Expert Review: Heart Failure

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials

Introduction
Statins inhibit cholesterol biosynthesis and decrease serum levels of low-density lipoprotein cholesterol (LDL-C) by inhibition of 3-hydroxy-3- methyl-glutaryl-coenzyme A reductase. Additional effects are widely recognized, including anti-inflammatory and anti-oxidant properties, improvement of endothelial function and angiogenesis1,2. Statins have primary and secondary effects that help to prevent against the development of coronary artery disease3. Heart failure (HF) is mainly characterized by a condition in which the heart cannot pump enough blood to the rest of the body. With an increasing number of patients, HF is becoming a major worldwide public health problem which requires a global response. In recent decades, significant advances have been made in the treatment of HF with the appearance of angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, β-blockers, aldosterone antagonists, ivabradine and device therapies. However, mortality and morbidity is still high and further strategies are needed to prevent or reduce adverse outcomes Although coronary artery disease is a frequent cause of and the treatment of coronary artery disease patients with statins results in a significant decrease in mortality4-6, the potential benefits of statins in HF remain unclear.

Trial design:
Systematic analysis evaluating the effect of statin therapy on HF events from 17 trials and over 570000 patient-years of follow-up for the main analyses.
Unpublished data were collected to provide reliable information on homogenous HF endpoints, which consisted on non-fatal hospitalisation, death, and a composite of both. Access to trial data allowed harmonization of data and assessment of relevant subgroup and sensitivity analyses. HF events occurring <30 days after within–trial myocardial infarction (MI) were excluded. They calculated risk ratios (RR) with fixed–effects meta–analyses.

Results:
The present study represents the largest systematic analysis evaluating the effect of statin therapy on HF events. It included over 132 000 participants (mean age 63 years; 29% females). The mean follow-up was 4.3 years.
The main findings were:
• Nonfatal-MI: 16 trials provided data on non-fatal MI, which was reduced by 26% with statin therapy (2287 first events in 65438 participants on statins vs. 3107 in 65530 on control: RR: 0.74, 95%CI: 0.70-0.78).
• First non-fatal HF hospitalization: based on 17 trials, statins reduced this endpoint by 10% (RR: 0.90, 95%CI: 0.84-0.97), with numbers needed to treat (NNT) of 1454 (non-significant: NS) in the primary prevention trials, 552 (NS) in mixed trials and 200 in secondary-prevention trials over 5 years.
• HF death was unaffected by statin therapy (RR: 0.97, 95%CI: 0.80-1.17).
• The composite HF outcome (first non-fatal HF hospitalization os HF death) was reduced by 8% with statin therapy, based on 14 trials (RR: 0.92, 0.85-0.99).
• Only 10-15% of first composite HF outcomes and non-fatal HF hospitalisations were preceded by a documented non-fatal MI (not including HF events within 30 days of MI). RR reduction of a first HF event was independent of its ischemic or non-ischemic origin.
• Mean LDL-C absolute reduction at 1 year was 0.97 mmol/L. In meta-regression analyses, no relationship was observed between this reduction and measeured outcomes.

Conclusion:
This analysis shows that statin therapy led to a lower number of participants with HF events in major primary and secondary prevention trials, with about 4 years of follow-up. The risk of the composite of non-fatal hospitalisation and HF death was reduced by 10%, mostly driven by a reduction in non-fatal hospitalisations.
The vast majority of participants experiencing an HF event did not have a preceding within-trial MI. The benefit of statins for HF outcomes did not appear to depend on whether patients previously experienced an MI.

Comment:
Previous evidence for statin therapy in HF mainly came from nonrandomized studies, subgroup and post hoc analyses of statin trials, and HF trials that evaluated other pharmacological agents. Several systematic reviews and meta-analyses have been conducted to synthesize evidence for statin therapy in reducing major adverse events in HF. We would like to make some points regarding statin therapy for HF:
Firstly, some of the results of these trials raised concerns about their potential detrimental effects and suggested three hypotheses defending some risks of statins in HF.
(1) lower cholesterol levels are associated with poorer outcomes in HF patients and may be related to the function of cholesterol as a scavenger for harmful endotoxins
(2) statins in HF may adversely affect mitochondrial function through inhibition of ubiquinone
(3) statins may decrease selenoproteins, which could result in decreased myocardial function.
If these effects are really present in patients with HF, the results presented might reasonably outwieight this risks, although further research should appropriately address this field.
Secondly, two recent meta-analyses performed on randomized clinical trials did not show improved survival with statin in HF7,8. The majority of patient data came from CORONA9 and GISSI-HF10 trials which randomized older patients to low dose rosuvastatin or matching placebo that may have skewed the summary statistic towards the results of these two large trials. Rosuvastatin, used in the CORONA and GISSI-HF studies, is hydrophilic and employs active transport into hepatocytes to exert its effect. It penetrates poorly into extra hepatic tissues; thus, it has a very low uptake by cardiac muscles to exert the pleiotropic effects believed to contribute greatly to attenuate HF symptoms. Conversely, atorvastatin and other lipophilic statins have very high uptake into cardiac muscles. It appears that the effect of statins should not be considered a class effect since small and large scale trials that employed rosuvastatin appeared not to have had a beneficial effect in HF.
Thirdly, the authors didn’t point out that statins may favorably modulate the pathogenesis of HF comorbidities and this ability to reverse and/or reduce progression could have had a role in the results obtained.
Finally, the results were not related to LDL-C reduction ior ischemic origin of HF, with provides additional evidence favouring statin-related mechanisms on various pathways to reduce or reverse progression of HF beyond the therapeutic actions of some of the mainstay medical therapies and could, in the worse scenario, merit second line or adjuvant therapy consideration in treatment guidelines for HF.

 

Corresponding author from original paper
David Preiss
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK
Tel: +44 141 3303076, Fax: +44 141 3306955,
Email: david.preiss@glasgow.ac.uk

References:
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2.- Takemoto M, Laio JK. Pleiotropic effects of 3-hydroxy-3- methyl-glutaryl-coenzyme A reductase inhibitor. Arterioscler Thromb Vasc Biol 2001;21:1712—9.
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7.- Zhang S, Zhang L, Sun A, Jiang H, Qian J, Ge J. Efficacy of statin therapy in chronic systolic cardiac insufficiency: a meta-analysis. Eur J Intern Med. 2011;22(5):478–484.
8.- Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. 2009;104(12):1708–1716.
9.- Kjekshus J, Apetrei E, Barrios V, et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357(22):2248–2261.
10.- Tavazzi L, Maggioni AP, Marchioli R, et al; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1231–1239.

Citation: Preiss D, Campbell RT, Murray HM, Ford I, Packard CJ, Sattar N, et al. The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials. Eur Heart J. 2015;36(24):1536-46.

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