Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.

Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level.

Patients with anemia of CKD irrespective of dialysis status.

We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.

ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.

All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement.

31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.

Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders.

In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.