Background-Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Methods and Results-Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction Յ0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (nϭ373) or subcutaneous etanercept in doses of 25 mg every week (nϭ375) or 25 mg twice per week (nϭ375). In RENAISSANCE, patients received placebo (nϭ309), etanercept 25 mg twice per week (nϭ308), or etanercept 25 mg 3 times per week (nϭ308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (Pϭ0.17) or RECOVER (Pϭ0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative riskϭ1.1, 95% CI 0.91 to 1.33, Pϭ0.33). Conclusions-The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

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