High doses of epoetin do not lower mortality and cardiovascular risk among elderly hemodialysis patients with diabetes

Abstract

Summary Background Whether exposure to high erythropoiesis-stimulating agents (ESA) doses results in adverse cardiovascular outcomes in hemodialysis patients based on the presence of diabetes has been suggested by an earlier randomized trial but remains inconclusive. Methods Data from the US Renal Data System were used to identify 35,593 Medicare patients on hemodialysis: 19,034 (53%) were diabetic. We fit a pooled logistic model to estimate the probability of mortality and a composite cardiovascular end point at each month using inverse probability (IP) weighting to adjust for time-dependent confounding by indication. IP weights were estimated separately for diabetic and nondiabetic cohorts. Findings The adjusted 9-month mortality risk difference between an ESA dose of 45,000 U/wk and 15,000 U/wk was 13% among diabetics and 5% among nondiabetics (p value = 0.002). Compared with a dose of 20,000 – 30,000 U/wk, the hazard ratio of mortality was 1.32 (95% CI 1.11, 1.58) and the hazard ratio of a composite endpoint of death and cardiovascular events was 1.26 (95% CI 1.07, 1.50) among diabetic patients exposed to the highest ESA doses (>40,000 U/wk). The corresponding hazard ratios in non-diabetic patients were 1.06 (95% CI 0.88, 1.28) and 1.10 (95% CI 0.92, 1.32), respectively. Interpretation Using higher ESA doses as usually necessary to achieve higher hemoglobins appears to be not beneficial, and possibly harmful, to diabetic patients. Little effect of dose was found in nondiabetic patients. Our study findings support the FDA’s recent advisories recommending that the lowest possible ESA dose be used when treating hemodialysis patients.

A Randomized Control Study on the Procedure for Switching Epoetin Beta (EPO) to Epoetin Beta Pegol (CERA) in the Treatment of Renal Anemia in Maintenance Hemodialysis Patients

“…Hirai et al reported that the dose of CERA could be reduced throughout the 28-week observation period by switching EPO to once-every-4-week CERA administration [19]. This is similar to our finding.…”

Epo and Non-hematopoietic Cells: What Do We Know?

“…Safety concerns were raised during treatment of anemia in diabetic patients with CKD when they showed a twofold higher risk of stroke, an increased risk of venous thromboembolism and cancer-related deaths (210). Several studies have suggested that exposure to high doses of Epo mimetics, when needed to achieve higher hemoglobin levels, is harmful and explains this phenomenon (211,212). Very high doses of Epo, in conjunction with hypoxia, has also been associated with a paradoxical neurotoxic effect suggesting dose-response conditions need to be optimized.…”

Association of a Change in Erythropoiesis-Stimulating Agent Dose During Hospitalization and Subsequent Hemoglobin Levels and Transfusions in Hemodialysis Patients

“…Targeting a higher hemoglobin level over a prolonged period has been shown to increase the risk of cardiovascular events and death in stable outpatients and is cause for concern. [6][7][8][9][10][11] In a well-conducted randomized controlled trial, Singh et al 10 showed that in patients with chronic kidney disease not on dialysis therapy, those with a higher targeted hemoglobin level (135 g/L) have a 34% increased risk of a composite event of death, myocardial infarction, hospitalization for congestive heart failure, and stroke. In another randomized trial, assignment to a higher targeted hemoglobin level (130 g/L) nearly doubled the risk of a stroke.…”

“…This may increase the risk of cardiovascular events, vascular access thrombosis, and possibly mortality in HD patients because previous studies have shown adverse outcomes in patients with higher targeted hemoglobin levels over a prolonged period. [6][7][8][9][10][11] Individuals with erythropoietin hyporesponsiveness appear to be at particular risk. 9,12,13 Given the lack of demonstrated benefit and the potential for increased risk of adverse events, we sought to determine whether increasing the ESA dose in HD patients during the first 14 days of hospitalization is associated with increased risk of exceeding recommended hemoglobin targets.…”