Correspondence
The Normal Hematocrit Study — Follow-up
N Engl J Med 2008; 358:433-434January 24, 2008
- Article
To the Editor:
We previously reported in the Journal the results of a randomized, prospective study comparing outcomes of normal versus low hematocrit values in 1233 patients with congestive heart failure or ischemic heart disease who were undergoing hemodialysis and receiving treatment with epoetin alfa; 618 patients were randomly assigned to the normal-hematocrit group, and 615 to the low-hematocrit group.1 The primary end point was the length of time to death or a first nonfatal myocardial infarction. The editors of the Journal requested that we now provide supplemental data, including end-point events that occurred after the data set was analyzed by the independent data and safety monitoring committee, as reported in the previous article. This invitation was prompted by a presentation by the Food and Drug Administration on September 11, 2007, in which higher numbers of patients and events than were reported in the article were discussed.
The data and safety monitoring committee recommended termination of the study after 29 months (median duration of treatment, 14 months). The committee was convened on June 3, 1996, and reviewed data for the 1233 patients available as of March 31, 1996; these data were the basis for the article. There were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group (target hematocrit, 42%) versus 150 deaths and 14 nonfatal myocardial infarctions among the patients in the low-hematocrit group (target hematocrit, 30%) (Table 1Table 1
Primary End-Point Events in the Two Data Sets.). Although the difference in event-free survival between the groups did not reach the prespecified statistical stopping boundary, the results were clearly heading in a direction that threatened the safety of the patients in the normal-hematocrit group. In addition, the incidence of vascular-access thrombosis was significantly higher in the normal-hematocrit group (39%) than in the low-hematocrit group (29%). We concluded that a target hematocrit value of 42% in this patient population cannot be recommended.The treatment intervention was halted on June 24, 1996, by which time a total of 1265 patients had been randomly assigned to a study group: 634 to the normal-hematocrit group and 631 to the low-hematocrit group. In the 3 months between March 31, 1996, and June 24, 1996, there were 25 additional deaths and 1 additional nonfatal myocardial infarction in the normal-hematocrit group, as compared with 23 additional deaths and 2 additional nonfatal myocardial infarctions in the low-hematocrit group. When these events are included, the risk ratio for death or myocardial infarction again fails to cross the prespecified statistical boundary for significance in this fourth analysis (Table 1).
Patients were followed for 1 year after cessation of the study intervention. Hematocrit values in the normal-hematocrit group declined over a period of 8 weeks to approximately 33%. During that year, there were 91 deaths and 0 nonfatal myocardial infarctions in the original normal-hematocrit group, as compared with 91 deaths and 1 nonfatal myocardial infarction in the low-hematocrit group. These near-identical findings suggest an absence of residual ill effects of the experimental intervention. The rate of vascular-access thrombosis did not differ significantly between the normal-hematocrit group and the low-hematocrit group (21% and 23%, respectively) during this follow-up period.
These additional data show no further evidence of detrimental outcomes associated with a normal hematocrit. We maintain our original conclusion that a target hematocrit value of 42% cannot be recommended in patients with cardiac disease who are undergoing hemodialysis. Two recent studies also suggest that lower target hematocrit values are more appropriate in patients with chronic kidney disease who are not undergoing dialysis.2,3
Anatole Besarab, M.D.
Henry Ford Hospital, Detroit, MI 48202
abesera1@hfhs.org David A. Goodkin, M.D.
Allen R. Nissenson, M.D.
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095for the Normal Hematocrit Cardiac Trial Authors
Drs. Besarab, Goodkin, and Nissenson report receiving consulting fees from Amgen and Affymax; Drs. Besarab and Nissenson, from Hoffmann–La Roche; and Dr. Nissenson, from Amgen, Prometic, OBI, FibroGen, and Medgenics. Dr. Besarab reports receiving lecture fees from Amgen and Hoffmann–La Roche; and Dr. Nissenson, from CME (sponsored by Hoffmann–La Roche) and Watson Pharma. Dr. Besarab reports receiving grant support from Affymax, Fibrogen, and Hoffmann–La Roche; and Dr. Nissenson, from Amgen, Hoffmann–La Roche, and OBI. Dr. Goodkin reports that he is an investigator for and coauthor of some of the publications of the Dialysis Outcomes and Practice Patterns Study (DOPPS), which is funded by Kirin–Amgen and conducted by Arbor Research Collaborative for Health. Dr. Nissenson reports holding stock options in Medgenics. Dr. Goodkin was employed by Amgen and held Amgen equity or stock options at the time the study was conducted. Dr. Bersarab reports having served as an expert witness for Hoffmann–La Roche. No other potential conflict of interest relevant to this letter was reported.
3 References1
Besarab A ,Bolton WK ,Browne JK , et al. 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;339:584-590
Full Text | Web of Science | Medline2
Drueke TB ,Locatelli F ,Clyne N , et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-2084
Full Text | Web of Science | Medline3
Singh AK ,Szczech L ,Tang KL , et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098
Full Text | Web of Science | Medline
- Citing Articles (18)
Citing Articles
1
L. Velly, L. Pellegrini, B. Guillet, N. Bruder, P. Pisano. (2010) Erythropoietin 2nd cerebral protection after acute injuries: A double-edged sword?. Pharmacology & Therapeutics 128:3, 445-459
CrossRef2
Jeffrey S Berns. (2010) Are there implications from the Trial to Reduce Cardiovascular Events with Aranesp Therapy study for anemia management in dialysis patients?. Current Opinion in Nephrology and Hypertension 19:6, 567-572
CrossRef3
Andrew A. House, Mikko Haapio, Johan Lassus, Rinaldo Bellomo, Claudio Ronco. (2010) Therapeutic Strategies for Heart Failure in Cardiorenal Syndromes. American Journal of Kidney Diseases 56:4, 759-773
CrossRef4
Steven Fishbane, Allen R Nissenson. (2010) Anemia management in chronic kidney disease. Kidney International 78, S3-S9
CrossRef5
Raymond T. Krediet, Olga Balafa. (2010) Cardiovascular risk in the peritoneal dialysis patient. Nature Reviews Nephrology 6:8, 451-460
CrossRef6
Irene M. Van Der Meer, Piero Ruggenenti, Giuseppe Remuzzi. (2010) THE DIABETIC CKD PATIENT-A MAJOR CARDIOVASCULAR CHALLENGE. Journal of Renal Care 36, 34-46
CrossRef7
Seul-Ki Jeong, Young I. Cho, Marc Duey, Robert S. Rosenson. (2010) Cardiovascular Risks of Anemia Correction with Erythrocyte Stimulating Agents: Should Blood Viscosity Be Monitored for Risk Assessment?. Cardiovascular Drugs and Therapy 24:2, 151-160
CrossRef8
Radica Z. Alicic, Katherine R. Tuttle. (2010) Management of the Diabetic Patient with Advanced Chronic Kidney Disease. Seminars in Dialysis 23:2, 140-147
CrossRef9
Lynda Szczech. (2010) Anemia trials: lessons for clinicians, politicians, and third-party payers. Kidney International 77:6, 479-480
CrossRef10
(2009) The D&T report. Dialysis & Transplantation 38:12, 484-487
CrossRef11
David A. Goodkin. (2009) The Normal Hematocrit Cardiac Trial Revisited. Seminars in Dialysis 22:5, 495-502
CrossRef12
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
CrossRef13
Ajay K. Singh. (2008) The Controversy Surrounding Hemoglobin and Erythropoiesis-Stimulating Agents: What Should We Do Now?. American Journal of Kidney Diseases 52:6, S5-S13
CrossRef14
F. Locatelli, A. Covic, K.-U. Eckardt, A. Wiecek, R. Vanholder, . (2008) Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP). Nephrology Dialysis Transplantation 24:2, 348-354
CrossRef15
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
CrossRef16
James E Novak, Jula K Inrig, Uptal D Patel, Robert M Califf, Lynda A Szczech. (2008) Negative trials in nephrology: what can we learn?. Kidney International 74:9, 1121-1127
CrossRef17
Lynda A Szczech, Huiman X Barnhart, Jula K Inrig, Donal N Reddan, Shelly Sapp, Robert M Califf, Uptal D Patel, Ajay K Singh. (2008) Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney International 74:6, 791-798
CrossRef18
Daniel W. Coyne. (2008) From Anemia Trials to Clinical Practice: Understanding the Risks and Benefits When Setting Goals for Therapy. Seminars in Dialysis 21:3, 212-216
CrossRef
