epoetin-alfa and Venous-Thromboembolism

Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties.. A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020).. Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; COVID-19; Epoetin Alfa; Erythropoietin; Expert Testimony; Forecasting; Guideline Adherence; Hematinics; Hematologic Neoplasms; Hematopoiesis; Humans; Iron; Medicine; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Neoplasms; Observational Studies as Topic; Pandemics; Practice Guidelines as Topic; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; Venous Thromboembolism

A "biosimilar" or "similar biological medicinal product" is a biological agent that is similar in terms of quality, safety, and efficacy to an authorized reference biological medicine. Since the expiration of the epoetin alfa patent in Europe, three agents have received marketing authorization from the European Medicines Agency: Binocrit (epoetin alfa; aka Abseamed and Epoetin Alfa Hexal), Retacrit (epoetin zeta; aka Silapo), and Eporatio (epoetin theta; aka Biopoin and Ratioepo).. Using the EMA dossiers and journal publications, this article reviews clinical safety data for these products, with emphasis on serious/severe adverse events and a special consideration of immunogenicity, venous thromboembolism, and mortality.. A review of the available safety evidence shows that all three agents discussed have similar safety profiles. None were statistically higher on safety parameters to what is known about ESA as a class, when stratified by population. As with ESAs in general, immunogenicity, venous thromboembolism, and mortality are all concerns. What is known about ESAs regarding safety can be extended to biosimilar erythropoietins. Since biosimilars are unique, complex biological molecules, safety profiles may evolve from common to differentiated, once long-term product-specific safety data are available. Large-sample, long-term, observational studies of real-world practice will provide the heterogeneity and statistical power to demonstrate product-specific effectiveness and safety profiles. Statistically, out of the commercially available formulations of the three products reviewed, no single product is less or more safe.

Topics: Animals; Biosimilar Pharmaceuticals; Drug Hypersensitivity; Drug Monitoring; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Incidence; Pharmacovigilance; Recombinant Proteins; Venous Thromboembolism

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Anemia; Castration; Double-Blind Method; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Male; Middle Aged; Prostatic Neoplasms; Quality of Life; Recombinant Proteins; Venous Thromboembolism

Venous thromboembolism (VTE) is a significant but poorly understood complication in patients with newly diagnosed multiple myeloma (NDMM). As a result, most patients receive thromboprophylaxis with low molecular weight heparin (LMWH). The purpose of this retrospective study was to identify risk factors for VTE in NDMM and evaluate the effectiveness of LMWH.. A total of 604 patients with newly diagnosed myeloma completed 3 induction cycles with multiagent chemotherapy with up-front randomization to thalidomide between 1998 and 2004. Prophylactic enoxaparin was given to thalidomide recipients beginning in June 2001, and 122 subjects received prophylactic epoetin alfa (EPO) as part of an exercise trial. The primary study endpoint was grades 3-4 VTE.. A total of 72 patients (11.9%) developed VTE (mostly deep venous thrombosis), with a higher incidence among EPO recipients (P = .001), although only significant for upper extremity DVT (P = .0002). The EPO-treated patients had higher hemoglobin (Hb) levels throughout the study (P < .0005), although no relationship between higher Hb levels and increasing incidence of VTE could be shown. A history of VTE was a strong predictor of VTE on univariate analysis (P < .000005). Enoxaparin did not reduce the rate of VTE (P = .158). Logistic regression analysis identified thalidomide therapy (P = .001; odds ratio [OR], 2.428; 95% confidence interval [CI], 1.418-4.159) and prophylactic EPO (P = .002; OR, 2.488; 95% CI, 1.432-4.324) as risk factors for VTE. Myeloma response and survival were not negatively affected by prophylactic EPO or VTE.. Prophylactic EPO, thalidomide therapy, and VTE history, but not higher Hb levels, were found to increase the risk of VTE among NDMM patients receiving multiagent chemotherapy. This risk was not found to be reduced in this population by LMWH thromboprophylaxis.

Topics: Adult; Aged; Anticoagulants; Enoxaparin; Epoetin Alfa; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Risk Factors; Thalidomide; Venous Thromboembolism

ESA therapy can increase hemoglobin, decrease blood transfusions, and improve quality of life in patients with chemotherapy induced anemia (CIA). Despite its benefits, ESA therapy increases the risk of venous thromboembolism (VTE) in cancer patients by 50% and can also cause iron restricted erythropoiesis in CIA patients, which may augment the tendency to develop VTE. We postulated that thrombocytosis, a risk factor for VTE in cancer patients, in CIA patients on ESA therapy might be a result of ESA induced iron restricted erythropoiesis. We performed a retrospective analysis of 187 CIA patients who were randomized to receive weekly Epoetin and IV ferric gluconate, oral ferrous sulfate, or no iron for 8 weeks. Nineteen patients experienced 29 VTEs, and patients, whose platelets increased to ≥350,000 cells/uL were three times more likely to experience a VTE (OR 2.9, P = 0.036, logistic regression) with a four times greater incidence of VTE (IRR 4.4, P = 0.001, Poisson regression). Patients treated with IV iron were significantly less likely to develop platelets of ≥350,000 cells/uL (IRR 0.7, P = 0.013, Poisson regression) and had a decreased incidence of VTE. Our study suggests that ESA associated VTE in CIA patients may be, in part, related to the thrombocytosis of ESA induced iron restricted erythropoiesis and may be countered by IV iron.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Antineoplastic Agents; Double-Blind Method; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferrous Compounds; Hematinics; Hemoglobins; Humans; Iron; Male; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Retrospective Studies; Thrombocytosis; Thrombophilia; Venous Thromboembolism