Randomized Etanercept North American Strategy to Study Antagonism of Cytokines - RENEWAL - RENAISSANCE

Aug 30, 2004
Font Size
A
A
A
Date Published:
01/01/2004
Date Updated:
08/30/2004
Original Posted Date:
08/30/2004
References

Description:

The goal of the Randomized Etanercept North American Strategy to Study Antagonism of Cytokine (RENAISSANCE) 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: 925
NYHA Class: Class II 23%; Class IIIA 47%; Class IIIB 25%
Mean Follow Up: Median 12.9 months
Mean Patient Age: Mean age 62 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

Exclusions:

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 class, and patient global assessment.

Drug/Procedures Used:

Patients were randomized to subcutaneous etanercept 25 mg twice per week (n=308) or 25 mg three times per week (n=308) or placebo (n=309). Etanercept is a recombinant human TNF receptor that binds to soluble (circulating) TNF and functionally inactivates TNF.

Concomitant Medications:

Digoxin 81%, angiotensin-converting enzyme (ACE) inhibitor 79%, angiotensin-receptor blocker 19%, beta-blocker 60%, and diuretic 99%

Principal Findings:

Baseline LVEF was 22% in each of the three groups, and ischemic etiology was present in 63%, 62%, and 60% for etanercept twice weekly, etanercept three times weekly, and placebo, respectively. Other baseline characteristics were similar in the three groups, with the exception of diabetes, which was present more frequently in the etanercept groups (41%, 37%, and 34%, respectively).

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 twice weekly (p=0.07) or three times weekly (p=0.17). In the placebo group, clinical status was worsened in 20% of patients, unchanged in 36%, and improved in 44%. For etanercept twice weekly, clinical status was 29%, 32%, and 39%, respectively and for etanercept three times weekly, 27%, 31%, and 42%, respectively.

There was no difference in death or CHF hospitalization for etanercept twice weekly versus placebo (n=112 vs. n=100, relative risk [RR] 1.21, 95% confidence interval [CI] 0.92-1.58, p=0.17) or etanercept three times weekly versus placebo (n=116 vs. n=100, RR 1.23, 95% CI 0.94-1.61, p=0.13). There was also no difference in mortality between etanercept twice weekly versus placebo (n=55 vs. n=44, RR 1.27, 95% CI 0.85-1.89, p=0.24) or etanercept three times weekly versus placebo (n=61 vs. n=44, RR 1.37, 95% CI 0.93-2.02, p=0.12).

Upper respiratory tract infections, dizziness, injection-site reaction, pain, diarrhea, chest pain, bronchitis, headache, flu syndrome, constipation, and cough occurred in more than 10% of patients. Injection-site reaction, bronchitis, and constipation occurred more frequently in patients receiving etanercept than placebo.

Interpretation:

Among patients with CHF and an 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 RENAISSANCE results were similar to the RECOVER trial, the sister trial of RENAISSANCE that compared etanercept 25 mg once per week or 25 mg two 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 speculate the trend toward increase in heart failure may have been related to excessive TNF antagonism or loss of the beneficial aspects of cytokine signaling or complement fixation.

References:

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.

Keywords: Immunoglobulin G, Respiratory Tract Infections, Diarrhea, Clinical Trials Data Monitoring Committees, Tumor Necrosis Factor-alpha, Headache, Complement System Proteins, Dizziness, Constipation, Chest Pain, Heart Failure, Receptors, Tumor Necrosis Factor, Stroke Volume, Bronchitis, Confidence Intervals, Cough, Diabetes Mellitus


< Back to Listings