Statement of Ajay K. Singh, M.D., Clinical Director, Renal Division, Director, Dialysis Services, Associate Professor of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Testimony Before the Subcommittee on Health
of the House Committee on Ways and Means

June 26, 2007

1.)    The Optimal Target Hemoglobin in Patients with Kidney Disease

2.)    The Extensive Off-Label Use and Over-Utilization of Epoetin in the United States

3.)    Bundling of ESRD services

1.      The Optimal Hemoglobin Concentration in patients with kidney disease.

·I fully support the recent FDA Black Box Advisory[1] that the hemoglobin level should be no higher than 12 grams per deciliter. Randomized controlled studies (RCTs), both in dialysis and in predialysis patients, demonstrate an increased risk of cardiovascular complications and death in patients targeted to a hemoglobin level that exceeds 12 grams per deciliter. In dialysis patients this was demonstrated in the Normal Hematocrit Study, published in 1998[2], and in non-dialysis CKD patients, this was demonstrated in the CHOIR study, published by us in 2006[3]. The CREATE study[4] reinforced the findings from CHOIR.

·Randomized controlled studies are superior to retrospective observational studies. While these retrospective studies have suggested benefit for cardiovascular outcomes or survival with targeting of a higher hemoglobin concentration, they are confounded by co-morbid factors and illness[5]. Continuing to cite these studies without providing RCT’s contextually, as companies have continued to do is unnecessary, generates confusion, and undermines the FDA’s strong safety message embodied in its Black Box advisory[6].

·Aiming for and achieving a hemoglobin concentration in a narrow band of 11 to 12 g/dL may only be possible in approximately 2 out of every 3 patients. As I have discussed elsewhere, expanding the target range to 10 to 12 g/dL seems not only prudent but also practical. This approach is prudent because of the safety concerns with hemoglobin concentrations greater than 12 g/dL as suggested by the RCT’s and further reinforced by a recent meta-analysis published in the Lancet[7] . This Lancet analysis aggregated studies of patients with kidney disease, whether on dialysis or not, and demonstrated a 17% increased risk of death with targeting a hemoglobin concentration of greater than 12 g/dl. While I agree with the notion that the target hemoglobin concentration level should b individualized based on patient need, in general, expanding the range to aim for a hemoglobin concentration greater than 10 g/dL but less than 12 g/dL should not result in a higher rate of blood transfusion, nor should it result in a worsening in quality of life.

·We should accept that the proven benefit of erythropoetic stimulating agent (ESA) therapy is in preventing blood transfusions. Although, the FDA has recently pointed out that blood transfusions are much safer than ever before[8] chronic kidney disease patients benefit from transfusions because of the avoidance of antibody sensitization (the latter decreases the likelihood of kidney transplant eligibility) and in reducing the risk of iron overload. Therefore, I continue to believe strongly that ESA treatment should be used to minimize the risk for blood transfusions; however, expanding the target hemoglobin range from 11 to 12 g/dL to 10 to 12 g/dL is reasonable, and should not meaningfully increase the proportion of patients requiring blood transfusion.  On the other hand, quality of life benefits of a higher hemoglobin concentration are, at best, inconsistent. Studies have been dogged by methodologic issues, open label design, and the variable use and reporting of quality of life instruments.  The CHOIR study showed no incremental benefit in quality in life with targeting a higher hemoglobin concentration and showed an increase in adverse events and complications.

• The FDA issued a Black Box for all ESA’s because of RCT data in kidney disease patients and because of emerging data from studies in cancer patients that suggested increased risk. The National Kidney Foundation (NKF) Kidney Disease Quality Initiative (KDOQI), in newly updated guidelines will also state that the target hemoglobin concentration in patients with kidney disease should generally be 11 to 12 g/dL.

·It is reassuring that the FDA, empowered with evaluating the efficacy and safety of drugs in the United States, has recommended caution in using ESA treatment. However, past experience both with respect to this issue and with other drugs teaches us that power factors can stimulate continued and even increased off-label use of drugs. Every effort should be made to avoid continued off-label use of ESA’s. Minimizing off-label use of ESA’s will not only reduce CMS expenditure but will also be beneficial to ESRD beneficiaries and CKD patients collectively by reducing risk of higher hemoglobin concentrations and possibly higher doses of ESAs.

2)      The Extensive Off-Label Use and Over-Utilization of Epoetin in the United States

• As a recent New York Times Editorial[9] , as well as articles by others[10], has pointed out, trends in ESA utilization illustrate much that is wrong with reimbursement of ESAs. Off-label use of ESAs, and its over-utilization, are common-place and largely driven by flawed reimbursement, rebates, and over-zealous marketing of the drug.

• In 1998, approximately 10% of patients had hemoglobin levels that exceeded 12 g/L, whereas by 2000 this had rapidly grown to 40% of all dialysis patients. Surprisingly, this steep increase in average hemoglobin levels occurred after the publication in 1998 of the Normal Hematocrit Study (NHS) showing a higher risk of death or myocardial infarction in aiming for a hematocrit of 42%. The authors of NHS indicated that concerns regarding excess mortality precipitated the decision to prematurely terminate the study. [11]Two years before the publication of NHS -- in 1996 -- the FDA added a new subsection in the Warnings section in the label of epoetin regarding higher mortality with hemoglobin levels of 12 to 140 g/L in patients with chronic renal failure (reviewed most recently at an FDA oncology advisory committee meeting). The steep increase in hemoglobin levels from 1996 onwards, coupled with a 50% increase in the average epoetin dose administered to dialysis patients during this time, needs to be further scrutinized.

• The study by Thamer and co-workers documents the overuse of epoetin in for-profit dialysis chains as compared to not-for profit chains, with for-profit facilities administering roughly a third more units of epoetin per week. Indeed, the for-profit chain DaVita utilized higher doses of epoetin at both lower and higher hemoglobin levels. Thamer and colleagues also confirmed an earlier observation that for-profit chains especially DaVita had a higher proportion of their patients achieving hemoglobin levels greater than 12 g/dL when compared to the non-profit chain DCI.

• There are several potential explanations for the Off-Label Overuse of Epoetin.

·Pervasive incentives for ESA Overuse in current CMS reimbursement guidelines. The current CMS reimbursement schedule, launched April 2006, facilitates over-utilization of epoetin[12].  In work that has been submitted for publication, we assessed the impact of the change in CMS guidelines on hemoglobin levels and EPO usage in DCI, the largest not-for-profit dialysis chain in the United States. We evaluated[13] the effect of a new protocol implemented on May 1, 2006 to reflect the CMS policy change. We found that reducing rather than discontinuing epoetin supplementation at hemoglobin >13 g/dL (the current CMS reimbursement schedule) was associated with a significantly greater proportion of hemodialysis patients at higher hemoglobin levels, higher cumulative epoetin use, and had no effect on the number of individuals with lower hemoglobin levels.  Given recent studies that have demonstrated potential harm with higher hemoglobin targets, our study suggests that discontinuation rather than reduction of epoetin is appropriate when hemoglobin reaches 13 g/dL.

·The use of anemia protocols by dialysis providers and facilities. Administration of epoetin to patients at dialysis has both a facility and a physician component. Dialysis facilities have centralized corporate committees that formulate an anemia algorithm. This algorithm defines anemia targets and formulates epoetin and hemogklobin measurement orders that are instituted as part of the patient’s standing orders. In addition, in many dialysis facilities, the dialysis facility has a designated employee who oversees anemia. In most facilities this is a nurse who evaluates the hemoglobin and iron values of individual patients, supervises the epogen over-fill utilization program, and ensures patient’s compliance with the anemia protocol. The dialysis facility also expects the medical director, who receives a stipend or medical director fee from the dialysis facility, to ensure adherence to the anemia goals of the facility and of the dialysis chain. Individual dialysis physicians can and sometimes do over-ride the standing orders of the dialysis facility since they are ultimately responsible for the treatment of the patient under their care. Dialysis chains vary by the extent to which they provide autonomy to their medical directors and treating dialysis physicians in regard to the anemia protocol. The more aggressive dosing of epoetin recommended by DaVita is the likely explanation for the over-utilization of epoetin in the DaVita chain as compared to DCI. For example, a corporate DaVita anemia protocol dated February 2007, recommends only a 10% reduction in epoeitin dose for hemoglobin concentration greater than 13.1 g/dl and less than 14 g/dL (and a dose reduction of 25% for hemoglobin concentration greater than 13.1 g/dl and less than 14 g/dL). In contrast, DCI recommends and immediate decrease in epoetin by 25% when the hemoglobin concentration exceeds 13 g/dL. In our own dialysis unit in Boston, we discontinue epoetin when the hemoglobin exceeds 12 g/dl. Since these anemia goals and epoetin dosing recommendations are protocolized and managed by the facility, the current structure of anemia management in dialysis chains is a powerful driver for off-label use of epoetin and over-utilization of epoetin.

·Marketing and Rebate Activities by Pharmaceutical providers in driving Off-Label use. The pervasive effect of marketing and rebates to physicians have driven physician off-label use of ESAs. This is supported by recent press articles in both the New York Times[14] and the Wall Street Journal[15] and the British Medical Journal[16]. This is currently being investigated by the Senate Committee on Finance[17]. This has been discussed extensively in the scientific literature with regards to the promotion of gabapentin[18]. The influence of marketing activities on molding opinions about epoetin use is also concerning and has also been brought to light[19].

·The limited use of subcutaneous epoetin in dialysis chains in the United States Evidence shows that approximately 1/3^rd less epoetin is used when it is administered subcutaneously (SC) as compared to the IV route[20]. The SC dosing is certainly commercially less attractive and will influence profits for both pharma and dialysis providers. However, it will save the CMS substantial amounts of money because cumulative epoetin doses will be lower. The saving is likely to be in the range of $500 million or more. While some have argued that it is less convenient to patients and provider this issue does not seem to have adversely affected the VA population or those insured by Kaiser or for that matter thousands of patients in Canada and Europe. As well the use of lower doses of epoetin if given SC could be important if high doses of epoetin are shown to be associated with worse outcomes.

3)      Bundling of injectibles, including ESAs, by including its reimbursement into the ESRD composite rate should be adopted.

·Bundle of injectible drugs into the reimbursement of the dialysis procedure, i.e., into the composite rate offers several benefits and should be adopted.

a.)    It removes incentives for over-treatment – aiming for higher hemoglobin levels using higher and higher doses of epoetin.

b.)    It will reduce the escalating costs for injectible drugs, particularly ESAs, in the treatment of dialysis patients.

c.)    It will encourage the use of subcutaneous administration of epoetin – a practice widely used in Europe, Canada, and in the VA system.

d.)    This should facilitate lower doses of ESAs in the treatment of anemia.

·Utilize the Kaiser Experience with ESRD Bundling. As I have pointed out elsewhere[21], the Kaiser Permanente system provides an accessible and functioning model of ESRD bundling. This system functions without risk adjustment of payments and has resulted in largescale use of subcutaneous epoetin administration.

·In the near-term, CMS should modify its reimbursement policy. This will be important in reducing epoetin over-utilization and to conform more robustly with the FDA Black Box Advisory. Indeed, CMS has done this with reimbursement of the oncology indications for epoetin therapy.

Summary

I recommend that the importance of following the FDA Black Box for epoetin in the treatment of anemia of kidney disease should be followed.

a.)    The hemoglobin target should be less than 12 grams per deciliter.

b.)    The extensive off-label use of epoetin and its overutilization requires greater scrutiny.

c.)    Medicare should modify its reimbursement policy to adopt a bundled reimbursement approach. This will, at least in part, remove the incentive for higher epoetin use, increase subcutaneous administration of epoetin, and restrain spending on ESAs.

Endnotes

[1] www.fda.gov/cder/drug/advisory/RHE2007.htm.

[2] Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998 Aug 27;339(9):584-90.

[3] Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98

[4] Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84

[5] Regidor DL, Kopple JD, Kovesdy CP, et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. Apr 2006;17(4):1181-1191.

[6] http://www.anemia.org/professionals/resources/slides/

[7] Phrommintikul A, Haas SJ, Elsik M, Klum H. Mortality and target haemoglobin concentrations in anemia patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007; 369:381-88

[8] www.fda.gov/OHRMS/DOCKETS/AC/07/briefing/2007-4301b2-02-FDA.pdf

[9] New York Times, May 14, 2007 Late Edition - Final, Section A, Page 18, Column 1

[10] Marlene Busko Is Medicare Reimbursement Policy for Erythropoietin in ESRD Flawed? http//www.medscape.com/viewarticle/550594

[11] The NHS study was stopped because: “Our study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group”.

[12] Cotter D, Thamer M, Narasimhan K, ZhangY, Bullock K Translating Epoetin Research Into Practice: The Role Of Government And The Use Of Scientific Evidence. Health Affairs, 25, no. 5 (2006): 1249-1259

[13] Weiner DE, Miskulin DC, Seefeld K, Ladik V, Zager PG, Singh AK, Johnson HK, Meyer KB: Erythropoietin Use and Hemoglobin before and after 2006 Changes in Medicare Reimbursement Guidelines. 2007. Submitted for publication

[14] Alex Berenson and Andrew Pollack, “Doctors Reap Millions for Anemia Drugs” The New York Times, May 9, 2007

[15] Heather Won Tesoriero and Avery Johnson, ‘Suit Details How J&J Pushed Sales of Procrit, Wall Street Journal, May 10, 2007

[16] Tonks A. Too much of a good thing. BMJ. 2007 May 12;334(7601):978-80. Singh AK: Marketing Epoetin: Too Much of a Good Thing. http://www.bmj.com/cgi/eletters/334/7601/978

[17] http://www.google.com/search?q=epogen+rebates+2007&hl=en&start=20&sa=N

[18] Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med. 2006 Aug 15;145(4):284-93. (Letters and Response Ann Intern Med. 2007 Feb 20;146(4):313; author reply 313-4.)

[19] Dyer O. Journal rejects article after objections from marketing department. BMJ. 2004 Jan 31;328(7434):244.

[20]  (a. Kaufman JS, Reda DJ, Fye CL, Goldfarb DS, Henderson WG, Kleinman JG, Vaamonde CA. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med. 1998 Aug 27;339(9):578-83. b. Parker KP, Mitch WE, Stivelman JC, Macon EJ, Bailey JL, Sands JM.  Safety and efficacy of low-dose subcutaneous erythropoietin in hemodialysis patients. J Am Soc Nephrol. 1997 Feb;8(2):288-93. c. Kaufman JS. Subcutaneous erythropoietin therapy: efficacy and economic implications. Am J Kidney Dis. 1998 Dec;32(6 Suppl 4):S147-51.

[21] Singh AK et al Letter to JAMA. 2007. In press.