Heart failure is common, and leads to substantial morbidity and mortality in most regions of the world.1 Medical and device therapies have been successfully developed to improve outcomes in patients with systolic heart failure. Beneficial treatments include inhibitors of the renin–angiotensin–aldosterone system and sympathetic nervous system, use of implantable cardioverter defibrillators, and cardiac resynchronisation therapy in selected patients (table).1 However, not all patients with systolic heart failure qualify for or tolerate these therapies and, even with the best treatment, heart failure remains a major cause of morbidity, mortality, and health-care expenditure. No drug or device has been definitively shown to improve outcomes in patients with heart failure and preserved systolic function.1 New therapies and management strategies need to be identified.

Table. Evidence-based therapies for systolic heart failure

* For patients with specific indications.

There has been much interest in the potential therapeutic role of statins in heart failure.2 Experimental studies, observational analyses, and limited prospective clinical investigations have suggested that statins improve ventricular function, heart-failure status, and clinical outcomes.2–6 The potential of statins in heart failure comes from their antiatherogenic properties and their ability to improve endothelial function and stabilise plaque, which together could reduce the risk of acute coronary events and the ischaemic burden on the failing ventricle.3,4 Additionally, statins might have beneficial effects independent of lipid lowering, including inhibition of pro-inflammatory cytokine activity, neoangiogenesis, downregulation of angiotensin-1 receptors, and favourable modulation of the autonomic nervous system.3,4

The first large-scale randomised trial with a clinical outcome for statin use in patients with symptomatic heart failure was reported last year. CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) randomised 5011 patients with a history of ischaemia to receive rosuvastatin 10 mg daily or placebo.7 All patients were in New York Heart Association (NYHA) class II–IV, with a left-ventricular ejection fraction no higher than 40%, or 35% for those in NYHA class II. Over a median follow-up of 33 months, there were no significant differences in the composite primary endpoint of all-cause mortality, cardiovascular mortality, or non-fatal coronary events. There were statistically significant, but modest, reductions in the number of admissions to hospital for cardiovascular events, and, in a post-hoc analysis, in non-fatal ischaemic events.

In today's Lancet, the GISSI-HF investigators report the results of their multicentre trial of statin therapy in patients with chronic heart failure.8 4574 patients in NYHA class II–IV were enrolled, irrespective of the cause of heart failure or left-ventricular ejection fraction, and randomised to rosuvastatin 10 mg or placebo, both added to standard background therapy for heart failure. During a median follow-up of 3·9 years, rosuvastatin had no effect on the primary endpoints of time to death and time to death or admission to hospital for cardiovascular events. By contrast with the findings in the CORONA trial, the secondary outcomes of hospital admission for any cause, cardiovascular cause, or heart-failure cause were not favourably affected. There were also no significant differences in myocardial infarction, stroke, or sudden cardiac death. There were no discernible improvements in clinical outcomes in any clinically relevant subgroup, including patients with either an ischaemic or non-ischaemic cause of heart failure and those with reduced and preserved systolic function, although the last subgroup was small. Together, these two well-conducted clinical trials establish that, although statin therapy lowers concentrations of LDL cholesterol, is well tolerated, and seems reasonably safe, it does not produce meaningful improvements in survival in patients with chronic heart failure.

How can the results of these clinical trials be reconciled with all the experimental, clinical investigation, and observational data? Pleiotropic effects of statins have yet to be found clinically. The proven clinical benefit of statins in patients with and at risk for coronary heart disease has been through reduction in acute coronary events. In GISSI-HF, CORONA, and other heart-failure trials, the rates of myocardial infarction and other atherothrombotic events were low compared with those in trials in patients with coronary artery disease without chronic heart failure.7–10 Once heart failure is established, statins may not allow patients to escape the mortality associated with the underlying heart-failure disease process.7,9 Also, in patients with heart failure, lower rather than higher levels of total cholesterol are associated with worse outcomes.11 Lipoproteins may remove endotoxins that enter the circulation through the intestinal wall, which can be oedematous and more permeable in patients with heart failure.12 Any potential benefits of statins in heart failure may be offset by detrimental effects of lowering cholesterol levels in this population.

Supplementation with n-3 polyunsaturated fatty acids has also been of potential interest as a therapy for heart failure. Trials in primary and secondary prevention of coronary heart disease showed that n-3 fatty acid supplementation results in a reduction in relative risk of 10–20% in fatal and non-fatal cardiovascular events.13 The GISSI-HF investigators also randomised 6975 patients in class II–IV chronic heart failure to 1 g daily of n-3 polyunsaturated fatty acids (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the ratio of 1:1·2) or matching placebo.14 Death from any cause was reduced from 29% with placebo to 27% in those treated with n-3 fatty acids (adjusted hazard ratio 0·91, 95·5% CI 0·833–0·998, p=0·041). The co-primary outcome of death or admission to hospital for a cardiovascular event was also reduced. Although the improvements in clinical outcomes were modest, they were additive to those of other therapies that are standard of care in heart failure. The therapy was safe and very well tolerated. Whilst questions remain about mechanisms of action, optimum dosing, and formulation, supplementation with n-3 polyunsaturated fatty acids should join the short list of evidence-based life-prolonging therapies for heart failure.

The new results from GISSI-HF reinforce the idea that findings in populations without heart failure may or may not extrapolate to patients with heart failure. Randomised trials to better define safety and efficacy in heart failure are required. For n-3 fatty acid supplementation, benefits observed in other populations apply to patients with heart failure. For statins, the benefits, unfortunately, seem not to. Although other promising treatments for heart failure are under investigation, every effort should be made to apply those therapies which are evidenced-based to all eligible patients with heart failure.

I have received research funding from GlaxoSmithKline and Pfizer, and consultancies, honorarium, or speaker fees from AstraZeneca, GlaxoSmithKline, Pfizer, Merck, and Schering Plough.

References

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