New therapeutic options in congestive heart failure: Part II.

Anticytokine and Immunomodulating Therapy Cytokines, such as tumor necrosis factor, are produced in increased amounts in a variety of tissues in patients with CHF.1 Higher plasma cytokine concentrations are associated with a worse prognosis.1 Experimentally, cytokines depress myocardial contractility, cause myocyte death, and induce heart failure.1 There is some evidence that anticytokine interventions improve ventricular function and clinical status in CHF.2,3 Two parallel trials (Randomized Etanercept North American Strategy to Study Antagonism of Cytokines [RENAISSANCE] and Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction Trial [RECOVER], pooled as the Randomized Etanercept Worldwide Evaluation [RENEWAL] program) examining the effect of the anti– tumor necrosis factor agent etanercept on morbidity and mortality in CHF, however, were recently discontinued because of futility (Table). Even more recently, a placebocontrolled phase II trial with an alternative anti–tumor necrosis factor chimeric monoclonal antibody, infliximab, was stopped early because of higher rates of mortality and hospitalization in the active-therapy group. Whether this means that the cytokine hypothesis is invalid, that etanercept and infliximab were the wrong drugs to use (or were used incorrectly), that inappropriate patients were chosen, or that the study designs were flawed is unknown.