Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis

Amato, Laura; Addis, Antonio; Saulle, Rosella; Trotta, Francesco; Mitrova, Zuzana; Davoli, Marina

doi:10.1007/s40620-017-0419-5

Cited by 16 publications

(5 citation statements)

References 55 publications

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“…The type of ESA may play a role in the risk of adverse outcomes, but the relative risk among individual ESAs remains controversial. In a large, long-term, randomized trial, patients with CKD receiving epoetin beta pegol had no increase in risk of all-cause mortality, nonfatal myocardial infarction, or stroke compared to those receiving either epoetin alfa or darbepoetin alfa [36], in agreement with prior meta-analyses that found no significant safety differences among ESAs [37][38][39]. A recent pooled analysis of prospective cohorts in Italy with non-dialysis-dependent (NDD) CKD stages 1-5 showed that the risk of the composite of end-stage kidney disease or death was not impacted by the type of ESA (e.g., short-acting [epoetin alfa or epoetin beta] or long-acting [darbepoetin alfa or epoetin beta pegol]) when all dosing levels were pooled but did increase at higher standardized ESA doses [40].…”

Section: Prevalence and Characteristics Of Esa Hyporesponsesupporting

confidence: 82%

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Weir

2021

Am J Nephrol

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Background: Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. Summary: The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

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Section: Prevalence and Characteristics Of Esa Hyporesponsesupporting

confidence: 82%

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Weir

2021

Am J Nephrol

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“…For biosimilars, both of the included meta-analyses 27,28 and one 29 of the two RCTs 29,30 involved patients with CKD. The only RCT in patients with cancer 30 had a high likelihood of bias based on inadequate sample size, lack of an intent-to-treat analysis, and industry funding and authorship.…”

Section: Resultsmentioning

confidence: 99%

“…The systematic review of biosimilar ESAs included two metaanalyses 27,28 and one RCT 29 in patients with CKD, and one RCT 30 and three cohort studies [31][32][33] in patients with cancer. In a 2017 meta-analysis of RCTs in CKD, Amato et al 27 reported that efficacy and safety outcomes did not differ significantly between patients treated with epoetin alfa originator or biosimilar but described the quality of evidence as low to very low. A 2017 Cochrane review by Hahn et al 28 focused on short-acting ESAs in predialysis patients.…”

Section: Recommendationmentioning

confidence: 99%

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update

Bohlius

Bohlke

Castelli

et al. 2019

JCO

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PURPOSE To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed. RESULTS The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited. RECOMMENDATIONS ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines .

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“…Several reviews also contributed to ascertaining the available evidence on the consequences of switching from originators to related biosimilars, although they were not focused exclusively on ESAs [20, 22, 32]. In particular, these three studies did not find any differences in terms of immunogenicity, safety or efficacy between those continuing therapy with originators or those switching to biosimilars, thus indicating that concerns related to switching have been so far unsupported.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and Safety of Switching Originator and Biosimilar Epoetins in Patients with Chronic Kidney Disease in a Large-Scale Italian Cohort Study

Belleudi¹,

Trotta

Addis³

et al. 2019

Drug Saf

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IntroductionReal-world data on the comparative effectiveness and safety of switching among different epoetins (including originators and biosimilars) are limited. In light of current debate about interchangeability, prescribers, some patient groups and decision makers are calling for additional post-marketing evidence on the clinical effects of switching between originator and biosimilar epoetins in chronic kidney disease (CKD) patients.ObjectiveThe objective of this study was to evaluate the effectiveness and safety of switching versus non-switching and of switching from originator/biosimilar epoetin alpha (ESA α) to any other epoetin in CKD patients.MethodsAn observational, record-linkage, multi-database, retrospective cohort study was carried out in four Italian geographical areas. All subjects with at least one ESA α dispensing between 1 January 2009 and 31 December 2015 were retrieved. Switching was defined as any transition between originator/biosimilar ESA α to any other epoetin in a series of two consecutive prescriptions up to 2 years. Switchers were matched 1:1 with non-switchers by baseline propensity score and by duration of ESA α treatment. Switchers and non-switchers were followed up from switching date to a maximum of 1 year. Lack of effectiveness and safety of switching versus non-switching were evaluated through Cox regression models (hazard ratio [HR], 95% confidence interval [CI]). A direct comparison between the two switcher categories (switchers from originator/biosimilar ESA α to any other epoetin) was also performed.ResultsOverall, 14,400 incident users of ESA α for anaemia due to CKD (61.4% originator, 38.6% biosimilar) were available for analysis. During the follow-up, we found no differences on effectiveness (HR 1.02, 95% CI 0.79–1.31 originators; HR 1.16, 95% CI 0.75–1.79 biosimilars) and safety outcomes (HR 1.08, 95% CI 0.77–1.50 originators; HR 1.20, 95% CI 0.66–2.21 biosimilars) between switchers and non-switchers of ESA α. Cumulative probabilities of recording an adverse event, either in terms of lack of effectiveness or safety issue, were the same for two switching categoriesConclusionsIn this large-scale Italian observational multi-database study, switching versus non-switching as well as switching from biosimilar/originator ESA α to any other epoetin in CKD patients is not associated with any effectiveness and safety outcomes.Electronic supplementary materialThe online version of this article (10.1007/s40264-019-00845-y) contains supplementary material, which is available to authorized users.

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Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis

Cited by 16 publications

References 55 publications

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update

Effectiveness and Safety of Switching Originator and Biosimilar Epoetins in Patients with Chronic Kidney Disease in a Large-Scale Italian Cohort Study

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