The Role of Statins in Preventing Stroke
The Role of Statins in Preventing Stroke
Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.
Hypercholesterolemia is a risk factor for coronary artery disease (CAD). Numerous clinical studies have shown that low-density lipoprotein (LDL) cholesterol plays a major role in the pathogenesis of CAD; however, based on epidemiological studies, there is no clear evidence for a relation between stroke risk and hypercholesterolemia.
Keeping the epidemiological studies in mind, it seems paradoxical that recent CAD prevention trials indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with a significant reduction in stroke risk. For example, the Cholesterol and Recurrent Events (CARE) trial showed that pravastatin significantly reduced the prespecified end point of stroke by 31%. Of note, stronger stroke reduction effect was noted in secondary coronary artery prevention trials than primary coronary artery prevention trials.
In addition, randomized trials show that stroke reduction occurs over a wide range of initial lipid levels. The Heart Protection Study (HPS) (which included over 20,000 patients) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study (which included over 10,000 patients) provide strong support for the role of statin therapy in reducing risk of stroke in patients with average or relatively low LDL cholesterol levels. In HPS, larger numbers of subjects suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events, but also of ischemic strokes (with no apparent effect on cerebral hemorrhage), even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischemic strokes by approximately 25%. HPS also provides definitive evidence that statins are beneficial for patients with preexisting cerebrovascular disease, even if they do not already have coronary disease.
These findings, coupled with the observation that lipid lowering by other means (e.g., fibrates, resins, or diet) has no impact on stroke incidence, suggest that statins may be unique among lipid-lowering drugs in relation to stroke reduction. Statins have more robust effects on LDL cholesterol reduction than other lipid-modifying agents; therefore, the effects may reflect better LDL cholesterol reduction. However, the disparity between epidemiological and clinical studies may indicate additional biologic effects of statins that contribute to stroke reduction. These effects have been loosely termed "pleiotropic" in the lipid literature. Pleiotropic effects which may be contributing to the decreased incidence of stroke in patients on statin therapy include atherosclerotic plaque stabilization, decreased inflammation, improvement in endothelial function, and altered thrombogenicity (Figure 1).
(Enlarge Image)
The aorta and carotid are pericerebral arteries that may contain a significant burden of atherosclerotic plaque. Plaque at these sites may become unstable through macrophage elaboration of matrix metalloproteinases that weaken the fibrous skeleton of plaque, making disruption more likely. Plaque disruption is accompanied by thrombosis that predisposes to artery-to-artery thromboembolism and stroke. Statins have a number of putative effects that may stabilize aortic and carotid plaque. These include effects on plaque lipid content, macrophage activation, protection of the endothelium through enhanced nitric oxide (NO) bioavailability, anti-inflammatory, and antithrombotic actions.
Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.
Hypercholesterolemia is a risk factor for coronary artery disease (CAD). Numerous clinical studies have shown that low-density lipoprotein (LDL) cholesterol plays a major role in the pathogenesis of CAD; however, based on epidemiological studies, there is no clear evidence for a relation between stroke risk and hypercholesterolemia.
Keeping the epidemiological studies in mind, it seems paradoxical that recent CAD prevention trials indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with a significant reduction in stroke risk. For example, the Cholesterol and Recurrent Events (CARE) trial showed that pravastatin significantly reduced the prespecified end point of stroke by 31%. Of note, stronger stroke reduction effect was noted in secondary coronary artery prevention trials than primary coronary artery prevention trials.
In addition, randomized trials show that stroke reduction occurs over a wide range of initial lipid levels. The Heart Protection Study (HPS) (which included over 20,000 patients) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study (which included over 10,000 patients) provide strong support for the role of statin therapy in reducing risk of stroke in patients with average or relatively low LDL cholesterol levels. In HPS, larger numbers of subjects suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events, but also of ischemic strokes (with no apparent effect on cerebral hemorrhage), even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischemic strokes by approximately 25%. HPS also provides definitive evidence that statins are beneficial for patients with preexisting cerebrovascular disease, even if they do not already have coronary disease.
These findings, coupled with the observation that lipid lowering by other means (e.g., fibrates, resins, or diet) has no impact on stroke incidence, suggest that statins may be unique among lipid-lowering drugs in relation to stroke reduction. Statins have more robust effects on LDL cholesterol reduction than other lipid-modifying agents; therefore, the effects may reflect better LDL cholesterol reduction. However, the disparity between epidemiological and clinical studies may indicate additional biologic effects of statins that contribute to stroke reduction. These effects have been loosely termed "pleiotropic" in the lipid literature. Pleiotropic effects which may be contributing to the decreased incidence of stroke in patients on statin therapy include atherosclerotic plaque stabilization, decreased inflammation, improvement in endothelial function, and altered thrombogenicity (Figure 1).
(Enlarge Image)
The aorta and carotid are pericerebral arteries that may contain a significant burden of atherosclerotic plaque. Plaque at these sites may become unstable through macrophage elaboration of matrix metalloproteinases that weaken the fibrous skeleton of plaque, making disruption more likely. Plaque disruption is accompanied by thrombosis that predisposes to artery-to-artery thromboembolism and stroke. Statins have a number of putative effects that may stabilize aortic and carotid plaque. These include effects on plaque lipid content, macrophage activation, protection of the endothelium through enhanced nitric oxide (NO) bioavailability, anti-inflammatory, and antithrombotic actions.
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