HEALTH NEWS

Study Title:

Statins Fail Patients with Heart Failure

Study Abstract

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 randomised controlled trials have been methodologically weak. We investigated the efficacy and safety of the statin rosuvastatin in patients with heart failure.

Methods. Up to 4574 patients (mean age 68±11 yr) with chronic heart failure of New York Heart Association class II-–IV, irrespective of cause and left ventricular ejection fraction, were included in a double-blind randomised trial testing rosuvastatin 10 mg daily (n=2285) against placebo (n=2289). Patients were followed-up for a median of 3·9 years. Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. This study is registered with ClinicalTrials.gov, number NCT00336336.

Findings. According to the intention to treat analysis, 657 (29%) patients died from any cause in the rosuvastatin group(28·8%) and 644 (28%) in the placebo group (adjusted hazard ratio [HR] 1·00, [95·5% CI 0·898-–1·122], p=0·943). No differences were found also with respect to the other primary end-point: 1305 (57%) patients in the rosuvastatin group died or were admitted to hospital for cardiovascular reasons and 1283 (56%) in the placebo group (adjusted HR 1·01, [99% CI [0·908-–1·112], p=0·903).

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

Commentary by study author:

Heart failure is common, detectable, treatable, associated with unpleasant symptoms, and the herald of death. The commonest cause is coronary heart disease (60% of patients) but it may also occur in the presence of normal coronary arteries (idiopathic dilated cardiomyopathy). Statins are known to reduce cholesterol and prevent clinical events such as myocardial infarction, the onset of heart failure and death in patients with coronary heart disease or at high risk of developing coronary heart disease.

Many non-randomised studies and meta-analyses of these studies have suggested that statins are beneficial in established heart failure. The possible mechanisms are a reduction in coronary events due to lower cholesterol or a reduction of the inflammatory response of the body in heart failure which has been considered to be critical to the progression of heart failure.

Two large well conducted trials (CORONA 5011 patients, follow-up 2.8 years, and GISSI-HF 4574 patients, follow-up 3.9 years) have now shown that statins have no benefit in patients with heart failure.

The GISSI-HF trial, presented for the first time at this Congress, has added substantially to the findings in the CORONA trial published in November 2007. Some of the important differences between the two trials are age (GISSI-HF 68 years, CORONA 73 years), aetiology of heart failure (40% coronary heart disease, vs 100%), and severity of heart failure (NYHA 3 or 4 37%, 63%). The lack of any benefit in GISSI-HF (death, or the combination of death or admission to hospital for cardiovascular reasons) in patients without coronary heart disease possibly indicates that any effect of statins on inflammation was minimal or that inflammation is not an important contributor to the progression of heart failure. Adverse events were few (drug safe).

As expected, LDL cholesterol was reduced by 27%. High sensitivity CRP (C-reactive protein, a marker of inflammation) was also reduced significantly. The possibility that the lower cholesterol might be harmful due to a reduction in the binding of lipopolysaccahrides (and other toxic agents) by cholesterol appears not to be of great clinical significance.

There are some limitations of the GISSI-HF trial. Insufficient numbers of patients with an ejection fraction above 40%, who make up half of the population of patients with heart failure, were included to reach any conclusion as to efficacy in this group. The proportion of women in the study was small (24%). Only one dose of one drug was tested (rosuvastatin 10 mg daily). More than one third of patients were no longer on treatment at three years. The baseline LDL cholesterol was 3.1 mmol/l so that the effect in patients with markedly elevated cholesterol remains uncertain.

The clinical consequences of this trial are that patients with heart failure should not be treated with statins. More difficult questions are whether patients already on statins should have them stopped (probably yes) and whether patients on statins should discontinue when heart failure develops (probably yes). It is most important to understand that statins are known to prevent the onset of heart failure in patients with coronary heart disease and these patients should continue on statins at least until heart failure develops.

Conclusion
The results of this trial, and the earlier CORONA trial, were disappointing in that they did not confirm expectations; were exciting because the discovery of no benefit will alter ideas on the understanding of heart failure; and were a lesson in humility because so many cohort studies, observational studies, and meta-analyses mistakenly predicted a positive result.

Study Information

Tognoni, Gianni (Italy) & Poole-Wilson, Philip Alexander (United Kingdom)
Effects of statins in patients with symptomatic chronic heart failure: GISSI-HF results.
Lancet
2008 September