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(Circulation. 2000;102:2700.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Limitation of Excessive Extracellular Matrix Turnover May Contribute to Survival Benefit of Spironolactone Therapy in Patients With Congestive Heart Failure

Insights From the Randomized Aldactone Evaluation Study (RALES)

Faiez Zannad, MD, PhD; François Alla, MD; Brigitte Dousset, MD, PhD; Alfonso Perez, MD; Bertram Pitt, MD; on behalf of the RALES Investigators

From the Centre d’Investigation Clinique INSERM-CHU (F.Z., F.A.) and the Laboratory of Biochemistry (B.D.), Centre Hospitalier Universitaire, University Henri Poincaré, Nancy, France; Searle Monsanto (A.P), Skokie, Ill; and the Department of Internal Medicine (B.P.), Division of Cardiology, University of Michigan, Ann Arbor.

Correspondence to Prof Faiez Zannad, Centre d’Investigation Clinique INSERM-CHU, Hôpital Jeanne d’Arc, 54200 Toul, France. E-mail cic{at}chu-nancy.fr

Background—In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF.

Methods and Results—A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 µg/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively.

Conclusions—In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.

Key Words: heart failure • collagen • tissue • hormones • trials