The Use of EPO-Stimulating Agents in Heart Failure Nora Sharaya, PharmD PGY2 Pharmacotherapy Resident Butler University & Community Health Network This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation

The Link Between Anemia and Heart Failure Anemia Hemodilution Functional Iron Deficiency Activation of the Inflammatory Cascade Impaired EPO Production Concomitant CKD ISRN Hematol 2012; 2012:

HF with preserved EF HF with unpreserved EF Anemia The Link Between Anemia and Heart Failure ISRN Hematol 2012; 2012:

A meta-analysis published in 2008 examined 153,180 patients with chronic heart failure  Of those patients, 37.2% were anemic After a minimum of six months follow up, 46.8% of patients with anemia died compared to 29.5% of the patients without anemia  Based on these results, in patients without an identifiable cause for their anemia, using erythropoietin-stimulating agents has been considered Mortality J Am Coll Cardiol. 2008;52:818–2.

Increased Risk of Mortality Reduced Exercise Capacity Impaired Quality of Life Increased Risk of Hospitalization Complications J Am Coll Cardiol 2008;52:818–2

Acknowledge the link between anemia and heart failure Discuss associated complications No cited recommendation on use of EPO stimulating agents for treatment Lack of definitive evidence ACCF/AHA Guidelines Circulation. 2013; 128: e240-e327.

US Boxed Warning: “Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, thromboembolic events, stroke, and mortality in clinical studies when administered to target hemoglobin levels >11 g/dL.” Concerns with EPO Stimulating Agents Darbepoetin (Package Insert)

van Veldhuisen DJ, et al. Study DesignResultsApplicability Randomized, multinational, double-blind, placebo-controlled Randomized to Wt- based dose of SQ darbepoetin alfa, a fixed dose, or placebo Q2W X25W targeting Hgb 14.0 PO iron supplement n=162 patients Darbepoetin vs. placebo trended towards : o  six-minute walk distance o Improvement in NYHA class o Improvement in health-care associated QOL In treated patients, there were trends towards improvement in: Walking distance NYHA class Health-care associated QOL Eur Heart J. 2007;28:2208–16.

Ghali JK, et al. Study DesignResultsApplicability Randomized, multicenter, double blind, placebo-controlled Randomized to darbepoetin alfa (starting dose, 0.75 ug/kg) or placebo subcutaneously Q2W for 52 weeks n=162 (treatment) n=157 (placebo) Mostly white males with NHYA Class III HF Well-tolerated, but no increase in exercise tolerance A trend towards ↓ mortality and hospitalization Darbepoetin is well tolerated and showed trends towards improvement: Exercise tolerance Mortality Hospitalization rate Circulation. 2008;117:526–35.

Study DesignResultsApplicability Randomized, double-blind, multinational, placebo-controlled Randomized to darbepoetin alfa 0.75 ug/kg (titrate to Hg>13.0) or placebo SQ Q2W Iron therapy given if TSAT <20% n=1136 (treatment) n=1142 (placebo) Primary composite outcome: o Treatment: 576 (50.7%) o Placebo: 565 (49.5%) Increased embolic and thrombotic events in the treatment group Do not support the use of darbepoetin to reduce the rate of hospitalization or death from any cause. A low hemoglobin value may be a marker of poor prognosis versus a treatment target Swedberg K, et al. N Engl J Med. 2013;368:1210–19.

Conclusions Treatment Target Poor Prognostic Sign

The Use of EPO-Stimulating Agents in Heart Failure Nora Sharaya, PharmD PGY2 Pharmacotherapy Resident Butler University & Community Health Network