Anti-TNF Therapy Against Congestive Heart Failure Trial - ATTACH
The goal of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial was to evaluate the efficacy and safety of infliximab, a chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha, in patients with moderate to severe heart failure.
Treatment with the TNF-alpha inhibitor infliximab will have favorable effects on clinical status in patients with moderate to severe heart failure.
Patients Enrolled: 150
NYHA Class: NYHA class III, 96% in placebo and 5 mg/kg arm; 92% in 10 mg/kg arm
Mean Follow Up: 28 weeks
Mean Patient Age: 62 years
Mean Ejection Fraction: Mean LVEF 24%
Age ≥18 years; stable NYHA class III or IV heart failure associated with a radionuclide LVEF ≤35% within 14 days; treatment with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin II receptor blocker if intolerant of ACE inhibitors) for at least 85% of the time during the prior three months. Heart failure is considered stable if none of the following occurred within two weeks before screening: change in NYHA functional class, hospitalization for heart failure, or administration of any intravenous medication for heart failure.
Hemodynamically significant obstructive valvular disease, cor pulmonale, restrictive or hypertrophic cardiomyopathy, constrictive pericarditis, or congenital heart disease; acute myocardial infarction or coronary revascularization procedure within two months; likely to undergo coronary revascularization or heart transplant during the anticipated duration of the study; resuscitated from sudden death or had a therapeutic discharge of an implanted implantable cardioverter defibrillator within three months; serious infection within two months; latent tuberculosis or had tuberculosis within three years; documented human immunodeficiency virus infection; any other opportunistic infection within six months' use of infliximab or other therapeutic agents that could interfere with the actions of TNF-alpha within three months; or had received within two weeks or were likely to receive during the study any of the following: a class IC or III antiarrhythmic other than amiodarone, a calcium channel blocker other than amlodipine for hypertension or angina, a positive inotrope other than digoxin, or a nonsteroidal anti-inflammatory drug other than aspirin
Change in clinical status at 14 weeks. Clinical status was assessed by the clinical composite score, and patients were categorized as: 1) improved if the patient showed an improved New York Heart Association (NYHA) class or moderate or marked improvement in global assessment; 2) worse if the patient died, was hospitalized for heart failure, or had worsening NYHA class or moderate or marked worsening of the patient global assessment; or 3) unchanged.
Change in inflammatory markers during the 28-week trial period; change in LVEF at 14 and 28 weeks; composite of death or hospitalization for worsening heart failure at 28 weeks; and change in Minnesota Living With Heart Failure score at 14 and 28 weeks
Potential trial participants underwent a screening evaluation two weeks before randomization. If eligible, patients were randomized in a double-blind manner to placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51). Patients were treated with the study drug immediately after randomization and at the two- and six-week visits as a two-hour intravenous infusion.
Beta-blockers, digoxin, and spironolactone were allowed, if started ≥3 months prior to screening and were to be continued throughout the study period. Vasodilator or nitrate use was permitted. All cardiac medication doses were to be constant for at least two weeks before and during screening.
There was no difference in the primary endpoint of change in clinical status at 14 weeks between treatment arms (improved: 32.7% for placebo, 38.0% for 5 mg/kg infliximab, 39.2% for 10 mg/kg infliximab; no change: 59.2% for placebo, 52.0% for 5 mg/kg infliximab, 39.2% for 10 mg/kg infliximab; worse: 8.2% for placebo, 10.0% for 5 mg/kg infliximab, 21.6% for 10 mg/kg infliximab; p=0.777 for 5 mg/kg infliximab vs. placebo and p=0.618 for 10 mg/kg infliximab vs. placebo). Similar results occurred at 28 weeks (worse: 14.3% for placebo, 16.3% for 5 mg/kg infliximab, 31.4% for 10 mg/kg infliximab; p=0.471 for 5 mg/kg infliximab vs. placebo and p=0.146 for 10 mg/kg infliximab vs. placebo).
Patients in the 10 mg/kg infliximab group were more likely to die or be hospitalized for heart failure than patients in the placebo group (hazard ratio 2.84, 95% confidence interval 1.01-7.97; p=0.043) and were more likely to be hospitalized for heart failure or for any reason (n=20) than patients in the placebo (n=13) or 5 mg/kg infliximab arms (n=10). Quality of life scores did not differ between the three treatment arms either at 14 weeks (-4.0, -6.5, and -4.0 for placebo, 5 mg/kg, and 10 mg/kg, p=0.829) or at 28 weeks (0.0, -3.0, and -6.0 for placebo, 5 mg/kg, and 10 mg/kg, respectively, p=0.811).
Left ventricular ejection fraction (LVEF) increased at 14 weeks in patients treated with infliximab (mean changes from baseline 3.5% with 5 mg/kg infliximab, 2.1% with 10 mg/kg infliximab, and 0.8% with placebo, p=0.039 for placebo vs. both infliximab groups combined), but did not differ by 28 weeks (4.2%, 1.3%, and 3.4%, respectively). C-reactive protein (CRP) and interleukin (IL)-6 levels were reduced compared with baseline in infliximab arms at weeks 1-14, but returned toward baseline levels by 28 weeks.
Among patients with moderate to severe heart failure, treatment with infliximab, a chimeric monoclonal antibody to TNF-alpha, was not associated with an improvement in the primary endpoint of clinical status at 14 weeks, despite reducing CRP and IL-6 as expected.
Additionally, the high dose (10 mg/kg) was associated with worse clinical outcomes of death and hospitalization. Similar results were observed in a large, randomized trial of another TNF-alpha antagonist, etanercept. Given these findings, it is unclear what, if any, role TNF-alpha antagonists will have in heart failure therapy.
Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. 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. Circulation. 2003;107:3133-40.
Keywords: Angiotensin Receptor Antagonists, Radioisotopes, Interleukin-6, Diuretics, Tumor Necrosis Factor-alpha, C-Reactive Protein, Quality of Life, Heart Failure, Receptors, Tumor Necrosis Factor, Stroke Volume, Confidence Intervals, Antirheumatic Agents
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