The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions

Figures & data

Figure 1 Relationship among anemia renal dysfunction and heart failure: possible mechanisms of reduced and blunted erythropoietin production.

Abbreviations: AVP, arginine vasopressin; EPO, erythropoietin; PO₂, partial pressure of oxygen; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Table 1 Randomized, controlled trials on ESA administration in patients with anemia and heart failure

Study	N	ESA versus control	Iron	Follow-up (months)	End point	Conclusion
Silverberg et al, 2000^Citation40	26	Epoetin alfa	Yes	7±5	NYHA class, LVEF, decrease in diuretic dose and hospitalizations	An increase in Hb was associated with an improvement in NYHA functional class and LVEF and a decrease in diuretic dose and hospitalization.
Mancini et al, 2003^Citation41	23	Epoetin alfa versus placebo	Yes	3	Exercise capacity, vasodilatatory function	EPO therapy was associated with significant increase in Hb values from 11.0±0.5 to 14.3±1.0 g/dL, with a concomitant increase in 6MWD and peak oxygen uptake (11.0±1.8 to 12.7±2.8 mL/min per kilogram, P<0.05).
Palazzuoli et al, 2007^Citation42	51	Epoetin beta versus placebo	Yes	12	Primary: LV dimensions, LVEF, Hb, Cr, BNP Secondary: cardiac events (sudden death, hospitalization, MI), weight, edema, NYHA	Hb increased; LV dimensions, volume, and mass decreased; and LVEF increased in the epoetin group with no change in the control group. The pulmonary artery pressure and BNP blood levels also decreased as well as the need for hospitalization in patients treated with EPO.
Ponikowski et al, 2007^Citation43	41	Darbepoetin alfa versus placebo	Yes	6	Primary: exercise capacity Secondary: change in peak VO2, exercise duration, Hb, NYHA QOL, BNP, weight, hospitalization	No differences were revealed regarding peak VO2, exercise duration, BNP, and renal function between treatment groups.
van Veldhuisen, 2007^Citation44	165	Darbepoetin alfa versus placebo	Yes	6	Primary: rate of rise in Hb Secondary: change in LVEF, 6MWD, NYHA, QOL, PGA	The rate of Hb rise was equivalent between darbepoetin alpha weight-based and fixed dosing groups. There were nonsignificant improvements in the combined darbepoetin alfa group versus placebo for 6MWD (P=0.074) and PGA (P=0.057).
Ghali et al, 2008^Citation45 STAMINA-HeFT	319	Darbepoetin alfa versus placebo	Yes	12	Primary: change in exercise toleration Secondary: NYHA QOL, time to death, first HF hospitalization	Darbepoetin treatment did not significantly improve exercise duration, NYHA class, or QOL score compared with placebo
Swedberg et al, 2013^Citation46 RED-HF	2,278	Darbepoetin alfa versus placebo	Yes	28	Primary: all-causes mortality or first HF hospitalization Secondary: death from CV cause or first HF hospitalization, MI, stroke, HF hospitalization, SCD, QOL	There was no significant difference between the darbepoetin alfa and placebo groups for the primary composite outcome of death from any cause or first HF hospitalization. An increased rate of thromboembolic events was seen in the treated patients compared with placebo.

Abbreviations: 6MWD, 6-minute walk distance; BNP, brain natriuretic peptide; Cr, creatinine; CV, cardiovascular; EPO, erythropoietin; ESA, erythropoiesis stimulating agent; Hb, hemoglobin; HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; QOL, quality of life; SCD, sudden cardiac death; VO₂, oxygen volume; PGA, Patient’s Global Assessment score.

Figure 2 ESA effects beyond erythropietic capacity: potential endothelial and intracellular signaling effects.

Abbreviation: ESA, erythropoiesis stimulating agent.

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