U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

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	PUBLIC HEALTH SERVICE

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	FOOD AND DRUG ADMINISTRATION

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	CENTER FOR DRUG EVALUATION AND RESEARCH

	DIVISION OF CARDIO-RENAL DRUG PRODUCTS

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	CARDIOVASCULAR AND RENAL DRUGS

	ADVISORY COMMITTEE

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	88TH MEETING

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	FRIDAY
	APRIL 30, 1999

		The meeting took place in the Jack Masur Auditorium, National Institutes of Health, Bethesda, MD, at 8:30 a.m., Milton Packer MD, Chairperson, presiding.

PRESENT:

Milton Packer, M.D., Chairperson
Joan C. Standaert, Exec. Secy.
John DiMarco, M.D., Member
Thomas Graboys, M.D., Consumer Representative
JoAnn Lindenfeld, M.D., Member
Lemuel Moye', M.D., Ph.D., Member

PRESENT: (cont.)

Ileana Piña, M.D., Member
Dan Roden, M.D.C.M., Member
Udho Thadani, M.D. FRCP, Member
A. John Camm, M.D., Guest Expert
Craig Pratt, M.D., Guest Expert
Jeremy Ruskin, M.D., Guest Expert
Robert Fenichel, M.D., FTIA Representative
Robert Temple, M.D., FTIA Representative

	I-N-D-E-X

The Evaluation of Antiarrhythmic Drug Efficacy Utilizing Patients with an ICD:
Unlimited Potential or Too Much Complexity 
and Problems?

Introduction
A. John Camm, M.D., St. Georges Medical 
School, London	7
 
Review of ICD Trial Design and Preliminary 
Results, Craig M. Pratt, M.D., Baylor College of Medicine	20

ICD Interrogation: Appropriateness Proarrhythmies     Monomorphic vs. Pause-dependent Polymorphic VT
Dan M. Roden, M.D., Vanderbilt University	43

ICD Endpoint Interpretation      
Relative Strengths of Various Endpoints
Extrapolation to Other Populations
A. John Camm, M.D.	76

Commentary, Jeremy N. Ruskin, M.D.            Massachusetts General Hospital	110

Questions and Discussion	134

	P-R-O-C-E-E-D-I-N-G-S
	(8:56 a.m.)
		DR. PACKER:  Can I have everyone take their seats.  I would like to apologize.  For some reason my own notes indicated the meeting was going to start at 9:00 so I really am very, very sorry that we are starting late.  It is entirely my misreading of my own schedule.
		Joan, do we have any special conflict of interest issues for this morning?
		MS. STANDAERT:  The following announcement addresses the interest of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of SCD at this meeting.  
		Since the issues to be discussed by the committee will not have a unique impact on any particular firm or product, but rather may have wide spread implications with respect to an entire class of products, in accordance with 18 U.S.C. 208 each participant has been granted a general matters waiver which permits them to participate in today's discussion.  
		A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12, A30, Parklawn Building.
		In the event that these discussions include 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 involvement with any firm whose products they may wish to comment upon.  That completes the conflict of interest statement.
		I would also like to make an announcement on behalf of our transcriber who has asked that all participants address the microphone directly because there appears to be quite a bit of feedback from the roof here and she has difficulty hearing.  Thank you.
		DR. PACKER:  Thank you very much, Joan.  Is there any public comment this morning?  Okay.  There being none, we will proceed with the topic for this morning.  Actually there is no NDA for this morning.  We are discussing general issues related to the evaluation of antiarrhythmic drugs in patients with an ICD.  
		The ICD is actually used in this case as a way of measuring antiarrhythmic drug efficacy.  There have been a number of studies and a significant amount of information of relatively recent vintage pertaining to this.  Therefore, it was felt that putting all this information together and trying to develop some sense of consensus or guidance would be useful.  
		With that in mind, we'll have actually five presentations by invited guests and experts.  Also by one member of the committee.  The idea is to develop an interchange and to reach some sense of what we may be doing or what direction we should go.
		The intent of this morning is to take a brief break but to complete these proceedings before lunch.  Lunch perhaps would start around 1:00.  We may adjourn about that time and hopefully we'll meet that deadline.  With no further ado, we will ask John Camm to come to us and introduce the topic for this morning's session.  John.
		DR. CAMM:  Thank you very much, Milton.  I would like to take this opportunity to thank Ray Lipicky and Craig Pratt for setting up this meeting today.  I don't know what the protocol is but I would also like to thank the members of the cardio-renal advisory board for staying to listen to this series of presentations.  
		As Milton already mentioned to you, we are going to address the issue of ICD endpoints as applied to clinical trials predominately pharmaceutical agents.
		My particular interest in this area was born from a wish on the part of the European Society of Cardiology Working Group in cardiac arrhythmias to design a trial using an ICD supported population to explore the antiarrhythmic interaction between beta-blockers and amiodorone.  
		The notion was a simple trial design, at least in theory, with a factorial design between amiodorone and beta-blockade and their respective placebos, acute testing in a population fitted with an ICD prior to the start of the trial.  Then acute testing followed by long-term follow-up.
		So far so good.  The issue that tantalized us was what endpoint could we use in this trial in order to access the antiarrhythmic activity of these two component drugs.  We know, of course, that there were other trials underway which were exploring antiarrhythmic efficacy drugs of other types using models of this kind of trial.  But we are unsure about the feasibility and the reality and the probity of using the endpoints that other investigators have decided to apply to their trials.
		I think it's germane in this very brief introduction to demonstrate to you that there are basically three trial designs in which ICD may play a part.  This is the traditional design in which the ICD is merely tested against another therapy.  For some years, as you recall, we had a concept of hypothetical or projected mortality which was developed such that patients fitted with ICD's could act as their own controls in such a way that the value of the ICD could be compared against the hypothetical patient who would not have had the ICD.
		However, after a good deal of debate in the cardiological arena, it was rapidly decided that the concept of hypothetical mortality was a dubious probity.  Instead the all-cause mortality endpoint was encouraged for all trials of this nature.  I've listed a few of the trials that you are very familiar with which have now been completed of this particular design.  This includes trials of so-called secondary prevention and primary prevention.
		Indeed, the so successful have been these three trials in secondary prevention, AVID, CASH, and CIDS, all of which show to a degree, and certainly together, support the fact that the ICD appears to be better than other conventional NDA antiarrhythmic therapies.  It is, I think, unlikely there will be other large-scale mortality trials for this design.  		We know that there are still a few such trials underway, but they are generally smaller trials and unlikely to produce any further data except in support of this general conclusion that the ICD is better than current antiarrhythmic therapy for the management of patients with life-threatening ventricular arrhythmia.  
		However, there is a second circumstance in which ICD's may play a part in a clinical trial of a pharmaceutical agent against another active control agent or against placebo.  This kind of trial will involve patients at high risk to sudden cardiac death but it may not involve patients who have already suffered from life-threatening ventricular arrhythmias that may include patients who have a high risk of suffering in the future from ventricular arrhythmia.
		In this kind of trial a drug is compared against a placebo or another active comparator.  This trial is not a trial of ICD efficacy.  The ICD is simply in place in various patients and may range from merely an instrument which will perturb the general mortality endpoint signal to one in which the device may be used to contribute to the mortality signal or to other endpoints within the trial.
		In many CHF trials that are currently underway, patients with an ICD may be enrolled unless specifically excluded by protocol.  That might end up at the present time with a smattering of ICD patients on one or the other or both sides of the equation.  In some trials there are large numbers of ICD patients.  I draw to your attention the CASCADE trial in which this was the case.  
		Such may be the case in future trials of pharmaceutical agents for the indication of congestive heart failure treatment.  In such trials thus far the major endpoint has been all-cause mortality but composite endpoints have been developed to include not only all-cause mortality but also a variety of events of a therapeutic nature which have been provided by the implantable cardioverter-defibrillator.
		I mentioned to you the example of CASCADE.  You will recall this very clever acronym which stood for Cardiac Arrest in Seattle:  Conventional versus Amiodorone Drug Evaluation which was reported in a number of papers.  The particular paper I allude to is that by Dolack in 1994.  The basic population was 228 patients with high risk of recurrence of out-of-hospital cardiac arrest.  
		The endpoints in this study were composite.  They included cardiac death, resuscitative ventricular fibrillation, and ICD shock of an appropriate type defined by its association with syncope.
		The basic trial result was that empiric amiodorone when compared against programmed stimulation guided class I drug therapy was successful with a 9 percent recurrence of the endpoint versus 23 percent.
		Within this trial there were a large number of patients with implantable cardioverter-defibrillators, 105 in all.  Here are the results for those patients alone expressed in terms of the composite endpoint of shock-free survival.  The patients were obviously still alive and they had not received a shock from the device.  You can see that using this composite endpoint, a result very similar to the result of the trial as a whole was achieved.  		Except I think you will notice that the actual numbers are substantially different with endpoints amounting to about 12 percent on the amiodorone side and about 58 percent or so on the class I side.
		The third trial design is the design which I think presents to us the greatest challenge at the present time.  In this trial the ICD is on both sides of the randomization and all patients within the trial a fitted with an ICD.  The design of the trial is two-fold or the purpose of the trial could be of two types.  Firstly, to explore the antiarrhythmic efficacy of a therapy for a patient who suffers arrhythmias despite or because of the presence of an ICD.
		On the other hand, the trial which stimulated my first consideration was a trial where the ICD was not specifically relevant to the therapy of the patient but it did provide at least in theory, and more of this later, a safety net which would allow ethically a trial of an active therapy against a placebo therapy in patients with life-threatening ventricular arrhythmia.
		In trials of this nature, the ICD acts as a passive monitor and an active therapy.  It is the interaction between these two roles that deserves particular attention this morning.
		I know that there are four trials which have been conducted of antiarrhythmic drugs using trial designs of this nature.  Later in the morning some of the results from these trials will be discussed in a generic fashion.  In other words, not attributed specifically to one or the other of these drugs.  I think that all four of the trials are now completed, although I have not seen official reports or peer review reports on any of these agents.
		My last slide in this introduction recalls for you that we are reentering a phase of argument that has gone before.  NASPE issued a policy statement in 1993 which discussed in large part the standardized reporting of ICD patient outcome.  At that time their concern was with trials of ICD therapy.  Today we must face the same arguments to consider trials utilizing the implantable as a protection on the one hand and as an instrument or monitor on the other.  
		Thank you very much.
		DR. PACKER:  John, we'll just pause for some brief questions from anyone on the committee on any of the issues that you brought up.
		Yes, Ileana.
		DR. PINA:  John, how would you classify a study such as MUS or the CABG patch trials that are going on right now which, I guess, you would call them primary prevention because none of those have had an event.
		DR. CAMM:  In the cardiological arrhythmilogical community these are casually known as primary prevent trials and there are a large bevy of these trials.  They are of the design I that I put up on the screen.  These trials are largely still proceeding, although three have been reported, MADIT and CABG patch and, more recently, MUS.
		DR. PACKER:  I guess they would be design I but primary prevent design I as opposed to secondary prevention design I.  Udho?
		DR. THADANI:  John, in your trial design II one of the concerns always is there is a proarrhythmic effect of drugs.  If you look at your second all-causes, fine, but when you look at the shock-free survival, how much you are really driven in the absence of the placebo group to be absolutely sure that the results are not artifactual, that it might favor a drug when another drug is actually making it worse.  That's point one.
		Point two also is some of the ICD patients, if you just put at random for trial III, for example, they might have nonsustained VT but they tolerate it.  The fact that VT was more than 30 seconds of algorithm at the moment of trial, how do you get around that?  There's no logical way unless one of the issues that each of the II and III trials is compared to all-cause mortality.  I was just wondering if you would comment on that.
		DR. CAMM:  Well, with respect to your second point about nonsustained ventricular arrhythmia that might trigger the device, we agree that is one of the complexities of using this instrument as a trial monitor because it also intervenes and perturbs and points signals.  A large part of the presentation this morning will, in fact, consider that in detail.
		With respect to your first point, could you just quickly remind me?
		DR. THADANI:  Proarrhythmic effect of drugs when you just evaluate in the endpoint of the shock free.
		DR. CAMM:  Yes.  I admit that in my second design I did admit the potential for having an active comparator rather than a placebo.  Under such situations I think in general terms we are faced with the predicament that you raised.  I don't think it is specifically greater in this particular form of trial except that proarrhythmia is also a consequence of an ICD and, therefore, adds another dimension to be considered.  That, again, will be considered later this morning.
		DR. MOYE:  I wonder if you could briefly speak for the sensitivities and specificity of the ICD?  
		DR. CAMM:  Again, we will discuss that as part of the program this morning.  I would rather than anticipate the contribution of others in that regard.
		DR. PACKER:  JoAnn.
		DR. LINDENFELD:  We may get into this later again, too, but could you just discuss for me the relative incidence of serious bradyarrhythmias and the validity of that as an endpoint and how we would measure that particularly as we talk more about people with heart failure.
		DR. CAMM:  Yes.  I am going to mention this particular point in my second presentation, but I was not going to talk specifically about the incidence of bradyarrhythmia.  That has been variously estimated in ICD populations from approximately 15 percent to 50 percent.  Because this depends on how you define bradyarrhythmia and the significance of that bradyarrhythmia.  
		Undoubtedly it is relevant because it is certainly again modifies electrophysiologic substrates and will modify the response of an antiarrhythmic therapy with may, for example, be particularly effective or ineffective or proarrhythmic or antiarrhythmic at particular rates.  It is very relevant when you seek to extrapolate the results in a trial supported by an ICD to a population that might not be so supportive.
		So it is certainly a very relevant question within the terms of the generalized ability of results flowing from ICD supported trials to populations at large.
		DR. PACKER:  John.
		DR. DiMARCO:  John, you may be talking about this later but maybe you can give us a hint.  If you are looking at drugs, either comparing a drug to placebo or comparing two drugs, do you think the device has to be kept standard?  In other words, do you have to have a single capability or a single set of capabilities in the device and does the programming of the device have to be relatively standard in the population?
		DR. CAMM:  Indeed I will be discussing this later.  Essentially my story line is that in the first place devices were nonprogrammable and, therefore, this issue did not arise as they are becoming increasingly programmable and some form of standardization should be contemplated for a variety of reasons that I will discuss later.
		DR. PACKER:  It sounds like we are very anxious to go forward and do the other presentations.  I just have one question.  I guess design III theoretically in a sort of crazy way could be used as a monitor, not only for antiarrhythmic interventions but for proarrhythmic interventions.  I don't know if that is something you'll be bringing up.
		DR. CAMM:  I believe it will be a fundamental part of the presentation.
		DR. PACKER:  Why don't we move forward.  Sounds like that's what we all want to do.
		DR. PRATT:  Well, first of all, before I begin, my thanks to Bob Fenichel and Ray Lipicky for organizing this.  Good morning to Dr. Temple and the committee.  
		My task will be to sort of review some of the designs that have actually been done and we're going to be talking about design type III.  There are a number of trials.  I'm just going to go over some general principles here and differences between four trials that have already been completed.  As John said, now three have been analyzed.  One actually probably never will be analyzed as the data has been accumulated.  All these trials have some primary ICD endpoint.  It could be one of many kinds and I'll talk about that a little bit.
		Secondly, the sample sizes have been in this range based upon some estimated placebo event rates.  The duration of the trials has primarily been at a year and some at six months.  One might argue this is long or not long enough to really appropriately evaluate both efforts and safety of an antiarrhythmic drug.
		Notice the estimated placebo event rate.  That is how often the investigators estimated that there will be a discharge within a year.  That's quite a range.  Needless to say the people that estimated this might have presumed a sample size here and the people of this a sample size here and that might be true.
		There's a lot of other issues that have been different in the trials.  One of them you have actually heard presented here had stratified randomization by ejection fraction.  One of the trials actually was smart enough to think that they might need an interim analysis to adjust for sample size; that is, if their ICD discharge rate and the way that they defined it was not adequate if they would go ahead and they would change the sample size.
		The degree of prespecified ICD interrogation is an interesting feature and I think you're going to hear a lot about that today.  Some people have done this with just an investigator analysis of whether or not there was an ICD shock if the investigators analyzed the appropriateness of that shock.  Others had a simple committee or a group of experts that looked at all the ICD interrogations and made their own independent guided decision regarding that.
		The definition of primary endpoint, we'll come back to this after I show you a couple of clinical trials.  I think there are some important issues here.  One can talk about time to first appropriate ICD shock, appropriate for VT or VF.  
		One can talk about total shocks.  I guess a patient doesn't really care whether it's appropriate or not.  That still bothers the person.
		Then one needs to ask whether you're talking about the tiered therapy; that is, the tachycardia/antitachycardia pacing or you are just talking about simply the number of shocks for VT/VF.
		One of these trials was smart enough to think that this might be a good way to explore a dose range of their drug.  Of course, that does have implications for their sample size.  There have been a number of these trials that have not only entered people when they have their new ICD put in at a time when they might be presumed to have a higher event rate but when they came back to have a new battery installed in a generator.  At that time one might wonder about the frequency of those events.  Different trials have tried to estimate that by having required a ICD discharge within three to six months but some have not.
		The degree to which there is in-hospital testing and the appropriateness of the follow-up testing varies greatly between these trials.  That might be of some interest.  Also, the timing of the efficacy evaluation.  Interestingly some of these are typical randomization intention to treat.  Some of them have a required waiting of X number of half lives prior to the counting of primary endpoint.
		My goal is not to talk about drugs.  My goal is only to talk about the trials so you see that we're going to talk about antiarrhythmic drugs, not individual files.  So that's antiarrhythmic drug.
		This first trial is one that took patients that had an ICD implanted for VT/VF or cardiac arrest.  The ICD had to have adequate electrogram recording capability, although different devices were allowed.  The design was 12 length randomized parallel placebo controlled design.  
		This primary endpoint is time to first appropriate ICD intervention.  It's quite different than the second trial in that they count shocks for VT/VF or tiered pacing for VT/VF.  This is a composite endpoint that does not include death but includes an independent committee that looks at the appropriateness of these shocks or pacing intervention.  
		The kinds of patients, these are patients that basically have low ejection fractions, some clinical heart failure, mostly male, and already on a variety of other antiarrhythmic drugs.  In both these trials sustained VT is about two-thirds of the patients and VF one-third.  Here it's more like three-quarters and one-quarter.  There is primarily patients that have had VT.  Here is one thing that you can do.  You can just look at the defibrillation threshold of these drugs.  That's one thing that is very worthwhile.  
		Here is the primary endpoint.  Remember, this endpoint here is timed to first appropriate ICD intervention for VT/VF whether it be pacing or whether it be shock.  We can see that there was pretty much a wash here.  The one year estimate of event rate was pretty on target here.  It was about 60 percent of the patients that had an event.  There was no difference between these two groups.
		Now, when one looked at other things like total shocks, the antiarrhythmic drug had less total shocks than placebo.  There was a longer time to the first ICD intervention in general, but when one looked at the endpoint that they picked as the primary endpoint, that was the result that they got.
		Here is a second trial.  It does have a significant number of differences.  In the first place, patients had to have either a new ICD or generator replacement within three months with evidence of a shock within three months.  Sample size was larger.  
		Primary endpoint this time is quite different.  Timed to first all-cause shock.  Any shock but not tiered pacing.  We have no information in this trial about pace termination.  It's all all-cause shock.  Stratified randomization by ejection fraction and the same kind of analysis that was done in the first trial.
		When we look at the characteristics here, these patients have higher ejection fractions but otherwise were patients with little or no congestive heart failure and they looked pretty much like the previous group, four-fifths male and a lot of patients with coronary artery disease.  A majority having presented with symptomatic or invisible sustained VT rather than aborted sudden death.
		Here was this result.  This result is quite different.  First of all, this drug does beat placebo for this primary endpoint but this is all-cause shock.  This could be due to VT/VF.  It could be due to a shock for atrial fibrillation and nonsustained VT.  It does not include the tiered pacing events.  At one year the event rate is actually smaller even on placebo of about 40 percent but it's accumulated by almost half with the antiarrhythmic drug.
		If you want to look at something that is closer, albeit not the same as the first trial, this is shocks for VT/VF.  Again, this is as judged by the investigator, not by a central committee or death.  I must say death in these trials makes them about -- if you make a composite endpoint of ICD plus death, it's only about 10 percent of the events.
		Here is another way of looking at it.  It would be nice to be shock free if you had one of these devices and antiarrhythmic drug over the one year period reduced from almost 4 to 1.5 shocks over that interval in the average patient if you think that's a more important way of looking at this.  
		So let's go back to this now and just talk about some of the specific differences.  We've talked about the fact that sample size varies and the placebo event rate is varied greatly.  I think the people who are in this trial, which is a trial that an agency has not evaluated, probably overestimated a placebo event rate.  
		They also had an interim look and they were allowed, if they wanted to, to change their sample size.  This may or may not be something important.  This is certainly something that could be done to make sure that you have enough events in your sample size.
		This is going to be a very important issue at the prespecified SCD interrogation.  I think you're going to see this as probably pretty important and needs more attention by the people that are planning these trials.  I think here will be the crux of a lot of discussion today.
		First of all, if the ICD discharge is appropriate for VT/VF they argue, and it will be argued today either yea or nay, that this is a reasonable surrogate for mortality.  So one might have a composite endpoint of appropriate ICD shock for VT/VF plus death as being a reasonable composite endpoint.  Other people might argue that any time the device goes off, that's pretty troublesome to the patient and all-cause shock is the most important endpoint.  
		Mostly importantly I think that it's possible that tiered therapy with pacing might be a very important element.  If not taken in consideration, patients may have a proarrhythmic effect in their antiarrhythmic drug and they may get paced out of that proarrhythmic effect and that would not show up in the primary endpoint.
		Finally, I think that when you hear Dan Roden's talk, you are going to realize that even if ICD shocks are reduced, the qualitative information of those shocks is very important, for instance, if this is an IKR blocker.  There is more polymorphic VT shocks in the ICD group with antiarrhythmic drug than placebo.  Event though the total shocks are reduced, it may be hiding a very potentially lethal proarrhythmic effect.
		So all these issues, the devils and the details here, and that's what we're here for, to talk about those details.  Clearly, this would be a reasonable place to explore in a very sick and high-risk population a dose responsive drug if you have enough money and enough time and enough patience with ICD's.
		I think the other thing is that the event rates may be quite different in these kinds of patients.  These patients may not behave the same.  I think that would have to be considered when one is analyzing this kind of information.  Certainly making a very vigorous attempt to make all the in-hospital testing and follow-up testing of the devices uniform and ideally making the devices self-uniform with adequate interrogation capacity and the ability to obtain and store these electrograms is an ideal situation.  In the real world that's no so easy.
		This is an important issue.  One of the two trials you saw today started counting endpoints after five half lives of the drug and there was not a typical at randomization and intention to treat evaluation.  So with all those sort of preliminary remarks, I'm giving you a feeling for what this data looks like.  I'll turn it over to Dan Roden to talk a little bit about more detail of this kind of interrogation.
		DR. PACKER:  Before we do that, let's just pause for questions from the committee if they are any.  Bob.
		DR. TEMPLE:  In the ones that use predominantly appropriate shock endpoints, would they also include appropriate pacing endpoints?  Sometimes that's the response.
		DR. PRATT:  Well, that's what I was saying.  In fact, one of the trials here even though the primary endpoint looks tremendous, it does not include the ATP pacing.  In fact, there is no information about that.
		DR. TEMPLE:  Even if the pacing was for sustained VT?
		DR. PRATT:  Correct.  And one would think that there would certainly be more information to be gained to look at that.  In the trial they combine both.  The ATP pacing made up almost half the composite endpoint.  That's why the event rate in the first trial appearing to be less general, there was no all-cause shock.  In fact, a higher event rate of one year.
		DR. PACKER:  And maybe we just clarify for those of us who are not electrophysiologists.  I was trying to ask Dan this question but I think it may be more general and important.  There are some devices that have ATP capability and some that do not.  All devices have ATP.  How does the device decide whether to shock or pace?
		DR. DiMARCO:  It's programmed.  You choose.
		DR. PACKER:  So for each individual patient, you dial in what criteria need to be met for pacing and which criteria need to be met for shock.  You could dial in parameters that would preferentially induce pacing as opposed to shock?
		DR. DiMARCO:  Usually.  I mean, typically you can set up varied zones.  Your top zone is usually a shock zone.  Then if you choose to have a second zone, and this would depend on what arrhythmia you expect the patient to have, you can set up zones below the top zone within which your first response may be antitachycardia pacing, it may be low-energy shock, or it may just be a shock again at a different rate, if you will, with a different duration of arrhythmia.  You have a lot of flexibility which makes it very complex.  
		DR. PRATT:  And you also can't standardize it.  I mean, I think that's the important part.  Milton.
		DR. DiMARCO:  Yes.  The zones are determined by rate or cycle length.  
		DR. PACKER:  Oh, you can do a pacing.
		DR. DiMARCO:  One of the things that Dan will probably get into is the duration for a response can also be set so you may choose a slow arrhythmia to let it go on for a certain period of time before you intervene, where in a very fast arrhythmia you wouldn't want to do that.
		DR. PACKER:  The reason that you would prefer pacing is that it is more pleasant.
		DR. DiMARCO:  It's usually asymptomatic.
		DR. PRATT:  But that does that other level of complexity.  Milton, when I had mentioned that one should try to have some kind of standardization of the times of ICD reprogramming, it doesn't mean you can standardize the programming.  It just means that you standardize the time.
		DR. PACKER:  Udho.
		DR. THADANI:  Craig, one of the problems sometimes with ATP is you can actually induce.  Say patient is going into VT and you pace them.  They will go into malignant VT.  So not only is pacing useful but it could also generate arrhythmias.  This algorithm might count like the drug induced arrhythmias, at least in our lab, to test the patient before they use the pacing because there might be actually induction of V. fib. in these patients triggering that.  That's point one.  That's one comment I think you should keep in mind.  I don't know how you get around it.
		DR. PRATT:  Let me make one comment about that.  I think these protocols can at least standardize the time of testing and mandate testing at some intervals.
		DR. THADANI:  But could it vary, say, you test them in the lab, make changes, and next time pacing actually could produce -- you have to pace them pretty fast.  That would be one issue.  The other issue is I've seen patients at least who arrest every two years.  There are patients who have arrested repeatedly who might be on IV amion or whatever.  		There are patients who have out-of-hospital cardiac arrest.  For some reason they don't have a device and they come back after five years and yet do not have an implant but maybe a small micro infarct.  Should you try to randomize those patients?  		Also, the same issue with patients who are only inducible in the cath. lab. but don't have necessarily spontaneous cardiac arrest because they have nonsustained VT.  Does randomization ever take that into account because that could have an influence if there is an imbalance just for that.  
		DR. PRATT:  The only stratified randomization that I've seen is for ejection fraction with the belief that there might be a difference in antiarrhythmic drug performance and preserved functioning and lower function.  You hope the randomization takes care of a lot of this issue.  
		I will tell you that it's very few patients that enter these trials that have only inducible arrhythmia.  Most of these people had a spontaneous arrhythmia.
		DR. THADANI:  But given the frequency of 35 and 75 with a sample size of 150 you might run into that hassle if you don't have a very large sample size.
		DR. PRATT:  Absolutely.  It gets back to the fact if you pick only new implants, you know now from a couple clinical trials your event rate will be 50 or 60 percent depending on what endpoint you pick.  If you pick old implants, it does goes down.
		DR. PACKER:  JoAnn and then John.
		DR. LINDENFELD:  I was wondering if you could educate us a little bit about how these studies are stratified by additional drug therapy.  You didn't mention that and maybe there's a standard way but if you look at total mortality --
		DR. PRATT:  Randomization.
		DR. LINDENFELD:  Just randomization?
		DR. PRATT:  That's it.  The underlying therapy is pretty stable.  I didn't spend a lot of time on it today because, again, we are not really talking about, you know, specific issues like that.  About 30 or 40 percent around a beta-blocker.  Fifty or 60 percent of these people are on ACE inhibitors.  They are typical LV dysfunction, post MI, multiple MI population.
		DR. PACKER:  John.
		DR. DiMARCO:  Craig, the event rates in the secondary prevention trials aren't that much different than the primary prevention trials.  In fact, sometimes they go higher.  Do you think both populations would be appropriate for a drug trial?  In other words, someone has an indication for an ICD, gets an ICD for primary prevention, say, on MADIT criteria.  Would that person be a candidate with an inducible rather than spontaneous arrhythmia?

		DR. PRATT:  Well, I guess it depends on the question you are trying to answer.  I mean, it's hard for me to imagine that the event rates are exactly the same.  I haven't really thought about it that much.  Clearly the idea of testing a drug in that situation seems equally valid.  You're only going to be limited by the event rate, a really appropriate shock for VT TDF.  If that's really 50 percent or near, that's pretty good.
		DR. DiMARCO:  And then if you're talking about secondary or primary prevention, do you think every drug needs a study with a SCD hep type design where there's a placebo group, a drug group, and a device group to see whether it is relative to the device alone?
		DR. PRATT:  I would kind of like to defer that to the end.  Let's hear them all.  It's a great question.
		DR. PACKER:  Just one comment.  It would seem that based on having nothing to do with the device but having a lot to do with the way this committee has considered outcome measures before.  All endpoints in trials of design III should include death as one of a composite.  
		In other words, to ignore death as an important outcome and just take ICD shocks would seem to be similar to using, for example, hospitalization or nonfatal myocardial infarction as an endpoint without considering outcomes that are clearly worse than the outcome that is being specified.  My sense is there's been at least one trial that didn't do that.
		DR. PRATT:  But not as its primary endpoint.  Correct?  The two I showed today, one of them did have it as primary endpoint.  I think in general, John didn't mention it, but he set up a workshop at the European Congress a year and a half ago where we certainly all agreed that made the most sense.  It would be more difficult to interpret it without it.  
		Obviously you would still have the death information.  It makes up about 10 percent of one of these composite endpoints.  But obviously if you are dead, you can't have a discharge and I think the analogies are perfect.  I think that's the way the agency has seen this.  When people have come to talk to them about these designs, they have encouraged them with that primary endpoint.  I know that Bob and Ray did.
		DR. PACKER:  I suppose a clinical and statistical basis.  The criminal court says that it's bad to be dead.  Second is that its competing risks.  That is, if you're dead, you can't have the shock.
		DR. TEMPLE:  I don't think one should be absolute on that question.  That's fine when the deaths are only 10 percent of the endpoint.  It doesn't matter.  You can throw them in and nothing happens.  But if you had a situation where the nonarrhythmic deaths were a very large majority of it, you would want to know whether that was increased certainly but you might not necessarily make it part of the endpoint.  I think that needs further* discussion.
		DR. PACKER:  This is a really interesting topic because there are all sorts of -- for example, the roll of anticoagulation in diseases where the number of involved events is going to be a very small number of the outcomes, that lots of other bad things happen and involved events is only one of them.  If you included all the bad things, you would overwhelm any treatment effect on the involved events.  I think that is the point which you're making.
		DR. TEMPLE:  I think one doesn't want to be absolute.  You certainly want to see if events are going the wrong way or something weird is happening.  That's not the same as including it in the endpoint.
		DR. PACKER:  Right.
		DR. TEMPLE:  It's a different issue.
		DR. PACKER:  In this patient population --
		DR. TEMPLE:  It seems okay.
		DR. PACKER:  -- I think it's more appropriate to include and one would be curious why the rationale for excluding death.  In other words, I think this is a disease where there is a lot more reason to include death than not to.
		DR. TEMPLE:  In here you are also specifically worried about some of the drugs making some of the other causes get worse like increasing the rate of death due to progressive heart failure.   That's a good case.  I'm not saying you wouldn't often want to do that but not absolutely.  I mean, I think that could be something one would discuss.
		DR. PRATT:  But one can certainly mask an occasionally lethal proarrhythmic effect by this ICD endpoint.  In a small number of patients it may arrhythmia worse and couldn't be defibrillated.
		DR. TEMPLE:  Actually, I have a question about that.  Wouldn't the committee looking at the appropriate discharges and things be able to say, oh, this was torsade and maybe you can't do that from the lead you have.  I don't know.  Could they be able to tell whether it was a likely proarrhythmic event?
		DR. PRATT:  It's a great segue to the next talk.  Perhaps you could introduce the speaker.
		DR. PACKER:  Well, JoAnn.  One more question.
		DR. LINDENFELD:  Brief question.  How do you differentiate from studies.  Several shocks for the same episode?  Does that count as three shocks or one?  
		DR. PRATT:  Well, there are many other endpoints and Dan will talk about them.  One could count every shock.  One could count shocks only at certain intervals but obviously these have been timed to first appropriate shock so the counting of all the shocks is a different issue.  Certainly for the patient lots of shocks aren't fun.
		DR. PACKER:  Dan.
		DR. RODEN:  I want to thank Craig for inviting me to talk.  It will become clear that the reason that I'm talking is that we conducted an analysis in one of the trials he presented to actually address the specific question of proarrhythmia.  He asked me to present some actual electrograms to sort of put this in more of a concrete context for those of you who don't think about these things every day.  It gives me a chance to show some pretty pictures.
		Here are some electrograms.  I never know whether it's a good thing to be talking before or after John Camm but I know that it's a bad thing to be talking both before and after him because he may have some of the same messages to tell you.
		This is what the ICD is supposed to do.  This is a patient who is having something.  I'm not sure what this rhythm is.  They have run a very fast tachycardia shock here that is ineffective but they feel it obviously.  More tachycardia, another shock that's effective and restores quality sinus rhythm.
		All the electrograms with one exception that I'll show you are from one vendor.  I'm sorry.   They just make prettier pictures than other vendors.  It's a device that I'm sort of more used to.  The other thing you should be aware of is that you don't see P waves on these electrograms.  These are highly filtered.  They are different from electrocardiograms.  You actually don't see a QT interval.  Each of these spikes is a ventricular complex but what it would look like on the surface is actually something we don't have a good handle on.
		This is as good as it gets for therapy but it does raise the question that JoAnn asked.  Does this count as a good thing or a bad thing because this patient got two shocks.
		I'm particularly fond of this slide.  This is a patient who had amiodorone pulmonary toxicity; got a defibrillator; had recurrent rapid ventricular tachycardia with shocks; got quinidine which slowed down the tachycardia cycling but made his tachycardia events much less frequent.
		One of the things that people who take care of patients with defibrillators will be aware of but may not be immediately apparent to everyone else is the way in which a shock is now treated compared to the way in which an episode of sustained ventricular tachycardia might have been treated 10 or 15 years ago.  
		A patient with an episode of sustained ventricular tachycardia, even if it's well tolerated, will end up in an emergency room, will end up getting semiemergently cardioverted, and, as likely as not, will end up getting admitted to the hospital to rule out myocardia infarction.
		This sort of gets to be a recurrent problem and a recurrent burden to the arrhythmia and the general cardiology communities.  
		The ability to just be able to interrogate the patient's defibrillator at a routine clinic where they say, "Oh, look.  Two months ago you had an episode of tachycardia that was terminated by the device and you went about your ordinary daily business," that's an advantage that I think can't be addressed necessarily directly in terms of a morbidity trial or a mortality trial.  There are quality of life issues that the defibrillator does fix.  
		The reason I like this slide in particular is this is exactly what happened to this man.  He came in February and we interrogated his device and said, "Oh, look.  You had an episode of sustained VT.  Good thing you had the defibrillator because otherwise you would have ruined your day."  The day that he would have ruined would have been his family's Christmas. This event occurred at 11:30 on Christmas morning.  I really think that's a real tangible benefit to this patient.
		This is sinus rhythm and then the onset of something followed by the onset of sustained monomorphic ventricular tachycardia.  A single episode of antitachycardia pacing restores normal rhythm.  Now, you could make the argument maybe if this had been left for 30 seconds he would have spontaneously terminated or not.  The fact is, this is an episode of which he was totally unaware.  This is as good as it gets it think.
		You talk about shocks for all causes.  I mean, there is a rare cause of shocks that we would prefer not to have to count and that's shocks for lead malfunction.  This is a patient who is actually having sinus rhythm but they have a lead fracture so they have a lot of electrical noise and this is the shock effect.  That probably has not much to do with whether they are on the drug or placebo but it may have something to do with whether they got the ICD in the first place in a MADIT type design.
		This is a problem that has been alluded to already.  I'm not sure how much of a problem it is or not.  The patient has irregular fast tachycardia which is atrial fibrillation.  The little dots indicate the times at which the defibrillator has finally decided that the rate is fast enough to require a shock.  
		This is what we're talking about before, Milton.  Once you dial in the rate, no matter how the patient gets to that rate, they get a shock.  There are ways of programming or monitoring defibrillators to ask the question, for example, did this rate start suddenly or did it start gradually.  This is an episode of gradual onset as opposed to sudden onset.  The shock is delivered here and, of course, does nothing.
		Craig alluded to the idea before that, you know, if you're a patient and you got a shock for this, then that is just as bad as getting a shock for VT or VF.  Maybe a composite endpoint that includes shocks for atrial fibrillation is not great from the patient's point of view.
		Udho alluded to this.  This is atrial fibrillation.  A shock is delivered.  This is very rapid sustained monomorphic tachycardia.  A second shock is delivered to rescue the patient.
		This is an issue because most defibrillators will cycle through five or six episodes.  If this goes on, will deliver five or six shocks.  If normal rhythm is not detected, the device will turn itself off with the assumption that it is treating noise or some undefibrillatable rhythm.  It is conceivable that you could get five shocks for atrial fibrillation.  The sixth one would then trigger the ventricular tachycardia which the device would then decide to ignore.
		So there is a potential, although I don't think I have seen a case.  Jeremy may have something.  There is certainly a potential that will have cases of defibrillator induced death.  I haven't seen one and I don't know of one.  I know of other kinds of defibrillator induced death which Jeremy may have a word to say about because there are occasional device malfunctions that can cause mortality.
		The question that I was asked to address is what can we learn from analysis and intracardia electrograms.  I think you get the flavor already that there are complex analysis issues.  Yes?
		DR. TEMPLE:  Just one thing about the previous slide.  I understood that you can train these things to recognize both rate and form.  If someone has fibrillation, maybe you could train it not to identify that complex or look at the URS or something.
		DR. RODEN:  I think you're looking at a movable feast right now.  There are devices that are dual chamber, for example, that will be able to tell us what is going on in the atrium and what is going on in the ventricle at the same time.  So, for example, that might be a way of detecting atrial defibrillation.  The philosophy underlying the design of those devices is that they will err on the side of assuming that the rhythm is ventricular and treat it.
		DR. TEMPLE:  So most of them just respond to rate?
		DR. RODEN:  At this point I think it's fair to say that most of the devices respond to rate but there is a lot of work going on in terms of trying to do discrimination but the discrimination is going to be difficult in terms of, for example -- I don't have a good example with me but ventricular tachycardia is not always dead regular and certainly polymorphic ventricular tachycardia can be very irregular.  
		That was the first one I showed you.  If you are in ICD or an ICD manufacturer, the last thing you want to do is not treat a rhythm that might be a lethal ventricular arrhythmia.
		DR. DiMARCO:  And it gets very complex because in the population who gets these things, a very large percentage of them have Y complexes to start with or will widen them in the presence of a faster rhythm so that your morphology characteristics are okay but they are often unreliable.  Even if you have a two-chamber device, you never want to miss the F arising out of AF.  If somebody goes into AF and has AF, well, then if they develop VT, you want to be able to shock that so it's very complex.  
		DR. RODEN:  The slide that I didn't put in because I thought it would get too messy, and it still ended up too messy, occasionally you actually have electrograms that look absolutely identical during VT and sinus rhythm.  We are convinced for other reasons that it's VT.  Even the morphology of these guys here can't be used as a good detector.
		DR. THADANI:  What happens with a patient who is (indiscernible) and he gets a tachycardia with sinus?  Would the device still fire?
		DR. RODEN:  The device generally fires because of rate unless there is some other -- some devices now have onset criteria that you can use but I don't use those.
		I think you already get the flavor that in trials like this it's not just a matter of sort of looking at and counting the number of shocks and saying this is what happens because there are issues of the diagnosis of nonventricular arrhythmias that the device may sense.  That comes obviously in all flavors including sinus tachycardia.  
		Then there is a theoretical issue, and I think it is a theoretical issue at this point, of ventriculary arrhythmias that don't get detected.  There's a variety of reasons that could happen, not just running out of episodes but device malfunctions.  There are causes for that.
		I'll come back to this issue in one second.  Think about the things that the drugs might do.  They might modify VT/VF frequency.  That's obviously what we would like to see.  They might make ventricular tachycardia slower and easier to pace terminate.  If a trial uses total events as it's endpoint, you won't find that but that would be a very, very desirable thing for the patient's point of view.  I showed you the Christmas day slide, I think.  It sort of speaks as eloquently as it can for that sort of issue.
		Obviously devices may modify the frequency of events such as atrial fibrillation.  Then drugs might modify the mechanisms of tachycardia that remodify defibrillation and efficacy.  Craig already alluded to that.
		The reason that I'm standing here is that we did an analysis of one of the databases looking at the question of whether we could detect drug induced torsade during long-term treatment in patients with ICD's.  That's what I'm going to sort of talk a little bit about.
		One of the questions is how do you diagnose torsade at the best of times.  The best of times you get a faxed ECG.  This is a person who has a very long QT interval particularly long after a pause.  That's rhythm strip No. 1 on the 21st of August.  Here is rhythm strip No. 2 on the 21st of August one minute later bearing a polymorphic tachycardia.
		That is pretty suspicious.  I would like to see the onset of a tachycardia to see if it is pause-dependent and we just don't have that from these rhythm strips.  I would end up saying this is probably torsade, at least by a sort of preset criteria that many trials use.
		In fact, this patient had an ICD.  This is an ICD case of a different kind of device.  You can see that they had an episode of tachycardia.  It stops, a pause, a sinus beat, and then the tachycardia starts up again.  This is a intracardiac electrogram.  It is filtered differently.  This presumably corresponds to this part here and somewhere up here.  Actually, I see the onset here and this is an episode of torsade.  You can only make that diagnosis with certainty from the intracardiac electrogram.
		Another issue that comes up in terms of thinking about this, here is a patient who is having ventricular fibrillation.  You will notice that the electrograms are very, very variable and there is a lot of what appears to be noise but that is fibrillatory activity.  They got a shock and normal rhythm is restored.  
		The difficulty here is that I'm not certain how this rhythm started.  It may have started as torsade and generated to VF but I can't say that because I don't see the onset of the tachycardia.  When you see an event like this during an analysis like the one I presented to you, we just can't make head or tail of what to do with that.  
		DR. TEMPLE:  Why is it that you don't see the onset?
		DR. RODEN:  Because of the device that was used in this particular trial by in large.  Most of the devices had limited recording capability.  That's programmable.  You can say you wanted to remember more of an episode, less of an episode.  Some of the devices now we'll remember started the episode which is actually pretty convenient.  You would see this and you would also see a strip that might be two minutes before recording the start of the device.  The trial that I'm going to present to you didn't use those kinds of devices.
		DR. DiMARCO:  But, Dan, isn't this probably single dropout here because you have such a long detect time?
		DR. RODEN:  Well, that's actually the problem.  I was presuming that somebody was going to ask the question why this person has 24 seconds of ventricular fibrillation before they get a shock.  actually, John, I think there's a shock right there.
		DR. DiMARCO:  Oh, really?
		DR. RODEN:  Here is another problem if you are looking for torsade.  This is a Holter monitor in a patient who has palpitations as their symptom.  This is a pretty typical episode of torsade.   This patient happens to have an ICD.  This is what the ICD looks like.  This is pause-dependent.  There's a pause, a sinus beat, and one more tachycardia.  This is what we would expect torsade to look like; pause-dependent, polymorphic tachycardia labeled conveniently enough VF but that's not what it is.  
		This is a person who actually has shocks on their Holter monitor.  This is marked five minutes before the actual events up to nine minutes before of events like this.  Even way before they had actually a shock, they were having echocardiograms that were typically torsade.
		This is what happens with the shock so the times are about right, a typical episode.  The intracardiac electrogram looks like you would expect it to look, pause-dependent.  I'm not sure how this starts exactly.  This is clearly pause-dependent.  This is a sinus beat and this is probably initiation of the torsade.  Not very quick at the beginning but then speeds up.  The shock right here restores normal rhythm.  So no secrets which drug this is, I'm afraid.
		So the analysis goal in our study was to look at the incidence of -- I guess I should say at the beginning that obviously the intent here is to study the phenomena enough.  Not necessarily this particular drug but to ask the question can we detect torsade occurring during long-term therapy.  
		What we decided to do is to compare the incidence of pause-dependent, polymorphic VT in these 174 patients randomized, half randomized to drug, half randomized to placebo.  
		We looked at 623 electrograms in 133 patients who had electrograms that were recorded.  There's a group of about 40 that had no events at all.  Of those electrograms we saw the onset of 411 and those were the ones we started with.  We don't know how many of the other 200 or so might have been torsade.  327 of those were monomorphic VT.  We're not so interested in them anymore.  72 were polymorphic VT.  Then there's a whole sort of little smattering of others.
		I must tell you that many of the patients in whom we didn't see the onset actually had ongoing atrial fibrillation as a result of their shocks it seemed to me.  So there were a lot more supraventriculary arrhythmias or atrial fibrillation that appear on this thing here.
		So let me just say a word about the patterns of onset.  Jeremy has published on this.  This is sinus rhythm with nonpause-dependent monomorphic VT.  This is sinus rhythm with pause-dependent monomorphic VT.  There's a break here because this would have been on the next line down.  I didn't want to do that for the slide.
		This is nonpause-dependent polymorphic VT and this is pause-dependent polymorphic VT.  This is the guy we're looking for because this is what we decided that has the electrogram characteristics of torsade.
		Then to just complicate life a little bit, here is a patient with monomorphic VT and no pause.  Here's the same patient with the same monomorphic VT but they have a positive onset.  I think you already get the flavor that you need to sort of be looking at each electrogram and thinking about each different patient as opposed to sort of adding numbers up.
		What we did was we found 20 polymorphic VT events, pause-dependent polymorphic VT events.  The way we found them was by electrograms in five cases.  Then there were five cases -- remember, this is the trial that looked at patients between day one for the first five half lives.  Didn't count events but there were events of torsade during the first three days of therapy in the five patients.  
		Many of those for a variety of reasons didn't actually have electrograms which is frustrating for a torsadesophile like me to not see all those electrograms.  One of those patients was actually a patient at our center so I'll take the credit for that as well.
		We have a total of 20 events where we have pause-dependent polymorphic VT.  Fifteen of them are on electrograms and five of them are patients who actually had torsade monitored from days one to three.
		In these 15 electrograms the first thing we did was we went back and looked at the case report forms for all of them to see whether, in fact, those are patients who had actual real-life torsade that had been missed on a surface electrogram.  Notice I'm using the term positive polymorphic VT as opposed to torsade.  Out of those case report forms we actually found three further episodes of torsade where surface ECG documented the arrhythmia.  I'll talk about those in a second.
		So basically we have cases that arose early within the first three days and we have cases that arose late.  So 15 on drug and five on placebo.
Of the early cases there were the five early torsade cases.  Those were all on drug.  There are 10 cases that occurred late during therapy and five on placebo.  		We have to remember we had eight cases of torsade and there are seven of them on this drug which is not a surprise, I guess.  There's one in the placebo arm and this is a patient who was on placebo and on day 62 was withdrawn from the study and started on amiodorone and on day 64 had clear cut torsade.  That's an intention to treat analysis as appropriate.  		So the torsades occurred mostly, again, five of them occurred early, the same five here, and two of them occurred late.  One I told you about on placebo and these two on drug.  The way they are detected is the patients coming to the hospital because of a shock.  They are monitored and they have further events that are recorded on the electrocardiogram, one on day eight, one on day 289.  		The QT's are not very important, I think, for this analysis.  Not surprisingly the QT's -- actually there was a point.  The QT is long here but interestingly the QT is quite long in the placebo treated patients as well.  I think this is just a manifestation of how sick this population is because I think QT prolongation occurs amount patients with advanced heart failure.  I think that is what we're seeing here.  This is a population with pretty advanced heart disease.
		That's really what I want to say at this point.  Just to summarize, I hope I've given you the sense -- I think I've given you the sense that an analysis of these electrograms is not something that should be undertaken lightly.  There are a lot of nuances to try to interpret the electrograms themselves and put them in the context for these kinds of trials.  Nuances like quality of life, like whether something is terminated by antitachycardia pacing or not, whether things are detected appropriately.  The sorts of things that we already talked about.
		I think one of the most interesting results of this analysis that I've presented to you actually is the fact that we still have five cases of pause-dependent polymorphic ventricular tachycardia in patients who were treated with placebo.  
		Given that, it's very, very difficult to say that we have an increased incidence of episodes of torsade, or strikingly increased incidence of episodes of torsade on drug.  I think that what you could say is that the phenomenon occurs with both.
		I guess the conclusion that I have is that the patterns of VT/VF onset are very interesting for those of us who are interested in mechanisms.  In terms of interpreting these large trials, they are probably less important than other outcomes such as a reduction in the number of shocks, perhaps a reduction in the number of events, and perhaps a reduction in the total number of shocks, issues that we are going to come back to later this morning.  That's all I want to say for now.
		DR. TEMPLE:  Well, that's pretty interesting.  I hesitate to call the results shocking but one might.  What do you make of the apparent torsade, although you didn't call it that, in people not known to be on a drug that causes it and what does that mean?  Does that mean people who are sick commonly die of that mechanism?
		DR. RODEN:  Yes.
		DR. TEMPLE:  Or is that just --
		DR. RODEN:  I would defer actually to JoAnn and Ileana and Milton.  There is certainly a flavor in the heart failure/arrhythmia literature.  It's hard to believe that there is such a thing, but there is such a thing which suggests that patients with advanced heart failure have alterdine channel regulation that, in fact, predisposes them to arrhythmias that may be mechanistically not dissimilar from torsade.  
		Those are a lot of words.  I'm sorry to sort of qualify it that way.  Not only might arrhythmias that patients get in those situations be morphologically similar, pause-dependent and polymorphic, but they actually may share some underlying mechanisms.  That's why I picked the conclusion.
		DR. TEMPLE:  I don't know if it's been discussed here or not.  Probably not.  One of the phenomena we observed with nofepradil was that apart from the torsade associated with inappropriate combinations, there were these mysterious ones almost as frequent in number where the only underlying thing was heart failure and frequently the presence of digoxin but, of course, that could be the heart failure.
		DR. RODEN:  We have a much more elaborate theory with regard to digoxin that actually implicates intracellular calcium overload as a final common pathway which would implicate digoxin in these kinds of arrhythmias or would indicate heart failure in these kinds of arrhythmias.
		DR. TEMPLE:  Okay.  So it may actually have been interactive.  But one of the points that a consultant to the company made was that there is a literature that says that heart failure alone is associated with torsade.
		DR. RODEN:  No.  There is theoretical literature that suggest that mechanisms like that may cause arrhythmias that look like that.  The arrhythmias I showed you, the real live torsade with the really long QT intervals and the pause-dependence, that doesn't occur in heart failure, the really long QT intervals.  
		One of the things that we haven't done is gone back and looked at things like coupling intervals to see whether we can sort that out or not.  I'm not sure what conclusion we would draw.  We are certainly going to do that.
		DR. TEMPLE:  I may have been misusing the term.  What they had was polymorphic VT.  I don't know that the QT was very prolonged.  It might have been just a little prolonged but it was identified that way.  One could say, however, that if you had a question about a drug, this method did detect an increase because of the population substrate there was plenty in the placebo controlled group too.  It's hard to think how you would do that.  I mean, I'm not sure how one could make use of that exactly but it does sound like one could.
		DR. RODEN:  Let me just put this in context.  I'm glad you asked me that question.  This is the dofetilide trial.  The overall result is a total wash.  The number of events is identical in the two groups.  One interpretation is that dofetilide doesn't change the incidence of arrhythmias but what it does is it makes them look different.  An arrhythmia that would have been nonpause-dependent monomorphic on drug is now pause-dependent polymorphic.  That's one possibility.
		Another possibility is that it's antiarrhythmic and that it's balanced by a proarrhythmic effect obviously.  I don't think you can make that interpretation from these data.
		DR. TEMPLE:  Actually, I was thinking of drugs that weren't intended as antiarrhythmic but are intended as antihistamines.  It's still hard to think how do you do this exactly.
		DR. PACKER:  Based on all this you've done on using electrograms in either high risk or heart failure populations or sudden death populations, what percentage of patients who have pause-dependent polymorphic VT have no clinical event?  In other words, of all of the events how many of them are clinically apparent?  
		I know that some of them.  For example, you showed three cases where you went back.  There was no clinical data reported but there happened to be a surface cardiogram that actually confirmed the event.  Of course, the fact that there was a surface cardiogram was a fortunate accident.  There might not have been a surface cardiogram at the time.
		One is getting the impression that these patients are actually having these events a lot.  A lot of them, maybe even 90 percent of them, are self-terminating.  That may be true as a result of the disease.  It may be exacerbated by a drug or there may be a disease/drug interaction.  These are really common.  What we've been picking up in clinical trials, which are primarily clinically apparent because they are symptomatic, is not just the tip of the iceberg but it's the extreme tip of the iceberg.
		DR. RODEN:  Well, the events that are detected by the device and not treated, the self-terminating events have to be of a certain duration.  Again, that's programmable what duration one might expect to see.  We're going to have a discussion.  At least, I think one of the questions that we're going to talk about is whether nonsustained VT events are things that are worth tracking, in which case reprogramming devices to detect more of them is one approach.
		We are coming back to the idea of ventriculary arrhythmias as predictors of mortality events in patients with advanced heart disease, which I guess is not a new concept.  Again, the question is what if people with very, very frequent events are at more risk than people with rare events because it's a  stochastic process.  
		The more frequent events you have, the more likely it is that you'll have one that happens to trigger VT or VF that is sustained and lethal.  That's always been my understanding of why frequent PDC's are a bad thing in the wrong population.  I think we are seeing the tip of the tip of an iceberg that we know is there.
		DR. PACKER:  The only reason is that in many of the discussions that have taken place where patients were given drugs that could cause torsade, the committee is always asked, "How do you know how many torsades could have occurred and you didn't pick them up?"  Of course, the sponsor says, "We don't know.  We didn't pick them up."  
		What you are indicating is, yes, you can pick up a lot more episodes than are clinically apparent.  But that raises the question are they things that are worth picking up because you are no longer talking about clinical outcome.  You are talking about a correlate of the clinical outcome.
		DR. RODEN:  I haven't shown you episodes of torsade that go on for two or three or four minutes and then self-determinate.  That happens.  That is well described.  Even if you had an event that was that long, it's not necessarily a mortality event.  But it's an event that might cause syncope or it might cause a car accident or that sort of thing.
		DR. TEMPLE:  But one of the things that was always odd was that torsade was a VT that you managed to get to the emergency room with.  A lot of VT's you don't get that opportunity.  It obviously can come and go.  At the same time, torsade inducers like d-sotalol sometimes show no torsade at all and just show an excess of death which we presume was a torsade mechanism, although it's hard to know for sure.
		DR. PINA:  Dan, do you think that in these ongoing trials like SCD hep, for example -- and I keep pointing to SCD hep because we're involved with SCD hep -- since a proportion of the patients are going to get ICD's, and it is primary prevention as we said, would we have the opportunity to scan the electrograms and look for what I suspect as you do, Milton, how many patients have these off and on?  
		Now, we are seeing this in patients waiting for hearts but, of course, some of the ones in the hospital are already on ionotrope so you have introduced an arrhythmic agent.  We are seeing these spontaneously, you know.  They make me very nervous every time I see them and you never know if it's the drug that you're giving them or is it the disease itself that's doing it.
		DR. RODEN:  I presume that somebody is going to look at the electrograms.
		DR. THADANI:  Dan, yesterday in the presentation I asked this question because they had three innovations with some of the ICD stuff and they did not really have much evidence of torsade.  At least, they didn't have the data.  The question is really are you right calling it torsade just because it is very dependent?  You have to have a QT prolongation in the torsade.  I have seen the T waves look really peaked in the class I arrhythmics.
		DR. RODEN:  Let me be explicit.
		DR. THADANI:  So it could be polymorphic VT.
		DR. RODEN:  I use the term torsade to apply to pause-dependent polymorphic VT associated with these QT deformities that you are talking about.  That's why I've made the distinction, although I obviously haven't done a very good job of it, between typical torsade de pointes and pause-dependent polymorphic VT.  
		I think when you look at electrograms all you can do is look for that phenomenon.  I'll just leave it at that.  The conclusion I think that we come to is that the phenomenon of pause-dependent polymorphic VT does occur in patients treated with placebo.  It occurs with at least equal frequency and possible increased frequency with that particular drug during long-term treatment.  How many of those were actually typical torsade and how many of those reflected the underlying severity of the disease.
		DR. THADANI:  Maybe that's the placebo.  That's why the incidence is high.  If you look at the classic torsade it may not be.  Other thing is now we are using more and more beta-blockers which also reduces your heart rate.  And if a patient on beta-blocker and something else, you might get a pulse.  It might be more complicated than what you are --
		DR. RODEN:  No.  Of course.  And the nofepradil data said there was an underlying brady arrhythmia issue.  The beta-blocker probably -- I don't want to get into this too much but beta-blockers while they slow the rate probably have an anti-torsade effect in general.
		DR. PACKER:  John and then JoAnn.
		DR. DiMARCO:  Dan, do you want to comment on the type of electrogram you want to analyze?  Fortunately I think we're out of the interval log.  Do you think we should record -- you know, you were showing one manufacturer's type of electrogram.  There are other types of things that look more like a cardiogram.  Which do you think is the best for this purpose?
		DR. RODEN:  Oh, I think probably the ones that make some assessment of at least low QT interval that one might believe in are probably more desirable.  Obviously the manufacturer that we used here was sort of first to the post with the intracardiac electrograms.  That was the one that was used in this particular trial.
		DR. LINDENFELD:  Dan, were most of the episodes paused-dependent polymorphic VT, were they associated with other clinical events or not?  Do you know that?
		DR. RODEN:  I don't know the answer to that.  Most of them were patients who came back for their routine three monthly visit, had their interrogation, and they said, "Oh, look.  You had an episode."  I take that back because when they had a shock they were seen, particularly if it was the first shock and then they were interrogated.
		DR. THADANI:  Then also the treatment other than beta-blocker for torsade at least is basic.  There are more of these devices than you would think to pace them out.  Is there a duration to see if the torsade expires when the pacing kicks off or would it kick off within the third or fourth beat of the onset of the VT?
		DR. RODEN:  They are two different kinds of pacing.  One is anti-bradycardia pacing.  That will be highly effective in treating or preventing further episodes.  In fact, in some of these patients, at least the patients that we took care of at our place, that was, in fact, the treatment.
		The second thing is whether antitacycardia pacing can terminate episodes of torsade.  This is probably the one time when one could prove that because in general once you put a pacemaker into someone who is having recurrent episodes, you don't have anymore episodes.  I must say I would have to go back and look and see whether these particular events were terminated by antitachycardia pacing.  I presume that this tachycardia could, like many other tachycardias, be terminated by antitachycardia pacing.  Often it self-terminates so it might be difficult to determine.
		DR. PACKER:  Okay.  Why don't we go on to the next presentation.  Gee, I hope you give us some answers soon.  I'm beginning to get the impression this is sort of like the Heysenberg uncertainty principle.  For those of us who were mildly depressed before are becoming increasingly depressed as the day goes on.  We are looking hopefully for some good news.
		DR. CAMM:  The word Heysenberg has been very high in the minds of all of those wrestling with this problem.  Our recognized goal, though we are trying to bring gifts to you today, those gifts may be poison chalices.
		Obviously I'm going to say a little about what has already been said because there's an essential overlap in presentations.  My purpose at this point is trying to give the committee an appreciation of what the potential endpoints might be in an ICD supported trial and how those endpoints may be effected by the details of the trial design, by the programming of the device, and by the kind of treatment that a patient is taking.
		I need to restate from the outset that the trial of design III could be undertaken for two specific reasons.  One of which is to identify complimentary drug therapy to patients who are fitted with an ICD for life-threatening arrhythmia.  The other is to explore the antiarrhythmic effect of the drug with an intention to extrapolate that antiarrhythmic effect out with the realm of patients who are fitted with an ICD.  I think it is that second potential purpose for the design of trials of this type that presents the greater problem.
		So if we consider an ICD discharge taking place during a trial, we have to wonder whether we should try and prevent this by excluding all patients from including in the trial if they have an ICD.  This has been certainly a policy which has been followed in trials of heart failure patients with heart failure drugs where the number of patients with an ICD was anticipated to be very small.  
		Other trials have included such patients and when discharges have occurred, they have censored the patient from further continuation in the trial.  They may or may not have counted the ICD discharge or therapy as an event depending on what endpoints or outcome parameters were being logged in the trial.
		In some trials, for example, these events have been counted as the equivalent of a resuscitated cardiac arrest.  Sometimes the endpoint is counted and added to a composite endpoint which includes all-cause mortality.  Sometimes any ICD intervention is added to a mortality endpoint.  Sometimes and increasingly the notion is to restrict the endpoint which is added to a composite including mortality for those ventricular tachycardias that might fairly be thought of or most appropriately thought of as a potential surrogate for death itself.  In other words, fast ventricular tachyarrhythmias.
		This issue has been covered just recently by Dan because I wanted to just remind you about the complicated events which surround or precede mortality from ventricular arrhythmia.  These data are from the papers Bayes de Luna, Kumel and LeClerg.  They looked at more than 100 patients who were wearing ambulatory recorders when they died.  They documented a variety of ways in which they died.  
		For example, they found some patients who seemed to go straight from sinus rhythm with some ventricular ectopy into rhythms which could be described as ventricular fibrillation.  They described such great patients as having primary ventricular fibrillation.  They had other patients who seemed to develop rhythms equivalent to torsade as defined by Dan, pause-dependent, long QT intervals, relatively slow polymorphic ventricular tachyarrhythmias accelerating into much faster ventricular arrhythmias.  Even in these ambulatory patients this constituted 13 percent of the group.  
		Finally, they described what in their experience in these ambulatory patients was by far the most common method of mortality in which sinus rhythm was interrupted by a fast monomorphic ventricular tachycardia which after some time degenerated into ventricular fibrillation which was the rhythm that killed them.
		Of interest, and since you were already discussing device-based diagnoses, recent information with dual chamber devices suggest that a number of patients who are fitted with these dual chamber devices have atrial fibrillation as an initiating arrhythmia and that atrial fibrillation converts to ventricular fibrillation which is then attended to or not by the implanted device.
		Now, I want to take you back some years to the idea of hypothetical mortality which was an issue first "invented" by Michel Mirowski.  On the left is a representation of a graph which appears in Mirowski's paper in 1983.  He plotted the actual mortality of the cohort under examination.  He plotted their sudden death mortality.  
		Since all his patients had ICD's, he was also able to construct a mortality which he described here as an expected mortality.  What he meant by that was if the patient's ICD had not discharged and kept that patient alive, they would have died.  Therefore, he constructed a hypothetical mortality for a group whose actual mortality is portrayed here.
		It's important to realize that in 1983 we were largely dealing with implantable devices which came from the factory preset for a single rate of intervention.  It had virtually no programmability.  So an event was only one event, a discharge, which occurred at a single rate that was not variable.  It was easy to see how Mirowski, his colleagues, and many like them could see this as an appropriate surrogate for mortality.  
		But there was considerable disconcert about whether this could be regarded as a surrogate for mortality and there were at that stage further develop.  Rich Fogoros, for example, in 1990 took this a stage further.  He said that we don't need to call to include all discharges or therapeutic interventions from a device as an expected mortality or hypothetical death.  We could adjust or recalculate the survival according to whether the shock or therapy was "appropriate."
		For example -- and here I apologize.  I've mislabeled these two curves -- he could change the crude expected mortality, or predicted survival as it is labeled here, to a recalculated value which included only appropriate shocks and compare that to the actual mortality in the group.
		We also had another small cadre of patients in this particular presentation who were described as controlled patients; that is, patients who did not have a device whose actual mortality was plotted on these same axis.  It is, I suppose, no accident that the controlled mortality is closer to the recalculated predicted mortality than to the crude recalculated mortality. 
		Now, what might constitute an appropriate shock?  What might turn a therapy into something that is equivalent to a mortal episode?  Well, originally symptomatic criteria were used.  Does the patient have syncope or no syncope?  Other groups varied this and became less demanding.  Was the patient lightheaded or did they have any form of hypotensive symptoms.  Others went on to say, well, any symptoms associated with the shock at least would sort out those who have sinus tachycardia from those who have an arrhythmia worthy of treatment.
		When electrograms or logs of events became available in implantable cardioverter-defibrillators and when programmability became available, it became possible to define specific interventions for specific tachycardias and call them appropriate, i.e., closer to a surrogate for mortality and not others.  For example, a higher rate or a longer duration of an arrhythmia.  In some reports an appropriate shock was merely defined as one that could not be demonstrated to be inappropriate.  
		In this series of patients reported from Germany, we can explore the value of syncope as indicating the appropriateness of an ICD shocks.  Bansch and colleagues reported in this rather recent publication that patients with syncope had a discharge frequency that gave a lower projected mortality than those who had any ventricular tachycardia or fibrillation.  
		They found that syncope occurred at a median heart rate frequency of 240 beats per minute with almost all tachycardias causing syncope were greater than 180 beats per minute and that only very rarely did slow tachycardias cause syncope.
		This is an example of an electrogram demonstrating the way in which the device ought to work and the kind of information that we can obtain from electrograms to help us refine the classification of the event treated by the device.  We are already well attuned to looking at these electrograms so I don't have to point out very much.  
		This is obviously a slow rhythm.  You see the electrogram shape enter in the slow rhythm and this is the equivalent of sinus rhythm.  You see the faster rhythm.  You see the electrogram shape during the faster rhythm in this case is different to that sinus rhythm.  This is not always the case.  You can see with this particular electrogram derived from the particular electrodes in use, the width of the electrogram during the ventricular arrhythmia is actually if anything narrower than that sinus rhythm.  		But with more modern devices, different electrode arrays are being used and morphological criteria and width criteria can certainly be employed to refine the diagnosis.  Certainly atrial events plus ventricular events can be used to refine the diagnosis.
		In this instance, tachycardia is recognized.  The response by the device is antitachycardia pacing.  As you can see in this instance, a slower rhythm is restored with the same electrogram characteristics as previously.  This is interpreted as the restoration of sinus rhythm.
		Now, let us return to the issue of hypothetical survival and consider if there is any characteristic other than ventricular tachycardia or "ventricular fibrillation" that would bring us close to a surrogate for mortality.  
		These are data available from the German group in Muenster published by Bocker in 1993.  The curves are at the top sudden death.  The solid line arrhythmia related death.  Not all of them specifically due to an arrhythmia at the point or including some arrhythmias that produce a rather lingering mortality.  
		Below that is cardiac mortality.  The bottom, any interventions recognized and/or treated by an implantable device.  There is an intermediate line which is labeled as fast VT or VF.  For this purpose the Germans selected the rate which they had identified as the median rate for syncope in their population and that rate was 240 beats per minute or a cycle length of less than 250 milliseconds.  
		So they suggested that the benefit for the device could be more fairly estimated by taking a rate of 240 beats per minute, i.e., this line, than by taking the rate of any ventricular tachycardia or ventricular fibrillation, i.e., this line.  This particular shaded area represented what they believed was the use of the benefit of the device.
		Of course, there is no particular single rate that we could identify that reliably separates those who would have lived from those who would have died had the defibrillator not been in place.  I think what we can say is that the faster the rate that we choose, the more likely it will be associated with hypotension, with syncope, and probably with death.  We can also perhaps say that the more likely it would pick up and identify ventricular fibrillation proarrhythmia.  Therefore, we could say, I think, that would be more specific but perhaps certainly less sensitive.
		We go to the other side of the equation, of course, and we reduce the rate that we take as the rate which will separate those who would have lived from those who would have died.  We are going to achieve a less specific but more sensitive measure and we are going to pick up, I think, more atrial fibrillation proarrhythmia by moving the line downwards.
		There is very little evidence in the literature for us to select any specific rate, but what there is is a history of this rate being selected in a number of publications.  
		I should say whilst I'm on that slide that it is important to consider the issue of when patients are censored from the trial because, for example, these patients, who are actually dying, are clearly censored by their death.  These patients who are receiving perhaps trivial logging of arrhythmia or asymptomatic termination of arrhythmia should almost certainly not be removed or censored from the trial.
		Often in many trial designs those patients who have sustained an arrhythmia, which is regarded as a primary outcome event, are also regarded as reaching an endpoint if not by protocol design, then certainly by the practice of the trial where the patients are then withdrawn from the trial or given alternative medications, so on and so forth.
		Now, the time to withdraw the patients from the trial is obviously critical because if we have a high frequency of time to first events early in the trial, then obviously we will effect the reliability of endpoints related to mortality because the patients are merely not there.  They have reached an endpoint, or part of a component endpoint, and they don't go on through the trial to potentially suffer from any mortality.
		As we heard earlier, the reverse is true, of course.  If they are dead, they certainly don't suffer any of the events that would contribute to the other composite of the endpoint.  In other words, the fast arrhythmias.
		The most serious problem in my view is how these patients leave the trial either by protocol driven withdrawals or censorship, or the practicalities of managing these patients when they are withdrawn because they stop taking trial agents and start taking other agents.
		As we heard, several trials have considered enrolling patients after the implantation of the device, but some have not started to countervent until late after the implantation at some stage when the drug has reached a steady state.  It's well known that events commonly occur in the first month following the implantation of the device and much more commonly in the first week following the implantation of the device.
		In part, this was related to the trauma of device implantation and because of the destablizing effect of the repeated testing of defibrillation specials and so on.  It is certainly greater in patients who have had thoracotomies than it is for patients who have had nonthoracotomies leads implantations.
		But it is not only that because we can see that those patients who have shocks within the first week and the first month also have far more frequent recurrences of shocks as we notice here on the follow-up of this particular group of patients.  You can also see that atrial fibrillation and sinus tachycardia is relatively uncommon in this first one but it doubles and such like in the second one.  The likelihood of other arrhythmias entering the fray becomes more important.
		I think it is very critical for all of us to appreciate that the ICD is not a passive monitor in this circumstance.  You cannot simply put it in and have it log events and assume that it is doing nothing to influence the likelihood that those events will or will not occur.
		One example that you raised with me earlier of a bradycardia support pacing being an important potential modulator of the frequency of attacks or the likelihood or arrhythmic events is another possibility and it is a frequently observed possibility.  
		In this particular circumstance of ventricular tachycardia is present.  It has a cycle length of 360 milliseconds.  It attracts a burst of antitachycardia pacing from the device.  This is not successfully converting the patient to sinus rhythm.  You can see that another tachycardia of a different morphology is present.  
		We can see that the rate of this tachycardia is faster than the rate of this tachycardia, in this case alternating between 302.70 or thereabouts in its first few beats.  Not fast enough to now enter this category of less than 250 milliseconds that I was talking about, but there are certainly examples of that also.
		But the important point is that the antitachycardia pacing mode converts a relatively benign arrhythmia that could have terminated spontaneously perhaps, or could have responded to a shock into an arrhythmia which is faster.  It may be much more difficult to terminate by pacing or by a shock.  It might convert an endpoint that we have defined in terms of a specific rate into another endpoint within the trial.
		How often does this happen?   Well, a couple of small series, 42 patients, 14 with antitachycardia pacing off, 28 with it on.  Of those 15 patients used their antitachycardia pacing and nine of those 15 had an acceleration to fast ventricular tachycardia or ventricular fibrillation.  That's none out of 42 patients with a device, 28 of whom had antitachycardia pacing program on.
		There's another series of 176 episodes.  166 invoked antitachycardia pacing.  They were successful in the vast majority but in 11 it was not.  Five had simply failed, but in six there was an acceleration and defibrillation.  If our trial was looking at defibrillation as its endpoint, we would log an event here which might not have happened if the particular program for antitachycardia pacing had been made, for example, better such that it terminated the tachycardia.
		Here are three series in which both the acceleration rate per patient is identified and the acceleration rate per VT episode.  The acceleration per VT episode is gratifyingly pretty small, 46 percent.  But, of course, in our trials we are looking at the way in which patients respond to our trial.  You see that the figures are rather alarmingly high in terms of acceleration to faster rhythms so 20 to 43 percent in these three particular series.
		This is an example of where an arrhythmia which perhaps does not deserve an intervention by the device, which does not deserve logged as an endpoint or outcome parameter in our trial, is converted to an output event by antitachycardia pacing.  For example, here we have atrial fibrillation recognized by irregularity, lapidity, treated by two bursts of antitachycardia pacing.  By the first burst probably it has converted to a ventricular tachyrhythmia and it certainly has by the end of the second burst. 
		Another example on this slide shows a proarrhythmia which is induced by random pacing or inappropriate pacing by the bradycardia element of the ICD where a ventricular tachyrhythmia is the result.  Another proarrhythmic artifactual endpoint but not from our drug necessarily but from the device that supports the trial and monitors the trial.
		We have seen an example of noise causing the activation and intervention by device.  Here is a straight supraventricular tachycardia inducing an antitachycardia pacing event and the second such event and converting the supraventricular tachycardia with one specific morphology into what is now called the ventricular tachycardia with another cycle length and another morphology which in the end invites a shock and the shock in the end produces a rhythm not fully defined but with a rate less than the VT trigger rate.
		If we look in this series of 29 patients who suffered 194 tachycardias, there were 74 ventricular tachycardias but there were 24 episodes of atrial fibrillation.  There were 30 episodes of supraventricular tachycardia.  There were six electrical problems.  There were four oversensing of T waves.  
		There were three vents; that is, interventions by the device that could not be categorized.  We had a total of 194 tachycardias.  Of those 101 electrograms.  Then the 74 of these were due to ventricular tachycardia that would have interested us as being an endpoint of the trial.
		We did give a little consideration earlier to whether devices should be programmed in some standardized fashion.  I think my comment in small print at the bottom of the slide is probably correct, that it is unlikely that specific clinical trial programming will be ethically appropriate.  However, it might be possible to make certain changes suited to the trial and/or to obtain some uniformity of programming.  
		The classical way of programming a device might be to select certain zones of rate which might be further qualified by other possible diagnostic parameters like stability of rate, or regularity of rate, or by electrogram widths, or by sudden onset, and so on and so forth.  But essentially different zones of rate which different therapies were delivered.  
		From a clinical perspective the idea generally is to make a diagnosis quickly and activate an intervention as quickly as possible.
		From a trial design, of course, it might be best for us to have the device only respond to the fastest of arrhythmias that is closest to out definition of mortality and then to wait for a fairly long time to make increasingly sure that the arrhythmia was not going to be nonsustained.  That, of course, is ethnically quite inappropriate.  We're not going to get that far, but we might at least be able to consider reserving one of these zones perhaps at one of the highest rate cutoffs for an early discharge which we would use, for example, as a component in the composite of trial endpoint.
		We have to ask in the so-called ICD protected trials whether there is any substantial evidence that the ICD will actually protect.  It must be admitted that there is considerable evidence that it might not in some circumstances.  The therapy might increase the defibrillation threshold and render the device incapable of defibrillating the patient.  
		The therapy may render the tachyrhythmia incessant such that if it is terminated by the device, it will only promptly start again.  The therapy may provoke a new arrhythmia, an arrhythmia in this instance not amenable to the therapy that is being programmed in the device.
		I'm not talking now about the pharmaceutical therapy that we are testing.  Heart failure may change the substrate, may change the circumstances in which the tachycardia occurs, may change the implications of the tachycardia.  The therapy may prevent tachycardia recognition by making it slower by changing the slue rate of the electrograms, and so on and so forth.  
		The therapy may provoke much more frequent arrhythmias.  I think that we have to give a resounding no to the question that we can guarantee protection from proarrhythmia.  That is not to say that the majority of proarrhythmia might not be well suited for by the device.  There is a level of uncertainty in this.  
		This simply illustrates the point of the rise of the defibrillation threshold.  In this case, with amiodorone and with older generation of devices.  There is a lot of controlicy about this and probably today this isn't much of a quint but I think it's important that we recognize that antiarrhythmic drugs will change the characteristics of ventricular tachycardia and fibrillation which may make them either harder or easier for the device to deal with.
		We should also ask whether we can use ICD data to refine death classification.  This has been well explored by several groups of investigators.  We have heard part of this this morning from Dan Roden already.  This refers to an analysis made by Craig Pratt and published in 1996 in a cohort of patients with defibrillators.  
		It is very convenient if we have a situation in which we have at the time of death a sudden tachycardia which we could see on electrograms and we have this very convincing log, but it's not like that all the time.  The ICD could well have been buried with the patient.  The ICD memory could certainly have been erased before you can get at it.  The terminal event might not be recorded.  The ICD might have been programmed off and the arrhythmias that you do note may merely have been bystanders in a process that had nothing to do with the arrhythmia causing the death.
		Finally, I want to remind you that in coming to some composite endpoint we do have some, I think, very significant difficulties.  On the one hand, we have a range of mortalities that might be considered relevant to our trial.  By in large I think all-cause mortality is the most relevant for the trials from the point of view of the primary endpoint, although other classic occasions of mortality perhaps aided and abetted by the device in terms of its logging ability of electrograms could be useful in our mechanistic appreciation of the trial results.
		On the other hand, we also have an infinite variation of ICD endpoints that we can choose from to add to the composite.  The problem, however, is that the ICD endpoint may vastly outweigh the mortal endpoint.  On the other hand, what mortality signal there is, and it may be a real signal, may be adverse whereas the signal for the reduction in shocks may be favorable.  We have to wrestle with how to handle such a result.
		I think I cannot bring to you a list of any firm recommendations or conclusions about how to handle all of this.  I do think one of two points deserve further discussion.  I think all-cause mortality should be included in the primary composite endpoint of a defibrillated, protected, and monitored trial.  Also, we should consider the inclusion of a high rate ICD shock rate endpoint and this could be considered as contributing as a surrogate for mortality.
		Certainly if there is an issue of removing the patient from the trial and treating this as an endpoint rather than an outcome parameter, the rate should be as high as possible and our certainty that this is a death equivalent as sure as we can be.
		We obviously do not want to disregard interventions and logged events at lower heart rates.  On the other hand, we certainly do not wish to use them as endpoints in the trial because the ready removal of such patients from the trial will degrade the power of the trial in the sense that patients persisting in the trial will be too few to allow the mortal contribution to the endpoint to be fully appreciated or securely appreciated.
		I think ICD supported trials are valuable.  They are a neat idea.  They are not, however, as easy as we once thought they might be.  We have to bear in mind that our cozy, comfortable view that they may protect our patients from proarrhythmia in particular is not necessarily true.  Thank you.
		DR. PACKER:  Thank you very much, John.  Questions from the committee?  We may all be shocked.
		DR. THADANI:  I have a question.  Although your rate is important, there are some patients who tolerate the slow rate when they are supine.  That's where when they stand up they get syncope.  That might be again a tricky issue.  Your last comment is very valid because you don't want to lose those, you know, the guys that come in with a heart rate of 140 which is not yet threshold for 240.  Yet, they go to 150, they stand up and they pass out on you because the pressure just dropped by itself.
		DR. CAMM:  I fully understand that.
		DR. THADANI:  When you interrogate them in the supine position when they are sleeping, you may not count it.  That's a dilemma.
		DR. CAMM:  I think that the whole ballpark is full of dilemmas and I acknowledge that is very much one of them.
		DR. TEMPLE:  You didn't actually read the last item on your last slide.  What sort of evidence of safety did you have in mind?
		DR. CAMM:  I had in mind that you know something about whether the drug effects the defibrillation threshold in particular.  I think you need some information probably about what effect it will have on heart rate and how that will interact with the device.  Some idea of what it will do to the tachycardia rate, whether it will render fibrillation still identifiable by the devices that you use.
		I think the only one of those concepts that I think is firmly understood at the moment is the defibrillation threshold.  I don't know that there are a lot of drugs out there that do much adversely to defibrillation.  The one that we came to think of as potentially being a disaster in that regard is amiodorone.  Even that is controversial with biphasic shock devices of the new order.
		DR. TEMPLE:  Actually, that leads to my other question which is that among the trials that have been carried out so far, I guess they would be of your design III which is to use the effect from these patients as a predictor of how we do in patients who didn't have defibrillators.  Have there been any that appeared to adversely affect survival apart from whatever effects they had on surrogates for survival?
		DR. CAMM:  I'm not treated to the results, Bob, but Craig I know has seen two sets of results.  I haven't seen any.
		DR. TEMPLE:  Okay.  I guess dofetilide was something of a watch on survival and maybe that's because it --
		DR. CAMM:  Yes.  I'm aware of that sort of headline but I don't know the details.
		DR. DiMARCO:  John, can I ask you just two questions.  One, for your heart rate VT's or arrhythmias you said the first shock should be 35 Joules.  Do you think that's important or do you think you could just set it with a 10 Joule safety margin like we clinically did?
		DR. CAMM:  Oh, I have absolutely -- on the left could be any detail at all.  I didn't mean to offer that as a prescription.  On the right it was purely nominal.  I think, yes, you could -- I think we are going to be forced into using the devices in a clinical mode.  To stray very far from that I think would be inappropriate.  
		The question, however, is if we can seek some standardization within the trial, that I think is just about possible.  But to suggest any trial specific programmation such as let's wait only for fast arrhythmias and let's wait a long time to make sure that they are equivalent at death, I think is, of course, not possible.
		DR. DiMARCO:  Do you think you could program some type of duration, say, like in your lower VT zone could you set in a 30 second delay?
		DR. CAMM:  Yes.
		DR. DiMARCO:  Because one of the problems with ATP accelerating arrhythmias is it accelerates these things after a few beats.  I think that may be a major problem.  But if you programmed in a 30 second delay, some of them may still stop but it might well be a good way to do it.
		DR. CAMM:  Yes.  I think that would be very helpful if one could eliminate device interventions for unnecessary arrythmia by extending the duration of the lowest ends.
		DR. PACKER:  I just wanted to clarify your response to John's question.  You could if you decide to only use very high rate VT/VF program all devices only to recognize that or leave the programming of the device to the investigator and only count those.
		DR. CAMM:  Yes.
		DR. PACKER:  The former has more appeal than the latter, but the former is unethical?
		DR. CAMM:  Yes.  I think it is.  That's the problem.
		DR. PACKER:  The reason it is unethical is because it just wouldn't be accepted by the community or because you would genuinely put people at risk if you did that?
		DR. CAMM:  Well, I think one could genuinely put people at risk by allowing the ventricular tachyarrthymias to degenerate to ventricular fibrillation to increase, for example, the ischemic insult consequent upon the fast arrhythmia and so on.  I think there would be many voices raised against doing that.  I agree, it's very attractive to do that.  
		If you come to the other side and say, well, let's just count them, that's fine provided you don't use the time to the first event of that nature as a reason to abandon the patient in the trial.  Once you do that because the numbers shrink quickly as the trial goes by and your opportunity to count more significant events whether it's farce effective arrhythmia or death becomes less and less secure.
		DR. PACKER:  And you could ethnically say that although it might be uncomfortable for the patient to undergo these interventions that, in fact, you could make the statement that the patient remains in the trial, has all of their data collected as long as they are alive regardless of what happens even if they experience a high rate VT/VF.
		DR. CAMM:  Indeed, you can.  Yes.  I would like to see that happen but it's inevitable, I think, in many of those instances the trial medication may be abandoned and the new medication introduced.  Not necessarily, of course, but it would happen in a logical fashion.
		DR. THADANI:  Another issue comes up, sir.  You have very early incidents of 25 percent within a week of inserting ICD.  Yet, unless patients are having recurring VT, that's really unusual.  You say it could be the device which is doing it.  Is it true also with the percutaneous devices?
		DR. CAMM:  It's in part true but it's not as big an effect as the effect that I've shown you on that slide.  I showed the effect both in terms of the events during the first month and then to show that there was more do it than simply cracking the chest or causing destablization from defibrillation testing.  		I showed you that if you followed those patients up in the months that followed, their event rate was very much greater.  My implication was that we want to recruit patients as early as possible following the implantation of the device in order to maximize the opportunity to see the drug effect.  
		DR. THADANI:  Although it could be artifactual because your discharge rate is so high, you might to wait for two weeks before you start the trial.
		DR. CAMM:  Yes.  If we still had the situation which I demonstrated on the slide.  I was seeking to explain that was no longer the case with nonthoracotomies leads.
		DR. TEMPLE:  I guess one implication of one of your suggestions is that if you only counted events that occurred after a very rapid rate as mortality endpoints, you could have a hierarchical series of endpoints where perhaps the main one being actual data plus these rapid event rates and that would be sort of a lower estimate of your benefit.  Then you could look at the others in addition and observe whatever skepticism one wanted associated with those endpoints.
		DR. CAMM:  That's very much the position that I take.
		DR. PACKER:  Okay.  Why don't we do this.  Today is different than most days because there is the possibility of a continued interaction and, in fact, there is the desire for a continued interaction between the presenters and the committee during the A&A which would not necessarily be typical for the sponsor's presentation.  I get the impression that Jeremy is going to try to summarize.  
		What we'll do is take a break now for 10 or 15 minutes, bring Jeremy back and use Jeremy's presentation as a segue into the questions and encourage all of the presenters to help us through the questions and to attempt to provide some answers.  We'll take a 10, 15 minute break.
		(Whereupon, at 11:10 a.m. a recess until 11:29 a.m.)
		DR. PACKER:  If we can have everyone take their seats.  We are getting really depressed up here.
		DR. RUSKIN:  Well, I would like to thank Ray Lipicky and Bob Fenichel and Craig Pratt for inviting me to participate.  
		Having watched this field since the early '80s and having expected a somewhat different outcome to these trials, not the results of the trials but their interpretability, I am humbled by everybody's experience.  I am not going to answer the questions obviously but I'll put my head on the block up front I suppose as a way of avoiding repeating what everybody else has said which is in large part what I'll end up doing.  
		Let me just say that I think at the present time I can't imagine a situation in which an ICD trial alone will constitute the basis for a sudden death or arrhythmic death claim.  I think that it will end up being part of a package of studies that may be useful in a number of respects.  Unlike what was hoped perhaps 10 or 15 years ago, I don't see these trials as standing alone as a substitute for a mortality trial.
		I'm going to just make some general comments about the devices and some of the issues that have been raised by previous speakers and then spend one minute talking a bit about future technology because if you think it's complicated now, wait until you see what we're going to be dealing with in about two or three years.
		The number of devices being implanted worldwide is really quite extraordinary.  It will exceed 70,000 worldwide in 1999 and will exceed 100,000 new implants by 2002.  The population of patients with ICD's is becoming quite large and they are accessible.  Certainly in addition to gaining protection from these devices, they serve as a useful resource in terms of clinical research.  The question is how to do that safely, ethically, and productively.
		DR. PACKER:  Jeremy, was that cumulative or annual?
		DR. RUSKIN:  No.  Those are new implants.
		DR. PACKER:  Those are new implants.
		DR. RUSKIN:  New implants.  In excess of 70,000 worldwide this year and in excess of 100,000 worldwide in 2002.
		As has been alluded to by several people including Udho, who made this point quite early on, the use of ICD's is largely dependent upon substrate so that since we're using endpoints here of shocks for arrhythmias, knowing which patients are entered into the trials becomes critically important.  
		These are old data from our cardiac arrest survivor series in which you see the frequency of ICD shocks for VT or VF as a function of left ventricular ejection fraction.  You can see that patients with impaired ventricular function use their ICD's for appropriate reasons twice as often as patients with well preserved LV function.  In fact, most of the survival benefit is in this subset.  We also found out from uncontrolled observations years ago and those observations have been confirmed by the AVID subset analyses based on EF at 40 or 35.
		This is important obviously in terms of patient selection because when you do small studies, it's entirely possible that one could have an unbalanced randomization.  I would be in favor when the trials are relatively small in size of limiting enlargement for this subset of patients although one could argue that point.
		The other is that the presenting arrhythmia is a very powerful determinative of ICD utilization.  Here these are data from the AVID trial showing you ICD shock rates, cumulative shock rates at three months, one year, two and three years as a function of the presenting arrhythmia, the clinical arrhythmia.
		You can see that people with ventricular tachycardia use their devices far more frequently than people in whom VF is the primary or initial presenting arrhythmia.  Again, this may be very important in small trials with regard to patient selection.
		So in selecting subsets of patients for drug trials, the etiology of the heart disease, and in particular the degree of LV dysfunction I think are very important.  The ICD systems, which have also been discussed by several people, are important.  To the extent to which these can be used in a uniform way, the trials will be easier to interpret.  
		First and foremost it is important to know now that about 30 percent of ICD's being implanted worldwide are dual chamber devices.  Although I have some concerns about overuse of these devices, when they are in the fact is that they provide a much higher level of discriminatory power with regard to separating supraventricular from ventricular arrhythmias than do single chamber devices.
		The detection algorithms differ among different devices.  Again, their sensitivity and specificity varies.  The lead configuration that is used to looking at electrograms, and John DiMarco got at this question a little earlier, can also be important because the earlier devices had only bipolar local electrograms from the rate sensing lead to look at.  
		Some of the newer devices allow you to use far field signals between a right ventricular coil or a right atrial coil and an active pulse generator electrode that gives you something that looks a lot more like a surface ECG and one's ability to discriminate supraventricular from ventricular arrhythmias may differ.
		In addition, the experience of the investigator in programming these devices may have an important impact on shock rates.
		What about endpoints?  Well, I agree very much with what John Camm said in his talk which is that I think one has to use a broad range of endpoints here and that one cannot simply rely on a single gold standard.  Time to first shock I don't think is going to be an acceptable or adequate surrogate for anything.  
		In using these devices to test drugs, it's going to be important to look at a whole host of variables including all ICD discharges; shocks for ventricular fibrillation, or fast VT as John detailed for you; antitachycardia pacing or shocks for slower VT; atrial fibrillation events, something that we are getting much better at diagnosing particularly with dual chamber systems; the whole issue of potential proarrhythmic effect which is a very complex issue.  I'll come back to it in a minute; and defibrillation energy requirements.
		This is a real life example of one of the ways in which you can be led astray by looking just at shock rates.  These are composite Kaplan Meier curves from two different mortality trials, both of them primary prevention trials in which the ICD was tested against conventional therapy to determine whether it would reduce all-cause mortality in two high-risk subsets of patients.  
		The first trial is the MADIT trial which, as you know, comprised patients with LV dysfunction and nonsustained ventricular tachycardia who had inducible sustained VT at ET study that was not suppressed with procainamide.  They were randomized either to an ICD or to conventional therapy which was about 70 percent of the time amiodorone.  This trial was markedly positive with a 54 percent reduction in all-cause mortality in the defibrillated group at about 18 months.  This was a sequential design and the study was rather small by the time that the boundary was crossed.
		This is another trial that was designed for prophylaxis and it's the CABG patch trial.  It was carried out in patients with coronary artery disease and comparable degrees of LV dysfunction to the MADIT population.  This was a group of EF less than 36 percent who also had a positive signal average ECG.  I think they required frequent VPP's on Holter.  
		This was a group thought to be a very high risk for sudden death and half of them got ICD's and the other half didn't.  You can see that the mortality curves here were absolutely superimposable.  In fact, the mortality rate in both groups was fairly close to what was seen in the ICD population in MADIT.
		Yet, if you look at the shock rates in the two studies, you see a very different picture and that is they look the same.  These are ICD shock rates in MADIT and ICD shock rates in CABG patch.  At a year you can see that 50 percent of patients in both trials had been treated by the defibrillator.
		Now, obviously the controlled group in these studies answers the question with regard to a mortality benefit.  But if you had used these two populations, the ICD recipients in these two populations to carry out a drug study, you might have been very seriously mislead.  For example, in the MADIT trial a reduction in shock rate.  The shock rate here, in fact, reflected a real endpoint that translated into a mortality benefit.  So if a drug reduced that shock rate significantly, one might have been close to being on target in terms of a clinically important effect.
		In CABG patch you saw that there was no difference between the drug treated group and the device treated group; that is, conventional therapy and device.  Yet, there was a very high shock rate in the device population.  
		A reduction in shock rate in this group couldn't have offered any mortality benefit.  Not only would you have missed the target, you would have missed the barn all together in this particular situation.
		Much of this is dealt with by having intracardiac electrograms and knowing a lot about the circumstances in which the shocks occur.  I think the important point is that we have to be very careful about using time defer shock as a soul method of evaluating efficacy.
		What about all-cause mortality?  Well, this is, I think, a critical issue.  It was raised by Milton and also by Bob Temple.  I think the critical points have been made, and that is that it is possible to die from a variety of mechanisms.  We are dealing with competing risks all the time.  Not only in this population but in all populations with heart disease.
		The modes of death, or the mechanisms of death in people with ICD's don't only involve ventricular tachycardia fibrillation but they may involve ischemia, heart failure death, bradyarrhythmias, and EM dissociation, and perhaps proarrhythmia.  
		It's not difficult to imagine a circumstance in which a composite endpoint of ICD shocks or time defer shock plus mortality might look very favorable for a drug that had an antiarrhythmic effect under some circumstances and reduced the frequency of shocks, but increased mortality by this mechanism or this mechanism or this mechanism.
		I think both Bob and Milton got at this point, and that is you could miss a very significant adverse effect of the drug with that kind of design.
		Clearly one has to look very closely at mortality and perhaps both in a composite way and separately to get a clear sense of whether or not you could be reassured by what a drug is doing or whether you ought to be worried about it.
		What about proarrhythmia?  Well, I think this issue was addressed very incisively by John Camm.  I just want to offer one slightly different perspective, or perhaps a real life example, in which one might have gotten into serious trouble using ICD's to assess the potential adverse effects of an anti arrhythmic drug.  
		It gets to the question of ethics.  The issue is is it ethical to use devices to evaluate drugs for proarrhythmia?  Now, it might be fine if the drug is an antihistamine.  But I'm not sure that it's always fine if the drug is really a potent sodium channel blocker or does other things that may have consequences that the device cannot deal with.  
		These are data from the CAST trial.  I suspect these are familiar to most people in the room.  Let me just take you through some of it to remind you of the fact that if you look at nonfatal ischemic events in the past.  There were far fewer on active drug than there were on placebo.
		Interestingly, and as you all know, there were far more sudden cardiac deaths and cardiac arrests on active drugs than there were on placebo.  There were also quite a few more nonsudden deaths and arrests.  That is, fatal myocardial infarction or myocardial infarction with cariogenic shock on drug than there were on placebo.  
		In fact, if you add these columns up you come up with almost an identical number suggesting that these drugs were converting nonfatal ischemic events to either fatal arrhythmic events or fatal pump dysfunction events.  If you did this study in an ICD population, it is possible, but not known with certainty that the ICD might have saved these patients.  It is very unlikely that it would have done anything for these patients.  
		In fact, one third of the excess mortality in CAST was nonarrhythmic.  In that circumstance the device would not have been protected.  It's not at all clear to me that CAST would have been an ethical trial were we to do it today in an ICD population.
		What about cost and quality of life?  In the AVID trial it is clear that the ICD is a very expensive therapy.  Certainly a lot more expensive than drug therapy.  It's a lot more effective, too, but there is a price to be paid for it.  We all know that patients with ICD's get rehospitalized for a variety of reasons, device related and sometimes drug related.  
		In this particular instance what you are looking at is time to rehospitalization in AVID.  You can see that there is a statistically significant increase in hospitalization rate in the ICD group compared to the antiarrhythmic drug group.  
		Well, would an intervention that improved this so that it moved the ICD curve down to here be useful separate and apart from a mortality benefit?  The answer is sure, it might be if it reduced morbidity and cut costs and did so with an acceptable mortality profile.  That might be another reason perhaps to look for an indication.  This is very similar to what you saw in one of John Camm's slides.  		This is an example of a very problematic clinical situation in which a patient with atrial fibrillation has a rapid ventricular response that exceeds the rate cutoff of the device.  This is detected as VT.  There is a burst of pacing here.  It converts the atrial fibrillation to ventricular tachycardia, delivers another burst of pacing which is ineffective.  If VT continues, it is redetected.  Another burst of pacing, the VT continues, and we then get to an initial shock which converts the patient back to atrial fibrillation.  This is normal device function.  It's a clinical problem that happens and it is one in which perhaps an antiarrhythmic is one of the commonest indications for antiarrhythmic drug therapy.  If you had a drug which in this situation completely prevented this sequence of events, that would be a real benefit provided it did so without any evidence of significant proarrhythmia or an adverse effect on mortality.
		I think everybody has agreed that antiarrhythmic drugs that can prevent this kind of event and do so reliably are important agents to add to our armamentarium.  This endpoint is obviously a very useful endpoint.  The difficulty is knowing how often we really are measuring this as opposed to other things.  I think other speakers have addressed that at great length.
		Just a couple of words about lesser endpoints.  We've talked a lot about monomorphic ventricular tachycardia and antitachycardia pacing for that problem.  That is a lesser painless intervention for perhaps a less significant endpoint.
		This is an example of a patient who was in sinus rhythm and had a very short burst of ventricular tachycardia.  This is a device that has a hair trigger for responding to VT within about 10 or 12 beats.  There's a burst of pacing and the patient's rhythm reverts to sinus.
		This event in this particular patient occurs 10 to 30 times a month.  This is always the response.  Does a drug that prevents this constitute a real benefit?  I don't know.  It certainly doesn't to this patient that I can see but there are circumstances in which it might to patients in whom the ATP is not highly effective.  
		I think again we have to be very cautious about evaluating the impact of drugs on lesser events and knowing the clinical settings in which they occur.  I think a drug that only improved a situation in this kind of patient and did not have a similarly favorable effect on fast VT and VF would not hold a lot of interest.
		The other point that I want to make is that when you use ADP as an endpoint in your trials, you really have to be very careful about looking at the distribution of events over time and over patients because we all have patients who do this 30 times a month and there are some people who do it 300 times a month.  If you have a drug that shuts off those 300 events in a couple of patients, it can have a profoundly favorable appearance in a trial but may turn out not to be very clinically relevant in a broad population of patients.  Again, patient selection and distribution of events are very important and they complicate this enormously.
		I think that at least for me the limitations of ICD endpoints are that clearly we are asking them to be a surrogate for arrhythmic death.  I think right now they probably can't be.  The reasons for that have been elucidated clearly by other speakers.
		The rate cutoff of 240 beats per minute I think is as logical as any one that I can think of and it makes sense to use.  The truth is that it remains arbitrary and it may overestimate or underestimate the benefit of devices.
		Finally, drug efficacy may vary with substrates so, again, we need to know what populations we're talking about.  Most important, I think, the duration of drug benefit may differ significantly from that of the ICD.  If we use only time to first shock, we may be very seriously misled.
		I think it's important that patients not be censored and dropped from studies and that they be followed for as long as possible.  Certainly if there is any hope of using these kinds of studies to substitute from mortality trials, that is absolutely necessary because even a 12-month study is very, very short in the life of a patient who ought to be around for five or 10 years.  Those are patients in whom the substrate is changing.  
		The one thing about ICD's is they don't care very much about changes in substrate.  They tend usually to keep working until end stage heart failure has developed.  But drugs do change with changing substrates.  If you add a little ischemia or some ventricular dilatation or more hypertrophy, a drug may go from antiarrhythmic to proarrhythmic.  A drug that is beneficial at three months may not be beneficial at two years.
		I am finished with my general comments.  I want to just say a few words about where the future of this technology is heading because I think it holds a lot of promise.  But also perhaps the makings of a lot more conferences like this with perhaps fewer answers about appropriate endpoints.
		The reason that we're able to do the kinds of studies that we are now doing with ICD's is that patients can get small pectoral systems with simple lead systems that can be implanted in the EP labs rather than in operating rooms.  The reason for that primarily are changes in capacitor size that have allowed manufacturers to create their own capacitors and downsize devices tremendously.
		There will be in the near future ceramic capacitors that have much higher capacity for energy storage than aluminum capacitors and that will cut device size probably by another 50 percent over the next five to 10 years allowing not only smaller devices but inclusion of other technologies into pectoral systems that will dramatically enhance the complexity and the diagnostic and therapeutic power of these systems.  And that's really the only comment I wanted to make about this.
		The other area of great interest and excitement is that of biosensors; that is, physiologic sensors that will give us tremendous amounts of diagnostic information primarily, I think, with regard to hemodynamics, but also electrical information and QT interval being one of those that will be used to assess patient status and will be very powerful tools for evaluating the impact of the variety of pharmacologic interventions, not necessarily antiarrhythmic.
		We are now dealing with dual chamber pacing almost as a rule, as you know, and dual chamber defibrillators comprise about 30 percent of ICD implants worldwide and that number is increasing.  Pacing is now involving to three and four chamber pacing in patients with heart failure, although mortality benefit is clearly not established there.
		We have, or will have very shortly, access to hemodynamic sensors and perhaps in the future metabolic sensors.  The technology for incorporating drug delivery systems within these implantable devices is already here.  What isn't here is a logical way to use them, or the knowledge of which drugs to use and under what circumstances.  But the technology to do it is already here.
		The areas in which these devices are likely to be applied include not only the treatment of ventriculary arrhythmias but certainly the treatment of atrial fibrillation.  This has already happened with atrial defibrillators and a variety of pacing technologies that are being used to attempt to prevent atrial fibrillation.  They will certainly be used in congestive heart failure and in ischemia as well.  
		I think the one area perhaps over the next couple of years where you will see the most data will be in this combined population.  Most of the patients with congestive heart failure, but also those with AF.  		It is important to emphasize that these two are fellow travelers and this is a unique opportunity, I think, to get information about both of these problems with regard both to understanding the physiology better, understanding pharmacological inventions better, and providing therapies that may actually prolong life.  
		What is happening is that you will, in fact within a year, be seeing merging of ICD and pacemaker platforms so that what we will be using will be arrhythmia controlled devices.  Not pacemakers or defibrillator, but rather arrhythmia controlled devices capable of three or four chamber pacing and dual chamber defibrillation equipped with very sophisticated long life physiologic sensors and perhaps three or four years down the pike with drug infusion systems.  
		The diagnostic power of these systems is extraordinary and they will provide us with not just intracardiac electrograms but hemodynamic data as well presented in a format that will allow us to follow the status of patients over days to weeks or months.  These devices will communicate seamlessly with patients and physicians both by warning systems and headless telemetric systems.  So we will have access to an extraordinary amount of not only therapeutic power, but I think perhaps equally exciting diagnostic power.  
		Certainly the heart failure experts on this panel I'm sure know more about this than I do.  But certainly the opportunity to evaluate the impact of pharmacologic interventions on the course of congestive heart failure will be a major aspect of these technologies in the future.  I think it will begin to extend to other areas as well.  
		This discussion about endpoints perhaps couldn't come too soon.  It will not solve any problems or provide any gold standards.  If there is one thing I can tell you with certainty, this is just the beginning.
		DR. TEMPLE:  I presume they are going to have satellite linkages with appropriate consultants.
		DR. PACKER:  I can only comment that there used to be a time when something was wrong with your automobile, you would go to a mechanic who would use his or her judgment to diagnose the problem.  Now your car is hooked up to a device that reads the computer in the automobile and makes all sorts of diagnostic evaluations similar to the pattern that you have described here.  
		The problem, of course, is sometimes the major reason for visiting the mechanic is that the computer isn't working very well.  I happen to have such an automobile and I spend more time trying to correct the computer communications than fixing any real problem with my automobile.
		DR. RUSKIN:  Well, it's certainly an appropriate caution.  I think one of the remarkable things about these technologies has been the reliability of the systems.  The level of accuracy and the robustness of the algorithms and the precision with which the microprocessors function is really nothing short of dazzling.
		The major weak links in these systems have been the lead systems; the lead factors and insulation breaks and so on.  The fact is that technology, I think, is a lot smarter than we the physicians who are using it right now.  That's my take on it.  I think we are the ones who probably need the tuneups, not the devices.
		DR. PACKER:  You can just imagine that you come in and interrogate the device and you tell the patient, "You know, you don't know this but you had an episode of septic shock four weeks ago.  It was asymptomatic and didn't require therapy just in case you wanted to know."
		DR. RUSKIN:  Well, I think in terms of the ability to use physiologic sensors, Milt, you may well be a decade or less from now telling patients that they were close to having pulmonary edema and that you aborted that based on information that you got or treated long before they ever had any symptoms.  That's entirely possible if not probable.
		DR. TEMPLE:  That's the implanted dobutamine infusion, I suppose.
		DR. RUSKIN:  Well, I was just talking about diagnostics, Bob.  I hadn't gone that far.
		DR. TEMPLE:  That's the next group.
		DR. RUSKIN:  I was just thinking about a change in the lasix prescription.
		DR. PACKER:  Okay.  Any specific questions to Jeremy?
		DR. TEMPLE:  The study that basically can never be done without the implanted defibrillator, I think, is one in which people have a history of life-threatening arrhythmias.  You can do studies on people who are at risk but it has become very difficult to do and always was difficult to do, the so-called life-threatening arrhythmia trial.  We had a lot of drugs labeled without ever having a proper trial in those settings.
		I guess one question is even though no one wants to make final judgments is how plausible is a trial in that population?  I guess one question is who would get the drug instead of the defibrillator.  Leaving that question aside, if one took as an endpoint death with rates of over 240, how plausible does that seem for that special case which can't really be studied any other way?  You can do comparative trials.  That seems like the one way you can actually get a treatment/no treatment answer that's safe enough to do.
		DR. RUSKIN:  I think that's right.  I think that's the most logical conclusion from today's discussion is what you've articulated.  I think that the hope that those trials would actually substitute for mortality trials and allow one to perhaps approve a drug for a reduction in arrhythmic death is not going to happen.  But in terms of reducing the frequency of life-threatening ventricular arrhythmias in an appropriate population, I think what you have articulated is the right way to do that.
		DR. TEMPLE:  So you don't think preventing rates over 240 reflects a -- well, you obviously do think it reflects a likely survival advantage but that would not lead you to think one could claim that?
		DR. RUSKIN:  Yes.  
		DR. PACKER:  Can we just have clarification of that, Jeremy?  Again, if a sponsor were -- I just want to hit this on the head.  If a sponsor were to come in with a trial with high-risk patients, say, sudden death survivors who had all received a device, the drug suppressed the combined endpoint of a debt and high rate VT/VF over 240 with 90 percent of the events being nonfatal as opposed to deaths, and the P value was robust and the data were internally consistent and no serious questions were raised about whether that was actually what was found in the trial, you would not feel comfortable -- I hope I'm phrasing this correctly -- you would not feel comfortable indicating that represented a drug benefit?  
		DR. RUSKIN:  No.  I would be very comfortable saying it represented a drug benefit.  What I would be uncomfortable saying is that you could label this drug as reducing mortality in patients with life-threatening ventriculary arrhythmias.
		DR. PACKER:  I see.
		DR. DiMARCO:  The labelling would only apply to people with defibrillators.  And, you know, in my mind you would have to have the two groups where you would have significant better survival in the drug plus defibrillator group and ICD.  That survival would have to be good enough that you could then anticipate a drug only study.  Right now the evidence is the defibrillator beats every drug it's been looked at against.  You wouldn't want a truly life-threatening arrhythmias a drug only recommendation.
		DR. PACKER:  So then in the example that we just spoke about, one, if I understand correctly, you would not provide a mortality claim for the drug.  That's one.  You might provide a drug benefit claim for the drug but only in conjunction with the use of a device.  John, that's the modifier that you added.
		DR. DiMARCO:  In this particular situation.
		DR. PACKER:  Of that were the case, one would almost be implying that the drug didn't have so much an impact on the disease process, although it may have, but it was really used as a way of suppressing a function of the device which is definitely unpleasant and potentially dangerous.  
		I don't want to over read this but I'm trying to figure out whether the nature of the claim because it would be put in on people already receiving an ICD.  John, I take your point very seriously.  You are calling this adjunctive therapy, (1) because of the patient population studied, and (2) because of the need for adjunctive therapy in the first place.
		The patient benefit is more likely to be described as an ICD adjunct.  That could be just the prevention of symptomatic shocks.  That would be the primary thrust of the claim as opposed to a claim that was more linked to the prevention of a process related to the underlying disease.  I hope I'm describing that accurately.
		DR. RUSKIN:  I think it would have to be taken in the context of the whole picture of the drug.  For example, if it was a drug that had a salutory effect on ATP events as well so that it reduced the frequency of slower monomorphic VT but had this very favorable  effect that you described on fast VT and VF and the mortality went in the right direction, then I think you could say a lot more about the drug.  
		For example, you might use it with a lot more comfort in patients with slower VT's in whom you don't want to use a device.  Or you might say to a patient who doesn't want a defibrillator that, "This drug has a extraordinary profile.  
		It doesn't look quite as good as a defibrillator but it's the best pharmacologic agent we've got and these are the data."  I take a lot of comfort in that.  The question I think where it gets really dicey is where you start to claim equivalence to a defibrillator in terms of prevention or death.  That gets very difficult.  
		DR. PACKER:  My understanding is that the design we're talking about would never allow you to get there.
		DR. RUSKIN:  Right.  Never.  I don't think it would allow you to make a mortality claim.  The other area where it might be helpful would be a drug that had some efficacy and atrial fibrillation.  If you saw those kind of data and you had some efficacy in AF, that would be a wonderful surplus.
		DR. TEMPLE:  There are a number of circumstances.  My presumption is not everybody wants an implanted device.  One doesn't like to think about cost in this but it seems likely that everybody who's at risk of sudden death is going to actually get one.  One possible claim that someone might seek is for use in patients at risk of sudden death to be defined when they don't want, can't tolerate, whatever, a defibrillator.  That raises the question of whether this kind of data would support that kind of use and whether, you said, if the prevented answer is death is sort of a minor consideration in some ways.
		Of course, the other implication is that in parts of the world where defibrillators are not everybody's expectation, these kind of data could be considered pretty important.  You would still say that until you actually have shown mortality improvement, you would still be uncomfortable actually saying anything about it even though one might expect a favorable result.
		DR. PACKER:  So that the only claim that they would get would be a claim for the patient population studied as opposed to the extrapolated claim?
		DR. TEMPLE:  No.  I didn't hear that.  For example, maybe you shouldn't say this specifically.  What about for people who don't want an implanted defibrillator?  Wouldn't this be a basis for a claimed -- I mean, would this or would this not be a basis for saying this is a reasonable thing to do in people at risk of sudden death because of whoever can't get a defibrillator?
		DR. RUSKIN:  Yes.  I think it would with the kind of uniformly positive profile that Milton described.  I think it would.
		DR. RODEN:  But if you had a drug with that kind of uniformly positive profile in an ICD trial, the logical next step for a sponsor would be to go ahead and do the known ICD based trial.  They would be comfortable with that in certain parts of the world perhaps or in certain other populations to do that.  That would, it would seem to me, provide very important data to support such a trial.
		DR. TEMPLE:  That's a tricky question though.  For example, it's going to be very hard to beat the ICD and it's going to be hard to even match it.  If you do a direct comparison you'll lose. 
		DR. PACKER:  He's not saying do a direct comparison.  
		DR. TEMPLE:  You do the placebo control.
		DR. PACKER:  John, you can step up and say anything at any point in time because this is really the purpose.  Can you just clarify this?  If a sponsor intending to do a large scale trial in a geographical area in which ICD is not uniformly available or utilized says based on a uniformly positive profile in an ICD trial -- I want to make it as clean as possible because clearly most databases will not be as clean as this -- would you allow the claim that in addition to an adjunct to ICD therapy, which is what John was saying before, that the drug could be used where an ICD was deemed to be undesirable or not feasible?
		DR. RUSKIN:  Yes.  I think I would.
		DR. FENICHEL:  Well, there is a problem here in sequence it seems to me.  If the intended claim is that the drug be used in people who don't want ICD's, and one believes for various reasons that have been described that efficacy in that population can only be uncertainly derived from a trial in the ICD population, then it might be not only incompletely effective but, in fact, unwise for a sponsor to begin with the credibility increasing, although not establishing effort of the ICD trial because once there's a very strong impression that the drug will indeed be effective in this ICD rejecting population, if that impression may be so strong, although not perfect, that trial is no longer ethical.  
		Necessary but no longer ethical.  The sponsor might have shot himself in the foot and it may be if that is, indeed, the intended target population, the thing to do is to go after it.
		In the case of an unproved therapy in a population rejecting ICD's abenicio, there's no ethical problem in doing a placebo controlled trial.
		DR. PACKER:  Yes, Bob.
		DR. TEMPLE:  Well, there could be.  The history with these drugs is that a lot of them make arrhythmias worse.  This would provide some assurance that the drug you are putting in the trial didn't do that.  I guess maybe I didn't understand what Jeremy was saying.  
		What I was asking was wouldn't the data we just described, as Milton said, bullet proof, perfect, wonderful data showing a reduction in unequivocally nasty arrhythmic events that are reversed by the defibrillator and a satisfactory endpoint on death plus those events, could that support use in a population of this drug in a population of patients who didn't have implanted defibrillators and couldn't get them because that's the best therapy without further data?
		DR. TEMPLE:  Now, that might or might not lead to a survival claim but that might still support that use.  When this all turned up 10 or 15 years ago, that was clearly the plan.  We thought this would be a way to pass drugs for life-threatening arrhythmias in an ethical way that would lead to a conclusion that would say, yes, it's a good thing without doing the placebo controlled trial that everybody thought would never be done and, in fact, never was done in people with life-threatening arrhythmias.
		DR. PACKER:  Bob, could I just take the offer to your question and ask Jeremy to clarify an answer to a previous question.  
		DR. RUSKIN:  I feel like I'm back on the committee.
		DR. PACKER:  You said you wouldn't give the mortality claim but you would describe a drug benefit.  Can you tell us what the wording would sound like?  Because if you could tell us what the wording would sound like, it would then help Bob get from where he is to where he wants to go.  Can you take a stab at it?
		DR. RUSKIN:  I'm not sure that I can give you labeling right now but let me see if I can clarify my response a bit.  Bob asked a very specific question about whether or not one could justifiably extend the results of this perfect looking drug within an ICD trial to benefit in the same population who would not be candidates for the defibrillator for whatever reason.  
		I think you could word it like that with appropriate caveats.  One of the caveats would be that equivalence or comparable degree of mortality protection to the ICD has not been demonstrated with this drug.  Essentially every other element that you need in place for protection is there.  That is, there is reduction in life-threatening events.  There is reduction in slower VT events.  There's no evidence of proarrhythmia.  There's a favorable mortality trend.  All of those things fit and atrial fibrillation goes away.
		That would be the context in which I would describe.  I can't give you the precise wording.  I think it would have to contain a caveat, though, that this study had not established the drug as a substitute for the defibrillator in all candidates, but that's not what I heard Bob say.
		DR. TEMPLE:  No.  Right.  It would just be that, well, there is more than one flavor of this.  It could say that it looks like it's useful and prevents the nasty events. It could also go further and say this appears likely to correspond to a survival benefit but that has not been specifically tested.  Don't think for a minute this is as good as having your own laboratory.
		DR. FENICHEL:  Yes.  Well, this is a classic situation of a second line therapy.  Isn't it?  At best it would come out synthesizing all the data which says that we never found anything as good as ICD.  It says.  "Look, if you can't take ICD's, if you re allergic to devices or if you don't want people cutting you or whatever your reason, or you can't afford it or whatever, this is a second line therapy."
		DR. PACKER:  I'm still confused.  Is the indication -- I understand that, Jeremy, you don't necessarily want to go there but I still want to know is the nonmortality component of the indication the suppression of the arrhythmia that triggered the device or the suppression of the operation of the device?
		DR. RUSKIN:  It's the former.
		DR. PACKER:  It's the former.  
		DR. DiMARCO:  Don't we already have sort of in a compressed form the indication?  If you look at intravenous amiodorone my interpretation, or my memory of the data is it decreased the frequency of arrhythmia events in several different measures, but the long-term survival at whatever measure you looked at was unaffected so that it was thought that it was clinically reasonable to decrease the frequency of events even though competing therapies and the disease process didn't affect overall mortality or didn't show a change in mortality.
		DR. TEMPLE:  That's true.  The only life-threatening arrhythmia setting where there has ever been any study is short term while people are monitored so they didn't have any planted defibrillator but they had defibrillator access from outside.  There aren't any long-term studies of that kind.  There are high-risk patients but not people who are known to have frequent nasty arrhythmias.
		Yes, you are right.  We concluded there it was useful to suppress the events.  The hope would be in implanted defibrillators that you could get closer to actually establishing mortality benefit because you're not in the laboratory so you would really be preventing things that are reasonable surrogates for that.
		DR. PACKER:  Okay.  Please, I would like to invite all of the guests to jump up at anytime.  Many of the issues that we have just been discussing in the last few minutes, in fact, are dealt with in questions No. 1 and 2.  I think we can reach consensus on one and two very quickly.  In fact, my sense is that we could probably go through all the questions fairly rapidly because there has been a discussion on all the issues except for No. 7.  
		The first question is to support approval for symptomatic claim that a new drug therapy reduces the frequency of ICD shocks.  It's not just the frequency of ICD shocks that Jeremy has clarified.  It's the suppression of the arrhythmia that the ICD shocks represent.
		DR. FENICHEL:  No. No.  Wait.  Because that's the mortality, the required mortality claim.  The symptomatic claim is the patients feel better and they can have lots and lots of arrhythmias not suppressed or even more arrhythmias presumably.  This is a pure symptom claim for patients who are walking around with one of these boxes.
		DR. PACKER:  As I understand it, there are three levels of claims that are being discussed.  One is a mortality claim, self-evident.  Two is a suppression of lethal arrhythmias which is not equivalent to a mortality claim but is considered to be clinically very relevant and represents a prevention of IDC shock which has a benefit other than through prevention of a uncomfortable symptomatic event.  
		Then there is the prevention of the ICD shock which itself can be viewed as benefit because the shock delivered by the device is unpleasant.  Am I correct, sir?
		DR. FENICHEL:  That's right.  This question deliberately dealt with the last one.
		DR. PACKER:  It's only the last one.
		DR. FENICHEL:  Patients feel better because they're not getting zapped.
		DR. PACKER:  Okay.  So if a sponsor were to come in -- as I understand now question 1 which I didn't understand before -- could a sponsor come in I suppose is really what the question is.  What would be the basis for a sponsor's claim only for level three?  That is, for the suppression of ICD shocks?  Could someone do that?  
		DR. FENICHEL:  The spirit of the question is exactly the spirit with which we've approached other symptomatic claims, which is that it is okay in congestive heart failure for a drug to make one feel better even if as with prosecramen, for example, it makes one lives shorter and the key message was the patient has to know that that's the bargain.  
		Perhaps if the mortality cost were sufficiently high, then we might decide no, it doesn't matter if the patient says he knows that.  That cost is prohibitive.  We will not approve a drug that is where the symptomatic benefits associated with that cost in mortality.  
		The question here is given that one might have a symptomatic claim, we should perceive that as a benefit.  How much of the cost side in terms of the true mortality or mortality quasi equivalent that has been discussed on and off during this morning, how much of that must be understood and to what extent must it go in the right direction?  That was the spirit of the question.
		DR. PACKER:  Does it not presume that the committee as well as the experts agree that a level III claim per se is achievable?  You are presuming that it is.  You are presuming that the prevention of shocks in itself is good and many of the experts have suggested that might be.  But a level III claim has to be viewed as being somewhat disappointing to a sponsor that might have been pursuing at a minimum a level II claim.  
		In other words, when the sponsor did their trials, they weren't shooting for mortality.  They were going for a level II claim which is the suppression of lethal arrhythmias which have they not been sought would have reasonably been associated with a bad outcome.  They missed that because if they had hit that, they would be asking for it.
		DR. FENICHEL:  Well, I suppose that's true that is a nicer claim but there is nothing wrong with the claim that here is a adjunct.  I mean, it's carbadopa.  It's paramtenine.  It's something that comes in to deal with the specific gap in the discerning capability of this device which is that this device does just fine with lethal arrhythmias but we couldn't figure out a way to design its algorithm to avoid picking up on this peculiar version of atrial fib.  
		Well, this stuff does nothing to the device's response or, indeed, for the patient's generation of serious arrhythmias.  The only effect it has is this peculiar version of atrial fib. is suppressed and, therefore, the patient feels a lot better because he's not getting zapped all the time.  That's a perfectly good claim.  It's not as good as some you can make up.
		DR. PACKER:  Tom.
		DR. GRABOYS:  I may be missing something.  I'm just not clear.  Also it sounds a little cavalier to be talking about separating these three.  I don't really understand how we can do that.  The population that Jeremy underscored is precisely that benefits of EF less than 40 percent is precisely the group that is going to be prone to proarrhythmia.  
		I don't know how we can allow a pharmaceutical company to come here with a drug that may make the patient feel better transiently but is associated with an understandable enhanced mortality.  What have I missed here?
		DR. TEMPLE:  I believe that for someone on a defibrillator any enhancement of mortality, even if you reduce the total number of shocks, would be largely considered unacceptable.  A second part of Bob's question is how much assurance would you need if it didn't increase mortality?  I mean, people on defibrillators have pretty -- well, if it's just for arrhythmia they have very low annual mortalities so you're going to need a fair number of patients to know that it's not doubled.  
		If the only benefit is decreasing the number of shocks, one question is, well, how many people do you have to have to be sure that you're not making something else worse and we are going to have to come to grips with that.  We might need 4,000 or 5,000 patients to be reasonably sure.  I don't know.
		DR. FENICHEL:  I would assume that in this programming, and I would like Jeremy to speak to this, that this tradeoff is made all the time.  As one increases the sensitivity and makes the device more of a hair-trigger device, patients feel worse and live longer and that decision must be made all the time.  I don't think this is so exotic.
		DR. RUSKIN:  I'm having trouble understanding why anybody would have any interest in a claim for a drug that reduced shocks without reducing the arrhythmic events that cause the shocks.  I mean, it strikes me as -- I agree with Tom completely.  It's just logically inconsistent.  
		The only way a drug could do that would be by perhaps converting sustained VT to nonsustained VT or just making the VT slower.  It's unlikely that you would find a drug that would do that and have a powerful impact on time to all-cause shocks and not have some favorable impact on the underlying arrhythmia.  If that were the case, that indication would hold no interest for me as a clinician.  I don't see why you would want to even consider it.
		DR. TEMPLE:  I'm surprised to hear that because five years ago this was widely talked about.  That is, reducing partly to maintain battery life.  That was one reason it was given.  Maybe that's all irrelevant now because the batteries are better.  In the past it was.  The idea was that being shocked is bad.  If you're driving a car it can make you lose control and having spurious unnecessary shocks was all by itself a bad thing. 
		If you added amiodorone or something like that at a lose dose and could reduce the number of shock events by 50 percent, even if you didn't change survival, which is not easy to do to change survivals since everybody is protected, that would have been considered a benefit. 
		DR. RUSKIN:  I couldn't agree more.  I am not arguing that point.
		DR. TEMPLE:  That's the answer to your question.
		DR. RUSKIN:  No.  I guess I'm hearing something different from Milton then.  What I heard was a drug that actually decreased ICD shocks but that didn't have a demonstrated improvement in arrhythmia frequency.  I don't see how you could get that.
		DR. TEMPLE:  Well, for someone --
		DR. RUSKIN:  One, I don't know how you could get there in the first place and, two, if you did, why would you have any interest in such an agent?
		DR. TEMPLE:  Bob gave an example.  It might be decrease the likelihood of having sinus tachycardia sufficient to trigger the thing.  Let's just take a trivial benefit.  Nonetheless, despite programming the thing so it wouldn't respond to that was leading people to have shock events.  
		Let's put the question in its most naked form.  That is obviously not a survival benefit.  It's not going to tell you to use the drug in a unprotected population but it decreases the number of shock events materially without apparent cause.  Wouldn't that be reasonable?
		DR. RUSKIN:  In that particular case it wouldn't because that's just not a clinical problem.  I mean, that's a problem that was dealt with by reasonably sophisticated programming so it's not a clinical reality.  The reality is that shocks occur because of atrial fibrillation and ventricular tachycardia and ventricular fibrillation.  
		Those are the reasons that are amenable to any sort of therapy.  The others are lead discontinuities and fractures.  I think to have an agent that will have a clinically relevant important impact on shock frequency, it will have to effect atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or all three.
		DR. TEMPLE:  Okay.  So any drug that could ever pass any test would probably have a favorable effect on results.
		DR. RUSKIN:  I would think so.  Even though it wouldn't affect survival in someone with a defibrillator.
		DR. PACKER:  Essentially the concept would be that if level III, my hypothetical level III, were considered to be the only claim that the sponsor could make because they hadn't shown level II, that it is likely to be a lot of discussion as to why level III was achieved asymptomatic reduction in shocks but level II wasn't enough to raise concerns about the safety.  In other words, was there a reduction in some kind of an event but an increase in another kind of event.
		DR. TEMPLE:  I think what we're hearing is that the only way to achieve level III is to either reduce true ventricular arrhythmias of some kind.  Maybe not the greater than 140 ones but at least the others or atrial fibrillation.  People would generally not argue that it's good to do those things.
		DR. DiMARCO:  I think we shouldn't underestimate the problem that comes up with arrhythmia frequency even in people with defibrillators.  If you look at AVID where there was specific rules that you were supposed to have had several shocks before you could have an antiarrhythmic drug I believe was about a 22 percent crossover to drug.  Even in a study where there was a prohibition and you had to call the center to get permission to use a drug, you did that.  
		We see the people often present with flurries and if you look at the AVID registry there were 4,500 people with eligible arrhythmias.  Only 1,000 ended up in the trial.  The two most common reasons were physician refusal and patient refusal.  I don't think all of that was because people just believed that the defibrillator was better.  
		I think a lot of it was because physicians were unwilling because of arrhythmia frequencies that they detected in people to commit somebody to just a defibrillator from the start.  They were already on a drug to suppress things and, therefore, they couldn't be randomized to device only.  It's not an uncommon problem.
		DR. TEMPLE:  The implication of that is that level III benefit would be highly worthwhile.
		DR. RUSKIN:  Just another comment.  I agree with what John says.  In fact, across the board about 50 percent of defibrillator recipients are on antiarrhythmic drugs precisely for the reason that everybody here has articulated.  The way that they do that, the way they achieve that efficacy is by arrhythmia suppression.  
		DR. PACKER:  Bob, maybe the best way in trying to synthesize it, level III is a perfectly reasonable claim in association with level II.  Pursuit of level III without the evidence for level II raises too many questions and inconsistencies.
		DR. TEMPLE:  Remind me what level II means.
		DR. PACKER:  It's arrhythmia suppression without mortality.  It's arrhythmia suppression represented by a shock.  In other words, the suppression of the high-rate VT or VF.  No mortality claim.
		DR. TEMPLE:  But not necessarily high rate.  You get zapped by your defibrillator even if you're not at 240.  There's usually a built-in lower response rate.  If I understand, you could not have a -- as I understand it, the plausible effect, although not necessarily one that anybody is going to stave, mortality would be found if you reduced high-level arrhythmias that elicited shocks and mortality and won on that.  That might have implications for people who wouldn't take defibrillators and so on.
		A lesser degree of effectiveness would be that you prevent what appear to be appropriate shocks but not these death surrogate shocks, if you like.  Ones where you are not sure what the consequence would have been.  It might have been nonsustained.  It might have been a lot of things.  It seems probable from everything that anybody has said that the reduction of discharges would occur because you suppress those things plus atrial events.  Maybe the distinction isn't all that helpful because nobody can quite imagine how to achieve level III without achieving level II.
		DR. PACKER:  I think that's a point.  If you showed level III but didn't show level II, people would ask all sorts of questions about the integrity and internal consistency of the data.
		DR. CAMM:  I'm sure that you are quite right that level II and level III go hand in hand.  One is mechanistic explanation of the other so to speak.  I'm sure you would expect them to run together in order to justify the claim.  
		We had a preliminary conversation earlier about whether or not one would have to demonstrate that there was no loss of life associated with achieving this level II or level III claim.  We have a slight difference of opinion between the two Bob's with Bob Fenichel telling us that we could perhaps accept a little extra mortality but let's give patients their freedom.  Bob Temple is telling us it wouldn't be very much if at all.
		I wonder if we need to now consider how helpful the surrogate mortality endpoint of shocks for very fast tachycardias would be in helping us come to some comfort level about whether or not mortality was going to be adversely affected in the face of improved symptomatology.
		DR. PACKER:  John, let me just ask a question and ask you to clarify.  Jeremy, I think, made the point that there are mortality issues related to drug therapy which are not related to sudden death which I guess would not be dealt with in a proposal to use as that surrogate based on arrhythmias.
		DR. CAMM:  Yes.  I understand that.  I'm assuming that we are looking at mortality to a degree.  		DR. PACKER:  The second, which is the biggest problem of all is what Bob Fenichel I think is driving at in question No. 1, is that the number of lethal events is likely to be sufficiently small but the confidence intervals will be very wide both for sudden and nonsudden events if one could even clearly distinguish between the two.  Consequently, you would be left in the final analysis with a high degree of uncertainty.  I don't think it would be a problem if there was a mortality reduction which was highly comforting, although not statistically significant.  
		I think what we're concerned about is that we are more likely than not to find mortality rates in the two treatment arms which are precisely on top of each other if not numerically slightly adverse in the drug group but with so few events over the period of observation that the competence intervals will led one to believe that no reasonable conclusion could be made.  That problem is unavoidable.
		DR. CAMM:  I understand every point you've made and agree with it right down the line.  All I'm asking is would it be helpful to ask the data about the mortality shocks to increase the level of comfort about the claim to level II and III.
		DR. TEMPLE:  I'm sure it would.  One of the other things you could do to give yourself comfort is to make sure there are enough people with bad heart disease and not just arrhythmia problems in it.  I mean, the unnerving figures generally show that there is plenty of opportunities to see if, in effect, it was a three-fold increase.  Even in a relatively low-risk population you might well be able to see it if it were that magnitude.  The trouble is how will you rule out a 30 percent increase when the rates are very low.  Part of it is to try to figure out what you're most worried about which I would think exacerbation of heart failure is a big candidate and make sure there is a reasonable number of people with defibrillators who also have fairly advanced heart failure for one thing.  Technically speaking, you'll have enough events to help foresee something.  Second, you are addressing the area of probably greatest concern other than proarrhythmia.  That one you ought to be able to see.
		DR. DiMARCO:  Bob, could you envision an antiarrhythmic drug coming in with just an ICD trial?  I mean, I think that from what you've just said and my own feelings would be that almost any antiarrhythmic drug is going to have to have a heart failure population or some high-risk primary prevention trial that is placebo controlled to also give us an idea in that population.  It's hard for me to imagine a drug coming in just with this secondary prevention ICD group.
		DR. TEMPLE:  I could imagine a drug, for example, with some torsade potential that people would say, "I don't think I want to study this as a primary prevention drug.  I want the protection of a defibrillator there.  I think in that setting we will actually net out with a considerable advantage.  The few cases where I might make things worse will be protected, but the many cases I'll suppress I won't."
		I don't know.  I can imagine that.  The goal would be to use it only in people protected with the defibrillator for two reasons.  First of all, the arrhythmia suppression potential may be of much more importance than in populations likely to have arrhythmias.  The proarrhythmic potential may be less important than in the primary prevention situation where you are preventing fewer events and provoking more events.  As someone said earlier, the risks and benefits could be highly population dependent.  I can imagine it but it would be a little odd.
		DR. CAMM:  Milton, I think it's important in this context to appreciate the rate at which ICD implantation is increasing.  We are still dealing with a highly unpenetrated market and a highly undeveloped market.  If industry projects that, we won't be implanting 100,000 units per annum in the United States, but within a few years from now it will be 400,000 or 500,000 units.  This represents a very significant patient cohort.  An adjunctive therapy for that cohort will, I'm sure, form a reasonable basis for claims to this agency.
		DR. PACKER:  Okay.  We have covered to a significant degree many of the issues surrounding 1 and 2, I think, to the degree that we have addressed all of the issues in 1 and 2. I'm not certain that we have answered all the issues but I think we have addressed all the issues.
		DR. FENICHEL:  Well, answers per se were not really expected.  The short preamble uses the word "suggest" some of the topics, etcetera.  I think the questions should be taken in that spirit.
		DR. PACKER:  Okay.  Let's move on to No. 3.  I think this has already been addressed as well.  Is it plausible that ICD patients could be recruited as patients in trials of a noncardiovascular drug, for example, an antihistamine, as an ethical means of coping with the suspicion that the drug was proarrhythmic?  Now, it was referred to briefly that it may be a crazy idea.  Dan, what do you think? 
		DR. RODEN:  Well, you know, the problem is a different one from the problem of arrhythmias in patients with heart failure or patients with ongoing arrhythmias.  I think, first of all, the ethics of giving a drug with the expressed goal of seeing whether that drug is proarrhythmic are dubious in my mind, No. 1.  
		No. 2, I think the event rates for some of those drugs are relatively low.  While you could enrich those event rates by studying them in patients with heart failure and what not, I think the reassurance that you would get from such a trial would be almost negligible.  
		In other words, if I wanted to know whether my antihistamine has a risk of 1 in 100,000 of being proarrhythmic, I think doing a trial in a large cohort of patients with heart failure and not seeing anything wouldn't reassure the others.
		DR. FENICHEL:  Let me explain the spirit of the question.  My idea was that we commonly tell people with drugs -- actually, we in the division work through intermediaries.  We tell people in other divisions to tell people coming forward with antihistamines or antibiotics or antinflammatory drugs and so forth that the thing to do is to give mega doses of this somewhat suspect drug to your healthy volunteers and see if the QT prolongation or whatever other phenomena you think you've detected really get significant.  
		The answer commonly is, "Well, they are healthy but they are not that healthy."   These people are destructible and so you can't give these mega doses.  We know what doses we want to give to achieve histamine blockade or whatever.
		The idea behind the question is that these people with structural heart disease, with everything else, who have been given these devices because they are at much greater risk than the general population of sudden death nevertheless are in their way the healthiest possible volunteers.  
		The spirit of the question was isn't this the population in whom to try out -- might this not be the population in whom to try out something like that.  I think it's a pretty wild idea too.  I was not saying this is a sure thing.  I wanted people more expert than I to speculate upon it.
		DR. RODEN:  Well, I guess there is conceptually probably not much difference between giving very, very large doses of the drug to normal volunteers and giving largest or normal doses of that same drug to a group that for some reason happened to be particularly sensitive, or you think might be sensitive.  The kind of result that you might see is similar in both trials.
		I guess the heart failure group has the virtue that they might be more susceptible to arrhythmias.  My answer is not very different from --
		DR. FENICHEL:  The claimed virtue was not that they might be more susceptible.  I'm willing to say that they might be equally susceptible.  The point is that if they get the toxic effect they are protected.
		DR. RODEN:  I understand what you're saying.  You would do the mega trials with normal volunteers under some monitored condition anyway.  I guess the discussion is not very different from the old discussion we were having this morning, and that is if you did this and if you saw such and such a result, what might you do.  I guess the answer is I would love to see the result and then I might be able to think more rationally about what I would do.

		DR. DiMARCO:  Yes.  I think that John Camm outlined it.  Even though we say they are protected, it's not an absolute thing and there are bad things that could happen.  I think you would have to design the consent form.  You know, if you had a drug that was effective in gram negative sepsis in people with defibrillators, that would be a nice population but, boy, I would hate to see any many centers you would have to have to try to evaluate that.
		For a no benefit trial or a minimal benefit trial to expose someone, which even with a defibrillator would have a substantial mortality risk on purpose would be hard for me to design.
		DR. TEMPLE:  I think the assumption is you have already -- you don't do this as your first trial.  You have already done trials and you push the dose a little bit and you haven't seen any QT prolongation or anything much but your animal data makes you worried and now you want to do something to really pin it down before you launch it on a large population in the U.S.
		I think the question really asks can you think of these people for some circumstances as normal volunteers even though they have an underlying disease and invite them to participate in a study that you are applying adequate protections to because they can probably do it somewhat more safely than other people.
		DR. PACKER:  And be paid?
		DR. TEMPLE:  Uh?
		DR. PACKER:  And be paid?
		DR. TEMPLE:  In the way that normal volunteers are.
		DR. PACKER:  They are usually paid.
		DR. TEMPLE:  Some.  It can't be excessive.
		DR. PACKER:  You could have a whole long four-day ethical conference on that.
		DR. RODEN:  Right.  Bob, I think just to sort of be concrete for second, if you wanted to, for example, decide whether ordinary doses of terfinidine without metabolic inhibitors cause arrhythmias in patients with heart failure.  Just like high doses of terfinidine or high concentrations might cause arrhythmia in volunteers, then you might do such a study.  I think the numbers required might be enormous and the ethics required we've already touched on.
		DR. TEMPLE:  Well, the ethics there actually are more straight forward because those people have an interest in the answer to that question.  There are people with heart failure you might want to use an antihistamine.
		DR. RODEN:  I understand that but you can always make that argument about many drugs.  You can make that argument about a drug that has efficacy (indiscernible) and more susceptible to that too.  When it comes time for them to have that drug, they may not be in a position to sort of discuss it with you.  
		I still think the likelihood that you get useful information is small and the efficacies are large, which is not to say somebody might not want to try it.
		DR. PACKER:  It just strikes me it leads one to the most interesting and complex.  I can just imagine that if this became widespread because a number of drugs that prolong QT became so common place and the issue became so important that one could imagine high school counselors talking to people, "Well, what do you want to be when you grow up?"  They say, "Well, I don't know."  They said, "Have you considered having an ICD implanted and charging as a volunteer?"  Never mind.
		DR. RODEN:  Well, you've got to make a living.
		DR. PACKER:  Okay.  I think we've covered No. 4 and we've covered No. 6.  We have 5.  Are there other observations, drug induced changes and fibrillation thresholds that can be made during trials in ICD patients and then extrapolated to non-ICD patient populations?  My question is for what purpose?  Dan?
		DR. RODEN:  Yes.  Well, there are observations and we've talked about them.  Fibrillation and defibrillation, energy requirements are of interest.  But you're right.  I'm not sure they would be of interest to other populations.  Slowing of tachycardias might be of interest.  Again, that assumes that there will be some population that eventually doesn't get implanted with an ICD -- fitted with an ICD.  I like that word better.  Fitted with an ICD and you would have some sense that the tachycardias would be slower or something like that.  I can't think of anything else off hand.
		DR. PACKER:  John.
		DR. CAMM:  I think that one of the parameters that was going to be explored in many of these trials was the ability of program stimulation using perhaps an ICD in this kind of trial to predict long-term events with the ICD with the implication that such information might be qualitatively useful in applications in non-ICD patients.
		DR. PACKER:  Okay.  Before we go onto 7, I just want to ask Bob Fenichel have we adequately at least discussed and addressed all the issues you wanted us to address in questions 1 through 6?
		DR. FENICHEL:  Well, as i said before, the questions were essentially a menu, a smorgasbord menu to be chosen among as you desire.  I think you have done that.
		DR. PACKER:  And I think we have gone through actually in reading this all the issues including the concept of surrogacy, the concept of what kinds of observations might lead to what kinds of claims, the kinds of patient population, the extrapolation of ICD studies to non-ICD studies.  		Although we would all hasten to add that all of the thoughts are going to be modifiable based on future data, and especially modifiable based on when they are applied to a specific data set, many of the situations we talked about had been described a priority as being "ideal" and data sets are rarely ideal.  These are simply thoughts that provide some sense of guidance.
		DR. FENICHEL:  I think there is something more about 6 before you get to 7.
		DR. PACKER:  Sure.
		DR. FENICHEL:  People have made various illusions in the course of the day to the -- Jeremy certainly referred to a number of coming developments and so forth.  What was behind 6 was the idea that there might be possible advances in ICD's which really were not especially valuable to ICD therapy per se that really didn't help the physician taking care of the patient with the ICD an awful lot, or not in any obvious way, but might be of considerable value when patients walked around with that ICD and then were used as subjects for other drug development.  
		So the idea was is it something that the antiarrhythmic community might somehow unite around and come and say, "Look.  This is the thing that we really want."  Every one of these things has a certain cost, although the cost now of some things like additional memory is very small.  Every one of these things has an evolutionary cost so that anything you have to carry around has a cost.  
		Is there something that the antiarrhythmic community might unite around saying, "Look.  This is something that ought to be in ICD's.  Some particular feature.  Not all these other potential features necessarily.  You were thinking about features with exact purposes obscure.  Here's where to put your money and we perhaps will even subsidize putting this into devices on the grounds that they allow data to be collected which is, indeed, in the patient's interest although it's not especially in the interest of the people who make devices.  It's not against their interest but it doesn't really serve their immediate purpose."  
		That was really the idea around 6.  Are there specific device enhancements that might serve the drug community which the device community might not be aware of.
		DR. CAMM:  I think that there are a few enhancements of this kind.  For example, the generation of atrial fibrillation can be logged by a device.  It is of very little relevance to the device manufacturers in their building of pacemakers, for example, or defibrillators but it could well be a parameter put to the agency as an indicator of the usefulness of a particular therapy.
		I think we ought to be well aware that the implantation of devices for monitoring purposes will become greater and greater.  Some of these devices will have therapeutic arms to them, therapeutic potential to them, which may perturb the signal in the same way that we've been discussing this morning with defibrillators.  
		Some will not have such therapeutic potential.  All of them will have some degree of difficulty associated with the interpretation of the data which they collect in exactly the same way that we have discussed today.  I can foresee in the next five years that the agency will be presented with many data sets of information derived from implantable diagnostics and it will be critical that the limitations of those data sets are well understood by the agency.
		DR. RUSKIN:  Just to add a few specifics.  There are a number of things that are being looked at.  I think that John's comment about the duration of monitoring is very important.  Since memory is getting a lot easier and cheaper to install, we will have the ability to do much more closely -- excuse me, get data that is closer to Holter monitoring than it is to the kinds of isolated events that we get now.
		QT sensing, heart rate variability assessment, hemodynamic monitoring.  The technology for all those things in implantable devices is here.  The key is, I think, as John suggested, is to learn how to use them productively in a way that alters our care of patients.  I think you will see them in devices and their use is primarily diagnostic right now.
		DR. DiMARCO:  Yes.  I think that the other thing is there is not enough market just in drug development to cause people to introduce something that has no clinical value.  Many of the things that we use in drug development have some clinical value and the device companies are in competition to provide things that are of clinical value so that if something gets established as being clinically relevant, it will be both useful in a device for a physician who is using it in a clinical setting as well as for some company that wants to use that parameter in their drug development program.
		DR. PACKER:  Especially if the primer was something that was a very common comorbid condition in patients who get a device like heart failure or coronary artery disease that you would monitor.  Something that is relevant to those, then it would provide, I guess, a marketing advantage and people would go out and do it.
		Lastly, is it plausible ICD's will become so effective, inexpensive, easily implanted that antiarrhythmic drug therapy for life-threatening ventricular arrhythmias will no longer be of interest to developers.  If not, what is to be done.  I have no idea what the last sentence means because it is sort of like saying if people declared peace on earth, what would happen to people who made military equipment?  
		We've already heard some specific descriptions of what antiarrhythmic drug therapy would still be used for including -- well, Jeremy?
		DR. RUSKIN:  I think the answer is that drugs won't go away.  The reason is that the devices as wonderful as they are in aborting these events; that is, converting a sustained event to an aborted sudden death, they do not prevent arrhythmias and there is nothing on the horizon that suggest that they will.  This will continue to be a hybrid therapy that involves both devices and drugs certainly for the foreseeable future.  Drugs that decrease the events will continue to be needed.
		DR. PACKER:  Bob, any other issues to the committee?  Does anyone on the committee have any other comments or questions or points to raise?  Bob.
		DR. TEMPLE:  I guess the only thing I would say is that there seems to be a fairly urgent need for updated -- actually, I'm not sure what the state of our guidelines is on all this.  I think nothing too recent.  It seems an urgent matter to start to put some of these thoughts into writing even where we are not quite sure what to do.
		DR. PACKER:  Let me just echo that by just indicating I think the sense that the committee has that the data which has been described today has been of enormous interest and I think represents a major educational experience at least to the nonelectrophysiologists and maybe to the electrophysiologists on the committee.  I know of no general knowledge of all of these issues in the cardiology community and it would be really valuable to write this up in documents other than guideline documents so that the issues are clearly understood by cardiologists who would prescribe devices as well as antiarrhythmic drug therapy.  That seems to be a general purpose for practitioners as well as from a regulatory purpose.
		With that, we are adjourned.
		(Whereupon, the meeting was adjourned at 12:58 p.m.)