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Table 1 Effects of subcutaneous titrated dosages of erythropoietin on cardiovascular endpoints in patients with CKD not on dialysis

From: Treating anemia of chronic kidney disease in the primary care setting: cardiovascular outcomes and management recommendations

Reference (study design) Level of renal function; study duration No. of pts Treatment regimen Endpoint Outcome
Left ventricular hypertrophy
Ayus et al. [54] (uncontrolled) CrCl 10–30 mL/min (diabetic) or 20–40 mL/min (nondiabetic); 6 mo 40 (Hb <10 g/dL) EPO to 12 g/dL Change-from-baseline LVMI In anemic pts, LVMI decreased vs baseline (142 vs 157 g/m2;P = 0.007) as Hb increased from 9.1 to 11.3 g/dL (P = 0.001).
   61 (Hb>10 g/dL) Standard care   
CREATE study [61] (r) GFR 15–35 mL/min/1.73 m2, Hb 11.0–12.5 g/dL;3 yrs 300 EPO to 13–15 g/dL Composite of 8 cardiovascular events (primary), LVMI (secondary) Baseline LVMI:
high-Hb group, 120.3 ± 35.0 g/m2
low-Hb group, 118.0 ± 34.3 g/m2
Change at year 1:
High-Hb group, -4.6 g/m2
Low-Hb group, -3.3 g/m2; P = 0.59
Change at year 2
High-Hb group, -6.4 g/m2
Low-Hb group, -7.8 g/m2
   300 EPO to 10.5–11.5 g/dL   
Levin et al. [56] (r) 24 mo 78 Early EPO to Hb 12–14 g/dL Mean change-from-baseline LVMI Mean LVMI change from baseline:
early EPO, +0.37 g/m2
deferred EPO, +5.21 g/m2
   58 Deferred EPO to 9.0–10.5 g/dL   
Roger et al. [57] (r, mc, uncontrolled) CrCl 15–50 mL/min, Hb 11.0–12.0 g/dL (in women) and 11–13 g/dL (in men);2 yr or until dialysis 75 EPO to Hb 12–13 g/dL Mean change-from baseline LVMI No statistically significant between group changes in LVMI over 2 years.
Based on per-protocol Hb levels:
Change from baseline LVMI:
Low Hb group +14 g/m2
High Hb group -1 g/m2.
   80 EPO to Hb 9–10 g/dL   
Congestive heart failure
Mancini et al. [77] (r) SrCr<2.5 mg/dL, NYHA functional class III-IV, Hct<35%;3 mo 15 EPO 15 000–30 000/wk Blood and exercise parameters Changes from baseline:
EPO group:
Peak VO2 11.0 to 12.7 mL·min-1·kg-1, P < .05 Exercise duration 590 to 657s, P < 0.004
Placebo group: no significant changes
   8 Placebo   
Silverberg et al. [45] (retrospective) Mean NYHA 3.66, SrCr 2.6 mg/dL, Hct 30%, Hb
10 g/dL;>6 mo
26 EPO + IV iron to Hb 12 g/dL NYHA functional status, LVEF, healthcare utilization Changes from baseline:
Functional status 3.7 to 2.7, P < 0.05
LVEF 28% to 35%, P < 0.001
No. of hospitalizations/pt 2.7 to 0.2, P < 0.05).
Silverberg et al. [47] (r) NYHA class III-IV, LVEF ≤40%, Hb 10–11.5 g/dL, 50% with CKD; 8.2 mo 16 EPO + IV iron to Hb ≥12.5 g/dL NYHA functional status, LVEF, furosemide requirements, healthcare utilization Changes from baseline:
EPO + iron group:
NYHA class, 42.1% improvement LVEF: +5.5%
Length of hospitalization: -79%
Standard care group:
NYHA class: 11% worsening
LVEF: -5%
Length of hospitalization: +58%
   16 Standard care   
Silverberg et al. [46] (nr) NIDDM or no NIDDM plus severe CHF, GFR decline >1 mL/min/mo; 11.8 mo 84 (NIDDM) EPO to Hb 12.5 g/dL + IV iron PRN NYHA functional class; VAS for fatigue and breathlessness; LVEF Changes from baseline:
NIDDM pts:
NYHA functional class 35% improvement LVEF +7%
non-NIDDM pts:
NYHA functional class:
32% improvement LVEF +12%
No statistically significant differences between NIDDM and non-NIDDM.
   95 (no NIDDM)    
Silverberg et al. [78] (nc) Symptomatic CHF despite optimal therapies, Hb<12 g/dL,91% had CKD (CrCl <60 mL/Min);20.7 mo 78 EPO + PRN IV iron to Hb 13 g/dL NYHA functional class, LVEF, healthcare utilization Changes from baseline: (all P < 0.01). NYHA class 2.5 (vs 3.7), LVEF 37% (vs 33%); No. of hospitalizations 0.7/year (vs 2.7/year)
  1. CrCl = creatinine clearance; db = double-blind; EPO = epoetin; GFR = glomerular filtration rate; Hct = hematocrit; IV = intravenous; LOHS = length of hospital stay; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; mc = multicenter; mo = months; nc = noncomparative; NYHA = New York Heart Association; PLA = placebo; PRN = as required; pts = patients; r = randomized; SrCr = serum creatinine; VAS = visual-analog scale; wk = week.