From the Department of Medicine, Division of Cardiology, University of California, Los Angeles Medical Center, Los Angeles, California
Morbidity and mortality in coronary artery disease (CAD) and other atherosclerotic vascular diseases have been shown to be reduced with HMG-CoA reductase inhibitor (statin) therapy.1-3 For patients with CAD, statins prevent the onset of heart failure.4 The impact of statin therapy on patients with established heart failure, however, has not been well studied.
Potential risks and benefits of statin therapy in heart failure patients have previously been described. Low cholesterol levels are associated with a poor prognosis in advanced heart failure patients, which raises the issue of whether statins are safe in this population.5 Statins also lower the level of coenzyme Q, which may negatively affect ventricular function and exercise tolerance.6 However, the anti-ischemic actions of statins are clearly of potential benefit to patients with heart failure and CAD. Additional actions of statins, which may benefit both ischemic and nonischemic heart failure patients, include improvement in endothelial function, inhibition of inflammatory cytokines, increased nitric oxide synthesis, normalization of autonomic function, and reversal of pathologic myocardial remodeling.7-11
Because of the uncertainty surrounding the use of statins in heart failure patients, we investigated the impact of statin therapy on survival in a large cohort of patients with advanced heart failure from various causes.
Patients and methods
Our cohort included 551 patients with a left ventricular ejection fraction of 40% or lower evaluated at a single university heart failure center between 2000 and 2002. Medications, which were determined by the patient’s heart failure physician or referring cardiologist, or both, were recorded at the initial visit and at every follow-up visit. A patient was considered to be taking statin therapy if the statin drug was started prior to referral or within 3 months of referral and continued during the study period. The primary end point was death or the need for urgent heart transplantation (status IA).
Patients ranged in age from 18 to 84 years, and 45% of patients had heart failure from ischemic causes. Forty-five percent of patients were taking statin medication; 73% of patients with ischemic heart failure were receiving statins, compared with 22% of patients with nonischemic heart failure. The statins used included atorvastatin (n = 150), simvastatin (n = 56), pravastatin (n = 30), fluvastatin (n = 7), lovastatin (n = 5), and cerivastatin (n = 1). Only 1.2% of the population was receiving nonstatin lipid-lowering therapy. Patient characteristics, including characteristics of statin-treated and untreated patients, are shown in the table.
Patients taking statins had significantly better survival free from death or urgent transplantation compared with patients not taking statins. The 1-year survival rate was 84% for the statin-treated group versus 70% in the no-statin group (hazard ratio [HR], 0.45; 95% con-fidence interval [CI], 0.30—0.67). The survival benefit was also seen at the 2-year follow-up; survival was 79% for patients treated with statins and 61% for those not treated with statins (HR, 0.47; 95% CI, 0.320.69). The significantly improved outcome associated with statins was seen in subgroups of both ischemic and nonischemic patients (figure 1).
Statin therapy was an independent predictor of mortality after adjustment for demographic variables and other known predictors of prognosis in heart failure. Multivariate Cox regression analysis, which included sex, age, medications, heart failure cause, New York Heart Association (NYHA) functional class, hemoglobin level, creatinine level, and pulmonary capillary wedge pressure, showed that statins were associated with a lower risk of death or urgent heart transplantation at both the 1-year (HR, 0.41 [0.18—0.94]) and 2-year (HR, 0.43 [0.20–0.94]) follow-up. Improved outcomes associated with statin ther-apy were also seen in subgroups of the total cohort based on sex, cholesterol level, and receipt of heart transplant (figure 2). Rates of all-cause mortality (excluding transplant as an end point) were 11% and 18% in statin-treated and untreated patients, respectively (HR, 0.52; 95% CI, 0.30–0.90).
Our data show a strong, independent association between statin treatment and improved survival for both ischemic and nonischemic heart failure patients. Statin therapy was associated with better survival despite the many poor prognostic factors in patients taking statins, including CAD, hypertension, diabetes, and smoking. Furthermore, a statin-associated survival advantage was observed in patients with both high and low cholesterol levels. There are several possible explanations for the improved survival associated with statin therapy in heart failure.
CAD is a major cause of heart failure, and for patients with heart failure and CAD, the potential benefits of statins are well recognized. Statins promote stabilization of atherosclerotic plaques and thus reduce atherothrombotic events, which may account for a significant proportion of heart failure mortality. Although symptomatic heart failure patients were not included in the major clinical trials of statins,1-3 the antiischemic benefits of statins could reasonably be expected to apply to a heart failure cohort. An important piece of evidence comes from the Cholesterol and Recurrent Events (CARE) trial, in which subjects with decreased left ventricular ejection fraction obtained significant benefit from pravastatin, similar to subjects without left ventricular dysfunction.3
The anti-inflammatory actions of statins may play a role in improving heart failure outcomes. Cytokines, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, have been associated with worse heart failure symptoms and increased heart failure mortality, and may play a pathophysiologic role in the progression of heart failure.12 Statins have been shown to decrease levels of both TNF-a and IL-6.13
Recent experimental evidence from animals and humans suggests that statins may play a direct role in reversing the pathologic myocardial remodeling seen in both ischemic and nonischemic heart failure. In one study, subjects with idiopathic, dilated cardiomyopathy who were treated with simvastatin for 14 weeks had significant improvement in left ventricular ejection fraction and left ventricular end systolic volume compared with subjects treated with placebo.13
Statins improve endothelial function, which is often impaired in heart failure, as characterized by increased vasoconstriction and decreased vasodilation. Endothelial dysfunction in heart failure contributes to decreased exercise capacity and end-organ dysfunction. Simvastatin treatment in idiopathic dilated cardiomyopathy was associated with improved endothelial function, as manifested by improved flow-mediated brachial artery vasodilation.13 Improvement in endothelial functioning is likely mediated through the ability of statins to stimulate the endothelium to produce nitric oxide.14
Finally, statins may contribute to better heart failure outcomes by modifying and normalizing the overactive sympathetic nervous system of heart failure. Sympathetic nervous system activation in heart failure, manifested as increased norepinephrine levels, is associated with increased morbidity and mortality.15 In one study, rabbits with heart failure induced by rapid pacing treated with simvastatin had decreased norepinephrine levels and renal sympathetic nerve activity, as well as normalized baroreceptor responses.11
It is safe to treat heart failure patients with statins, based on the results of our study. Our study also suggests that statin therapy may lead to improved heart failure outcomes. The survival advantage associated with statin therapy in our cohort occurred regardless of cholesterol levels or cause of heart failure. Statins may represent a new therapy for both ischemic and nonischemic heart failure. Ongoing randomized, controlled trials are needed to confirm this benefit.