Elsevier

The Lancet

Volume 372, Issue 9645, 4–10 October 2008, Pages 1231-1239
The Lancet

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Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial

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Summary

Background

Large observational studies, small prospective studies and post-hoc analyses of randomised clinical trials have suggested that statins could be beneficial in patients with chronic heart failure. However, previous studies have been methodologically weak. We investigated the efficacy and safety of the statin rosuvastatin in patients with heart failure.

Methods

We undertook a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy. We enrolled patients aged 18 years or older with chronic heart failure of New York Heart Association class II–IV, irrespective of cause and left ventricular ejection fraction, and randomly assigned them to rosuvastatin 10 mg daily (n=2285) or placebo (n=2289) by a concealed, computerised telephone randomisation system. Patients were followed up for a median of 3·9 years (IQR 3·0–4·4). Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00336336.

Findings

We analysed all randomised patients. 657 (29%) patients died from any cause in the rosuvastatin group and 644 (28%) in the placebo group (adjusted hazard ratio [HR] 1·00 [95·5% CI 0·898–1·122], p=0·943). 1305 (57%) patients in the rosuvastatin group and 1283 (56%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 1·01 [99% CI 0·908–1·112], p=0·903). In both groups, gastrointestinal disorders were the most frequent adverse reaction (34 [1%] rosuvastatin group vs 44 [2%] placebo group).

Interpretation

Rosuvastatin 10 mg daily did not affect clinical outcomes in patients with chronic heart failure of any cause, in whom the drug was safe.

Funding

Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca.

Introduction

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (known as statins) are among the most successful drugs discovered and incorporated into clinical practice over the past decades for both primary and secondary prevention of atherothrombosis. In addition to their lipid-lowering action, statins have been postulated to have so-called pleiotropic actions,1 including anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects; improvement of endothelial dysfunction; inhibition of neurohormonal activation; and prevention of cardiac arrhythmias.1, 2, 3, 4, 5 Most of these effects can target important components of the complex physiopathology of heart failure.6

Large observational studies,2, 7 several post-hoc analyses of randomised clinical trials testing drugs that differ from statins,8, 9, 10, 11, 12, 13, 14, 15 and small prospective trials16, 17, 18, 19 have suggested that statins could be beneficial to patients with heart failure. Furthermore, two meta-analyses of statin use in observational and randomised clinical trials2, 8 confirmed a reduction in cardiovascular mortality in patients with heart failure of both ischaemic and non-ischaemic cause. However, randomised controlled trials specifically investigating the efficacy and safety of statins in heart failure were needed because of the methodological weaknesses that were inherent in previous studies.

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca (GISSI) decided to undertake a study in patients with symptomatic heart failure of any cause and with any level of left ventricular systolic function, to test the hypothesis that the administration of the statin rosuvastatin would be effective and safe.

Section snippets

Patients

We did a randomised, double-blind, placebo-controlled, multicentre study, involving 326 cardiology and 31 internal medicine centres in Italy (figure 1). The design of the GISSI-HF trial has been described in detail elsewhere, including the randomisation, monitoring, and follow-up procedures.20

Eligible patients were men and women aged 18 years or older, with symptomatic heart failure that was classified as New York Heart Association (NYHA) functional class II–IV, who were being treated according

Results

4631 patients were randomly assigned (figure 1). We disqualified information from 57 patients at one site after randomisation, before unblinding, because the adequacy of the informed consent process and quality of data could not be ensured. Of the remaining 4574 patients, 2285 were assigned to receive rosuvastatin and 2289 to receive placebo. Follow-up ended on March 31, 2008. The median duration of follow-up was 3·9 years (IQR 3·0–4·4).

Table 1 shows the baseline characteristics of all

Discussion

This trial aimed to investigate the efficacy and safety of rosuvastatin at the usual start dose (10 mg daily) in a broad population of symptomatic patients with heart failure, irrespective of age, ischaemic and non-ischaemic cause, and LVEF. We consistently noted no effect on primary and secondary endpoints, and on all planned subgroup analyses.

Almost uniformly, several observational studies undertaken in different experimental and clinical conditions, and post-hoc analyses of randomised

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