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FEATURE: Alison Tonks Too much of a good thing BMJ 2007; 334: 978-980 [Full text]

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Chronic Kidney Disease: Physiology argues against targeting high haemoglobin levels

Francisca Ferrer, José Rivera, and Vicente Vicente   (18 May 2007)

Marketing Epoetin: Too Much of a Good Thing

Ajay K. Singh, MBBS, MRCP(UK)   (26 May 2007)

Chronic Kidney Disease: Physiology argues against targeting high haemoglobin levels 18 May 2007
Francisca Ferrer, PhD, MD Centro Regional de Hemodonación. Murcia. Spain, José Rivera, and Vicente Vicente Send response to journal: Re: Chronic Kidney Disease: Physiology argues against targeting high haemoglobin levels	The recent paper by A. Tonks further rises the controversy about the best haemoglobin target for patients with chronic kidney disease (1). Indeed, erythropoietin-stimulating agents has became the most widely used treatment for anaemia management in this disorder, despite high cost and uncertainty regarding the haemoglobin levels at which to start this therapy and the optimum haemoglobin target concentrations. Two recent randomised trials (2,3) and a meta-analysis (4) sharply suggest most caution in full correction of anaemia in patients with chronic kidney disease, by showing that targeting higher haemoglobin concentrations, despite being within the normal physiological range, may provide no benefit or even put the patients at increased risk of adverse complications and death. Suggested mechanisms underling this worse outcome associated to higher haemoglobin concentrations includes increase in blood viscosity and also erythropoietin-mediated rise in inflammation, anti-fibrinolytic activity, vascular growth, and production of vasoactive factors (4). For the shake of the debate, we would like to comment on a physiologic mechanism that may favour the unnecessary full correction of anaemia in patients with chronic kidney disease. It is well known that adequate oxygen delivery (DO2) is needed to meet the tissue oxygen requirements (VO2) for aerobic metabolism. DO2 is defined as the product of cardiac output, oxygen saturation, the haemoglobin concentration, and a constant K (coefficient for haemoglobin-oxygen binding capacity) (4). Noteworthy, VO2 is largely DO2 independent, since the oxygen extraction ratio (VO2/DO2) rises as supply diminishes or demand increases. Only if a maximum VO2/DO2 is attained, a reduction of DO2 below a critical value leads to insufficient VO2 and tissue hypoxia (5). Thus, above a minimum DO2 value further increasing haemoglobin level by erythropoietin administration would not improve VO2. In addition, it is recognised that in chronic anaemia, 2-3-diphosphoglycerate increases and the oxygen- haemoglobin dissociation curve may shifts to the right, and in uremic patients the haemogliobin-O2 affinity is not increased, all these suggesting that lower haemoglobin levels may provide appropriate oxygen availability (6). Thus, not only the available data from recent trials and meta- analysis, but also the physiology of the oxygen delivery under anaemic condition in chronic kidney disease, point against complete as compared to partial correction of haemoglobin level in this disorder. 1.Tonks. Too much of a good thing. BMJ 2007; 334: 978-80. 2.Drüeke 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: 2071-84. 3.Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085-98. 4.Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erytropoietin: a meta-analysis. Lancet 2007; 369: 381-8. 5.Treacher DF, Leach RM. Oxygen transport-1. Basic principles. BMJ 1998, 317: 1302-6. 6.Monti JP, Brunet PJ, Berland YF, Vanuxem DC, Vanuxem PA, Crevat AD. Opposite effects of urea on hemoglobin-oxygen affinity in anemia in chronic renal failure. Kidney Int 1995; 48: 827-31. Competing interests: None declared
Marketing Epoetin: Too Much of a Good Thing 26 May 2007
Ajay K. Singh, MBBS, MRCP(UK), Clinical Director, Nephrology, Brigham & Women's Hosp; Assoc. Prof of Med, Harvard Medical School Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA Send response to journal: Re: Marketing Epoetin: Too Much of a Good Thing	Dear Editor: In her article titled “Too Much of a Good Thing” Tonks (May 12th issue (1)) discusses some of the factors contributing to epoetin over- treatment in the United States. Data from the United States Renal Data System (2) from 2004 reveals that >50% of dialysis patients in the US had haemoglobin (Hgb) levels beyond 120 g/L. However, it is important to point out, this was not always the case. In 1998, approximately 10% of patients had Hgb levels of >120 g/L, whereas by 2000 this had rapidly grown to 40% of all dialysis patients (2). Surprisingly, this steep increase in mean Hgb levels occurred after the publication in 1998 of the Normal Haematocrit Study (NHS) (3) showing a higher risk of death or myocardial infarction in aiming for a haematocrit of 42% (relative risk of 1.3, 95% CI: 0.9, 1.9). The authors of NHS addressed why the study was stopped: “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- haematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal haematocrit group” (3). 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 Hgb levels of 120 to 140 g/L in patients with chronic renal failure (reviewed most recently at an FDA oncology advisory committee meeting (4). The steep increase in Hgb levels from 1996 onwards, coupled with a 50% increase in the average epoetin dose administered to dialysis patients during this time (5), needs to be further scrutinized. More recently, publication of two studies in non-dialysis chronic kidney disease patients has further reinforced the increased risk associated with targeting of higher haemoglobin levels (6,7). Tonks cites the possibility that guidelines and perverse incentives could have contributed to this epoetin over-treatment. Coyne and others have been central to this debate and have voiced their concerns (8,9). However, Tonks does not discuss two other potential possibilities, namely the aggressive marketing of off-label use of epoetin by the pharmaceutical industry during this time-frame (discussed extensively in the lay-press), and the widespread acceptance of standing orders and automated protocols in dialysis centers that, in effect, reduce the input dialysis physicians have in the day-to-day management of anemia (10). Indeed, marketing strategies aimed at doctors are frequently very effective in driving off-label use of a drug. This has been discussed extensively with regards to the promotion of gabapentin (11). The pervasive influence of marketing activities on molding opinions about epoetin use has also been brought to light (12). The salutary lesson in this tale is that despite processes already in place (for example, the Accredited Council for Continuing Medical Education (ACCME) in the United States) more tightening in the marketing of drugs is warranted. Furthermore, physicians need to become more involved in the details of anemia management in their patients on dialysis. References 1 Tonks A. Too much of a good thing. BMJ. 2007 May 12;334(7601):978- 80. 2. USRDS 2006 annual data report: atlas of end-stage renal disease in the United States. Minneapolis: U.S. Renal Data System, 2006. (http://www.usrds.org/adr.htm.) 3. 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. 4. www.fda.gov/OHRMS/DOCKETS/AC/07/briefing/2007-4301b2-02-FDA.pdf (p 10). 5. Report to the Chairman, Committee on Ways and Means, House of Representatives. End-stage renal disease: bundling of Medicare's payment for drugs with payment for all ESRD services would promote efficiency and clinical flexibility. Washington, DC: Government Accountability Office, November 2006. (GAO-07-77.) (http://www.gao.gov/cgi-bin/getrpt?GAO-07-77.) 6. 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 7. 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):2071-8 8. Coyne DW Influence of Industry on Renal Guideline Development Clin J Am Soc Nephrol 2: 3-7, 2007 9. Kassirer JP Clin J Am Soc Nephrol 2: 212, 2007 10. Hossli S. Developing an anemia management protocol. Case study of the anemic patient. ANNA J. 1997 Dec;24(6):678-84; quiz 685. 11. 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.) 12. Dyer O. Journal rejects article after objections from marketing department. BMJ. 2004 Jan 31;328(7434):244. Competing interests: Dr. Singh reports having received consulting fees from Ortho Biotech Clinical Affairs, Amgen, Roche, Merck (Germany), Abbott, Watson, and Horizon Blue Cross Blue Shield and lecture fees from Ortho Biotech Clinical Affairs, Wyeth, Roche, Amgen, Abbott, Watson and Genzyme; having served on advisory boards for Ortho Biotech Clinical Affairs, Roche, Watson, Advanced Magnetics, and Amgen; and having received grant support from Ortho Biotech Clinical Affairs, Dialysis Clinic, Roche, Amgen, Baxter, Watson, Genentech, and the National Institutes of Health (NIH). Medical Director, Dialysis Clinic Inc.