Observational Studies of Statins in Systolic Heart Failure

doi:10.1016/j.hfc.2008.01.006

Heart Failure Clinics

Volume 4, Issue 2, April 2008, Pages 201-208

https://doi.org/10.1016/j.hfc.2008.01.006 Get rights and content

This article reviews the results of observational statin use in clinical trials of patients who have systolic heart failure, in post-myocardial infarction with left ventricular dysfunction, and in cardiac device trials. This article shows a consistent benefit of statins on mortality (approximately 25%) in heart failure patients of both ischemic and nonischemic etiology. The benefit is not altered by concomitant heart failure medications or device therapy. The benefit of statins in heart failure is being investigated in large prospective trials in a broad range of heart failure patients.

Section snippets

Heart failure in randomized statin clinical trials

There was some evidence that statins might reduce heart failure hospitalization. This was first seen in 4S, where treatment of severe hypercholesterolemia with simvastatin 20 to 40 mg/day, was associated with a 30% reduction in mortality [21]. Within this trial, the diagnosis of heart failure was reduced by 21% (P<.015). The risk of death in those who developed heart failure was reduced by 19% (25.5% versus 31.9%). There was nonsignificant 42% reduction in the hospital days attributable to

Observational statin use in clinical systolic heart failure trials

Reports like these led to analysis of heart failure clinical trial and other databases (reviewed in previous article) to determine if statins might be a potential therapy for heart failure as an immune modulator, potentially unrelated to the effects on cholesterol. In observational and clinical trial databases, it is always very difficult to adjust for differences between patients who are and those who are not on statins. This may be somewhat less problematic in a clinical trial database where

Observational statin use in clinical trials of patients with left ventricular systolic dysfunction post–acute myocardial infarction

OPTIMAAL was a randomized trial of captopril versus losartan in 5301 patients with left ventricular dysfunction or heart failure after an acute myocardial infarction [31]. Statin therapy was used at hospital discharge in 2467 (47%) of the patients. The low statin usage in this patient population was likely caused by the NCEP recommendation to use these agents if the low-density lipoprotein is greater than 130 mg/dL at the time of the trial [20]. Statin use was associated with a 26% reduction in

Observational statin use in clinical device trials of patients with left ventricular systolic dysfunction

In AVID, sudden cardiac death survivors were treated with amoidarone or an ICD [32]. Although the mean ejection fraction was severely reduced at 31%, only 45% had previous heart failure. Those who were on early and consistent statin use (N = 149 out of 713) had a 36% reduction in mortality (P = .03) and a 40% reduction in ventricular tachycardia (P = .003).

The DEFINIT trial was a randomized trial of ICD versus no ICD in 458 nonischemic heart failure patients [33]. A total of 110 patients (24%)

Meta-analysis of statins in heart failure

A recent meta-analysis included PRAISE, ELITE2, CIBIS II, SCD-HeFT, and Val-HeFT trials along with observational databases and the randomized trial, CORONA [37]. There were a total of 30,107 of 131,449 patients on statin therapy (23%). Statin therapy was associated with a 26% reduction in all-cause mortality. In the trials reporting the etiology of heart failure, the benefit was consistent in the patients with an ischemic etiology (27%) or nonischemic etiology (27%) [38].

Summary

In the observational studies of statin use in clinical trials, the magnitude of benefit has been consistently in the 20% to 60% range for most trials with a 26% benefit in a recent meta-analysis. This is consistent with a meta-analysis of statin use in randomized clinical trials with a 22% reduction in cardiovascular mortality [39]. The magnitude of benefit seems to be similar in both ischemic and nonischemic heart failure patients. Except for the subgroup report with biosoprolol, the benefit

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Prevalence and Prognostic Significance of Polyvascular Disease in Patients Hospitalized With Acute Decompensated Heart Failure: The ARIC Study
2022, Journal of Cardiac Failure
Citation Excerpt :
Similarly, patients with prior vascular disease who presented with acute coronary syndrome were less likely to receive lipid-lowering therapy, smoking-cessation counseling and angiotensin-converting enzyme inhibitors.12 Statins have shown benefit in some, but not all, investigations of patients with HF.30–32 with the general consensus that they should not be prescribed for HF alone in the absence of another compelling indication for use.
Polyvascular disease is associated with increased mortality rates and decreased quality of life. Whether its prevalence or associated outcomes differ for patients hospitalized with heart failure with reduced vs preserved ejection fraction (HFrEF vs HFpEF, respectively) is uncertain.
The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of acute decompensated heart failure (ADHF) from 2005–2014. Polyvascular disease (coexisting disease in ≥ 2 arterial beds) was identified based on the finding of prevalent coronary artery disease, peripheral artery disease or cerebrovascular disease. Mortality risks associated with polyvascular disease were analyzed separately for HFpEF and HFrEF, with adjustment for potential confounders. All analyses were weighted by the inverse of the sampling probability.
Of 24,937 weighted (5460 unweighted) hospitalizations due to ADHF (52% female, 32% Black, mean age 75 years), polyvascular disease was prevalent in 22% with HFrEF and in 17% with HFpEF. One-year mortality risks increased sequentially with 0, 1 and ≥ 2 arterial bed involvement, both for patients with HFrEF (29%–32%–38%; P trend = 0.0006) and for those with HFpEF (26%–32%–37%; P trend < 0.0001). After adjustments, polyvascular disease was associated with a 26% higher mortality hazard for patients with HFrEF (HR = 1.26; 95% CI: 1.07–1.50) and a 29% higher hazard for patients with HFpEF (HR = 1.29; 95% CI: 1.03–1.62), with no interaction by HF type (P interaction = 0.9).
Patients hospitalized with ADHF and coexisting polyvascular disease have an increased risk of death, irrespective of HF type. Clinical attention should be directed toward polyvascular disease, with implementation of secondary prevention strategies to improve the prognosis of this high-risk population.
Polyvascular disease is known to be associated with myocardial infarction, stroke or cardiovascular death and is a major risk factor for decreased quality of life. This study sought to evaluate the relationship between polyvascular disease and mortality in patients hospitalized with acute decompensated heart failure (ADHF), and to understand whether the associations differ based on ejection fraction. Patients hospitalized with ADHF and coexisting polyvascular disease had an increased risk of death, irrespective of heart failure type, implying the need for increased clinical attention directed toward polyvascular disease, along with implementation of secondary prevention strategies to improve prognosis.
Patients hospitalized with acute HF and coexisting polyvascular disease face an increased risk of death, irrespective of HF type.
Statins and Exercise Training Response in Heart Failure Patients: Insights From HF-ACTION
2016, JACC: Heart Failure
The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response.
Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF).
HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates.
Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values >0.05).
In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)
Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial
2008, The Lancet
Citation Excerpt :
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,8–15 and small prospective trials16–19 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.
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.
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.
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).
Rosuvastatin 10 mg daily did not affect clinical outcomes in patients with chronic heart failure of any cause, in whom the drug was safe.
Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca.
Clinical efficacy of attovastatin in treating patients with heart failure after myocardial: A systematic review
2019, Drug Evaluation Research
Pleiotropic effects of statin in therapy in heart failure: A review
2014, Current Vascular Pharmacology
Treatment with atorvastatin is associated with a better prognosis in chronic heart failure with systolic dysfunction: Results from The Daunia Heart Failure Registry
2013, Netherlands Heart Journal

View all citing articles on Scopus

: Dr. Levy has consulted for or participated in speakers bureaus for the following companies in the last 12 months: Pfizer, GlaxoSmithKline, Novartis, BoehringerIngelheim, Thoratec, and Medtronic. He serves on the steering committee for clinical trials by Amgen and Scios. He is on the end point committee for clinical trials by General Electric. He has received research funding from Scios, Medtronic, Vasogen, Astellas, and Thoratec. He has equity in Cardiac Dimensions. The University of Washington holds the copyright for the Seattle Heart Failure Model.

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Observational Studies of Statins in Systolic Heart Failure

Section snippets

Heart failure in randomized statin clinical trials

Observational statin use in clinical systolic heart failure trials

Observational statin use in clinical trials of patients with left ventricular systolic dysfunction post–acute myocardial infarction

Observational statin use in clinical device trials of patients with left ventricular systolic dysfunction

Meta-analysis of statins in heart failure

Summary

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Card Fail

J Card Fail

Am J Kidney Dis

J Am Coll Cardiol

Am J Cardiol

Int J Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

J Am Coll Cardiol

Am J Cardiol

The Seattle Heart Failure Model: prediction of survival in heart failure

Circulation

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

Br J Pharmacol

Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL)

Circulation

Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial

Circulation