Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial.
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.


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.
Chung
Eugene S
ES
The Lindner Center and Ohio Heart Health Center, Cincinnati 45219, USA. chunge@ohioheart.org
Packer
Milton
M
Lo
Kim Hung
KH
Fasanmade
Adedigbo A
AA
Willerson
James T
JT
D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000069285:Infliximab; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011788:Quality of Life; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab