Mr Michał Tendera
Prof. Maciej Sosnowski,
Clinical benefit of statins, irrespective of their lipid-lowering effects, justify their use in mild and moderate heart failure of atherosclerotic origin. Such a conclusion can be drawn from growing evidences for improved survival of heart failure patients treated with statins.
A retrospective analysis of the ELITE II study brought evidence for potentially beneficial effects of statins in HF. Total mortality of 10.6% in 359 statin users was significantly lower compared to 17.6% in non-users (non-randomised comparison). Additionally, the use of lipid-lowering drugs (mostly statins) was associated with a 36% reduction in relative hazard for death in a retrospective analysis of the AVID study. Two most recent studies support the above observations. The first study reported on statin therapy being an independent predictor of improved survival without the necessity of urgent transplantation (hazard ratio 0.41, 95% CI 0.18-0.94) in patients with advanced (1/3 of total in IV NYHA class, mean EF 25%), both ischemic and non-ischemic HF. The second study was a retrospective analysis of the OPTIMAAL Trial. The effect of initiating statin or beta-blocker treatment in patients with HF or LV dysfunction following acute MI was compared with the effect of neither or both treatments. Early initiation of statins alone was associated with a 26.1% decrease of all-cause mortality. The effect of statins appeared to be additive to that of β-blockers, and the combination of statins and β-blockers was associated with a 48.3% risk reduction (after adjustment for age, gender, diabetes, smoking, lipids abnormality and Killip class). Mortality analysis in prespecified subgroups in the EPHESUS trial showed a similar all-cause death reduction with eplerenone, irrespective of statins administration. Similarly, no differences were found between statin users and non-users in respect to overall effect of candesartan on CV death or first admission for congestive HF in the CHARM study.
One observational prospective study investigated the effect of statins on the incidence of congestive HF in elderly patients (mean age 81 ± 9 years) with prior myocardial infarction and elevated serum LDL cholesterol ≥ 125mg/dl. The frequency of HF at 36 months follow-up was 31% in patients treated with statins and 42% in those with no lipid-lowering drug (a 26% reduction in HF). Use of statins was found as an independent predictor of HF development (risk ratio 0.52, 95%CI 0.43-0.62).
An elevated serum cholesterol level was a risk factor for the development of HF in the Framingham study. However, the presence of HF was an exclusion criterion in nearly all trials of statins. Only two large lipid trials (CARE, HPS) did allow to include patients with mild to moderate HF. However, the proportion of such patients was hardly the one in the real world of patients with coronary heart disease, which is a primary cause of heart failure. Consequently, in recent HF randomised controlled trials the use of statins is increasing. In the COMET,BEST and MERIT-HF trials, in which more than half of patients suffered from CHD, the proportion of patients on statins was 21, 23 and 26%, respectively. Out of 7601 participants of the CHARM trial, including 53% survivors of myocardial infarction, 41.5% received statins. In postinfarction trials focusing on patients with LV systolic dysfunction this proportion varied from 34% in the VALLIANT study through 47% in the EPHESUS study up to 65% in conventionally-treated arm of the MADIT II trial.
Prospective analysis of secondary end-points in the ASCOT-LLA trial showed neutral effects of atorvastatin use in HF prevention, with a hazard ratio (95%CI) being 1.13 (0.73-1.78). Retrospective analysis of the 4S study showed a 20% lower rate of HF incidence (p=0.017) along with significant absolute risk reduction (-6.2%) of all-cause mortality in simvastatin users in whom HF did develop. The preventive role of atorvastatin against HF development (-50%, p=0.021) was confirmed in the GREACE study.
Statins were shown to reduce inflammation and restore endothelial function, actions that may be beneficial in patients with HF. In experimental and clinical studies on HF, statins appeared to improve the autonomic cardiac control (heart rate variability, baroreflex sensitivity), to prevent post-infarction ventricular remodeling and reduce LV mass, as well as to improve renal function. Other important benefits included promotion of bone-marrow endothelial progenitor cells mobilisation and re-endothelisation of injured arteries. Clinically proven antiarrhythmic effects of statins in the AVID study and in patients with atrial fibrillation may provide additional gains. In addition, antithrombotic action lengthens the list of beneficial effects of statins that may prove promising in HF patients.
An inverse relationship between cholesterol and mortality in advanced HF and the elderly has raised concerns about statins use in elderly patients with HF. One of potential harms of statin use in HF is related to their lipid-lowering effects. Lipoproteins (LDL, HDL) downregulate inflammatory immune responses to bacterial lipopolysaccharides (the endotoxin-lipoprotein hypothesis). Statins may attenuate this protective role of lipoproteins in HF which may in turns lead to further activation of inflammatory cytokines (TNF-α). Another restriction on the use of statins in HF is related to their inhibitory effects on ubiquinon (CoQ10) synthesis, which may precipitate or aggravate myopathy or polyneuropathy. However, the absolute risk is small and the number of patients needed to treat to cause harm (NNTH) is approx. 5000-10000. Finally, interactions between statins and drugs used in HF treatment (e.g. digoxin, warfarin) may bring about undesirable effects.
Clinical benefit of statins, irrespective of their lipid-lowering effects, may justify their use in mild and moderate heart failure of atherosclerotic origin. As there are limited data on statins’ action in advanced HF, it would be premature to advise their administration in this population. The ongoing large-scale clinical outcome trials in patients with congestive HF (CORONA, GISSI-HF, UNIVERSE) will likely give more conclusive solutions in this area.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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Dr. Maciej Sosnowski and Prof. Michał Tendera, FESC, FACC 3rd Division of Cardiology, Silesian Medical School Ziolowa St 47, 40-635 Katowice, Poland
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