BACKGROUND: Preclinical and preliminary clinical data have suggested that tumor necrosis factor-alpha (TNFalpha) may play a role in the evolution and progression of heart failure and that inhibition of TNFalpha may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNFalpha, in patients with moderate-to-severe heart failure. METHODS AND RESULTS: One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction <or=35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (P=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043). CONCLUSIONS: Short-term TNFalpha antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.
RCT Entities:
BACKGROUND: Preclinical and preliminary clinical data have suggested that tumor necrosis factor-alpha (TNFalpha) may play a role in the evolution and progression of heart failure and that inhibition of TNFalpha may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNFalpha, in patients with moderate-to-severe heart failure. METHODS AND RESULTS: One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction <or=35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (P=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043). CONCLUSIONS: Short-term TNFalpha antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.