.  We haven't always followed that as well as we should have.
		ACTING CHAIRMAN CALIFF:  All right.  So we just need to -- you have to make a decision.  Is it in or out?
		DR. Di MARCO:  In
		ACTING CHAIRMAN CALIFF:  Okay.  I vote yes.
		DR. BORER:  No.
		DR. LINDENFELD:  Yes.
		DR. ARMSTRONG:  No.
		DR. FLEMING:  No.
		DR. THADANI:  No.
		ACTING CHAIRMAN CALIFF:  Okay.  The noes have it by a nose, that's right.
		All right.  We now move to the last question.  
		Five to three was the vote on that.  We now move to the last question.
		Were there effects of ramipril on congestive heart failure?
		DR. LINDENFELD:  I would say that this is not a new finding.  Hospitalizations were the prespecified endpoint and were not affected.  I know overall heart failure was, but it wasn't a prespecified endpoint and I don't think I'd put this in the indications.
		ACTING CHAIRMAN CALIFF:  Ileana, you had raised this before.
		DR. PINA:  (Inaudible.)
		ACTING CHAIRMAN CALIFF:  Any other --
		DR. THADANI:  I think there's more than a problem because nobody defines what heart failure was.  One day a patient comes in with a little swelling.  The other days -- so I think given that even the heart failure trend is in the right direction.  Hospitalization is not, and what one is more concerned with a hospitalization.  So I think we should not include that at all.
		ACTING CHAIRMAN CALIFF:  Is there a standard definition of heart failure that's used in clinical trials?
		DR. THADANI:  Well, when you're recruiting patients in a clinical trial usually, well, just leaving aside systolic or diastolic dysfunction, the patient either has to have shortness of breath or they have some other clinical signs like edema; you're sure it's not due to (unintelligible) or JVD or other issues, and I think not giving -- all that does is allows the patient -- the physician to take yes or no.  It's possible the physician wanted to put the patient on open label.  It's just a guess.  I don't know.
		I know they collected the data for the reasoning either to -- a lot of patients with heart failure have rate increase or some other issues, and I think I'd be more comfortable if the hospitalization had gone in the right direction, and since they were not, I've got a major problem with this indication.
		ACTING CHAIRMAN CALIFF:  I guess I'm in the minority here, too, but you know, to me if you do a blinded study and you ask doctors is the patient in heart failure or not, at least I think that's a pretty good way to do things, and the more stringent you make the definition, the more money you spend on fewer patients.
		DR. THADANI:  Wouldn't you see some trend in the hospitalization?
		ACTING CHAIRMAN CALIFF:  What's that?
		DR. THADANI:  Wouldn't you see the right trend in the hospitalization at least?
		ACTING CHAIRMAN CALIFF:  Well, I think you'd like to, but things don't always happen the way you'd like them to happen.
		Paul, you've spent a lot of time in heart failure.  Are you going to -- is it inappropriate to do a trial where you don't have a prespecified definition that you ask clinicians to adhere to?
		DR. ARMSTRONG:  Well, not necessarily if you want to influence the behavior of those physicians, but if you're asking me whether -- how I'm going to vote on a label or an indication, that's a separate question.  So I feel a responsibility relative to the defined secondary endpoint to vote one way, but I believe this probably makes a difference.
		DR. TEMPLE:  Rob, the trend was in the usual direction.  There just weren't enough events.
		DR. ARMSTRONG:  Yes.
		DR. TEMPLE:  The hazard ratio is .86.
		DR. THADANI:  Rob, the definition is more complicated.  When I'm doing wrong with the residents, you know, they can't even -- you know, they say JVD is negative, and you go and see that JVD is positive.  
		So I think it's very complicated just going on definition unless you have got some concrete other evidence.
		DR. PINA:  (Inaudible.)
		DR. THADANI:  We're not given the definition.
		DR. PINA:  Well, that's what I'm saying.
		DR. LINDENFELD:  But this says heart failure was not reviewed as an endpoint because it wasn't an endpoint; is that correct?
		DR. THADANI:  But here is the prevention part of this.
		ACTING CHAIRMAN CALIFF:  Okay.  Well, so I think we've had a good discussion on this.  I guess the vote would be would you include it or not include it in the indications?
		DR. MOLITCH:  No.
		DR. GRABOYS:  No.
		DR. PINA:  No.
		DR. Di MARCO:  No.
		ACTING CHAIRMAN CALIFF:  Yes.
		DR. BORER:  No.
		DR. LINDENFELD:  No.
		DR. ARMSTRONG:  No.
		DR. FLEMING:  No.
		DR. THADANI:  No.
		ACTING CHAIRMAN CALIFF:  Okay.  That concludes our session.  I want to thank the panelists for a lot of attention over a long period of time, and we'll reconvene tomorrow morning.
		(Whereupon, at 5:11 p.m., the meeting was adjourned, to reconvene on Tuesday, May 2, 2000.)