Cholesterol Reduction and the Risk for Stroke in Men

Table. SI Units and Drug Stroke and ischemic heart disease share important risk factors such as age, hypertension, diabetes, and cigarette smoking [1]. Although serum cholesterol is a strong and consistent risk factor for coronary heart disease, its importance in stroke remains controversial [1-5]. Although the incidence of thromboembolic stroke appears to increase with elevated serum cholesterol levels, a J-shaped association between cholesterol and risk for total stroke has been observed in several studies, due to an increased number of hemorrhagic strokes at the lowest cholesterol levels [6, 7]. 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 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 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 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. Table 1. Design and Patient Population of Included Trials* 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 patie