epoetin-alfa and Hypertension

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014.. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD.. In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion.. Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certa. Los fármacos estimulantes de la eritropoyesis (FEE) se suelen utilizar para tratar la anemia en personas con nefropatía crónica. Sin embargo, su uso se ha asociado a eventos cardiovasculares. Esta es una actualización de una revisión Cochrane publicada por primera vez en 2014.. Comparar la eficacia y la seguridad de los FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi‐polietilenglicol epoetina beta y FEE biosimilares) entre sí, con placebo, o ningún tratamiento, para el tratamiento de la anemia en adultos con nefropatía crónica. MÉTODOS DE BÚSQUEDA: En esta actualización, a través del contacto con el documentalista, y con el uso de términos de búsqueda pertinentes para esta revisión, se realizaron búsquedas en el Registro de estudios del Grupo Cochrane de Riñón y trasplante (Cochrane Kidney and Transplant) hasta el 29 de abril de 2022. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en resúmenes de congresos, en el portal de búsqueda de la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov. CRITERIOS DE SELECCIÓN: Se consideraron para la inclusión los ensayos controlados aleatorizados (ECA) que incluían una comparación de un FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi‐polietilenglicol epoetina beta, una epoetina biosimilar o una darbepoetina alfa biosimilar) con otro FEE, placebo o ningún tratamiento en adultos con NC. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores independientes examinaron los resultados de la búsqueda y extrajeron los datos. La síntesis de los datos se realizó mediante un metanálisis pareado de efectos aleatorios (expresada como odds ratio [OR] y sus intervalos de confianza [IC] del 95%) y un metanálisis en red. Se evaluó la heterogeneidad y la inconsistencia dentro de los metanálisis con técnicas estándares y se planeó crear subgrupos y una metarregresión para explorar las fuentes de heterogeneidad o la inconsistencia. Se evaluó la certeza en las estimaciones del tratamiento para los desenlaces principales (prevención de transfusiones de sangre y muerte [por cualquier causa]) mediante el método Grading of Recommendations Assessment, Development and Evaluation (GRADE).. En esta actualización se incluyeron 62 nuevos estudios (9237 participantes), por lo que la revisión incluye ahora 117 estudios con 25 237 participantes. La mayoría de los estudios tuvieron riesgo alto o incierto de sesgo en la mayoría de los dominios metodológicos. En general, los resultados siguen siendo similares en esta actualización en comparación con la revisión anterior de 2014. Para prevenir la transfusión de sangre, la epoetina alfa (OR 0,28; IC del 95%: 0,13 a 0,61; evidencia de certeza baja) y la epoetina beta (OR 0,19; IC del 95%: 0,08 a 0,47; evidencia de certeza baja) podrían ser superiores al placebo, y la darbepoetina alfa fue probablemente superior al placebo (OR 0,27; IC del 95%: 0,11 a 0,67; evidencia de certeza moderada). La metoxi‐polietilenglicol epoetina beta (OR 0,33; IC del 95%: 0,11 a 1,02; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,34; IC del 95%: 0,11 a 1,03; evidencia de certeza muy baja) y una darbepoetina alfa biosimilar (OR 0,37; IC del 95%: 0,07 a 1,91; evidencia de certeza muy baja) tuvieron efectos inciertos sobre la prevención de la transfusión de sangre en comparación con el placebo. Los efectos comparativos de los FEE comparados con otro FEE sobre la prevención de las transfusiones de sangre fueron inciertos, en evidencia de certeza baja a muy baja. Los efectos sobre la mortalidad (por cualquier causa) fueron inciertos para la epoetina alfa (OR 0,79; IC del 95%: 0,51 a 1,22; evidencia de certeza baja), la epoetina beta (OR 0,69; IC del 95%: 0,40 a 1,20; evidencia de certeza baja), la metoxi‐polietilenglicol epoetina beta (OR 1,07; IC del 95%: 0,67 a 1,71; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,80; IC del 95%: 0,47 a 1,36; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,63; IC del 95%: 0,51 a 5,23; evidencia de certeza muy baja) en comparación con el placebo. Es probable que no hubiera diferencias entre la darbepoetina alfa y el placebo en las probabilidades de muerte (por cualquier causa) (OR 0,99; IC del 95%: 0,81 a 1,21; evidencia de certeza moderada). Los efectos comparativos de los FEE comparados con otro FEE sobre la mortalidad (por cualquier causa) fueron inciertos en evidencia de certeza baja a muy baja. Es probable que la epoetina beta aumentara el riesgo de hipertensión en comparación con el placebo (OR 2,17; IC del 95%: 1,17 a 4,00; evidencia de certeza moderada). En comparación con el placebo, la epoetina alfa (OR 2,10; IC del 95%: 1,22 a 3,59; ev. Los efectos comparativos de los diferentes FEE sobre las transfusiones de sangre, la mortalidad (por cualquier causa y cardiovascular), los eventos cardiovasculares mayores, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal, el cansancio y la disnea fueron inciertos.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Dyspnea; Epoetin Alfa; Erythropoiesis; Hematinics; Humans; Hypertension; Myocardial Infarction; Network Meta-Analysis; Renal Insufficiency, Chronic; Thrombosis

Risk factors like female sex, fistula location, hypertension, albumin, diabetes, arteriovenous graft (AVG), age, and other factors are related to arteriovenous fistula thrombus (AVFT), but the consistency and magnitude of their associations have not been confirmed by meta-analysis.. The purpose of this study was to provide a comprehensive and up-to-date synthesis of evidence on the association between potential risk factors and AVFT.. In this systematic review and meta-analysis, PubMed, Embase, Cochrane Library, and Web of Science databases were searched for articles published up to April 20th, 2022, and cohort, cross-sectional, and case-control studies examining the association (odds ratio [OR]) between potential risk factors and AVFT were identified. The other inclusion criteria were sufficient data for analysis and nonoverlapping datasets, excluding reviews, meta-analyses, and articles with overlapping datasets. Extracted variables included first author, publication year, study type, sample size, percentage of women, vascular access type, risk or protective factors, and measure of association (adjusted estimates of effect of all risk factors). The study protocol is registered at PROSPERO (CRD42020201884) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.. Among the 27 identified studies, data from 24 cohort, 2 case-control, and 1 cross-sectional study were included in this review. When compared to non-AVFT, our data showed that the significant risk factors were AVG (pooled OR = 6.28, 95% CI = 1.79-22.02, p = 0.004, I2 = 87%), age (pooled OR = 1.06, 95% CI = 1.00-1.13, p = 0.05, I2 = 98%), female sex (pooled OR = 2.62, 95% CI = 2.56-2.69, p < 0.00001, I2 = 0%), C-reactive protein (pooled OR = 1.18, 95% CI = 1.08-1.30, p = 0.0005, I2 = 90%), fistula site (distal) (pooled OR = 3.64, 95% CI = 1.74-7.62, p = 0.0006, I2 = 47%), hypertension (pooled OR = 1.21, 95% CI = 1.00-1.47, p = 0.05, I2 = 46%), CD34+KDR+ cell (pooled OR = 1.85, 95% CI = 1.33-2.57, p = 0.0002, I2 = 0%), and eprex use (pooled OR = 5.36, 95% CI = 1.82-15.77, p = 0.002, I2 = 0%).. The meta-analysis suggests that AVG, age, female sex, CRP level, fistula site (distal), hypertension, CD34+KDR+ cell, and the use of eprex are independent risk factors for AVFT. Therefore, clinical medical staff should treat these risk factors carefully, identify them early, and prevent them early to reduce the occurrence of AVFT.

Topics: Arteriovenous Fistula; Cross-Sectional Studies; Epoetin Alfa; Female; Humans; Hypertension; Male; Risk Factors; Thrombosis

Hypertension among patients on hemodialysis is predominantly systolic (either isolated or combined with diastolic hypertension), whereas the scenario of isolated diastolic hypertension is rare and more common in younger patients. Uncontrolled hypertension that persists despite aggressive antihypertensive drug therapy is a reflection of the volume overload that is a prominent mediator of systolic and diastolic BP elevation. Clinical-trial evidence supports the notion that dry-weight probing is an effective strategy to improve BP control, even when overt clinical signs and symptoms of volume overload are not present. Accelerated arterial stiffness influences the patterns and rhythms of interdialytic ambulatory BP and is a major determinant of isolated systolic hypertension in hemodialysis. Posthoc analyses of the Hypertension in Hemodialysis patients treated with Atenolol or Lisinopril (HDPAL) trial, however, suggest that arterial stiffness does not make hypertension more resistant to therapy and is unable to predict the treatment-induced improvement in left ventricular hypertrophy. A combined strategy of sodium restriction, dry-weight adjustment, and antihypertensive medication use was effective in improving ambulatory BP control regardless of the severity of underlying arteriosclerosis in HDPAL. Other nonvolume-dependent mechanisms, such as erythropoietin use, appear to be also important contributors and should be taken into consideration, particularly in younger hemodialysis patients with diastolic hypertension. In this article, we explore the role of volume overload, arterial stiffness, and erythropoietin use as causes of systolic vs diastolic hypertension in patients on hemodialysis. We conclude with clinical practice recommendations and with a call for a "volume-first" approach when managing hemodialysis hypertension.

Topics: Atenolol; Diastole; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Lisinopril; Male; Renal Dialysis; Risk Assessment; Systole; Vascular Stiffness; Water-Electrolyte Imbalance

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).. To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis

Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies.. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.. We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion.. Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high.. We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses.. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Polyethylene Glycols; Recombinant Proteins; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial.. The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting).. Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment).. In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups.. Celgene and Acceleron Pharma.

Topics: Aged; Anemia; Body Weight; COVID-19; Dyspnea; Epoetin Alfa; Erythropoiesis; Female; Hematinics; Hemoglobins; Humans; Hypertension; Male; Myelodysplastic Syndromes; Neutropenia

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.. In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.. A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.. Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).

Topics: Adult; Aged; Analysis of Variance; Anemia; Cholesterol; Double-Blind Method; Epoetin Alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hyperkalemia; Hypertension; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic

This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.. One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.. One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).. This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium; Canada; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Heart Ventricles; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Lipids; Male; Middle Aged; Organ Size; Parathyroid Hormone; Phosphates; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Treatment Failure; Ultrasonography

Clinical guidelines recommend concurrent treatment of anemia in end-stage renal disease with erythropoiesis-stimulating agents (ESAs) and iron. However, there are mixed data about optimal iron supplementation. To help address this gap, the relationship between iron markers and hemoglobin (Hb) response to ESA (Epoetin alfa) dose was examined. Electronic medical records of 1902 US chronic hemodialysis patients were analyzed over a 12-month period between June 2009 and June 2010. The analysis included patients who had at least one Hb value during each 4-week interval for four consecutive intervals (k - 2, k - 1, k, and k + 1; k is the index interval), received at least one ESA dose during intervals k - 1 or k, had at least one transferrin saturation (TSAT) value at interval k, and at least one ferritin value during intervals k - 2, k - 1, or k. Effect modification by TSAT and ferritin on Hb response was evaluated using the generalized estimating equations approach. Patients had a mean (standard deviation) age of 62 (15) years; 41% were Caucasian, 34% African American, 65% had hypertension, and 39% diabetes. Transferrin saturation, but not ferritin, had a statistically significant (P < 0.05) modifying effect on Hb response. Maximum Hb response was achieved when TSAT was 34%, with minimal incremental effect beyond these levels. Of the two standard clinical iron markers, TSAT should be used as the primary marker of the modifying effect of iron on Hb response to ESA. Long-term safety of iron use to improve Hb response to ESA warrants further study.

Topics: Diabetes Mellitus; Electronic Health Records; Epoetin Alfa; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Models, Biological; Practice Guidelines as Topic; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis; United States

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Drug Evaluation; Epoetin Alfa; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Hematocrit; Humans; Hypertension; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Thrombosis

Topics: Blood Pressure; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Stents; Thrombosis

Hypertension is the most significant complication from treatment with erythropoietin (Epo). Can Epo-induced hypertension be eliminated? We examined systemic and local effects of our genetically engineered products, Epo-binding protein (Epo-bp) and anti-Epo-bp antibodies, on randomly assigned Sprague-Dawley rats at midnight, 4 am, 8 am, noon, 4 pm, and 8 pm. Blood pressure, hematocrit, and body weight were measured immediately before and after the completion of a 4-week, twice-weekly course of Epo (50 U/kg), Epo-bp, anti-Epo-bp antibodies, or physiological saline injections. Epo treatment increased hematocrit markedly overall as compared with the saline, Epo-bp, and anti-Epo-bp antibody groups (0.616 versus 0.427, 0.439, and 0.441, respectively) and at each of the 6 test times (all P<0.0001). Epo-bp and anti-Epo-bp antibody treatment with Epo had almost no effect on the Epo-induced hematocrit increase (0.616 versus 0.580 or 0.591, respectively). Circadian blood pressures for Epo versus saline, Epo-bp, and anti-Epo-bp antibody groups were 136.2+/-2.3 versus 116.2+/-1.7, 118.4+/-2.1, and 116.6+/-2.1 mm Hg, respectively (each P<0.0001). Significantly increased blood pressure was detected at noon, 4 pm, 8 pm, and midnight in Epo treatment. When Epo was given with Epo-bp or anti-Epo-bp antibodies, blood pressure was maintained at similar levels as in saline treatment (each P<0.0001) as compared with Epo treatment alone. Overall, body, brain, and heart weights were significantly lower in Epo treatment than those of other groups. Thus, Epo-bp and anti-Epo-bp antibodies eliminate Epo-induced hypertension without affecting hematocrit and blood volume.

Topics: Animals; Blood Pressure Determination; Body Weight; Circadian Rhythm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematocrit; Hypertension; Probability; Protein Binding; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reference Values; Risk Factors; Sensitivity and Specificity

Current guidelines give evidence-based advice on how best to manage anaemia in patients with renal disease, but these guidelines do not consider individual patient needs, so tailoring anaemia management to each patient still remains a challenge for the treating physician. Two case studies are described that illustrate some of the key factors that need to be considered. The first case emphasizes that haemoglobin (Hb) targets recommended in current guidelines may not suit all patients. The patient had been stably maintained on subcutaneous epoetin therapy with an average Hb concentration of >13.0 g/dl because he developed angina symptoms when his Hb level fell to 12.2 g/dl. Iron deficiency was identified as the likely cause of falling Hb in this patient. After the patient's iron supplementation was increased, his Hb level was normalized back to >13.0 g/dl without increasing the epoetin dose, and the angina symptoms were resolved. The second case involved a pre-dialysis patient with diabetes, who required a higher dose of epoetin after beginning concomitant antihypertensive treatment with an angiotensin-converting enzyme inhibitor. Previously, the treatment of renal anaemia in pre-dialysis patients has not been the focus of attention. Two ongoing randomized controlled trials have been designed to study early initiation of epoetin treatment in pre-dialysis patients and will provide much needed information in this area.

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Abdominal Pain; Adult; Analgesics, Non-Narcotic; Anemia, Iron-Deficiency; Appendicitis; Epoetin Alfa; Erythropoietin; Fever; Gastrointestinal Hemorrhage; Glomerulonephritis; Hematinics; Humans; Hypertension; Ibuprofen; Kidney Failure, Chronic; Male; Nursing Diagnosis; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Recombinant Proteins; Renal Dialysis

Topics: Epoetin Alfa; Erythrocyte Count; Erythropoietin; Humans; Hydronephrosis; Hypertension; Kidney; Nephrectomy; Polycystic Kidney Diseases; Polycythemia