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Schiller B.,Satellite Healthcare | Locatelli F.,Dialysis and Renal Transplant | Covic A.C.,Spitalul Clinic | Provenzano R.,Ford Motor Company | And 9 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis- stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point - death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia - with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].) Copyright © 2013 Massachusetts Medical Society. All rights reserved.

Cunningham J.,University College London | Locatelli F.,Dialysis and Renal Transplant | Rodriguez M.,Hospital Universitario Reina Sofia
Clinical Journal of the American Society of Nephrology | Year: 2011

Secondary hyperparathyroidism (SHPT) is a challenge frequently encountered in the management of patients with chronic kidney disease (CKD). Downregulation of the parathyroid vitamin D and calcium-sensing receptors represent critical steps that lead to abnormalities in mineral metabolism: high phosphate, low calcium, and vitamin D deficiency. These imbalances result in parathyroid hyperplasia and contribute to vascular calcification. New studies have established a central role for fibroblast growth factor 23 (FGF-23) in the regulation of phosphate-vitamin D homeostasis. FGF-23 concentration increases in CKD and contributes to SHPT. Achieving current targets for the key mineral parameters in the management of SHPT set by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines can be challenging. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients. Treatment should include a combination of dietary phosphorus restriction, phosphate binders, vitamin D sterols, and calcimi-metics. Parathyroidectomy is effective in suitable candidates refractory to medical therapy and the standard against which new approaches should be measured. Future strategies may focus on the stimulation of apopto-tic activity of hyperplastic parathyroid cells. © 2011 by the American Society of Nephrology.

Locatelli F.,Dialysis and Renal Transplant
The oncologist | Year: 2011

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.

Locatelli F.,Dialysis and Renal Transplant | Vecchio L.D.,Dialysis and Renal Transplant
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: Anemia, a frequent and early complication of chronic kidney disease (CKD), not only impairs quality of life but is also an independent risk factor for adverse cardiovascular outcomes. Erythropoiesis-stimulating agents (ESAs), together with iron, are the main therapeutic tool to correct anemia in CKD patients nowadays. Areas covered: Following a literature search on PubMed using 'anemia', 'hemoglobin', 'erythropoietin' and 'target' as keywords, we critically analyzed ESAs, looking in depth at their distinct characteristics and possible advantages in the clinical setting. The introduction of biosimilars into the European market is also discussed. Finally, we reviewed current evidence about the optimal hemoglobin (Hb) target to aim at in CKD patients receiving ESA and possible treatment indications by international guidelines or health institutions. Expert opinion: All ESAs are effective agents to correct anemia. Newer molecules have been developed with an improved pharmacokinetic and pharmacodynamic profile. This translates into longer administration intervals than can be a true advantage, mainly for CKD patients not receiving dialysis. Short-acting epoetins, including biosimilars, should be administered more often, but can be cheaper than last-generation molecules. Following publication of the TREAT study, there is considerable confusion about the optimal Hb target to aim for in CKD patients using ESA. While waiting for Kidney Disease Global Outcome (KDIGO) guidelines recommendations, we believe that the general approach to anemia management in CKD patients should still aim at Hb levels of 11 12 g/dl; however, it is wise to use caution in those patients who are hyporesponsive to ESA or have a previous history of stroke or malignancies. © 2012 Informa UK, Ltd.

Del Vecchio L.,Dialysis and Renal Transplant | Locatelli F.,Dialysis and Renal Transplant | Carini M.,University of Milan
Seminars in Dialysis | Year: 2011

Patients with chronic kidney disease (CKD) experience accelerated atherosclerosis leading to excessive cardiovascular death. This cannot be fully explained by traditional cardiovascular risk factors. Oxidative stress is currently receiving attention as an important pathogenetic mediator of tissue damage. Oxidative stress is highly prevalent in patients with CKD. Increased prooxidant activity (age, diabetes, hypertension, inflammation, incompatibility of dialysis membranes, and solutions) goes together with reduced antioxidant defense (reduced activity of the glutathione system, low levels of vitamin E, C). Oxidative stress has been linked to several surrogate markers of atherosclerosis in patients with CKD, such as endothelial dysfunction and intima-media thickness. However, large epidemiological studies testing hard endpoints are lacking. Oxidative stress may also influence response to erythropoiesis-stimulating agents. Among possible therapeutic approaches, the use of vitamin E seems to be the most promising. Given orally, it has been shown to significantly improve cardiovascular outcomes in a relatively small clinical trial. When bonded to biocompatible dialysis membranes, it may be effective in improving erythropoiesis-stimulating agents' responsiveness. Similarly, vitamin C may be effective in reducing cardiovascular events in haemodialysis patients. Further well-designed, randomized controlled clinical trials with antioxidants are required to establish their potential to make a substantive difference in clinical practice. © 2011 Wiley Periodicals, Inc..

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