Correspondence
An Ongoing Study of Anemia Correction in Chronic Kidney Disease
N Engl J Med 2007; 356:959-961March 1, 2007
- Article
To the Editor:
Evidence-based medicine assimilates available data to direct decisions regarding the care of patients. Extrapolations from epidemiologic observations and laboratory or clinical markers of disease severity have supported new treatments that were subsequently found to be without value in randomized, controlled clinical trials.1 In addition, therapies considered to be beneficial and safe owing to their effect on surrogate markers have been found to be ineffective or harmful in such trials.1,2 Even the results of randomized, controlled trials can be misleading, especially when the trials are not adequately powered.3
The use of erythropoietic agents to treat anemia in patients with chronic kidney disease is based on the epidemiologic association of anemia with poorer outcomes, on the improvement in surrogate end points with therapy, and on extrapolation from populations of patients undergoing dialysis.4 The results of the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)5 and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)6 studies are sobering and relevant to the care of millions of patients. In the CREATE trial, which involved 603 patients with chronic kidney disease and anemia, the use of epoetin beta to raise the hemoglobin level to a normal target range of 13.0 to 15.0 g per deciliter (as compared with a subnormal range of 10.5 to 11.5 g per deciliter) did not alter the primary composite outcome of cardiovascular events, left ventricular mass, quality of life, and the progression of chronic kidney disease. The CHOIR trial randomly assigned 1432 patients with chronic kidney disease and anemia to receive epoetin alfa to raise hemoglobin to a target of either 13.5 g per deciliter (high-hemoglobin group) or 11.3 g per deciliter (low-hemoglobin group). The CHOIR trial was stopped prematurely owing to a lack of efficacy and subsequently showed an increased risk of the composite of death, myocardial infarction, hospitalization for congestive heart failure, and stroke in the high-hemoglobin group (surprisingly, the imbalance was in the rate of heart failure, not of stroke or myocardial infarction).6
In considering these results, it is essential to recognize that P values for data from trials that have been stopped early can lack reliability.7 In 2004, the Trial to Reduce Cardiovascular Events with Aranesp [darbepoetin alfa] Therapy (TREAT; ClinicalTrials.gov number, NCT00093015) began enrolling 4000 patients with diabetes, chronic kidney disease, and anemia to determine whether the risk of death, nonfatal myocardial infarction, hospitalization for myocardial ischemia, heart failure, or stroke would be reduced by treatment with darbepoetin alfa to raise the hemoglobin level to 13.0 g per deciliter, as compared with placebo.8 TREAT is the only randomized, placebo-controlled, double-blind, clinical-outcomes trial in anemia and chronic kidney disease and has already enrolled even more patients than the CHOIR and CREATE trials combined. Recently, the data and safety monitoring committee reviewed “the totality of evidence, including CHOIR, CREATE, the phase II data from darbepoetin alfa heart failure trials, and the emerging data on safety and efficacy in TREAT” and found “no cogent evidence to recommend alteration or termination of TREAT.”
TREAT highlights the uncertainty that currently envelops this field: initial overwhelming concern about possible harm from withholding erythropoietin (using placebo) has shifted to worry about the potential harm of active treatment. A recent editorial demand to terminate TREAT on the basis of a meta-analysis without actual TREAT data is irresponsible and usurps the role of its designated data and safety monitoring board, which continues to monitor patient safety.9 This potentially sets a dangerous precedent for how future clinical trials will be conducted. Whether the treatment of anemia will alter events in patients with chronic kidney disease can be answered only by properly powered, randomized, placebo-controlled trials and deserves a definitive answer.
Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women's Hospital, Boston, MA 02115for the TREAT Executive Committee
Dr. Pfeffer reports receiving consulting fees from Alza, Amgen, AstraZeneca, AtheroGenics, Bristol-Myers Squibb, Daiichi Sankyo, Genzyme, GlaxoSmithKline, Guidant, Mitsubishi Pharma, Novartis, and Via Pharmaceuticals and grant support from Amgen, AstraZeneca, AtheroGenics, Novartis, Sanofi Synthelabo, and Bristol-Myers Squibb. Dr. Pfeffer is named as a coinventor on a patent awarded to Brigham and Women's Hospital regarding the use of inhibitors of the renin–angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement between Novartis and Brigham and Women's Hospital that is not linked to sales.
9 ReferencesSource Information
Members of the TREAT Executive Committee included Marc A. Pfeffer, M.D., Ph.D., Mark E. Cooper, M.D., Emmanuel de Almeida Burdmann, M.D., Ph.D., Dick deZeeuw, M.D., Ph.D., Kai-Uwe Eckardt, M.D., Andrew Levey, M.D., Janet McGill, M.D., John J.V. McMurray, M.D., Patrick Parfrey, M.D., Hans-Henrik Parving, M.D., Giuseppe Remuzzi, M.D., Ajay K. Singh, M.D., Scott D. Solomon, M.D., and Robert Toto, M.D.
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Mix TC ,Brenner RM ,Cooper ME , et al. Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J 2005;149:408-413[Erratum, Am Heart J 2005;150:53.]
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- Citing Articles (18)
Citing Articles
1
Patrick R. Lawler, Kristian B. Filion, Mark J. Eisenberg. (2010) Correcting Anemia in Heart Failure: The Efficacy and Safety of Erythropoiesis-Stimulating Agents. Journal of Cardiac Failure 16:8, 649-658
CrossRef2
Pfeffer, Marc A., Burdmann, Emmanuel A., Chen, Chao-Yin, Cooper, Mark E., de Zeeuw, Dick, Eckardt, Kai-Uwe, Feyzi, Jan M., Ivanovich, Peter, Kewalramani, Reshma, Levey, Andrew S., Lewis, Eldrin F., McGill, Janet B., McMurray, John J.V., Parfrey, Patrick, Parving, Hans-Henrik, Remuzzi, Giuseppe, Singh, Ajay K., Solomon, Scott D., Toto, Robert, . (2009) A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. New England Journal of Medicine 361:21, 2019-2032
Full Text3
T.S. Dharmarajan, David Widjaja. (2009) Erythropoiesis-Stimulating Agents in Anemia: Use and Misuse. Journal of the American Medical Directors Association 10:9, 607-616
CrossRef4
Marc A. Pfeffer, Emmanuel A. Burdmann, Chao-Yin Chen, Mark E. Cooper, Dick de Zeeuw, Kai-Uwe Eckardt, Peter Ivanovich, Reshma Kewalramani, Andrew S. Levey, Eldrin F. Lewis, Janet McGill, John J.V. McMurray, Patrick Parfrey, Hans-Henrik Parving, Giuseppe Remuzzi, Ajay K. Singh, Scott D. Solomon, Robert Toto, Hajime Uno. (2009) Baseline Characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). American Journal of Kidney Diseases 54:1, 59-69
CrossRef5
Donald S. Silverberg, Dov Wexler, Adrian Iaina, Doron Schwartz. (2009) The correction of anemia in patients with the combination of chronic kidney disease and congestive heart failure may prevent progression of both conditions. Clinical and Experimental Nephrology 13:2, 101-106
CrossRef6
Jalal K Ghali. (2009) Anemia and heart failure. Current Opinion in Cardiology 24:2, 172-178
CrossRef7
Marc A. Pfeffer. (2008) Anemia treatment in chronic kidney disease: shifting uncertainty. Heart Failure Reviews 13:4, 425-430
CrossRef8
DONALD S. SILVERBERG, DOV WEXLER, ADRIAN IAINA, DORON SCHWARTZ. (2008) Anemia, chronic renal disease and chronic heart failure: the cardiorenal anemia syndrome. Transfusion Alternatives in Transfusion Medicine 10:4, 189-196
CrossRef9
James E Novak, Lynda A Szczech. (2008) Triumph and tragedy: anemia management in chronic kidney disease. Current Opinion in Nephrology and Hypertension 17:6, 580-588
CrossRef10
Francesco Locatelli, Allen R Nissenson, Brendan J Barrett, Rowan G Walker, David C Wheeler, Kai U Eckardt, Norbert H Lameire, Garabed Eknoyan. (2008) Clinical practice guidelines for anemia in chronic kidney disease: problems and solutions. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International 74:10, 1237-1240
CrossRef11
Cataldo Abaterusso, Nicoletta Pertica, Antonio Lupo, Vittorio Ortalda, Giovanni Gambaro. (2008) Anaemia in diabetic renal failure: is there a role for early erythropoietin treatment in preventing cardiovascular mortality?. Diabetes, Obesity and Metabolism 10:10, 843-849
CrossRef12
Inder S. Anand. (2008) Anemia and Chronic Heart Failure. Journal of the American College of Cardiology 52:7, 501-511
CrossRef13
Willem-Peter T. Ruifrok, Rudolf A. de Boer, B. Daan Westenbrink, Dirk J. van Veldhuisen, Wiek H. van Gilst. (2008) Erythropoietin in cardiac disease: New features of an old drug. European Journal of Pharmacology 585:2-3, 270-277
CrossRef14
B Daan Westenbrink, Rudolf A de Boer, Adriaan A Voors, Wiek H van Gilst, Dirk J van Veldhuisen. (2008) Anemia in chronic heart failure: etiology and treatment options. Current Opinion in Cardiology 23:2, 141-147
CrossRef15
Marc A. Pfeffer. (2008) Critical Missing Data on Erythropoiesis-Stimulating Agents in CKD: First Beat Placebo. American Journal of Kidney Diseases 51:3, 366-369
CrossRef16
A. M. S. Belonje, R. A. Boer, A. A. Voors. (2008) Recombinant Human Epo Treatment: Beneficial in Chronic Kidney Disease, Chronic Heart Failure, or Both?. Cardiovascular Drugs and Therapy 22:1, 1-2
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Eberhard Ritz, Christoph Wanner. 2008. Cardiovascular Complications of End-Stage Renal Disease. , 773-782.
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K Iseki, K Kohagura. (2007) Anemia as a risk factor for chronic kidney disease. Kidney International 72, S4-S9
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