Statin therapy in heart failure

Is statin therapy an essential treatment in congestive heart failure?

Congestive heart failure (CHF) affects up to 2% of the population, and recent data indicate dramatic increases in its incidence and prevalence, especially in western societies. It is a very disabling and debilitating illness. Over the past 10 to 20 years there have been dramatic changes in the management of CHF, based on large-scale, randomized, controlled trials. Currently, angiotensin-converting enzyme inhibitors, β-blockers and diuretics are the mainstay of treatment. The use of these medications is based on the basic understanding of the pathophysiologic mechanisms of heart failure. Furthermore, the understanding of CHF has evolved from a rather simplistic model of mere pump failure to that of a multisystem disorder that affects, not only the cardiovascular system, but also the musculoskeletal, renal, neuro-endocrine and immune systems. Thus, the pathophysiology of CHF is exceedingly complex. Therapies to block excessive neuro-endocrine activation have become a cornerstone of treatment. However, does treatment that targets the activated inflammatory cascade and the neurohormonal imbalance in patients with CHF have an additive effect on the currently available drugs; or would it have a prognostic benefit on those patients? Specifically, do statins have an essential role in the treatment of heart failure patients?

Effects of statins

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are of well-established benefit for the prevention and treatment of coronary artery disease (CAD) – the major etiologic factor in the development of CHF. Consequently, in the treatment of CHF, statins confer the greatest benefit to patients with CAD. Importantly, patients with CAD constitute the bulk of the randomized trials studying the beneficial effects of statins in CHF. The beneficial effects of statins in this group of patients clearly relate to their plaque-stabilization properties and the associated improvement in endothelial function, which together should reduce the risk of further infarction and the ischemic burden on an already failing ventricle. Beyond their lipid-lowering properties, statins have numerous effects on the cardiovascular system, commonly referred to as pleotropic properties. However, which of these properties has the major impact on CHF; and do these properties justify their use in the treatment of CHF independent of lipid lowering? The other beneficial effects of statins include actions on neoangiogenisis, downregulation of angiotensin (AT)₁ receptors, which play a key role in the progression of CHF, and restoration of autonomic function as the sympathetic limb is over activated in CHF. It has also been found that statins inhibit the proinflammatory cytokines that are activated in CHF, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 [1].

Statins in chronic heart failure: what is the evidence?

Clinical data on the use of statins in CHF are scarce. Recent studies in animal models have demonstrated that statins can prevent the development of CHF. Simvastatin given to rats with left ventricular hypertrophy significantly improved left ventricular function, prevented the transition of hypertrophy to CHF and resulted in reduced superoxide levels and cardio-myocyte apoptosis [2]. In the Scandinavian Simvastatin Survival Study (4S) there was a 20% reduction in heart failure with simvastatin compared with placebo [3]. This was in line with the reduction (30%) of recurrent myocardial infarction (MI) observed during the study. Simvastatin reduced the risk of mortality by 19% in patients with heart failure, compared with 28% in those without heart failure. However, the important message was that the absolute reduction of death was 6.1% in heart failure patients compared with 2.6% in patients without heart failure. The clinical benefit associated with statin treatment was also independent of baseline cholesterol values in WOSCOPS (West Of Scotland COronary Prevention Study). The hypothesis is further supported by a retrospective analysis in chronic heart failure patients in the Losartan Heart Failure Survival Study (ELITE II). Of the 3152 patients enrolled, 11% were on a statin. The study demonstrated that overall mortality was reduced from 17.6% in patients without statins, to 10.6% among patients on a statin (p < 0.003). The OPtimal Trial In Myocardial infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) provided the opportunity to examine the relationship between lipoproteins and New York Heart Association (NYHA) functional classes. When the patients were stratified according to Killip class, the reduction in mortality with simvastatin in class IV was significantly greater compared with classes I and II. These results corroborate observations in previous trials. Thus there is strong evidence of benefit from simvastatin treatment among patients with moderate and severe heart failure [4]. A post hoc analysis of 5010 patients enrolled in the VALsartan HEart Failure Trial (Val-HeFT), 1602 of whom were taking statins, showed that the mortality rate over a 2-year follow-up period was 17.9% for patients on statins compared with 20.3% for patients not on statins (p = 0.029) [5]. The Cardiac Insufficiency BIsoprolol Study (CIBIS) II, included 2647 patients with ischemic and nonischemic cardiomyopathy, who were randomized to receive bisoprolol or placebo. A total of 226 (8.5%) patients were receiving statin at baseline. Statin therapy at baseline was associated with a significant survival benefit compared with no statin therapy (p < 0.005). This benefit remained after adjusting for other significant predictors of survival (p < 0.05). Furthermore, a significant interaction effect was noted with bisoprolol, survival being greatest in the bisoprolol/statin group (p < 0.001). However, this study was also limited by the fact that it was a post hoc analysis study; furthermore, it was not powered to differentiate the effect between ischemic and nonischemic cardiomyopathy [6].

Statins in nonischemic chronic heart failure

If therapy with statins is justified and is an established indication in patients with ischemic CHF, should their anti-inflammatory and vascular protective effects be extrapolated to nonischemic CHF? In the first prospective, randomized study to show that statins may have therapeutic benefits in patients with nonischemic heart failure, investigators found that short-term statin therapy improved cardiac function and functional class in 51 patients studied with idiopathic dilated cardiomyopthy [7]. It was concluded that statins may have a therapeutic benefit irrespective of serum cholesterol levels or atherosclerotic heart disease. The beneficial effect was seen as an improvement in the functional class in the group of patients who received simvastatin for 14 weeks. Left ventricular ejection fraction improved from 34% at baseline to 41% at the end of the study in patients receiving simvastatin. There was a reduction in the markers of inflammation (TNF-α and IL-6), which may be a direct action of the statins with their presumed anti-inflammatory effect, or simply a consequence of the improvement in left ventricular function.

A retrospective study by Horwich and colleagues found that statin therapy is associated with improved survival in ischemic and nonischemic heart failure patients [8]. In this study, a cohort of 551 patients with systolic heart failure (left ventricular ejection fraction ≤40%) were referred to a single university center for clinical management and/or transplant evaluation. A total of 45% of the cohort had CAD, and 45% were receiving statin therapy, including 73 and 22% of CAD and non-CAD patients with heart failure, respectively. Patients receiving statins were significantly older and more likely to be male, with higher rates of hypertension, diabetes and smoking. The ejection fraction and cholesterol levels were similar between treated and nontreated patients. Statin use was associated with improved survival without the necessity of urgent transplantation in both nonischemic and ischemic heart failure patients (91 vs. 72%; p < 0.001, and 81 vs. 63%; p < 0.001 at 1-year follow-up, respectively). Following risk adjustment for age, gender, CAD, cholesterol, diabetes, medications, hemoglobin, creatinine and NYHA functional class, statin therapy remained an independent predictor of improved survival (hazard ratio: 0.41; 95% confidence interval: 0.18–0.94). The investigators note that despite the greater abundance of poor prognostic variables, statin therapy was associated with improved outcomes in patients with ischemic and nonischemic heart failure.

Even more evidence came from using the data from the Prospective Randomized AmlodIpine Survival Evaluation (PRAISE) trial [9]. The associations of statin therapy with total mortality among 1153 patients with severe heart failure (ejection fraction <30% and NYHA class IIIB or IV symptoms) of ischemic and nonischemic etiologies were examined. Statin therapy was administered to 134 patients (12%) during the study period. Over a 1.3-year mean follow-up, there were 413 deaths (29 deaths/100 person-years). Adjusting for age, gender, diabetes, smoking, heart failure etiology, ejection fraction and NYHA class, statin therapy was associated with a 62% lower risk of death (hazard ratio: 0.38; 95% confidence interval: 0.23–0.65), or one fewer death/five patients taking statin therapy for 1 year. This association was not greatly altered by additional adjustment for a variety of other patient characteristics, including serum cholesterol levels. After propensity score analyses, statin therapy was still associated with a 48% lower risk of death (hazard ratio: 0.52; 95% confidence interval: 0.30–0.89).

Laufs and colleagues have conducted a randomized, double-blind study of 15 patients with heart failure NYHA class II to III, randomized based on nonischemic dilated cardiomyopathy to receive 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks [10]. Quality of life and exercise capacity increased significantly with statin treatment but not in the placebo group (judged using the Minnesota Living with Heart Failure Questionnaire and 6 min walking test). Concomitantly, there was a trend towards increased left ventricular ejection fraction and improved endothelial function. Statins decreased plasma concentrations of troponin T, high-sensitive C-reactive protein, plasminogen activator inhibitor-1 and TNF-α. The study supported the beneficial effects of statins in patients with nonischemic cardiomyopathy leading to improvement of quality of life and exercise capacity and again disclosing a promising novel treatment strategy for patients with heart failure.

Do we have enough evidence?

The question raised with the evidence presented on the beneficial effects of statins in CHF is whether we believe that these benefits (if confirmed) are due to the effects of statins other than their lipid-lowering effects, such as improvement in endothelial function [11], and what is the optimal dose of statin therapy required to achieve these desired benefits. Statins are readily available and, compared with other heart failure therapies, relatively inexpensive. This has important public-health implications for this very prevalent and expensive disease.

In the meantime, the expert opinion is that heart failure of ischemic origin should be treated with statins, irrespective of cholesterol levels, but more evidence is needed to support their use in CHF of nonischemic etiologies with large scale randomized trials.