Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-α, in Patients With Moderate-to-Severe Heart Failure

Abstract

for the ATTACH Investigators* Background-Preclinical and preliminary clinical data have suggested that tumor necrosis factor-␣ (TNF␣) may play a role in the evolution and progression of heart failure and that inhibition of TNF␣ may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNF␣, 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 Յ35% were randomly assigned to receive placebo (nϭ49), infliximab 5 mg/kg (nϭ50), or infliximab 10 mg/kg (nϭ51) 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 (Pϭ0.013). 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 Pϭ0.043). Conclusions-Short-term TNF␣ 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. (Circulation. 2003;107:3133-3140.)

TNFα blockade in human diseases: An overview of efficacy and safety

“…These data resulted in clinical trials to study a possible therapeutic role of TNFα inhibition in CHF. However, two large trials with ETA and a pilot trial with INF in clinical heart failure failed to show any improvement in morbidity and mortality [75,76]. While these disappointing results may have various explanations, anti-TNF agents should not be used to treat patients with NYHA Class III or IV heart failure, given the lack of evidence of beneficial effect.…”

“…Congestive heart failure (CHF)-Randomized controlled clinical trials of anti-TNF agents in CHF showed dose-dependent trends toward worse prognosis [75,76]. Other studies did not indicate an increased risk of CHF from TNFα antagonist use [91,104].…”

Prevalence of Trypanosoma cruzi antibodies and inflammatory markers in uncompensated heart failure

“…The increased levels of TNFα is a consequence of the production by the failing heart and by the inflammatory cells due to Trypanosoma cruzi infection in chagasic patients, causing fibrosis and apoptosis, and inducing negative inotropic effects with systolic dysfunction 30 . In the present study, we observed elevated levels of this cytokine only in 6.9% of patients; this result is similar to that reported by van Riemsdijk-van Overbeeke et al 31 , who failed to detect serum levels of free TNFα in HF patients notwithstanding their finding of elevated levels of TNFα soluble receptors with increased binding capacity, which explained the low TNFα bioavailability.…”

Leukocyte Activity in Patients with ST-Segment Elevation Acute Myocardial Infarction Treated with Anakinra

“…This result is in contrast to the use of tumor necrosis factor (TNF)-α blockers, which resulted in a significant and worrisome increase in opportunistic infections, death due to overwhelming sepsis and worsening heart failure (20)(21)(22). A direct comparison between Figure 1.…”