Although interventions to lower serum cholesterol reduce mortality from heart disease, treatments have not affected total mortality rates in trials of high-risk persons without heart disease [8, 9]. This observation has raised concerns that treatments adversely affect noncardiac mortality and has fueled a debate over the risks and benefits of treating elevated serum cholesterol in asymptomatic patients [10, 11]. Although stroke remains the third leading cause of death in the United States, it is not known whether cholesterol-lowering treatments have favorable or unfavorable effects on stroke. None of the completed clinical trials of cholesterol reduction reported a sufficient number of strokes to estimate precisely the effect of treatment on stroke. Because the number of deaths from stroke in middle-aged U.S. men is roughly one tenth of that resulting from heart disease [12], much larger trials are needed to confirm an effect on stroke mortality. Using meta-analysis to combine results from independent studies [13-15], however, we evaluated completed primary and secondary prevention trials to examine the association between cholesterol reduction and risk for fatal or nonfatal stroke.

We conducted a meta-analysis of randomized trials of cholesterol reduction to address three questions: 1) Does reducing serum cholesterol, through diet or medication, affect mortality risk for stroke in men? 2) Does reducing cholesterol affect the incidence of fatal and nonfatal stroke in men? and 3) Do the various interventions to lower cholesterol have the same effect on risk for stroke? Because nearly all trials of cholesterol reduction enrolled men exclusively, we could not explore similar questions for women.

Methods

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Our study used a meta-analysis of all published randomized trials that examined the cardiovascular effects of diet or medications used to lower cholesterol. The end points of interest were fatal and nonfatal strokes occurring within the treatment period of the trial. We did not include transient ischemic attacks because diagnostic criteria for such events are more variable than are those for stroke. Before reviewing studies, we established eligibility criteria requiring that individual participants were randomized to active treatment or to a control group; that end points were assessed without knowledge of treatment group; and that stroke deaths or morbidity were reported separately. We included trials enrolling participants free of heart disease at baseline (primary prevention), trials selecting participants with a history of heart disease (secondary prevention), and trials that included interventions in addition to cholesterol reduction (multiple intervention). Controls received placebo or standard treatment in various trials. We excluded crossover trials [16, 17], short-term efficacy trials using serum cholesterol level as the primary end point, trials using surrogate end points such as coronary stenosis [18-20], and trials that randomized groups rather than individuals [21-23]. To ensure comparability of included studies, we excluded one study that was restricted to patients with previous strokes [24] and one study that used surgical interventions (ileal bypass) to lower cholesterol level [25].

Eligible trials were located using three independent approaches: 1) a computed MEDLINE search of all English-language reports published between 1966 and 1992 that cited "cholesterol" and "clinical trials" as major descriptors; 2) a review of references from five recent meta-analyses that examined the effects of cholesterol reduction on ischemic heart disease and total mortality rate [8, 26-29]; and 3) a review of bibliographies of each eligible trial identified using the first two methods. When multiple reports were published from a single trial, we relied on the report that contained the most complete data on cause of death. Where possible, data on women was excluded from trials that enrolled both men and women. Some women were included, however, in the Stockholm Ischemic Heart Disease study (20% of 555 participants) because the investigators did not report sex-specific outcomes [30]. All trials reported results based on an "intention-to-treat" analysis. Events that occurred after the conclusion of any trial [31-35] were not included in the quantitative analysis but were examined for evidence of a delayed effect of treatment. Numbers of participants and deaths in excluded trials were recorded to estimate the potential influence of excluded trials on the observed results.

We used Peto's modification of the Mantel-Haenszel method for combining data from 2 x 2 tables to examine the relation between cholesterol reduction and the risks for fatal stroke, nonfatal stroke, and fatal coronary heart disease in our primary analysis [14, 36]. Study size was the major determinant of the statistical weight given to individual trial results using this model. Although the study population (middle-aged, white men with elevated serum cholesterol levels) and the interventions (cholesterol reductions from 6% to 14%) were similar among included trials, we tested the assumption of a uniform effect of treatment by comparing treatment effect in subgroups of studies.

Homogeneity of the treatment effect among the eligible trials was tested as described by Peto. A finding of significant heterogeneity indicated that the variation in treatment effect among studies exceeded that expected from random variation, possibly due to fundamental differences in the interventions, study samples, or designs. Summary estimates of effect may be inappropriate in cases of significant heterogeneity [37, 38]. A pooled estimate of the mean effect of treatment among all studies was calculated and expressed as an odds ratio, using the Peto method. We also used the maximum likelihood estimates described by Rothman [39] to calculate a pooled effect of treatment in terms of strokes per person-year in treated patients compared with controls.

Finally, we explored whether the treatment effect was constant for different treatments or different study samples. Estimates of treatment effects pooled across all trials may not be appropriate if important differences exist between subgroups, and these differences may not be evident in an overall test of homogeneity [37, 38]. Using the methods described by Greenland [37], the effect of treatment was compared among the following subgroups: single-intervention compared with multiple-intervention trials; primary-prevention compared with secondary-prevention trials; drug compared with dietary treatments; clofibrate compared with nonclofibrate therapies; long ( 5 years) compared with shorter interventions; and greater ( 10%) compared with lesser reductions in cholesterol level. The effect of cholesterol reduction on the end points of fatal and nonfatal stroke, fatal coronary heart disease, and cerebral infarction was also compared. Because the smoking and blood pressure interventions included in multiple-intervention trials may have independent effects on stroke, all analyses were repeated after excluding these three trials. To test for a dose-response relation between magnitude of cholesterol reduction and risk for fatal stroke, we used a weighted linear regression of individual trial results, with percentage change in cholesterol as the independent variable and log relative risk as the dependent variable [37].

Results

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Our search located 18 independent trials of cholesterol-lowering therapy that met the first two criteria for trial design outlined previously. Five of the 18 (all secondary prevention trials begun before 1965) were excluded because they did not report separate data on strokes for experimental and control participants [40-44].

Study Characteristics

The 13 remaining eligible trials are described in Table 1. Four primary-prevention trials used different drugs to lower cholesterol [45-48]. Two trials used modified diets among institutionalized patients with and without established heart disease [49, 50]. Two secondary-prevention trials used drugs [30, 51] and two used dietary supplements [52, 53]; the Coronary Drug Project, which included separate treatment arms using clofibrate and niacin, accounted for most participants in secondary trials. We did not consider data from three other treatment arms in this trial (dextrothyroxine; estrogen, 5 mg/d; or estrogen, 2.5 mg/d), which were terminated early [54]. The clofibrate and niacin groups from the Coronary Drug Project were combined in our initial analyses but were treated as separate trials when we compared the effects of different therapies. Three multiple-intervention trials enrolled men who were identified as high-risk patients by a multifactorial risk score [55-58]. The interventions in one trial [57] varied among treated patients, using either diet or drugs to lower cholesterol.

The 13 trials together randomized 46 538 men, roughly two thirds in the 10 single-intervention trials. The age of the enrolled participants and the effects of treatment are summarized in Table 2. Due to variation in sample sizes, overall averages are presented by study and by participant. The average baseline cholesterol level for randomized participants was 6.53 mmol/L (252 mg/dL). Although the mean cholesterol reduction from baseline in treated patients compared with controls over the length of the trial was 7.3%, it was substantially greater for participants in single-intervention trials (11.6%) than for those in the multiple-intervention trials (3.3%). The mean treatment period for all randomized participants was 5.5 years.

Table 3 describes the interventions used in each trial and summarizes cardiac death and stroke events in treated patients and controls. During more than 256 000 patient-years of follow-up, 133 deaths were due to stroke, and 1906 were due to fatal myocardial infarction or sudden cardiac death. Eight trials reported both fatal and nonfatal strokes. These trials included 77% of all participants and observed 94 fatal and 297 nonfatal strokes.

Summary Estimates of Treatment Effect

Fatal Stroke

Cholesterol reduction was associated with a slight but statistically insignificant increase in the risk for fatal stroke (odds ratio = 1.32, P = 0.11). Restriction of the analysis to the 10 single-intervention trials produced nearly identical results (Table 4). Using Peto's method, heterogeneity of the effect of treatment was not statistically significant among all eligible studies or among the single-intervention trials.

Nonfatal and Total Stroke

Among trials providing data on nonfatal strokes, the pooled estimate of the effect of treatment (see Table 4) indicated a slight, statistically insignificant reduction in nonfatal strokes [odds ratio = 0.88]. The risk for fatal plus nonfatal stroke, however, was unaffected by cholesterol reduction in these trials (odds ratio = 0.98). Excluding multiple-intervention trials did not alter the observed association.

Fatal Coronary Heart Disease and Total Mortality Risk

In contrast to its effect on stroke, cholesterol reduction was associated with a modest but statistically significant reduction in the number of deaths from coronary heart disease: The odds ratio of fatal myocardial infarction or sudden cardiac death was 0.87 (95% CI, 0.79 to 0.95; P = 0.004) for treated patients compared with controls. Heterogeneity among all studies was not statistically significant (P = 0.17). The studies reported 1580 deaths from all causes among treated patients and 1741 among controls. The pooled odds ratio for total mortality in treated patients was 0.98 (CI, 0.91 to 1.06) and heterogeneity among studies was not statistically significant (P = 0.12).

Person-Year Analysis

Use of patient-years as the unit of analysis produced similar results. The pooled estimate of risk difference suggested that cholesterol-lowering treatment was associated with an increase of 9 fatal strokes per 100 000 patient-years (CI, –4 to 22 fatal strokes per 100 000 patient-years; P > 0.2) but a decrease in coronary heart disease deaths of 55 deaths per 100 000 patient-years (CI, –126 to 17 deaths per 100 000 patient-years; P = 0.07). Heterogeneity for the effect of treatment on fatal stroke was not statistically significant using this model (P > 0.2).

Subgroup Comparisons

Because clofibrate had been associated with increased mortality risk in reports from one trial [35, 48], we examined the three trials using clofibrate to determine if they differed from the remaining trials in the effect of treatment on stroke and coronary heart disease (Table 5). Clofibrate treatment was associated with a significantly increased risk for fatal stroke (P = 0.002), with a pooled odds ratio of 2.64, whereas non-clofibrate treatments had a negligible effect on stroke deaths (pooled odds ratio = 1.04). The difference in risk for fatal stroke between clofibrate and other treatments was statistically significant (P = 0.02). Data from the Coronary Drug Project also suggested that this adverse effect may be specific to clofibrate [31]. The relative risk for fatal stroke with clofibrate treatment compared with niacin treatment was 2.3, almost reaching statistical significance (P = 0.07) despite a relatively small number of strokes. As seen in Table 5, clofibrate treatment was not associated with an increased risk for nonfatal stroke (odds ratio = 0.87) or fatal coronary heart disease (odds ratio = 0.90) and did not differ from other treatments for these end points.

Among the eight studies that reported fatal and nonfatal strokes, the effect of cholesterol reduction on fatal stroke (odds ratio = 1.33) differed significantly (P = 0.04) from that on nonfatal stroke (odds ratio = 0.88). Most of this difference appeared to be due to the increase in fatal stroke in the three trials using clofibrate.

We tested for but did not detect significant differences between other subgroups in the effect of treatment on risk of fatal stroke: primary-compared with secondary-prevention studies, multiple- compared with single-intervention studies, and drug compared with dietary therapies. We detected no significant differences between subgroups defined by magnitude of cholesterol reduction or duration of intervention, and regression analysis showed no statistically significant association between magnitude of cholesterol reduction and relative risk for fatal stroke.

Two trials [46, 49] reported deaths attributed specifically to cerebral infarction (excluding intracranial hemorrhages). Despite the small number of events, cholesterol-lowering treatments were associated with a significantly reduced risk for fatal cerebral infarction (odds ratio = 0.36; CI, 0.13 to 0.97; P = 0.04). Although only one trial [46] reported specific data on hemorrhagic events, the association was reversed: fatal intracranial hemorrhages were more common in gemfibrozil-treated patients (five deaths) than in controls (one death).

Figure 1 summarizes the effect of cholesterol reduction on the risk for fatal stroke in cholesterol-reduction trials. The confidence intervals of each study are wide, and all but one overlap unity. However, the only trial to suggest a benefit of treatment on total stroke mortality rate (odds ratio < 1) was the Wadsworth Veterans Affairs study, which reported only cerebral infarction and enrolled only older veterans [49].

View larger version (27K): [in this window] [in a new window]   Figure 1. Individual study and summary odds ratios for individual trials. Two arms of one study [51] are depicted as separate trials; three trials [47, 52, 57], which observed a total of three strokes, cannot be depicted because the estimated odds ratio was zero or infinite. Point estimates and lines indicate odds ratios and 95% confidence intervals for fatal stroke in treated patients compared with controls. An odds ratio greater than 1.0 indicates that cholesterol-lowering treatment increases the risk for fatal stroke. N = number of pooled trials; total stroke = fatal plus nonfatal strokes; CHD = coronary heart disease.

Discussion

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Our meta-analysis of 13 randomized trials found no evidence that treatments to lower serum cholesterol reduced the risk of fatal stroke in middle-aged men. Although some trials suggested that cholesterol reduction may have favorable effects on nonfatal strokes or fatal cerebral infarction, the overall effect on combined fatal and nonfatal strokes was minimal. In contrast, the reduction in coronary heart disease mortality estimated from all studies was clinically and statistically significant. Analysis of specific interventions showed that clofibrate treatment was associated with a significantly increased risk for fatal stroke. Although not a primary hypothesis of our study, the association was strong, statistically significant, and consistent in all three trials. Three major hypotheses exist to explain the failure of cholesterol reduction to influence death from stroke: 1) serum cholesterol is not an important risk factor for cerebrovascular disease; 2) the interventions, as tested, are inadequate to reverse established cerebrovascular disease; or 3) beneficial effects of cholesterol reduction are offset by adverse effects of therapies on stroke.

Whether cholesterol is a risk factor in cerebrovascular disease remains controversial [1-4]. The 1984 report of the Stroke Council concluded that if high cholesterol level is a risk factor for stroke, it is so only in men younger than 50 [1], reflecting the failure of several cohort studies to identify cholesterol as a significant risk factor for stroke or cerebral infarction [3, 59]. As noted by Marquardsen [60], it is likely that "the heterogeneity of stroke cases is the main reason for the discrepant findings of the importance of lipids." Risk factors for cerebral infarctions due to atherosclerosis of large and medium-sized arteries are likely to differ from risk factors for intracerebral hemorrhage, subarachnoid hemorrhage, or small-vessel (lacunar) infarction.

Elevated cholesterol levels are fairly consistently associated with atherosclerotic disease of carotid and cerebral arteries [61, 62]. The 6-year follow-up of 350 977 middle-aged men screened for the Multiple Risk Factor Intervention Trial (MRFIT) showed that elevated cholesterol significantly increases the risk for fatal nonhemorrhagic stroke, which increased more than 50% as baseline cholesterol level increased from a range of 5.18 to 6.22 mmol/L (200 to 240 mg/dL) to a range of 6.22 to 7.25 mmol/L (240 to 280 mg/dL) [7]. The inability of previous studies to detect an association between cholesterol and cerebral infarction [3, 59, 60, 63-65] may have been due to errors in the clinical diagnosis of infarction [66, 67], random variation in cholesterol values [68], the inclusion of lacunar (small vessel) infarctions [69, 70], and the study of Japanese cohorts, in whom the pathogenesis of cerebrovascular disease appears to be distinct from Western populations [71]. The failure of cholesterol-lowering trials to reduce the total stroke mortality rate in middle-aged men cannot exclude a possible connection between cholesterol level and specific types of stroke. The accumulated evidence suggests that an elevated serum cholesterol level is a risk factor for stroke due to atherosclerotic cerebrovascular disease, a finding supported by the two trials that reported fewer cerebral infarctions with cholesterol-lowering therapies. The association between serum cholesterol and strokes due to cardiac emboli, lacunar infarction, intracerebral bleeds, or subarachnoid hemorrhage remains uncertain.

A second possibility is that the interventions, as instituted in these trials, were inadequate to influence cerebrovascular disease. More intensive regimens to lower serum cholesterol appear to stabilize lesions in coronary arteries [18-20], and regression of carotid plaques has been observed after extreme measures such as extracorporeal low-density lipoprotein elimination [72]. The relatively modest changes in cholesterol level achieved in these trials may not be sufficient to affect progression of atherosclerosis in carotid or cerebral arteries or to interrupt the events that culminate in stroke. Our analysis of six different drug regimens and seven dietary programs provides the best available estimate of how standard cholesterol-lowering treatments affect stroke mortality and morbidity rates. Post-trial follow-up, available over periods of 3 to 10 years from four trials [31-34], suggested no delayed benefit in stroke mortality risk nor any evidence of greater benefit with greater reductions in cholesterol. The changes in cholesterol achieved in these trials yielded modest and statistically significant reductions in cardiac deaths, yet only 2 of the 13 studies even suggested a beneficial trend of treatment on stroke mortality risk. Nonetheless, we cannot preclude the possibility that more effective lipid-lowering regimens, administered for longer periods, may confer significant protection against stroke.

A final explanation is that lowering cholesterol reduces the risk for cerebral infarction but has adverse effects on other types of stroke. The limited data available on stroke type from two trials suggest a benefit against fatal cerebral infarction, but 12 of the 16 fatal infarctions occurred in the Wadsworth Veterans Administration trial [49], in which participants were significantly older (mean age, 66 years). Protection against cerebral infarction may not be generalizable to other trials, which enrolled younger participants and did not report stroke type. A secondary stroke prevention trial, excluded from our analysis, observed a similar reduction in fatal infarction with treatment (two deaths in the clofibrate group compared with five deaths in the control group) [24]. Protection against cerebral infarction (nonhemorrhagic stroke) could also account for the more favorable trend observed for nonfatal than for fatal strokes. Cerebral infarctions account for most (80%) nonfatal strokes in middle-aged populations but fewer than one half of fatal strokes, due to the higher case-fatality rate of intracranial hemorrhage [7, 73].

Fatal intracerebral hemorrhage was more frequent among treated participants in the only trial specifying numbers of intracranial hemorrhages. Epidemiologic data also suggest that serum cholesterol may have opposing effects on hemorrhagic and nonhemorrhagic stroke. In both the MRFIT follow-up and the Honolulu Heart Study, a positive association between cholesterol and nonhemorrhagic stroke was accompanied by a significant negative association between baseline cholesterol and intracerebral hemorrhage [7, 74]. Several Japanese cohorts have shown increases in cerebral hemorrhage at low cholesterol levels [59, 63, 64, 75, 76], and serum cholesterol was negatively associated with death from stroke (P = 0.001 for persons 65 to 94 years old; P = 0.09 for persons 35 to 64 years old) in the Framingham Study [77]. Low cholesterol levels may simply be a marker for other factors (diet, alcohol intake, malnutrition, or systemic illness) that influence the risk for cerebral hemorrhage. However, in-vitro and animal studies suggest that low cholesterol may impair platelet function [78] or membrane integrity. High-cholesterol diets in hypertensive rats retard the angionecrotic lesions that are thought to increase the likelihood of hemorrhage [79], and both hemorrhagic stroke and angionecrosis are more prevalent in Japan, where dietary and serum cholesterol are low, than in Japanese residents of Hawaii, where cholesterol levels are higher [71, 80].

Whether modest reductions from elevated cholesterol levels produce effects similar to sustained low levels of cholesterol—generally well below 5.18 mmol/L (200 mg/dL)—is unknown. We did not have sufficient data to determine what proportion of fatal strokes was due to hemorrhage or to determine whether large decreases in cholesterol level identified patients at greater risk for fatal stroke. Additional data on the specific types of stroke in patients receiving cholesterol-lowering treatment is needed to determine whether cholesterol reduction influences the risk for intracranial hemorrhage.

The statistically strongest effect we observed was the increase in fatal strokes among patients treated with clofibrate. Although this finding resulted from the analysis of a small subgroup of trials, the effect was strong and consistent. Adverse effects of clofibrate were not observed, however, for other cardiovascular end points: clofibrate effects on nonfatal stroke and fatal heart disease were favorable and similar to those of other regimens. Post-trial follow-up from two of these trials suggests that the increase in fatal stroke is limited to the treatment period [31, 34]. Alterations in hemostasis could explain why the adverse effects of clofibrate appear limited to fatal strokes during active treatment, given that hemorrhagic strokes account for most fatal strokes in this population [7, 73]. Similar effects were observed with aspirin treatment in the Physicians' Health Study, in which a reduction in coronary events was accompanied by an increase in serious intracranial hemorrhage [81]. Fibrates have two effects that might alter hemostasis—reducing plasma fibrinogen activity [82] and altering platelet aggregability [83]. It is notable that gemfibrozil, which shares these properties with clofibrate and other fibric acid derivatives [84, 85], appeared to increase intracranial hemorrhage in the Helsinki Heart Study. The incidence of intracerebral and subarachnoid hemorrhage in patients treated with various fibrate medications deserves further study in light of our findings.

Several potential issues may affect the validity of conclusions based on meta-analysis. Publication bias may arise from the under-reporting of "negative" results when analyzing only published studies [86-88]. However, such selection would be expected to bias the results from meta-analysis toward a significant effect, and we think it unlikely that long-term, randomized trials of cholesterol treatments were completed but never published. Excluding the trials that did not report separate stroke data could introduce bias, but no evidence exists to suggest that these studies differed systematically from included studies. Excluded trials were smaller and observed fewer cardiovascular events; including the five excluded trials would have increased our overall sample by only 10%.

Differences in study quality may create problems in combining independent results in meta-analysis, but variation in the quality of included trials was minor. We found no suggestion of important heterogeneity other than that due to clofibrate studies. One trial excluded subarachnoid hemorrhage [34], one included only cerebral infarctions [49], and one included all "cerebrovascular deaths" [50], but all others used generally accepted definitions for fatal and nonfatal stroke and assessed end points blindly.

If clofibrate has unique adverse effects, our study may not have had sufficient power to rule out a small favorable effect of other treatments on stroke. After excluding clofibrate trials, we still had reasonable power to detect a 20% or 15% reduction in stroke mortality rate (0.8 and 0.7, respectively). We compared a limited number of subgroups based on an analytic plan established before inspection of the data, but some differences may have arisen by chance. Clofibrate had been previously implicated as a cause of increased deaths, but we had no reason to suspect an adverse effect on stroke before our analysis. We see the main value of subgroup comparisons as the generation of hypotheses to be tested as further data become available.

Our analysis cannot address the role of cholesterol reduction in the secondary prevention of stroke or identify patient subgroups in whom cholesterol reduction may be more beneficial. Patients who have had a previous transient ischemic attack or ischemic stroke are more likely to have underlying atherosclerotic disease and may therefore benefit more from cholesterol reduction. However, the sole trial of secondary stroke prevention observed no difference in the overall rate of subsequent stroke with clofibrate treatment when compared with placebo [24].

The failure of cholesterol-lowering trials to reduce total mortality, despite a reduction in coronary deaths, has raised concerns that treatment may increase noncardiac mortality [8, 9, 11, 89]. Although our data raise the possibility of a small, adverse effect of treatment on fatal stroke (odds ratio = 1.31), stroke deaths had little influence on total mortality in the groups studied. For the predominantly middle-aged, white men included in our analysis (in whom stroke risk is relatively low), the cardiac benefits of lowering cholesterol appear to outweigh any adverse effects on stroke. Stroke, however, accounts for an increasing proportion of the cardiovascular deaths and morbidity in older men and women [12]. The importance of serum cholesterol as a predictor of ischemic heart disease in older men and in women has been debated [90-92], and trials of cholesterol-lowering drugs in these patients have not yet been completed. Adverse or beneficial effects on stroke may emerge as an important component of the overall risks and benefits of cholesterol-lowering treatments in these important populations. Because the incidence of cerebral infarctions increases steeply with age, cholesterol reduction might confer more benefit in elderly than in middle-aged persons. In Framingham, however, the negative association between cholesterol and death from stroke was strongest in men older than 65 years [77].

In summary, we conclude that interventions to lower serum cholesterol are unlikely to reduce deaths from stroke in middle-aged men and appear to have little effect on the combined morbidity and mortality associated with stroke. Whether these findings extend to other populations (women, older persons, patients with previous stroke) cannot be determined from the available data. Clofibrate appears to increase the risk for fatal stroke, but further data are needed to confirm this finding and to clarify the mechanism of this effect. In conjunction with epidemiologic data, our analysis raises the possibility that cholesterol reduction (especially with clofibrate and, possibly, with gemfibrozil) may adversely affect the risk for hemorrhagic strokes. Trials in older populations, in whom strokes are much more frequent, may clarify whether cholesterol-lowering treatments influence the risk for hemorrhagic or nonhemorrhagic strokes. Our findings are a reminder of the important distinctions between the pathogenesis of specific types of stroke and of coronary heart disease. Strategies to reduce total cardiovascular disease must examine the impact of therapies on separate categories of stroke as well as heart disease. Clinicians may choose to treat patients for elevated cholesterol levels, based on the potential cardiac benefits of therapy, but should not assume that treatment will provide additional benefits against stroke.