Research Into Etanercept Cytokine Antagonism in Ventricular Dysfunction - RENEWAL - RECOVER


The goal of the Research Into Etanercept Cytokine Antagonism in Ventricular Dysfunction (RECOVER) trial was to evaluate the efficacy of etanercept, a recombinant human tumor necrosis factor (TNF) receptor, compared with placebo among patients with chronic heart failure (CHF) and a left ventricular ejection fraction (LVEF) ≤30%.

Study Design

Study Design:

Patients Enrolled: 1,123
NYHA Class: Class II 27%; class IIIA 44%; class IIIB 25%
Mean Follow Up: Median 5.7 months
Mean Patient Age: Mean age 65 years
Female: 22

Patient Populations:

Age 18-85 years; NYHA class II to IV; ischemic or nonischemic etiology; LVEF ≤30%; stable doses of diuretic, ACE inhibitor, and beta-blocker and/or spironolactone for ≥3 months; and six-minute walk distance of <375 m


Severe infection within one month, surgically correctable causes of heart failure, other serious illness, acute MI or hospitalization, and recent or planned surgery/coronary revascularization

Primary Endpoints:

Change in clinical status from baseline to 24 weeks. Clinical status was based on a composite score of improved, worsened, or unchanged on the basis of death, CHF hospitalization, New York Heart Association (NYHA) class, and patient global assessment.

Drug/Procedures Used:

Patients were randomized to subcutaneous etanercept 25 mg once per week (n=375) or 25 mg twice per week (n=375) or placebo (n=373). Etanercept is a recombinant human TNF receptor that binds to soluble (circulating) TNF and functionally inactivates TNF.

Concomitant Medications:

Digoxin 54%, angiotensin-converting enzyme (ACE) inhibitor 85%, angiotensin-receptor blocker 13%, beta-blocker 63%, and diuretic 99%

Principal Findings:

Baseline LVEF was 24% in each of the three groups, and ischemic etiology was present in 62%, 61%, and 60% for etanercept once weekly, etanercept twice weekly, and placebo, respectively. Other baseline characteristics were similar in the three groups.

The study was stopped early at the recommendation of the Data Monitoring Committee after meeting the prespecified criteria for lack of treatment benefit. The primary endpoint of change in the clinical composite score from baseline to 24 weeks did not differ between placebo and etanercept either once weekly (p=0.76) or twice weekly (p=0.27). In the placebo group, clinical status was worsened in 19% of patients, unchanged in 50%, and improved in 32%. For etanercept once weekly, clinical status was 21%, 47%, and 33%, respectively and for etanercept twice weekly, 20%, 43%, and 36%, respectively.

There was no difference in death or CHF hospitalization for etanercept once weekly versus placebo (n=68 vs. n=66, relative risk [RR] 1.01, 95% confidence interval [CI] 0.72-1.41, p=0.97) or etanercept twice weekly versus placebo (n=60 vs. n=66, RR 0.87, 95% CI 0.61-1.24, p=0.45). There was also no difference in mortality between etanercept once weekly versus placebo (n=22 vs. n=33, RR 0.68, 95% CI 0.39-1.17, p=0.16) or etanercept twice weekly versus placebo (n=27 vs. n=33, RR 0.83, 95% CI 0.50-1.39, p=0.47).

Upper respiratory infection, injection-site reaction, bronchitis, dizziness, pneumonia, chest pain, abdominal pain, angina pectoris, flu syndrome, increased cough, and dyspnea occurred in more than 5% of patients, but there were no differences between the treatment groups. The adverse event of any infection trended higher in the etanercept groups (39% for once weekly and 40% for twice weekly vs. 33% for placebo, p=0.067), but there was no difference in severe or life-threatening infection (4% vs. 5% vs. 3%, respectively, p=0.373).


Among patients with CHF and a LVEF ≤30%, treatment with etanercept was not associated with a difference in the primary endpoint of change in clinical status at 24 weeks compared with placebo. The negative RECOVER results were similar to the RENAISSANCE trial, the sister trial of RECOVER that compared etanercept 25 mg twice per week or 25 mg three times per week with placebo.

Additionally, the ATTACH trial, which compared the antibody to TNF-alpha infliximab with placebo, showed no difference in the primary endpoint of change in clinical status, but did show an increase in hospitalization for heart failure in the infliximab group. The authors suggest several possible explanations for the lack of clinical benefit, including that proinflammatory cytokines may not play a role in the pathophysiology of CHF or the doses of etanercept were insufficient.


Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594-602.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Immunoglobulin G, Respiratory Tract Infections, Pneumonia, Ventricular Dysfunction, Cytokines, Clinical Trials Data Monitoring Committees, Tumor Necrosis Factor-alpha, Dyspnea, Dizziness, Abdominal Pain, Heart Failure, Receptors, Tumor Necrosis Factor, Stroke Volume, Bronchitis, Confidence Intervals, Cough

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