Drug Insight: Statins for Nonischemic Heart Failure
Drug Insight: Statins for Nonischemic Heart Failure
While 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, have a well-established in role in the treatment and prevention of ischemic coronary artery disease, their utility in the setting of heart failure (HF) and left ventricular (LV) dysfunction remains under investigation. Although a reduction in LDL is the major effect of statin therapy, pleiotropic effects have been demonstrated, which could be responsible for the reduction in morbidity and mortality seen with statin use in patients with HF. Patients with both ischemic and nonischemic HF have been shown to have improved survival with statin therapy, and patients receiving statin therapy are less likely to develop HF. Studies have demonstrated that statins reduce inflammation, improve endothelial function, decrease thrombogenicity, and improve LV and autonomic function. In this Review, we present the literature supporting the pleiotropic effects of statin therapy in patients with HF or LV dysfunction, and discuss the mechanisms by which statins might elicit the improvements in morbidity and mortality seen in these patients.
The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors—statins—reduces the incidence of cardiovascular events and death not only in patients with coronary artery disease but also in the setting of primary prevention. The beneficial effects of statins on cardiovascular-related morbidity and mortality have even been demonstrated in the setting of normal and low cholesterol levels. Researchers have postulated that statins could reduce mortality through effects other than those on cholesterol reduction, since statins have been shown to have beneficial effects on inflammation, and endothelial and platelet function. A recent meta-analysis by Robinson and colleagues has combined data from studies on cholesterol-reducing therapies (5 studies on diet, 3 on bile acid sequestrants, 1 on surgery, and 10 on statins) including a total of 81,859 participants, to see whether the reduction in cardiovascular events observed with statin therapy is beyond that expected on the basis of the degree of LDL cholesterol reduction. This study demonstrated that the regression lines for statin and nonstatin therapies were similar and consistent with a one-to-one relationship between LDL cholesterol reduction and a decrease in cardiovascular events over 5 years of treatment. This finding implies that statins did not have an impact on cardiovascular risk reduction beyond that expected with the degree of LDL cholesterol lowering achieved, indicating that the pleiotropic effects of statins do not reduce mortality further. The majority of studies referenced in this meta-analysis did, however, focus primarily on the reduction of cholesterol in patients at high cardiovascular risk.
The hypothesis that pleiotropic effects from statin therapy improve survival is supported by the reduction in mortality seen in patients treated with statins, in whom stabilization of atherosclerotic disease and prevention of ischemic events is unlikely to be the mechanism for improved survival. For example, improved outcome with statin therapy might be a result of cholesterol reduction and plaque stabilization in the setting of ischemic left ventricular (LV) dysfunction or heart failure (HF); whereas a large increase in survival with statin therapy for patients with nonischemic HF would not be explained by a reduction in ischemic events alone. The goal of this paper, therefore, is to review and discuss the theoretical role of statin therapy in the setting of ischemic and nonischemic HF and discuss how the pleiotropic effects of statin therapy could result in improved survival.
Summary and Introduction
Summary
While 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, have a well-established in role in the treatment and prevention of ischemic coronary artery disease, their utility in the setting of heart failure (HF) and left ventricular (LV) dysfunction remains under investigation. Although a reduction in LDL is the major effect of statin therapy, pleiotropic effects have been demonstrated, which could be responsible for the reduction in morbidity and mortality seen with statin use in patients with HF. Patients with both ischemic and nonischemic HF have been shown to have improved survival with statin therapy, and patients receiving statin therapy are less likely to develop HF. Studies have demonstrated that statins reduce inflammation, improve endothelial function, decrease thrombogenicity, and improve LV and autonomic function. In this Review, we present the literature supporting the pleiotropic effects of statin therapy in patients with HF or LV dysfunction, and discuss the mechanisms by which statins might elicit the improvements in morbidity and mortality seen in these patients.
Introduction
The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors—statins—reduces the incidence of cardiovascular events and death not only in patients with coronary artery disease but also in the setting of primary prevention. The beneficial effects of statins on cardiovascular-related morbidity and mortality have even been demonstrated in the setting of normal and low cholesterol levels. Researchers have postulated that statins could reduce mortality through effects other than those on cholesterol reduction, since statins have been shown to have beneficial effects on inflammation, and endothelial and platelet function. A recent meta-analysis by Robinson and colleagues has combined data from studies on cholesterol-reducing therapies (5 studies on diet, 3 on bile acid sequestrants, 1 on surgery, and 10 on statins) including a total of 81,859 participants, to see whether the reduction in cardiovascular events observed with statin therapy is beyond that expected on the basis of the degree of LDL cholesterol reduction. This study demonstrated that the regression lines for statin and nonstatin therapies were similar and consistent with a one-to-one relationship between LDL cholesterol reduction and a decrease in cardiovascular events over 5 years of treatment. This finding implies that statins did not have an impact on cardiovascular risk reduction beyond that expected with the degree of LDL cholesterol lowering achieved, indicating that the pleiotropic effects of statins do not reduce mortality further. The majority of studies referenced in this meta-analysis did, however, focus primarily on the reduction of cholesterol in patients at high cardiovascular risk.
The hypothesis that pleiotropic effects from statin therapy improve survival is supported by the reduction in mortality seen in patients treated with statins, in whom stabilization of atherosclerotic disease and prevention of ischemic events is unlikely to be the mechanism for improved survival. For example, improved outcome with statin therapy might be a result of cholesterol reduction and plaque stabilization in the setting of ischemic left ventricular (LV) dysfunction or heart failure (HF); whereas a large increase in survival with statin therapy for patients with nonischemic HF would not be explained by a reduction in ischemic events alone. The goal of this paper, therefore, is to review and discuss the theoretical role of statin therapy in the setting of ischemic and nonischemic HF and discuss how the pleiotropic effects of statin therapy could result in improved survival.