Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis

Abstract

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

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

Setting & population: Patients with anemia of CKD irrespective of dialysis status.

Selection criteria for studies: 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.

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

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

Results: 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.

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

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

Figure 1

Literature search and selection. ESA denotes erythropoiesis-stimulating agent.

Figure 2

Association of the total-study-period mean weekly ESA dose with all-cause mortality. Continuous line, unadjusted analysis (IRR 1.09; 95% CI 1.02, 1.18; P = 0.02); Dashed line, target hemoglobin-adjusted (fixed at 11 gm/dL) analysis (IRR, 1.41; 95% CI, 1.08–1.82; P = 0.01). Each circle represents a study arm. The radius of a circle corresponds to a study arm’s weight in the metaregression. Here, “erythropoietin α” refers to epoetin alfa.

Figure 3

Subgroup meta-regression analyses examining the association of total-study-period ESA dose (per epoetin alfa–equivalent 10,000-U/wk increment) with all-cause mortality. The incidence rate ratio (IRR) and 95% confidence interval (CI) is displayed on a logarithmic scale. Here, “erythropoietin” refers to epoetin (alfa or beta); “darbepoetin” refers to darbepoetin alfa.

Figure 4

Meta-regression analyses examining the association of total-study-period ESA dose (per epoetin alfa–equivalent 10,000 U/wk increment) with the secondary outcomes [4A, unadjusted; 4B, adjusted for target hemoglobin; and 4C, adjusted for mortality rate (expressed per 1000 person-years) in the control group]. The incidence rate ratio (IRR) and 95% confidence interval (CI) is displayed on a logarithmic scale. ESRD denotes end-stage renal disease.