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• W1986339985 abstract "Commentary on Macdougall IC, Provenzano R, Sharma A, et al (Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med. 2013;368[4]:320-332) and Fishbane S, Schiller B, Locatelli F, et al (Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med. 2013;368[4]:307-319). Commentary on Macdougall IC, Provenzano R, Sharma A, et al (Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med. 2013;368[4]:320-332) and Fishbane S, Schiller B, Locatelli F, et al (Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med. 2013;368[4]:307-319). Anemia often occurs in patients with advanced chronic kidney disease (CKD) as a result of erythropoietin deficiency and thus is responsive to erythropoiesis-stimulating agents (ESAs). Usually, anemia in patients with stages 3 and 4 CKD is moderate (arbitrarily defined as hemoglobin [Hb] level >10 g/dL, but lower than normal) and marked by a slow decline in Hb level1Skali H. Lin J. Pfeffer M.A. et al.Hemoglobin stability in patients with anemia, CKD, and type 2 diabetes An analysis of the TREAT (Trial to Reduce Caradiovascular Events With Aranesp Therapy) placebo arm.Am J Kidney Dis. 2013; 61: 238-246Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar; it is asymptomatic and its treatment rarely requires transfusions. However, in dialysis patients, anemia typically is more severe, Hb level may decrease rapidly, quality of life often is impaired, and transfusions frequently are required.2Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar Four recombinant human erythropoietins (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol–epoetin beta) have been used to treat anemia. Recently, a new approach using the peptide-based erythropoietic agent peginesatide, a dimeric pegylated peptide, was evaluated in 2 randomized controlled trials published in NEJM in early 2013, EMERALD and PEARL.3Macdougall I.C. Provenzano R. Sharma A. et al.Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis.N Engl J Med. 2013; 368: 320-332Crossref PubMed Scopus (83) Google Scholar, 4Fishbane S. Schiller B. Locatelli F. et al.Peginesatide in patients with anemia undergoing hemodialysis.N Engl J Med. 2013; 368: 307-319Crossref PubMed Scopus (77) Google Scholar Based on the then-unpublished results from these studies, on March 27, 2012, the US Food and Drug Administration (FDA) had approved peginesatide for use in dialysis patients, but given the finding of increased risk in nondialysis CKD discussed next, the FDA did not permit use in patients with non–dialysis-dependent CKD. On February 23, 2013, shortly after publication of EMERALD and PEARL, Affymax and Takeda, the producers of peginesatide, announced a nationwide voluntary recall of all lots of peginesatide injection as a result of new postmarketing reports of serious hypersensitivity reactions, including life-threatening or fatal anaphylaxis.5US Food and Drug AdministrationOmontys (peginesatide) Injection by Affymax and Takeda: Recall of All Lots - Serious Hypersensitivity Reactions.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm340895.htmGoogle Scholar The rate of hypersensitivity reactions reported was 0.2%, of which approximately one-third were serious in nature. A safety signal for hypersensitivity reactions was not reported in the 2 NEJM articles, which supports the belief that these noninferiority studies were too small to provide adequate data for safety. The purpose of this editorial is to review these trials and the lessons learned. Anemic patients with CKD who were not treated with dialysis or ESAs were enrolled in 2 randomized controlled trials with 3 treatment arms, called PEARL I and PEARL II. One group of patients received peginesatide once a month at a starting dose of 0.025 mg (n = 328) or 0.04 mg (n = 328) per kilogram of body weight; the other group received darbepoetin once every 2 weeks at a starting dose of 0.75 μg/kg (n = 327).3Macdougall I.C. Provenzano R. Sharma A. et al.Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis.N Engl J Med. 2013; 368: 320-332Crossref PubMed Scopus (83) Google Scholar These trials were open-label studies that used a noninferiority design. Inclusion required 2 consecutively measured Hb levels of 8.0-11.0 g/dL in the 4 weeks prior to randomization regardless of whether symptoms related to anemia were present. Mean baseline Hb level was 10.0 g/dL. For both peginesatide and darbepoetin, doses were adjusted to reach and maintain Hb levels of 11.0-12.0 g/dL for 1 year or longer. An adjudicated composite end point was used to assess cardiovascular safety. At both starting doses in the PEARL studies, peginesatide was not inferior to darbepoetin in increasing and maintaining Hb levels. Compared with darbepoetin, the hazard ratio (HR) for the cardiovascular safety end point was 1.32 (95% confidence interval [CI], 0.97-1.81) for peginesatide, with greater incidences of unstable angina, arrhythmia, and death in this group. Not surprisingly in view of the relatively small patient numbers, there were study imbalances in several baseline variables. In the multivariate model, the adjusted HR for the composite safety end point was not significant (HR, 1.20; 95% CI, 0.87-1.64). No information was provided for symptoms or quality-of-life outcomes. Hemodialysis patients who already were treated with epoetin were studied in 2 more randomized controlled trials, EMERALD I and EMERALD II, each of which had only 2 treatment arms.4Fishbane S. Schiller B. Locatelli F. et al.Peginesatide in patients with anemia undergoing hemodialysis.N Engl J Med. 2013; 368: 307-319Crossref PubMed Scopus (77) Google Scholar Peginesatide was provided once a month to 1,066 patients and compared to epoetin administered 1-3 times per week in 542 patients; doses were adjusted to maintain Hb levels at 10.0-12.0 g/dL for 1 year or longer. These trials also were open-label noninferiority studies, and inclusion required 4 consecutive screen Hb measurements with a mean value of 10.0-12.0 g/dL. Peginesatide was not inferior to epoetin in maintaining Hb levels. The HR for the composite cardiovascular end point was 0.95 (95% CI, 0.77-1.17). In the article reporting findings of the EMERALD studies, the investigators also reported results of a prespecified pooled analysis of PEARL and EMERALD, looking at the composite safety end point. In this analysis, which included patients with stages 3-5 CKD, it was estimated that 553 patients experiencing a positively adjudicated cardiovascular event would correspond to at least 89% power to exclude an HR of more than 1.3 (peginesatide vs epoetin) based on a 1-sided 95% CI.4Fishbane S. Schiller B. Locatelli F. et al.Peginesatide in patients with anemia undergoing hemodialysis.N Engl J Med. 2013; 368: 307-319Crossref PubMed Scopus (77) Google Scholar The actual HR with peginesatide was 1.06 (95% CI, 0.89-1.26). There is no evidence regarding the benefit to harm ratio of darbepoetin compared to placebo in patients with Hb levels of 8.0-11.0 g/dL with a target of 11.0-12.0 g/dL. TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) randomly allocated 4,038 patients with diabetes, CKD, and anemia to placebo or darbepoetin treatment to achieve an Hb level of 13 g/dL.6Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1652) Google Scholar Stroke occurred in 5% of darbepoetin group participants, with the risk of stroke increased almost 2-fold compared to placebo (HR, 1.92; 95% CI, 1.38-2.68). In TREAT, there was no difference in the composite outcome of death or cardiovascular events between the 2 groups, unlike the risk reported by the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial,7Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2283) Google Scholar in which the HR for the high-Hb group was 1.34 (95% CI, 1.03-1.74). CHOIR studied a smaller number (N = 1,432) of patients who were randomly allocated to epoetin alfa treatment targeted to achieve an Hb level of 13.5 or 11.3 g/dL. Cardiovascular outcomes in the stages 3-4 CKD peginesatide trials are a concern. However, the unadjusted HR compared to darbepoetin did not achieve statistical significance, and when adjusted for baseline imbalances in clinical characteristics, the HR was lower than it was in unadjusted analyses. It should be noted that judgments of safety are limited by the small sample size and use of a composite end point, which could obscure an important effect on one of the composite events. There is no evidence to determine the benefit to harm ratio in large randomized trials comparing partial correction of anemia (target Hb, 10.0-2.0 g/dL) to placebo, although using epoetin to achieve a target Hb level of 9.5-11.0 g/dL has been reported to substantially lower transfusion rates and significantly improve fatigue, physical function, and results of a 6-minute walking test.2Canadian Erythropoietin Study GroupAssociation between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.BMJ. 1990; 300: 573-578Crossref PubMed Google Scholar The Normal Hematocrit Study randomly allocated 1,233 prevalent hemodialysis patients with symptomatic heart failure or ischemic heart disease treated with epoetin to full correction of anemia or partial correction.8Besarab A. Bolton W.K. Browne J.K. 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: 584-590Crossref PubMed Scopus (1883) Google Scholar The HR of full correction for the primary outcome (death or myocardial infarction) was 1.3 (95% CI, 0.9-1.9). The trial was stopped early because the primary hypothesis was unlikely to be proved and the intervention was causing harm: 39% of patients in the full correction group experienced vascular access clotting versus 29% in the partial treatment arm. In the Canada-Europe trial (N = 596), patients without symptomatic cardiac disease who were randomly assigned to full anemia correction experienced a significantly higher incidence of stroke than those in the partial correction group; however, the absolute number that developed a stroke was very small.9Parfrey P.S. Foley R.N. Wittreich B.H. et al.Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.J Am Soc Nephrol. 2005; 16: 2180-2189Crossref PubMed Scopus (323) Google Scholar The peginesatide trials in hemodialysis patients only examined the outcomes of maintaining Hb levels at 10.0-12.0 g/dL in patients who were already treated with epoetin.4Fishbane S. Schiller B. Locatelli F. et al.Peginesatide in patients with anemia undergoing hemodialysis.N Engl J Med. 2013; 368: 307-319Crossref PubMed Scopus (77) Google Scholar Consequently, it is possible that the risk of cardiovascular events caused by ESAs may have been low because only survivors of epoetin therapy could have entered these trials. Nonetheless, there was no safety signal. The objective of pooling data from the 4 trials was to demonstrate that peginesatide was as safe as the comparator ESA by excluding an HR with peginesatide of more than 1.3. The relatively small number of patients enrolled precluded exclusion of a lower and more desirable safety margin. Furthermore, pooling individual studies from groups with different clinical characteristics can yield spurious or counterintuitive results.10Bravata D.M. Olkin I. Simple pooling versus combining in meta-analysis.Eval Health Prof. 2001; 24: 218-230Crossref PubMed Scopus (104) Google Scholar The peginesatide trials of patients with stages 3 and 4 CKD were different from those in patients with stage 5 CKD: not only were the patients at an earlier phase of CKD, but they were older (mean ages, 68 vs 58 years), had lower proportions of men (42% vs 57%), and had a higher proportion with diabetes as the cause of kidney disease (50% vs 38%). Furthermore, the intervention was different: in one trial, ESA-naive patients with stages 3-4 CKD were initiated on treatment with an ESA, whereas the other patients with stage 5 CKD already treated with dialysis and ESAs were enrolled in a trial that maintained Hb levels. Therefore, the reassuring pooled HR for cardiovascular events in patients with stages 3-5 CKD does not negate the higher and concerning HR in patients with stages 3-4 CKD. For initiating ESA treatment, the recent KDIGO (Kidney Disease: Improving Global Outcomes) guidelines urged nephrologists to take into account the presence or absence of anemia-related symptoms and the extent of the transfusion risk, rather than treating particular Hb levels.11McMurray J.J. Parfrey P.S. Adamson J.W. et al.KDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Crossref Scopus (675) Google Scholar The guidelines suggest that ESA therapy not be initiated in adults with Hb levels ≥10.0 g/dL. If Hb level is <10.0 g/dL, the guidelines suggest basing the decision of whether to initiate ESA therapy on the individual's rate of Hb level decline, prior therapeutic response to iron therapy, risk of requiring a blood transfusion, presence or absence of symptoms attributable to anemia, and risks related to ESA treatment. In view of its uncertain benefit to harm ratio, it would be advisable not to use peginesatide in patients with stages 3 and 4 CKD even if a patient's Hb level is <10.0 g/dL regardless of the potential risk of anaphylaxis reported in postmarketing studies. The KDIGO guidelines suggest initiating ESA treatment when Hb level is within the range of 9.0-10.0 g/dL in dialysis patients to prevent Hb levels from decreasing to <9.0 g/dL.11McMurray J.J. Parfrey P.S. Adamson J.W. et al.KDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Crossref Scopus (675) Google Scholar The guidelines suggest that ESAs not be used to maintain Hb levels at >11.5 g/dL. Peginesatide is not inferior to conventional recombinant ESAs in maintaining Hb levels, and from the data reported in EMERALD, it may be as safe.4Fishbane S. Schiller B. Locatelli F. et al.Peginesatide in patients with anemia undergoing hemodialysis.N Engl J Med. 2013; 368: 307-319Crossref PubMed Scopus (77) Google Scholar However, the numbers studied are small and the drug has not been tested as an initial treatment in ESA-naive hemodialysis patients. Less frequent dosing may be an advantage in peritoneal dialysis patients, but less so in hemodialysis patients. Peginesatide would be beneficial in the rare patient who develops red blood cell aplasia as a result of antibodies to recombinant ESA. Critically, for all ESAs, large randomized placebo-controlled trials of partial correction of anemia with ESAs in patients with Hb levels of 8.0-10.0 g/dL would be of interest to determine whether such an intervention would improve symptoms, quality of life, and cardiovascular outcomes without causing harm. The long-term impact of antibodies to peginesatide, particularly on its efficacy, also would be of interest. Finally, if peginesatide re-emerges as a safe anemia management option, data for the cost-effectiveness of peginesatide in comparison to other ESAs or other approaches to treating anemia will determine the extent of its use. Support: None. Financial Disclosure: Dr Parfrey is an executive committee member of TREAT, which is funded by Amgen, and has received remuneration from Amgen for traveling and speaking. Drs Warden and Barrett declare that they have no relevant financial interests." @default.
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• W1986339985 title "On Peginesatide and Anemia Treatment in CKD" @default.
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