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Lipid-lowering therapy in ischemic stroke: Underappreciated and underutilized
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In the United States, someone suffers a stroke every 40 seconds, and someone dies from a stroke every four minutes. Statin therapy can reduce the risk of ischemic stroke, which comprises 87% of all strokes, by as much as 50%. Remarkably, these therapies remain grossly underutilized in patients at elevated risk of stroke. What is the evidence for statins reducing the risk of stroke, and why are they underutilized?
Recent evidence for the use of high-dose statins in stroke prevention comes from the JUPITER trial. JUPITER was a double-blind, randomized, placebo-controlled trial of rosuvastatin 20 mg per day in patients without pre-existing CVD who had normal LDL (<130 mg/dL) and elevated high sensitivity CRP (≥2.0 mg/L). Despite a median LDL at enrollment of only 108 mg/dL, fatal and non-fatal stroke fell 48% (HR= 0.52; 95% CI, 0.34 to 0.79; P=0.002) in participants assigned to rosuvastatin. This finding was consistent across all examined subgroups and was mostly due to a 51% reduction in the rate of ischemic stroke (HR=0.49; 95% CI, 0.30 to 0.81; P=.004). Importantly, there was no increase in hemorrhagic stroke in the active therapy arm. When these data were combined in a meta-analysis with data from three previous primary prevention trials (WOSCOPS, AFCAPS/TexCAPS, and MEGA), a net 25% reduction in stroke risk was observed (RR=0.75; 95% CI, 0.57 to 0.99; P=.03).
Among patients with established vascular disease or diabetes, statin therapy has proven remarkably effective, reducing the risk of stroke by 19% (LIPID) to 48% (CARDS). While most of these studies focused on assessing the reduction in CHD risk with statin therapy, the observed reduction in stroke was substantial and clinically important. Only one study has specifically assessed the role of high-dose statins in patients with a prior stroke who do not have known CHD. The SPARCL trial was a randomized, double-blind, placebo-controlled trial of atorvastatin (80 mg daily) in 4,731 patients with a recent transient ischemic attack or stroke but no known CHD. A 16% reduction in the risk of recurrent stroke was observed in the statin-therapy arm (HR=0.84; 95% CI, 0.71 to 0.99; P=.03). A small increase in the rates of hemorrhagic stroke was observed in the active-therapy arm (55 active vs. 33 placebo).
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Several possible explanations have been proposed for the relatively modest benefit observed with high-dose statin therapy in SPARCL. Participants were not required to undergo CT or MRI of the brain prior to enrolling in SPARCL, and patients with known hemorrhagic stroke were allowed to enroll (although only 93 did). These conditions, combined with the exclusion of patients with pre-existing CHD, raise the possibility that the SPARCL study population was enriched for patients at risk for non-ischemic stroke. The qualifying event for approximately 30% of patients in the study was TIA, a diagnosis that is a difficult to make with certainty. In general, statin trials do not show a consistent reduction in the risk of TIA with active therapy.
Data from SPARCL suggest that in the absence of other indications for lipid-lowering therapy, statins are not appropriate for patients with a history of recent cerebral hemorrhage. While there was no increase in hemorrhagic stroke in the active-therapy arm of JUPITER, epidemiologic studies suggest that low cholesterol may relate to an increase in the risk of cerebral hemorrhage.
Statins likely have effects on arterial biology that could help explain why they appear to protect from stroke despite a weak relationship between LDL and cerebrovascular disease. Statins produce nitric oxide-dependent improvement in experimental ischemic strokes in mice, likely through mechanisms involving reduced prenylation of small G proteins. In vitro studies show that statins can promote endogenous fibrinolytic pathways by elevation in plasminogen activator and reduction in plasminogen activator inhibitor-1 (PAI-1.) Statins also activate the transcription factor Krüppel-like factor 2 (KLF-2), promoting thrombomodulin activity and limiting inflammatory activation of endothelial cells.
Many factors could contribute to the underappreciated value of statin therapy in stroke prevention. First, epidemiologic evidence suggests that elevated lipids have a somewhat weaker relationship with stroke than with CHD. Subclinical vascular inflammation, in fact, may be a more important risk factor for stroke than hyperlipidemia and may explain the large reduction in risk observed in JUPITER. Second, many statin trials in patients with established vascular disease or diabetes reported substantial reductions in stroke incidence with statin therapy, but these trials may not have altered the way neurologists practice. Third, in three primary prevention trials that used elevated cholesterol levels as criteria for entry (WOSCOPS, AFCAPS/TexCAPS, and MEGA), statin therapy did not demonstrate a statistically significant reduction in stroke risk.
The stakes are high. Approximately 800,000 new or recurrent strokes occur every year in the United States. The American Heart Association estimates that 6.4 million people are living with stroke, many with significant long-term disability. Among stroke survivors 65 years of age and older, 50% were hemiparetic, 30% were unable to walk without assistance, 26% were dependent on others to accomplish their activities of daily living, and 19% had aphasia. The total direct and indirect costs of strokes in 2010 will exceed $73 billion.
Data from hospitals enrolled in the decade-old Get with the Guidelines Programs from the AHA and American Stroke Association reveal that among patients admitted with stroke, only 77% of patients with LDL >100 mg/dL were discharged on lipid-lowering medication. On average, each 39 mg/dL reduction in LDL leads to a 17% reduction in the incidence of stroke risk in all patients. While patients with prior stroke may require a slightly more nuanced approach, they are also likely to see benefit if statins are used correctly.
Given the data from JUPITER and other primary prevention trials, and the wealth of data from trials conducted in patients with pre-existing vascular disease, the primary prevention of stroke in at-risk patients should be an important therapeutic goal for primary care physicians, neurologists and cardiologists. As physicians who are familiar with the indications, benefits and side effects of statins, cardiologists can make an substantial contribution to public health by helping their patients and their colleagues understand the importance of evidence-based preventive strategies to reduce risk of stroke.
Peter Libby, MD, is the chief of cardiovascular medicine at Brigham and Women’s Hospital, and is the Mallinckrodt Professor of Medicine at Harvard Medical School. Libby is also a co-section editor of the Vascular Medicine/ Intervention section of Cardiology Today.
Paul A. Ridker. MD, MPH, is an associate physician at Brigham and Women’s Hospital and the Eugene Braunwald Professor of Medicine at Harvard Medical School.
Brendan M. Everett, MD, MPH, is an associate physician working in the preventive medicine division at Brigham and Women’s Hospital, and is an instructor in medicine at Harvard Medical School.