NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Chou R, Dana T, Blazina I, et al. Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Nov. (Evidence Syntheses, No. 139.)

Cover of Statin Use for the Prevention of Cardiovascular Disease in Adults

Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force [Internet].

Show details

3Results

Key Question 1a. What Are the Benefits of Treatment With Statins in Reducing the Incidence of CHD- or CVA-Related Morbidity or Mortality or All-Cause Mortality in Asymptomatic Adults Age 40 Years or Older Without Prior CVD Events?

Summary

Nineteen RCTs with 6 months to 6 years of followup evaluated effects of statins versus placebo or no statin in adults at increased cardiovascular risk but without prior CVD events. Statins were associated with reduced risk of all-cause mortality (15 trials; RR, 0.86 [95% CI, 0.80 to 0.93]; I2=0%; absolute risk difference [ARD], -0.40% [95% CI, -0.64 to -0.17]; number needed to treat [NNT], 250 after 1 to 6 years), cardiovascular mortality (10 trials; RR, 0.82 [95% CI, 0.71 to 0.94]; I2=0%; ARD, -0.20% [95% CI, -0.35 to -0.05]; NNT, 500 after 2 to 6 years), stroke (13 trials; RR, 0.71 [95% CI, 0.62 to 0.82]; I2=0%; ARD, -0.38% [95% CI, -0.53 to -0.23]; NNT, 263 after 6 months to 6 years), MI (12 trials; RR, 0.64 [95% CI, 0.57 to 0.71]; I2=0%; ARD, -0.81% [95% CI, -1.19 to -0.43]; NNT, 123 after 2 to 6 years), revascularization (7 trials; RR, 0.63 [95% CI, 0.56 to 0.72]; I2=0%; ARD, -0.66% [95% CI, -0.87 to -0.45]; NNT, 152 after 2 to 6 years), and composite cardiovascular outcomes (13 trials; RR, 0.70 [95% CI, 0.63 to 0.78]; I2=36%; ARD, -1.39% [95% CI, -1.79 to -0.99]; NNT, 72 after 1 to 6 years). Findings were robust in sensitivity analysis, based on study quality, duration of followup, mean lipid levels at baseline, and other factors.

Evidence

Nineteen randomized trials (in 53 publications) assessed the effects of statins on health outcomes in adults at increased cardiovascular risk but without prior CVD events (Appendixes B and C1).52-104 Duration of followup ranged from 1 to 6 years (median, 4 years) in 18 trials, and one trial followed patients for 6 months.92 Two trials60,74 with planned 5-year followup were stopped after 2 and 3 years due to observed cardiovascular benefits among patients randomized to statins. One other trial with planned 4-year followup was also stopped 2 years prior to anticipated study completion due to observed benefits in the statin group, although median duration of followup for enrolled participants was 4 years.70 Eighteen trials compared a statin versus placebo and one trial83 compared a statin plus cholesterol-lowering diet versus diet alone. Five trials used a 2×2 factorial design in which, in addition to randomization to statin therapy versus placebo, patients were also randomized to treatment with warfarin versus placebo,52 different antihypertensive regimens,60,104 lifestyle interventions versus usual care,73 or fosinopril versus placebo.95

The statins evaluated in the trials were pravastatin (5 trials),67,82,83,95,96 atorvastatin (4 trials),60,63, 66,69 rosuvastatin (4 trials),64,74,93,103 lovastatin (2 trials),52,54 simvastatin (2 trials)72,92 and fluvastatin (1 trial).73 Cerivastatin was initially used in one trial but later replaced with simvastatin when cerivastatin was withdrawn from the market due to reports of fatal rhabdomyolysis.65 We identified no trials evaluating pitavastatin. Sixteen trials used fixed-dose statin therapy.60,63-67,69,72-74,82,92,93,95,96,103 Based on the classification method in the 2013 ACC/AHA guideline,30 the statin therapy in these studies was classified as low intensity in one trial,73 moderate intensity in 10 trials,60,63,65,67,69,72,82,95,96,103 and high intensity in three trials.64,74,93 One trial randomized patients to different doses of atorvastatin (10, 20, 40, or 80 mg, corresponding to moderate- or high-intensity therapy)66 and one trial randomized patients to different doses of simvastatin (10 or 40 mg for low- or moderate-intensity therapy).92 Three trials performed dose titration.52,54,83 In one trial, patients were randomized to lovastatin 20 mg/day (low-intensity) and could be titrated to 40 mg/day (moderate-intensity) for a target LDL-C level of less than 110 mg/dL.54 In another trial, patients were initially randomized to lovastatin 20 mg/day (low-intensity) and could be titrated to 10 mg/day (also low-intensity) or 40 mg/day (moderate-intensity) for a target LDL-C level of 90 to 110 mg/dL.52 In the third trial, patients were initially randomized to pravastatin 10 mg/day, which could be titrated to 20 mg/day for a target TC level of less than 220 mg/dL (both doses low-intensity).83

The trials enrolled between 95 and 17,802 study participants (median, 919; n=71,344). The mean ages of participants ranged from 51 to 66 years. Four trials64,65,92,95 permitted enrollment of persons younger than age 40 years and one trial72 did not specify ages for inclusion, but none reported the proportion of participants who were younger adults. Three trials only enrolled men73,82,96 and one trial only enrolled women.66 In the remaining trials, the proportion of women ranged from 15 to 69 percent (median, 39%). Of the 13 studies that reported race/ethnicity, the predominant racial/ethnic group was white (range, 59% to 99%) in 12 of the studies, while the predominant racial/ethnic groups in the remaining study103 were Chinese (29%) and Hispanic (27%); whites accounted for 20% of the study population.

Criteria for enrollment varied across trials (Table 2); however, all trials enrolled patients at increased cardiovascular risk. In six trials, presence of dyslipidemia was the main criterion for enrollment, although definitions for dyslipidemia varied.54,66,82,83,92,96 In these trials, mean baseline TC levels ranged from 195 to 272 mg/dL, LDL-C levels from 150 to 192 mg/dL, and HDL-C levels from 36 to 62 mg/dL. Three trials were restricted to patients with early-onset cerebrovascular disease (mean baseline TC level, 229 to 263 mg/dL; LDL-C level, 154 to 182 mg/dL; HDL-C level, 46 to 59 mg/dL).52,67,93 Four trials were restricted to patients with diabetes.63,65,69,72 Three of these trials excluded persons with diabetes with severe dyslipidemia (enrollment restricted to patients with an LDL-C level of <160 mg/dL63,65 or TC level of 155 to 267 mg/dL69); in these trials, mean TC levels at baseline ranged from 195 to 217 mg/dL, LDL-C levels from 114 to 139 mg/dL, and HDL-C levels from 47 to 55 mg/dL. The fourth trial did not report lipid parameters for inclusion but reported higher mean TC and LDL-C levels (mean baseline TC level, 235 to 243 mg/dL; LDL-C level, 168 to 171 mg/dL; HDL-C level, 39 to 43 mg/dL).72 Two trials focused on patients with hypertension (mean baseline TC level, 212 to 232 mg/dL; LDL-C level, 131 to 151 mg/dL; HDL-C level, 49 to 50 mg/dL).60,73 One trial enrolled patients with mild to moderate aortic stenosis (mean baseline TC level, 205 mg/dL; LDL-C level, 120 to 124 mg/dL; HDL-C level, 62 mg/dL),64 one trial enrolled patients with microalbuminuria (mean baseline TC level, 224 mg/dL; LDL-C level, 155 to 159 mg/dL; HDL-C level, 39 mg/dL),95 and one trial enrolled patients with elevated CRP levels (≥2.0 mg/dL) and nonelevated LDL-C levels (<130 mg/dL).74 One trial enrolled patients with one or more prespecified risk factors, including elevated waist-to-hip ratio (87%), low HDL-C level (36%), dysglycemia (18%), mild renal dysfunction (3%), family history of early-onset CHD (26%), or hypertension (38%).103 Three trials included some patients with a history of clinical CVD but were included because the proportion was below our predefined threshold of 10 percent (Appendix C1).60,82,95

Table 2. Study Characteristics of Randomized Trials of Statins Versus Placebo or No Statins.

Table 2

Study Characteristics of Randomized Trials of Statins Versus Placebo or No Statins.

Six trials were rated good-quality,64,69,74,82,96,103 one trial poor-quality,72 and the remaining 12 trials fair-quality (Appendix C2).52,54,60,63,65-67,73,83,92,93,95 Methodological limitations in the fair-quality trials included unclear methods of randomization and/or allocation concealment and unclear blinding of outcome assessors, care providers, and/or study participants. The poor-quality trial also did not report attrition. Only two trials52,92 reported no industry funding; the remaining trials were either fully or partially industry-funded.

All-Cause Mortality

Fifteen trials reported all-cause mortality (Table 3; Appendix C1).52,54,60,63,65,66,69,73,74,82,83,93,95,96, 103 Absolute event rates ranged from 0 to 5 percent in the statin groups and 0 to 6 percent in control groups. Statins were associated with statistically significant reduction in risk of all-cause mortality versus placebo in two trials. The large JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial74 (n=17,802; 2 years followup), which enrolled patients with elevated CRP levels and LDL-C levels of less than 130 mg/dL, reported a hazard ratio (HR) of 0.80 after 2 years of statin therapy (95% CI, 0.69 to 0.97; ARD, -0.6%). The smaller ACAPS (Asymptomatic Carotid Artery Plaque Study) trial (n=919; 3 years followup),52 which enrolled persons with early-onset cerebrovascular disease, also found reduced risk of all-cause mortality with statin therapy, though the estimate was less precise (RR, 0.12 [95% CI, 0.02 to 0.99]; ARD, -0.02%). Pooling evidence from all trials resulted in a very similar risk estimate to that in the JUPITER trial (RR, 0.86 after 1 to 6 years [95% CI, 0.80 to 0.93]; I2=0%; ARD, -0.40% [95% CI, -0.64 to -0.17]; I2=4%) (Appendix D1). Across studies, the NNT ranged from 47 to 294 over 2 to 6 years in nine trials, and six trials reported no benefit from statins; the pooled NNT was 250. The risk estimate was heavily influenced by the JUPITER and ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm) studies, both of which were stopped early and together accounted for about 40 percent of the total sample and more than 35 percent of mortality events. The point estimate and ARD from ASCOT-LLA (3.6% vs. 4.1% after 3 years; RR, 0.87 [95% CI, 0.71 to 1.05]; ARD, -0.55%), which focused on patients with hypertension, was similar to the point estimate from JUPITER.

Table 3. Clinical Outcomes and Pooled Risk Estimates From Randomized Trials of Statins Versus Placebo.

Table 3

Clinical Outcomes and Pooled Risk Estimates From Randomized Trials of Statins Versus Placebo.

Results were similar in sensitivity analyses (Table 4). Excluding results from JUPITER and both JUPITER and ASCOT-LLA had little effect on pooled estimates (RR, 0.88 [95% CI, 0.80 to 0.96]; I2=0% and RR, 0.88 [95% CI, 0.80 to 0.97]; I2=0%, respectively). Restricting the analysis to good-quality studies69,74,82,96,103 also did not affect estimates (RR, 0.85 [95% CI, 0.77 to 0.94]; I2=0%), and results were similar when trials were stratified according to duration of followup of 3 years or less (RR, 0.83 [95% CI, 0.72 to 0.94]; I2=0%)52,60,65,66,74,82,93 versus more than 3 years (RR, 0.88 [95% CI, 0.80 to 0.98]; I2=0%).54,63,69,73,83,95,96,103 There were also no differences in estimates when three trials60,82,95 that included patients with prior CVD were excluded (RR, 0.86 [95% CI, 0.78 to 0.94]; I2=4%) or when two trials63,74 that enrolled patients with mean baseline TC levels of less than 200 mg/dL were excluded (RR, 0.87 [95% CI, 0.79 to 0.95]; I2=0%). Results were also similar when trials were stratified according to baseline LDL-C level of less than 160 mg/dL (RR, 0.87 [95% CI, 0.80 to 0.95]; I2=0%) versus 160 mg/dL or greater (RR, 0.79 [95% CI, 0.62 to 1.01]; I2=0%).

Table 4. Sensitivity Analysis: Pooled Estimates for Statins Versus Placebo.

Table 4

Sensitivity Analysis: Pooled Estimates for Statins Versus Placebo.

Cardiovascular Mortality

Cardiovascular mortality was reported in 10 trials (Table 3; Appendix C1).52,54,60,64,74,82,83,95,96,103 The effect of statin use on cardiovascular mortality was somewhat inconsistent. Although the large WOSCOPS (West of Scotland Coronary Prevention Study) (n=6,595)96 trial found a statistically significant difference between statins versus placebo and risk of cardiovascular mortality (RR, 0.68 [95% CI, 0.48 to 0.98]), the JUPITER (n=17,802),74 AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) (n=6,605),54 and MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) (n=7,832)83 trials reported similar point estimates that did not reach statistical significance (0.3 % versus 0.4 % after 2 years; RR, 0.78 [95 % CI 0.48 to 1.27 ]0.5% vs. 0.8% after 5 years; RR, 0.68 [95% CI, 0.37 to 1.26] and 0.3% vs. 0.5% after 5 years; RR, 0.63 [95% CI, 0.30 to 1.33], respectively), and the ASCOT-LLA (n=10,305)60 and HOPE-3 (Heart Outcomes Prevention Evaluation-3) (n=12,705)103 trials found no effect (1.4% vs. 1.6% after 3 years; RR, 0.90 [95% CI, 0.66 to 1.23] and 2.4% vs. 2.7% after 6 years; RR, 0.90 [95% CI, 0.72 to 1.11], respectively). In pooled analysis, statin therapy was associated with decreased risk of cardiovascular mortality (RR, 0.82 after 2 to 6 years [95% CI, 0.71 to 0.94]; I2=0%) (Appendix D2). The pooled ARD was -0.20 percent (95% CI, -0.35 to -0.05; I2=11%) and the pooled NNT was 500 (range, 76 to 1,111 in 8 trials; 2 trials found no benefit with statin therapy).

Findings were similar in sensitivity analyses (Table 4). Restricting the analysis to good-quality trials64,74,82,96,103 resulted in a similar risk estimate (RR, 0.82 [95% CI, 0.44-69 to 0.98]; I2=0%). The point estimates were similar when studies were stratified according to duration of followup of 3 years or less (RR, 0.85 [95% CI, 0.65 to 1.10]; I2=0%)52, 60,74,82 or more than 3 years (RR, 0.81 [95% CI, 0.68 to 0.95]; I2=0%). Removing three trials60,82,95 that included a small proportion of persons with prior CVD events also did not affect the risk estimate (RR, 0.80 [95% CI, 0.68 to 0.93]; I2=0%). Excluding the JUPITER trial,74 which enrolled persons with baseline TC levels of less than 200 mg/dL and was stopped early, also resulted in a similar pooled estimate (RR, 0.82 [95% CI, 0.71 to 0.95]; I2=0%). The estimate was also similar when excluding both JUPITER74 and ASCOT-LLA60 (RR, 0.80 [95% CI, 0.68 to 0.95]; I2=0%).

Stroke

Thirteen trials reported incidence of fatal and nonfatal stroke (Table 3; Appendix C1).52,60,63,64, 69,72,74,82,83,92,95,96,103 One trial reported results separately for nonhemorrhagic and hemorrhagic stroke;83 the other trials did not clearly specify the type of stroke. Results from individual trials generally favored statin therapy over placebo or no statin, though estimates were not always statistically significant. Although four trials enrolled patients with mild cerebrovascular disease at baseline, none were designed to evaluate effects of statins on risk of stroke, given relatively small sample sizes (n=250 to 919) and relatively short duration of followup (6 months to 3 years).52,65,67,92 Two52,92 of these trials reported stroke events, though one trial only reported one event.92

Statins were associated with decreased risk of fatal or nonfatal stroke (RR, 0.71 after 6 months to 6 years [95% CI, 0.62 to 0.82]; I2=0%) (Appendix D3). The pooled ARD was -0.38 percent (95% CI, -0.53 to -0.23; I2=0%) for a NNT to prevent 1 fatal or nonfatal stroke of 263. Excluding one trial that reported a NNT of 11, the NNT ranged from 92 to 625 in 10 trials after 1 to 6 years; two trials reported no benefit with statins. A good-quality systematic review reported a similar risk estimate (10 trials; RR, 0.78 [95% CI, 0.68 to 0.89]; I2=26%).105

Findings were similar in sensitivity analyses (Table 4). There were no clear differences in pooled estimates when one poor-quality trial72 was excluded from the analysis (RR, 0.72 [95% CI, 0.62 to 0.83]; I2=0%), when the analysis was restricted to good-quality trials (RR, 0.68 [95% CI, 0.56 to 0.83]; I2=0%), when one trial with 6 months of followup was excluded (RR, 0.71 [95% CI, 0.62 to 0.82]; I2=0%), and when studies were stratified according to duration of followup of 3 years or less (RR, 0.64 [95% CI, 0.51 to 0.80]; I2=0%) or more than 3 years (RR, 0.77 [95% CI, 0.64 to 0.92]; I2=0%). Removing three trials60,82,95 that included persons with prior CVD events (RR, 0.70 [95% CI, 0.60 to 0.83]; I2=0 %) or two trials63,74 that enrolled patients with mean baseline TC levels of less than 200 mg/dL also did not affect the estimate (RR, 0.73 [95% CI, 0.61 to 0.85]; I2=0%). Estimates were also similar when trials were stratified according to baseline LDL-C levels of less than 160 mg/dL versus 160 mg/dL or greater (RR, 0.70 [95% CI, 0.60 to 0.81]; I2=0% vs. RR, 0.83 [95% CI, 0.58 to 1.19]; I2=0%, respectively). Estimates were also similar when JUPITER (RR, 0.75 [95% CI, 0.63 to 0.89]; I2=0%) and both JUPITER and ASCOT-LLA (RR, 0.75 [95% CI, 0.63 to 0.90]; I2=0%) were excluded.

When stratified by fatal and nonfatal stroke, statins were associated with decreased risk of nonfatal (3 trials; RR, 0.57 [95% CI, 0.41 to 0.81]; I2=0%; ARD, -0.32% [95% CI, -0.52 to -0.12])69,74,92 and fatal stroke (2 trials; RR, 0.38 [95% CI, 0.12 to 1.22]; I2=0%; ARD, -0.11% [95% CI, -0.38 to 0.15]),69,74 although few trials reported separate results for fatal and nonfatal stroke, estimates were imprecise, and the difference in risk of fatal stroke was not statistically significant.

MI

Twelve trials reported incidence of fatal and nonfatal MI (Table 3; Appendix C1).52,54,60,63,64,67, 69,74,82,83,96,103 Results from individual trials were mixed but most large trials found that statin use was associated with a significant reduction in risk of MI. For example, risk estimates in the AFCAPS/TexCAPS (2% vs. 3%; RR, 0.60 [95% CI, 0.43 to 0.83]), ASCOT-LLA (1.7% vs. 2.9%; RR, 0.67 [95% CI, 0.53 to 0.84]), HOPE-3 (0.7% vs. 1.1%; RR, 0.65 [95% CI, 0.45 to 0.95]), JUPITER (0.3% vs. 0.7%; RR, 0.45 [95% CI, 0.29 to 0.69]), MEGA (0.5% vs. 0.8%; RR, 0.53 [95% CI, 0.29 to 0.95]), and WOSCOPS (5.3% vs. 7.5%; RR, 0.69 [95% CI, 0.56 to 0.86]) trials all favored statin use. Differences between statin and placebo groups in smaller trials such as ACAPS (1.1% vs. 1.1%; RR, 1.00 [95% CI, 0.29 to 3.42]), ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) (0% vs. 2.2%; RR, 0.14 [95% CI, 0.008 to 2.76]), CAIUS (Carotid Atherosclerosis Italian Ultrasound Study) (1.3% vs. 1.3%; RR, 1.02 [95% CI, 0.15 to 7.15]), and KAPS (Kuopio Atherosclerosis Prevention Study) (1.4% vs. 3.8%; RR, 0.36 [95% CI, 0.09 to 1.39]) were not statistically significant. In pooled analysis, statins were associated with decreased risk of MI (RR, 0.64 after 2 to 6 years [95% CI, 0.57 to 0.71]; I2=0%; ARD, -0.81% [95% CI, -1.19 to -0.43]; I2=70%) (Appendix D4). The pooled NNT to prevent 1 MI was 123; the NNT ranged from 45 to 263 in 10 trials, and two trials reported no benefit with statin therapy. Results based on six good-quality trials were consistent with the overall pooled estimate (RR, 0.61 [95% CI, 0.51 to 0.72]; I2=8%).64,69,74,82,96,103

Findings were similar in sensitivity analyses (Table 4). Restricting the analysis to the seven trials54,63,64,69,83,96,103 with more than 3 years of followup did not affect the estimate (RR, 0.65 [95% CI, 0.56 to 0.74]; I2=0%). Excluding two trials60,82 that enrolled some participants with a history of CVD events (RR, 0.63 [95% CI, 0.55 to 0.72]; I2=0%), excluding two trials63,74 that enrolled patients with baseline TC levels of less than 200 mg/dL (RR, 0.64 [95% CI, 0.57 to 0.73]; I2=0%), and restricting the analysis to trials that enrolled patients with baseline LDL-C levels of less than 160 mg/dL (RR, 0.61 [95% CI, 0.54 to 0.70]) had little effect on estimates. Estimates were also similar when JUPITER (RR, 0.68 [95% CI, 0.58 to 0.73]; I2=0%) and both JUPITER and ASCOT-LLA (RR, 0.65 [95% CI, 0.57 to 0.74]; I2=0%) were excluded.60,74

Seven trials reported separate results for fatal and/or nonfatal MI.52,54,67,74,82,83,96 When analyzed separately, estimates for fatal MI (RR, 0.70 [95% CI, 0.50 to 0.99]; I2=0%; ARD, -0.16% [95% CI, -0.42 to 0.11]) and nonfatal MI (RR, 0.64 [95% CI, 0.46 to 0.91]; I2=50%; ARD, -0.46% [95% CI, -0.90 to -0.02]) were similar.

Revascularization

Incidence of revascularization was reported in seven trials (Table 3; Appendix C1).54,69,74,82,83,96, 103 The five largest trials, AFCAPS/TexCAPS,54 HOPE-3,103 JUPITER,74 MEGA,83 and WOSCOPS,96 all found that statins were associated with reduced risk of revascularization (RR estimates ranged from 0.54 to 0.68). The two smaller trials69,82 reported similar risk estimates (RR, 0.70 [95% CI, 0.42 to 1.17] and RR, 0.79 [95% CI, 0.22 to 2.91]), though differences were not statistically significant. When results were pooled, statins were associated with reduced risk of revascularization (RR, 0.63 after 2 to 6 years [95% CI, 0.56 to 0.72]; I2=0%) (Appendix D5). The ARD was -0.66 percent (95% CI, -0.87 to -0.45; I2=8%; NNT range, 65 to 244; pooled NNT, 152). Findings were similar in sensitivity analyses (Table 4). Restricting the analysis to the five good-quality trials did not affect this estimate (RR, 0.62 [95% CI, 0.52 to 0.74]; I2=0%).69,74,82,96,103 Excluding two trials74,82 that had followup of 3 years or less resulted in a similar estimate (RR, 0.66 [95% CI, 0.57 to 0.77]; I2=0%). Results were similar in the subgroup of five trials54,69,74,83,103 in which the mean baseline LDL-C level was less than 160 mg/dL (RR, 0.63 [95% CI, 0.55 to 0.73]; I2=0%) (Table 3).

Composite Cardiovascular Outcomes

Thirteen trials reported on composite cardiovascular outcomes (Table 3; Appendix C1).52,54,60,63, 65,69,72-74,83,95,96,103 In two trials, the composite outcomes were not well defined,65,72 and the composite outcome definition varied in the remainder of the studies (Appendix C1). In general, statin therapy was associated with decreased risk of composite cardiovascular outcomes versus placebo or no statin. Despite the variability in how cardiovascular outcomes were defined, we pooled rates of composite cardiovascular outcomes, as event rates for some individual outcomes were low in many trials. When pooled, statin therapy significantly reduced incidence of composite cardiovascular outcomes compared with placebo (RR, 0.70 [95% CI, 0.63 to 0.78]; I2=36%) (Appendix D6). The ARD ranged from -2.26 to -0.35 percent over 1 to 6 years of followup, and the pooled ARD was -1.39 percent (95% CI, -1.79 to -0.99; NNT range, 8 to 286; pooled NNT, 72). Excluding JUPITER (RR, 0.72 [95% CI, 0.64 to 0.80]; I2=29%)74 and both JUPITER and ASCOT-LLA (RR, 0.71 [95% CI, 0.63 to 0.81]; I2=35%)60 resulted in similar estimates, as did restriction to good-quality trials (RR, 0.69 [95% CI, 0.61 to 0.78]; I2=28%) or trials in which mean baseline LDL-C levels were less than 160 mg/dL (RR, 0.70 [95% CI, 0.61 to 0.79]; I2=46%) (Table 4).

Assessment for Publication Bias

We did not identify funnel plot asymmetry based on funnel plots for all-cause mortality, fatal and nonfatal stroke, and fatal and nonfatal MI (Appendixes D7-11). Funnel plot asymmetry was present for cardiovascular mortality (p for Egger test=0.049), but few small trials were available (Appendix D8).

Key Question 1b. What Are the Benefits of Treatment With Statins That Target LDL-C Versus Other Treatment Strategies in Adults Age 40 Years or Older Without Prior CVD Events?

Summary

No study directly compared treatment with statins titrated to attain target cholesterol levels versus other (e.g., fixed-dose) treatment strategies. There were no clear differences in risk of all-cause or cardiovascular mortality, MI, or stroke between three trials of statins versus placebo or no statin that permitted limited dose titration and 15 trials of fixed-dose statin therapy.

Evidence

No trial directly compared treatment with statins titrated to attain target cholesterol levels versus other (e.g., fixed-dose) treatment strategies. In three of 19 trials of statins versus placebo or no statin in patients without prior cardiovascular events, limited dose titration of statins was permitted, providing some indirect comparisons against trials of fixed-dose statins (Table 2; Appendix C1).52,54,83 ACAPS enrolled participants with early-onset carotid atherosclerosis,52 and AFCAPS/TexCAPS54 and MEGA83 enrolled patients with hyperlipidemia without a prior history of CVD. In ACAPS, patients were initially randomized to lovastatin 20 mg/day and could be titrated up to 40 mg/day or down to 10 mg/day after 5 months to achieve a target LDL-C level of 90 to 110 mg/dL.52 In AFCAPS/TexCAPS, patients were initially randomized to lovastatin at 20 mg/day, with titration to 40 mg/day if the LDL-C level exceeded 110 mg/dL at 3 months of followup.54 In MEGA, patients were initially randomized to pravastatin 10 mg/day, which could be titrated to 20 mg/day for a target TC level of less than 220 mg/dL.83 Mean baseline levels in the trials ranged from 150 to 157 mg/dL for LDL-C and from 221 to 242 mg/dL for TC.

There were no clear differences in estimates between the trials that permitted limited dose titration to achieve target cholesterol levels and those that used fixed-dose therapy. Pooled estimates for trials that permitted limited dose titration were primarily based on AFCAPS/TexCAPS54 and MEGA,83 as estimates from ACAPS52 were very imprecise due to small numbers of deaths and cardiovascular events. When trials were stratified according to whether they permitted limited dose titration, the pooled estimates were very similar for all-cause mortality (RR, 0.78 [95% CI, 0.48 to 1.28]; I2=75% for trials that permitted limited dose titration vs. RR, 0.86 [95% CI, 0.79 to 0.94]; I2=0% for fixed-dose trials), cardiovascular mortality (RR, 0.61 [95% CI, 0.37 to 1.02]; I2=9% vs. RR, 0.71 [95% CI, 0.53 to 0.94]; I2=64%, respectively), composite cardiovascular outcomes (RR, 0.63 [95% CI, 0.53 to 0.76]; I2=0% vs. RR, 0.72 [95% CI, 0.63 to 0.81]; I2=43%, respectively), and fatal or nonfatal MI (RR, 0.60 [95% CI, 0.45 to 0.79]; I2=0% vs. RR, 0.64 [95% CI, 0.57 to 0.73]; I2=0%, respectively). In addition, for all-cause mortality, among the trials that permitted limited dose titration, results from AFCAPS/TexCAPS (RR, 1.04 [95% CI, 0.76 to 1.41]) and MEGA (RR, 0.71 [95% CI, 0.51 to 1.00]) showed some inconsistency. For fatal or nonfatal stroke, there were no clear differences between the trials that permitted limited dose titration (RR, 0.42 [95% CI, 0.07 to 2.59]; I2=50%) and the fixed-dose trials (RR, 0.72 [95% CI, 0.62 to 0.83]; I2=0%), but AFCAPS/TexCAPS did not report effects on stroke and ACAPS only reported five events, all of which occurred in the placebo arm. MEGA, which reported 82 nonhemorrhagic strokes, reported an RR of 0.83 (95% CI, 0.57 to 1.20).83

Key Question 1c. Do the Benefits of Treatment With Statins in Adults Age 40 Years or Older Without Prior CVD Events Vary in Subgroups Defined by Demographic or Clinical Characteristics?

Summary

Seven trials stratified results according to predefined subgroups based on demographic or clinical characteristics, including age, sex, race/ethnicity, lipid parameters, hypertension, diabetes, metabolic syndrome, cardiovascular risk score, renal impairment, and CRP levels. There were no clear differences in RR estimates associated with statin therapy versus placebo or no statin in subgroups defined by demographic and clinical factors, though absolute benefits were greater in higher-risk groups.

Evidence

Seven trials of statins versus placebo or no statin in patients without prior cardiovascular events reported results stratified according to baseline demographic characteristics or clinical characteristics (Table 5; Appendix C1).54,60,69,74,83,96,103 Prespecified subgroups varied across trials. Analyses tended to focus on composite cardiovascular outcomes, presumably because of higher numbers of events, though three trials reported subgroup effects on specific cardiovascular outcomes.69,74,83

Table 5. Statins Versus Placebo: Effects in Subgroups Based on Demographic Characteristics.

Table 5

Statins Versus Placebo: Effects in Subgroups Based on Demographic Characteristics.

Demographic Characteristics

Age

Twelve trials of statins versus placebo restricted enrollment to persons age 75 years or younger,54,63,66,67,69,73,82,83,92,93,95,96 and four trials enrolled patients up to ages 79 to 82 years (mean, 58 to 63 years).52,60,64,65 Three trials reported no upper limit for age, though the average age in these studies ranged from 61 to 66 years.72,74,103

Seven trials evaluated how effects of statins versus placebo or no statin varied in subgroups defined by age.54,60,69,74,83,96,103 In all trials, statins were associated with reduced risk of cardiovascular events across patient subgroups stratified according to age (older or younger than 55, 60, 65, or 70 years), though some estimates were imprecise. The cardiovascular outcomes evaluated were primarily composite and varied across trials (Table 5). There was no clear pattern to suggest an effect of age on risk estimates. None of the trials that enrolled patients older than age 75 years reported results in this subgroup.

Although age had no clear effect on risk estimates, the absolute benefit associated with statin therapy was higher in older persons due to a higher risk of events (Table 5). For example, in the JUPITER trial, the ARD between statin and placebo groups for the composite outcome of cardiovascular events was -1.06 percent (NNT, 94) in those younger than age 70 years and -1.62 percent (NNT, 62) in those age 70 years or older, and in the HOPE-3 trial, the ARD was -0.88 percent (NNT, 114) in those age 65 years or younger and -1.83 percent (NNT, 55) in those older than age 65 years.103 Similar trends for CHD events were observed in the CARDS (Collaborative Atorvastatin Diabetes Study) and ASCOT-LLA trials, with ARDs of -1.77 (NNT, 56) and -2.13 percent (NNT, 47) in those younger than age 65 years and 65 years or older, and -0.78 (NNT, 128) and -1.22 percent (NNT, 82) in those age 60 years or younger and older than age 60 years.60,69

Sex

Six trials evaluated how effects of statins versus placebo or no statin varied according to sex (Table 5).54,60,69,74,83,103 In these trials, the proportion of female participants ranged from 15 to 69 percent. None found clear evidence of an effect of sex on risk estimates on (variably defined) composite cardiovascular outcomes. JUPITER also reported effects of sex on specific cardiovascular outcomes.74 It found that statins versus placebo were associated with lower risk of nonfatal stroke in men (HR, 0.33 [95% CI, 0.17 to 0.63]; ARD, -0.45%; NNT, 222) than in women (HR, 0.84 [95% CI, 0.45 to 1.58]; ARD, -0.10%; NNT, 1,000; p=0.04 for interaction), although the opposite pattern was observed for risk of revascularization or hospitalization (HR, 0.63 [95% CI, 0.46 to 0.86]; ARD, -0.75%; NNT, 133 vs. HR, 0.24 [95% CI, 0.11 to 0.51]; ARD, -0.74%; NNT, 135, respectively; p=0.01 for interaction). One other trial that evaluated effects of statins in men versus women found no difference in effect on incidence of stroke.83

Race

Among 13 trials of statins versus placebo or no statin in patients without prior cardiovascular events that reported race/ethnicity, whites made up the majority of study participants in 12 of the trials.52,54,60,63-66,69,74,92,93,95,103 In nine of the 12 trials, the proportion of participants that were white was greater than 85 percent.52,54,60,63,64,66,69,92,95 In the other three trials, the proportion of participants that were white ranged from 59 to 71 percent.65,74,93 In the remaining study that reported race/ethnicity, HOPE-3,103 the predominant racial/ethnic group was Chinese (29%), followed by Hispanic (27%); whites accounted for 20% of the study population. One additional trial that did not report race was conducted in Japan.83

The JUPITER and HOPE-3 trials evaluated clinical outcomes stratified according to race/ethnicity.74,77,103 Estimates in JUPITER were similar for white (n=12,683) and nonwhite (n=5,117, including black, Hispanic, and Asian) persons for a composite outcome that included cardiovascular mortality, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for angina (HR, 0.55 [95% CI, 0.43 to 0.69] and HR, 0.63 [95% CI, 0.41 to 0.99]; p=0.57 for interaction) (Table 5). The HOPE-3 trial found no clear interaction between race/ethnicity and effects of statins on composite cardiovascular events (p=0.78 for interaction).103

In JUPITER, estimates were less precise, with no clear differences on more specific cardiovascular outcomes (such as all-cause mortality, cardiovascular mortality, MI, stroke, and revascularization) or when the nonwhite group was further stratified by black (n=2,224) or Hispanic (n=2,261) race (Appendix C1). Estimates for Asian race were not reported separately due to a small sample.

Clinical Characteristics

Lipid Parameters

Six trials (AFCAPS/TexCAPS, ASCOT, HOPE-3, JUPITER, MEGA, and WOSCOPS) reported effects of statin treatment on cardiovascular outcomes in subgroups defined by baseline lipid levels.54,60,83,103,106,107 Relative effect estimates favored statin therapy in all lipid subgroups, with no clear pattern suggesting differential risk estimates according to baseline TC, LDL-C, HDL-C, or TG levels in five of the trials (Table 6). The fifth trial (MEGA)83 found no difference in risk of CHD events between statins versus no statins in patients with baseline LDL-C levels of less than 155 mg/dL (HR, 0.90 [95% CI, 0.56 to 1.44]) and decreased risk in patients with baseline LDL-C levels of greater than 155 mg/dL (HR, 0.54 [95% CI, 0.35 to 0.81]), but the interaction was not statistically significant (p=0.06).103

Table 6. Statins Versus Placebo: Effects in Subgroups Based on Clinical Characteristics.

Table 6

Statins Versus Placebo: Effects in Subgroups Based on Clinical Characteristics.

We also found no clear differences in risk estimates in trials of statins versus placebo in sensitivity and stratified analyses based on baseline TC, HDL-C, or TG levels, though statistical heterogeneity was reduced in some cases (see Key Question 1a).

Hypertension

Three trials (n=38,339) reported effects of statins versus placebo or no statin on cardiovascular outcomes stratified by the presence of hypertension at baseline (Table 6).74,83,103 None of the trials found clear differences in risk estimates in patients with or without hypertension.

Two trials (n=10,305 and 568) of statins versus placebo specifically enrolled patients with hypertension.60,73 Effects on most outcomes in these trials were generally consistent with other trials of statins versus placebo, though one of the trials (ASCOT-LLA) found no statistically significant effect of statins versus placebo on cardiovascular mortality (RR, 0.90 [95% CI, 0.66 to 1.23]).60

Cardiovascular Risk Score

Three trials reported effects of statins versus placebo or no statin on cardiovascular outcomes stratified by baseline cardiovascular risk score (Table 6).54,57,74,103 Each trial found relative estimates of statin effects to be similar across higher and lower cardiovascular risk groups. In the JUPITER trial, there were no differences in risk estimates between patients with a Framingham 10-year risk of less than or greater than 10 percent (p=0.99 for interaction);74 in AFCAPS/TexCAPS, there were no differences in risk estimates between patients with a 10-year risk of less than versus greater than 20 percent;54,57 and in HOPE-3, there were no differences in estimates among low-, moderate-, or high-risk patients based on the INTERHEART108 score (p=0.57 for interaction).103 In AFCAPS/TexCAPS, the absolute reduction in risk was 6.64 per 1,000 person-years in the higher-risk group and 3.29 per 1,000 person-years in the lower-risk group.57

An analysis on the association between degree of lipid reduction achieved and clinical outcomes may provide indirect evidence about effects of statin therapy intensity in patient groups defined by baseline cardiovascular risk.48 Based on data from 22 trials of statins versus placebo or no statin (including trials of patients with prior cardiovascular events), similar estimates for effects of LDL-C reduction with a statin on risk of major cardiovascular events (nonfatal MI, CHD death, stroke, or coronary revascularization) were reported across patient subgroups defined by projected 5-year risk of cardiovascular events (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, and ≥30%). The RR per 39 mg/dL reduction in LDL-C ranged from 0.62 to 0.79 across subgroups. In patients with a 5-year risk of less than 10 percent, each 39 mg/dL reduction in LDL-C was associated with an absolute reduction in major cardiovascular events of about 11 per 1,000 patients over 5 years. Estimates were also consistent across cardiovascular risk subgroups for specific cardiovascular outcomes (including major coronary events [nonfatal MI and CHD death], fatal or nonfatal stroke, and coronary revascularization). Estimates for all-cause and cardiovascular mortality in patients with less than 5 percent projected cardiovascular risk were too imprecise to determine effects of LDL-C reduction.

Renal Dysfunction

Three trials reported effects of statins versus placebo or no statin on cardiovascular outcomes in patients with baseline renal dysfunction (Table 6).54,60,102 In all trials, point estimates favored statin therapy, although some estimates were imprecise and did not reach statistical significance. In the two trials that reported results stratified according to presence or absence of renal dysfunction, there were no clear differences in risk estimates.54,60

Diabetes

Two trials reported effects of statins versus placebo or no statin on cardiovascular outcomes stratified according to diabetes status (Table 6).60,83 Estimates favored statin therapy in both trials in persons with and without diabetes, with no clear differences in risk estimates.

Four trials of statin therapy versus placebo were restricted to patients with diabetes63,65,69,72 and five trials excluded patients with diabetes.54,66,74,92,93 Pooled estimates were similar in the trials of persons with diabetes and those that excluded persons with diabetes for all-cause mortality (3 trials; RR, 0.84 [95% CI, 0.64 to 1.09]; I2=5% and 4 trials; RR, 0.86 [95% CI, 0.73 to 1.01]; I2=1%, respectively), fatal and nonfatal stroke (3 trials; RR, 0.71 [95% CI, 0.50 to 1.01]; I2=0% and 2 trials; RR, 0.54 [95% CI, 0.36 to 0.82]; I2=0%, respectively), and fatal and nonfatal MI (2 trials; RR, 0.64 [95% CI, 0.43 to 0.97]; I2=38% and 2 trials; RR, 0.48 [95% CI, 0.29 to 0.79]; I2=68%, respectively).

Metabolic Syndrome

Two trials reported effects of statins versus placebo or no statin on cardiovascular outcomes in patients stratified according to presence of metabolic syndrome (Table 6).60,74 In both trials, risk estimates favored statin therapy in persons with or without metabolic syndrome, with no clear differences in risk estimates.

Other Characteristics

The AFCAPS/TexCAPS trial stratified results according to baseline LDL-C and CRP levels in a post-hoc analysis.100 Among patients with an LDL-C level of less than 149 mg/dL, statin therapy was associated with decreased risk of acute major coronary events in those with a CRP level greater than 0.16 mg/dL (RR, 0.58 [95% CI, 0.34 to 0.98]) but not in those with a CRP level less than 0.16 mg/dL (RR, 1.08 [95% CI, 0.56 to 2.08]); although the interaction among statin therapy, baseline lipid level, and CRP level did not reach statistical significance (p=0.06) (Table 6).100 Among patients with an LDL-C level of 149 mg/dL or greater, statin therapy was associated with reduced risk of major coronary events in patients with a CRP level less than 0.16 mg/dL (RR, 0.38 [95% CI, 0.21 to 0.70]) and a CRP level greater than 0.16 mg/dL (RR, 0.68 [95% CI, 0.42 to 1.10]). Subsequently, the JUPITER trial, which enrolled patients with a CRP level of 2.0 mg/L or greater at baseline (median, 4.2 to 4.3 mg/L) and an LDL-C level of less than 130 mg/dL (median, 108 mg/dL), found that statin therapy was associated with decreased risk of all-cause mortality (RR, 0.80 [95% CI, 0.67 to 0.96]), cardiovascular mortality (RR, 0.53 [95% CI, 0.41 to 0.69]), and other cardiovascular outcomes versus placebo.74 The more recent HOPE-3 trial (mean baseline LDL-C level, 128 mg/dL; median CRP level, 2.0 mg/L)103 reported findings somewhat discordant from AFCAPS/TexCAPS. HOPE-3 found no difference in effects of statins on composite cardiovascular events when patients were stratified according to a CRP level of 2.0 mg/L or less (HR, 0.82 [95% CI, 0.64 to 1.06]) or greater than 2.0 mg/L (HR, 0.77 [95% CI, 0.60 to 0.98]; p=0.70 for interaction).

Three trials reported no interaction between effects of statins versus placebo and body mass index (BMI).60,80,87 The MEGA trial also reported no interaction between effects of statins and smoking status (smokers: HR, 0.69 [95% CI, 0.42 to 1.13] vs. nonsmokers: HR, 0.64 [95% CI, 0.43 to 0.96]).87 JUPITER found similar effects of statin therapy on the primary composite cardiovascular endpoint in the subgroup of patients with an elevated CRP level and no other risk factors other than increased age (HR, 0.63 [95% CI, 0.44 to 0.92]) and the overall sample (HR, 0.56 [95% CI, 0.46 to 0.69]).74

No trial reported stratified results for patients with or without familial hypercholesterolemia.

Key Question 2. What Are the Harms of Statins in Adults Age 40 Years or Older Without Prior CVD Events?

Summary

Seventeen trials reported harms of statin treatment versus placebo or no statin in adults without prior CVD events. Statin therapy was not associated with increased risk of withdrawal due to adverse events (9 trials; RR, 0.95 [95% CI, 0.75 to 1.21]; I2=86%; ARD, 0.02% [95% CI, -1.55 to 1.60]), serious adverse events (7 trials; RR, 0.99 [95% CI, 0.94 to 1.04]; I2=0%; ARD, 0.07% [95% CI, -0.29 to 0.42), any cancer (10 trials; RR, 1.02 [95% CI, 0.90 to 1.16]; I2=43%; ARD, 0.11% [95% CI, -0.39 to 0.60]), new-onset diabetes (6 trials; RR, 1.05 [95% CI, 0.91 to 1.20]; I2=52%; ARD, 0.12% [95% CI, -0.31 to 0.54]); myalgia (7 trials; RR, 0.96 [95% CI, 0.79 to 1.16]; I2=42%; ARD, 0.03% [95% CI, -0.53 to 0.60]), or elevated aminotransferases (11 trials; RR, 1.10 [95% CI, 0.90 to 1.35]; I2=0%; ARD, 0.08% [95% CI, -0.04 to 0.19]). Evidence on the association between statins and renal or cognitive harms was sparse but did not clearly indicate increased risk. One trial found that statins were associated with increased risk of cataract surgery (3.8% vs. 3.1% after 6 years; RR, 1.25 [95% CI, 1.03 to 1.49]; ARD, 0.73% [95% CI, 0.10 to 1.36]), but this was not a prespecified outcome, and none of the other trials reported risk of cataracts or cataract surgery. Few serious adverse events were reported.

Evidence

Seventeen trials (in 19 publications) and two observational studies reported harms of statin treatment in adults age 40 years or older without prior CVD events (Appendix C1).52,54,60,64-67,73, 74,82,83,92,93,95,96,101-103,109-111Sample sizes ranged from 250 to 17,802, and mean age ranged from 53 to 66 years. Mean LDL-C levels at baseline ranged from 108 to 192 mg/dL. Most trials (11 of 17) evaluated moderate-potency statin therapy;54,60,65-67,82,92,95,96,102,103 five trials assessed low-potency statin therapy52,54,73,83,92 and four trials assessed high-potency statin therapy.64,66,74,93

Withdrawal Due to Adverse Events

Nine trials reported withdrawal due to adverse events (Table 7).52,54,82,83,92,93,95,102,103 Seven trials found no difference between statins versus placebo in rates of withdrawal due to adverse events. In the MEGA trial, patients who received statins were more likely than patients receiving placebo to withdraw due to adverse events (11.0% vs. 8.4%; RR, 1.31 [95% CI, 1.15 to 1.51]),83 while in the HOPE-3 trial, fewer patients taking statins than placebo withdrew due to adverse events (8.5% vs. 9.1%; RR, 0.70 [95% CI, 0.62 to 0.79]).103 The pooled estimate showed no difference in risk (9 trials; RR, 0.95 [95% CI, 0.75 to 1.21]; I2=86%; ARD, 0.02% [95% CI, -1.55 to 1.60]) (Appendix D12).

Table 7. Harms of Statins Versus Placebo in Randomized Trials.

Table 7

Harms of Statins Versus Placebo in Randomized Trials.

Serious Adverse Events

Eight trials reported risk of serious adverse events (Table 7).54,64,66,73,74,93,102,103 There were no significant differences between treatment and placebo groups reported in any trial or when trials were pooled, based on seven trials with poolable data (RR, 0.99 [95% CI, 0.94 to 1.04]; I2=0%; ARD, 0.07% [95% CI, -0.29 to 0.42]) (Appendix D13). Rates of serious adverse events with statin therapy varied substantially between trials (0.9%93 to 34%54) due to variability in how serious adverse events were defined, methods used to ascertain adverse events, duration of followup, and other factors.

Cancer

Eleven trials (in 12 publications) reported risk of cancer (Table 7).52,54,64,65,67,69,74,82,83,96,102,103 Ten trials reported any incident cancer, with none finding significant differences between statins and placebo in risk.54,64,65,67,74,82,83,96,102,103 Rates of any cancer with statin therapy ranged from 0.5 to 7.6 percent. Incidence of fatal cancer was reported in five trials.52,54,69,74,103 The JUPITER trial found that statins were associated with lower risk of fatal cancer versus placebo (0.4% vs. 0.7%; RR, 0.60 [95% CI, 0.40 to 0.92]).74 The other four trials reported no differences.

In pooled analyses, there were no difference between statin therapy and placebo or no statin in risk of any cancer (10 trials; RR, 1.02 [95% CI, 0.90 to 1.16]; I2=43%; ARD, 0.11% [95% CI, -0.39 to 0.60]) (Appendix D14) or fatal cancer (5 trials; RR, 0.85 [95% CI, 0.59 to 1.21]; I2=61%; ARD, -0.17% [95% CI, -0.50 to 0.16]) (Appendix D15).

New-Onset Diabetes

Four trials (in 5 publications) and two observational studies reported risk of new-onset diabetes (Table 7).60,74,101,103,109-111 Unpublished data on risk of diabetes from two other trials of statins in adults without prior cardiovascular events (MEGA and AFCAPS/TexCAPS) were also reported in a systematic review.112 Based on a pooled analysis of published and unpublished trial data, there was no difference in risk of diabetes (6 trials; RR, 1.05 [95% CI, 0.91 to 1.20]; I2=52%; ARD, 0.12% [95% CI, -0.31 to 0.54]) (Appendix D16). Analysis using the profile likelihood method resulted in a similar estimate (RR, 1.06 [95% CI, 0.93 to 1.18]). Results from these studies were inconsistent. The JUPITER trial found an increased risk of diabetes with statin use (3.0% vs. 2.4%; RR, 1.25 [95% CI, 1.05 to 1.49]).74 In stratified analysis of JUPITER data, participants with one or more diabetes risk factors (including metabolic syndrome, impaired fasting glucose, BMI >30 kg/m2, and a hemoglobin A1c level of >6.0%) were at higher risk of incident diabetes than those without diabetes risk factors (HR, 1.28 [95% CI, 1.07 to 1.54] vs. HR, 0.99 [95% CI, 0.45 to 2.21]).109 The other five trials found no clear association between statin use and increased risk of diabetes. The WOSCOPS trial found that statin use was associated with reduced risk of diabetes (1.9% vs. 2.8%; HR, 0.70 [95% CI, 0.50 to 0.98]),101 and the ASCOT-LLA (3.5% vs. 3.6%; RR, 1.02 [95% CI, 0.86 to 1.23])60 and HOPE-3 (3.0% vs. 2.6%; RR, 1.15 [95% CI, 0.91 to 1.44], respectively)103 trials found little difference in risk. Both trials (MEGA and AFCAPS/TexCAPS) with unpublished data on risk of diabetes found no association between statin use and diabetes (5.7% vs. 5.3%; RR, 1.07 [95% CI, 0.87 to 1.32] and 2.3% vs. 2.3%; RR, 0.98 [95% CI, 0.71 to 1.35]).112

Potential reasons for the discrepancy in estimates of diabetes risk include differences in the methods used to diagnose diabetes and differences in the potency of the statins evaluated. In JUPITER, diagnosis of diabetes was based on physician report.109 In WOSCOPS,101 diagnosis of diabetes was based on a fasting plasma glucose level of greater than 126 mg/dL on at least two occasions, with an increase of at least 36 mg/dL from baseline; in ASCOT-LLA,60 as a fasting plasma glucose level of greater than 126 mg/dL; and in HOPE-3, as a fasting plasma glucose level of greater than 126 mg/dL or a hemoglobin A1c level greater than 110% the upper limit of normal.103 Methods for diagnosing diabetes in the MEGA and AFCAPS/TexCAPS trials were physician report, use of medication, or fasting plasma glucose of level of greater than 126 mg/dL.112 The pooled estimate was similar in a sensitivity analysis in which WOSCOPS diabetes incidence was based on less stringent alternative criteria for diabetes112 that excluded the requirement for an increase of at least 36 mg/dL from baseline (RR, 1.07 [95% CI, 0.95 to 1.19]; I2=33%). JUPITER was the only trial to evaluate use of a high-potency statin (see Key Question 3).

Two large observational studies also found mixed evidence on statin use and diabetes. A matched case-control study that used the U.K. General Practice Research Database to identify 588 diabetes cases and 2,063 matched controls (patients with prior MI excluded) found an odds ratio (OR) of 1.01 (95% CI, 0.80 to 1.40) with statin use versus nonuse, after adjustment for BMI, hypertension, steroid use, smoking history, and number of visits to a general practitioner within 3 years.110 However, an analysis from the Women's Health Initiative of 10,834 postmenopausal women using statins and 143,006 women with no statin use and no history of self-reported CVD found that statin use significantly increased risk of incident diabetes (adjusted HR, 1.48 [95% CI, 1.38 to 1.59]).111 The WHI results included multivariate adjustment for age, race/ethnicity, education, smoking history, BMI, physical activity, alcohol use, energy intake, family history of diabetes, and use of hormone therapy. The studies used slightly different methods to determine presence of diabetes. The U.K. General Practice Research Database used computerized medical records of two or more prescriptions of insulin or an oral hypoglycemic or at least three recorded entries of diet management for diabetes.110 Cases with a new diabetes diagnosis within 90 days of first treatment for hyperlipidemia were excluded. WHI relied on self-reported new diabetes diagnosis based on patient questionnaires.111

Muscle-Related Harms

Myalgia was reported in seven trials,54,65,66,82,93,96,102 rhabdomyolysis in eight trials,54,60,66,74,83,93, 102,103 and myopathy in four trials (Table 7).54,74,102,103 One small trial found that statins were associated with decreased risk of myalgia versus placebo (RR, 0.53 [95% CI, 0.31 to 0.90]), though it did not report how myalgia was defined;65 the other six trials reported no difference between groups (7 trials; RR, 0.96 [95% CI, 0.79 to 1.16]; I2=42%; ARD, 0.03% [95% CI, -0.53 to 0.60]) (Appendix D17). Rates of myalgia with statin therapy ranged from 0.3 to 22.8 percent.

There was also no increased risk of myalgia in two trials that evaluated high-potency statin therapy (RR, 1.03 [95% CI, 0.97 to 1.11]74 and RR, 1.05 [95% CI, 0.73 to 1.52]93).

None of the trials found a significant difference between statins versus placebo in risk of rhabdomyolysis, although the number of events was very small (3 events in one study,54 1 event in three studies,60,74,103 and none in four studies).66,83,93,102 The pooled estimate for rhabdomyolysis showed no difference but the estimate was imprecise and based on only four trials that reported events (RR, 1.57 [95% CI, 0.41 to 5.99]; I2=0%; ARD, 0.01% [95% CI, -0.02 to 0.03]) (Appendix D18). Three trials found no difference between statins versus placebo in risk of myopathy (RR, 1.09 [95% CI, 0.48 to 2.47]; I2=0%; ARD, 0.01% [95% CI, -0.05 to 0.06]) (Appendix D19),74,102,103 and another trial reported no cases of myopathy in either group.54

Liver-Related Harms

Eleven studies reported no difference between statin therapy versus placebo in risk of elevation in alanine or aspartate aminotransferase, although the definitions varied (degree of elevation, aspartate and/or alanine aminotransferase, single or repeatedly elevated levels) (Table 7).52,54,64-66,69,74,82,83,93,96 There was no difference between statin therapy versus placebo or no statin in risk of aminotransferase elevation based on any definition (11 trials; RR, 1.10 [95% CI, 0.90 to 1.35]; I2=0%; ARD, 0.08% [95% CI, -0.04 to 0.19]) (Appendix D20) or when the analysis was restricted to trials that reported risk of an alanine aminotransferase level greater than 3 times the upper limit of normal, which was the most consistently used definition (5 trials; RR, 1.11 [95% CI, 0.78 to 1.57]; I2=0%).64,65,69,74,82,93,96 One trial reported no difference between statins versus placebo in risk of (undefined) hepatic disorders (RR, 1.16 [95% CI, 0.96 to 1.41]).74 Very few serious liver-related harms were reported.

Other Harms

Two trials of primary prevention populations reported no difference between statins (one using high-intensity rosuvastatin74 and one using moderate-intensity atorvastatin60) versus placebo in risk of renal impairment (HR, 1.29 [95% CI, 0.76 to 2.19]60 and RR, 1.11 [95% CI, 0.99 to 1.26]74). One trial reported the effect of statin treatment on a series of cognitive tests.92 The study found that statin-treated patients showed less improvement on tests previously shown to be sensitive to statin treatment (group difference in mean change of summary z-scores, 0.18 [95% CI, 0.07 to 0.29]; p=0.002) and on several other tests (group difference in mean change of summary z-scores, 0.17 [95% CI, 0.05 to 0.29]; p=0.007) but not on tests previously shown to be statin-insensitive (group difference in mean change of summary z-scores 0.02 [95% CI, -0.07 to 0.10]; p=0.72), although the clinical importance of these findings is difficult to interpret (Table 7).

The HOPE-3 trial found that statin use increased risk of cataract surgery, which was unanticipated and not a predetermined outcome of the trial (3.8% vs. 3.1%; RR, 1.24 [95% CI, 1.03 to 1.49]).103 None of the other primary prevention trials reported this outcome.

Key Question 3. How Do Benefits and Harms Vary According to Potency of Statin Treatment?

Summary

Direct evidence on clinical outcomes associated with differential intensity of statin therapy is extremely limited. The two trials of statin therapy of different intensities were underpowered to evaluate clinical outcomes.

Based on trials of statins versus placebo or no statin, risk estimates for all-cause mortality were similar in trials of low-intensity (RR, 0.72 [95% CI, 0.52 to 1.00]; I2=0%), moderate-intensity (RR, 0.88 [95% CI, 0.80 to 0.97]; I2=0%), and high-intensity (RR, 0.80 [95% CI, 0.67 to 0.97]; I2=0%) statins. For other clinical outcomes, there were too few trials of low- and high-intensity statins to conduct meaningful comparisons. A meta-analysis of randomized trials based on individual patient data found an association between the degree of LDL-C reduction and reduced risk of clinical outcomes. Evidence on effects of statin intensity on harms was sparse. The only trial to find statin therapy associated with an increased risk of diabetes used high-intensity statin therapy.

Evidence

In 19 trials of statins versus placebo or no statin, statin intensity (based on 2013 ACC/AHA guideline categories)30 was low (<30% estimated average LDL-C reduction) in three trials,73,83,92 moderate (30% to <50% average LDL-C reduction) in 10 trials,60,63,65-67,69,72,82,92,95,96,103 and high (≥50% LDL-C reduction) in three trials (Table 2).64,66,74,93 Two trials66,83 evaluated fixed-dose statin regimens in multiple categories and one trial permitted dose titration within the low-intensity category.83 Two other trials started patients with low-intensity therapy but permitted dose titration to moderate intensity if target cholesterol levels were not achieved.52,54

Benefits

Direct evidence on clinical outcomes associated with differential intensity of statin therapy is extremely limited. The two trials of statin therapy at different intensities were underpowered to evaluate clinical outcomes.66,92 One trial of women (n=485 randomized to statin therapy) with moderate hyperlipidemia reported no deaths in women randomized to either atorvastatin 10 or 20 mg/day (moderate-intensity) or 40 or 80 mg/day (high-intensity).66 The other trial, which enrolled men or women (n=206 randomized to statin therapy) with moderate hyperlipidemia, reported no stroke events in patients randomized to simvastatin 10 mg/day (low-intensity) and one event in patients randomized to 40 mg/day (moderate-intensity).92 A third trial, which initially randomized patients to lovastatin 20 mg/day (low-intensity), did not report on differences in clinical outcomes between patients who remained on low-intensity therapy (n=1,647) versus those who were titrated to 40 mg/day (n=1,657) (moderate-intensity therapy).54 It also found no difference in risk of aminotransferase elevation more than 3 times the upper limit of normal (0.7% vs. 0.4%; RR, 1.64 [95% CI, 0.64 to 4.23]).

Indirect comparisons of trials of statins versus placebo or no statin stratified according to the intensity of therapy were also limited. For all-cause mortality, risk estimates were similar in trials of low-intensity (RR, 0.72 [95% CI, 0.52 to 1.00]; I2=0%; ARD, -0.55% [95% CI, -1.10 to 0.00]), moderate-intensity (RR, 0.88 [95% CI, 0.80 to 0.97]; I2=0%; ARD, -0.55% [95% CI, -0.97 to -0.13]) and high-intensity statins (RR, 0.80 [95% CI, 0.67 to 0.97]; I2=0%; ARD, -0.44% [95% CI, -0.70 to -0.18]). For other clinical outcomes, there were too few trials of low- and high-intensity statins for meaningful comparisons.

An analysis on the association between degree of lipid reduction achieved and clinical outcomes may also provide some indirect evidence about effects of statin therapy intensity.48 Based on data from 22 trials of statins versus placebo or no statin (including some trials that included patients with prior cardiovascular events), the Cholesterol Treatment Trialists' Collaboration found that LDL-C reduction with a statin was associated with decreased risk of all-cause mortality (RR, 0.91 [95% CI, 0.88 to 0.93] per 36 mg/dL reduction in LDL-C) and a composite outcome of major cardiovascular events (nonfatal MI, CHD death, stroke, or coronary revascularization) (RR, 0.79 [95% CI, 0.77 to 0.81] per 36 mg/dL reduction in LDL-C). The estimate was similar when the analysis was restricted to participants without a history of vascular disease (RR, 0.75 [95% CI, 0.70 to 0.80]). Estimates were also consistent for specific cardiovascular outcomes (including major coronary events [nonfatal MI and CHD death], fatal or nonfatal stroke, and coronary revascularization).

Harms

Evidence on how harms of statin therapy vary according to statin potency is limited. JUPITER, the only study among those that reported diabetes incidence to evaluate high-intensity statin therapy (rosuvastatin 20 mg/day), reported a significantly increased risk of diabetes with statin use.74,109 There was no increased risk of diabetes with moderate-intensity statin use in the ASCOT-LLA, HOPE-3, and WOSCOPS trials (atorvastatin 10 mg/day, rosuvastatin 10 mg/day, and pravastatin 40 mg/day, respectively) (RR, 0.96 [95% CI, 0.75 to 1.22]; I2=67%).60,96,103 The MEGA trial, which used low-intensity statin therapy (pravastatin 10 to 20 mg/day),83 and the AFCAPS/TexCAPS trial,54 which used low- to moderate-intensity statin therapy (lovastatin 20 to 40 mg/day), also found no association between statin therapy and increased risk of diabetes.

Analysis of patient-level data from primary prevention trials found no association between the degree of LDL-C reduction and risk of cancer or cancer mortality.48

Contextual Question 1. What Is the Comparative Accuracy of Different Cardiovascular Risk Assessment Methods?

A number of tools are available to predict global cardiovascular risk,113-121 although they vary in the populations, risk factors, and outcomes addressed (Table 8).122,123 Until recently, the most commonly used risk calculator in the United States was the ATP III modification of the Framingham Risk Score (FRS).115 The ATP III modification was more accurate than prior models developed using Framingham cohort data, in part because it excluded patients with diabetes and focused on “hard” CHD events (MI and CHD death). The FRS ATP III model includes age, TC and HDL-C levels, smoking, systolic blood pressure, and antihypertensive medication use in sex-specific equations. The FRS ATP III model performed well when externally validated against multiple U.S. cohorts, though accuracy was decreased when it was applied to populations substantially different from the source cohort, such as Japanese American and Hispanic men and Native American women, for whom it overestimated risk.124

Table 8. Selected Cardiovascular Risk Calculators.

Table 8

Selected Cardiovascular Risk Calculators.

Although other risk assessment calculators generally include the same “traditional” risk factors as the FRS ATP III, some also include other risk factors, such as presence of diabetes, family history of early-onset CHD, or CRP levels. However, a systematic review that focused on direct (within-study) comparisons of established risk assessment models found that differences in the area under the receiver operating curve were generally small (only 10 of 56 comparisons exceeded a 5% relative difference).125 Analyses based on other discrimination, calibration, and reclassification statistics were less consistent. A limitation of head-to-head comparisons is that the models were developed to predict different outcomes; models performed worse in head-to-head comparisons when the analysis was based on an outcome not used in their original development.

In 2013, the ACC/AHA Pooled Cohort Equation risk calculator was introduced with the release of new statin therapy guidelines.113,126 The ACC/AHA Pooled Cohort Equation was developed based on pooled data from five large cohort studies that included white and black men and women, including the Framingham and Framingham Offspring studies. Important differences between the ACC/AHA Pooled Cohort Equation and the FRS ATP III modification are that it includes diabetes as a risk factor and stroke events as a hard cardiovascular outcome (in addition to MI and CHD death). The ACC/AHA Pooled Cohort Equation uses race- and sex-specific equations for black and white persons, though equations are not available for other ethnic subpopulations. Although the developers found that it performed relatively well in the pooled derivation cohort with regard to discrimination (c-statistic, 0.71 to 0.82, stratified by black or white race and sex) and calibration (calibration chi-square, 6.4 to 7.2), it performed less well in two more contemporary external validation cohorts (c-statistic, 0.56 to 0.66 in the REGARDS [Reasons for Geographic and Racial Differences in Stroke] cohort and 0.67 to 0.77 in the MESA [Multi-Ethnic Study of Atherosclerosis] cohort; calibration chi-square, 45 to 67 and 15 to 24, respectively). The MESA cohort differed from the derivation cohorts in that it included Asians and Hispanics; in addition, followup was limited to 6 years in the MESA cohort and 4 years in the REGARDS cohort. A subsequent analysis of the REGARDS cohort using 5-year data reported better predictive accuracy, with a c-statistic of 0.72 (95% CI, 0.70 to 0.75) and a Hosmer-Lemeshow chi-square of 19.9. Calibration was further improved when the analysis was limited to the subset of the population (n=6,121/18,498) with Medicare-linked data (Hosmer-Lemeshow chi-square, 11.4) but discrimination was slightly reduced (c-statistic, 0.65 [95% CI, 0.62 to 0.67]).127 However, a subsequent analysis on the MESA cohort found that the ACC/AHA Pooled Cohort Equation and three Framingham-based risk scores (including the FRS ATP III score) all overestimated risk of cardiovascular events by 37 to 154 percent in men and 8 to 67 percent in women; overestimation occurred at all cardiovascular risk levels.128 The study also found that the Reynolds Risk Score overestimated risk by 9 percent in men and underestimated risk by 21 percent in women. For all risk assessment instruments, discrimination was fair (c-statistic, 0.68 to 0.72), with no clear differences. An analysis of the Framingham cohort found that persons eligible for statin therapy based on the 2013 ACC/AHA guideline (eligibility based on the Pooled Cohort Equation) were at higher risk of CVD events than persons eligible for statin therapy based on the ATP III guideline (eligibility based on Framingham risk factors and LDL-C thresholds) (HR relative to noneligible persons, 6.8 [95% CI, 3.8 to 11.9] vs. 3.1 [95% CI, 1.9 to 5.0], respectively).40

Analyses have also been performed to determine the performance of the ACC/AHA Pooled Cohort Equation in cohorts not used to develop the instrument. One study found that it overestimated risk by 75 to 150 percent in three external U.S. cohorts (the Women's Health Study, the Physicians' Health Study, and the Women's Health Initiative Observational Study), with the greatest degree of overestimation in persons in the highest risk group (10-year risk ≥10%).36 Some critiques of this analysis include its use of cohorts with lower risk of cardiovascular events than observed in the general population, potential imprecision due to patient self-report for some risk factors, and publication as an editorial without detailed methods or peer review.37 A subsequent analysis on the Women's Health Study cohort found that the degree of overestimation was similar after adjusting for intervention effects of statins and revascularization, and that underascertainment of cardiovascular events was unlikely due to the high rate of followup (>97%).129 A study performed on a Kaiser Permanente database (data collected from 2008 to 2013) found that predicted rates of cardiovascular events based on the ACC/AHA Pooled Cohort Equation were substantially higher than observed rates.130 In persons with a predicted 5-year risk of less than 2.50 percent, the observed risk was 0.20 percent; for 2.50 to 3.75 percent predicted risk, the observed risk was 0.65 percent; for 3.75 to less than 5.00 percent predicted risk, the observed risk was 0.90 percent; and for 5.00 percent or greater predicted risk, the observed risk was 0.74 percent. Discrimination was fair across subgroups defined by sex, race/ethnicity, and socioeconomic status (c-statistic, 0.68 to 0.74).40

Contextual Question 2. How Do Lipid Levels Change Over Time in Adults Age 40 Years or Older?

Few longitudinal studies have assessed how lipid levels change over time in adults age 40 years or older. Cohort studies conducted in the United States and Europe showed relatively small changes over time in lipid levels, though changes appeared more pronounced in women than in men. In analysis of 2,912 FRS participants, the mean biennial difference in serial cholesterol measurements among adults ages 45 to 54 years at enrollment was 3.3±6.9 mg/dL in men and 7.3±7.6 mg/dL in women.131 For those ages 55 to 64 years at enrollment, changes were somewhat less pronounced (2.0±7.4 mg/dL in men and 3.6±8.2 mg/dL in women). When including all adults ages 30 to 62 years at enrollment, the rate of change was higher in those with a TC level of less than 200 mg/dL (6.7±5.6 mg/dL in men and 9.2±6.6 mg/dL in women) than in those with an initial cholesterol level of 240 mg/dL or greater (0.6±7.4 mg/dL in men and 3.7±11.2 mg/dL in women). In the Nijmegen Cohort Study (n=2,335), conducted in the Netherlands, TC levels increased an average of 4.5 percent over 18 years among men age 40 years at baseline but were essentially stable in men ages 45 to 50 years at baseline.132 In women, TC levels increased 16 percent after 18 years among those ages 40 to 44 years at baseline and 12 percent among those ages 45 to 50 years at baseline. In the Rancho Bernardo Heart and Chronic Disease study, which analyzed lipid levels in 917 U.S. residents ages 50 to 93 years, TC, HDL-C, and LDL-C levels all decreased by about 1 percent per year over an 8-year period.133

A factor that complicates interpretation of longitudinal data on lipid levels is differentiating true long-term changes from short-term biological variation or analytic error. In an analysis of cholesterol data from the Long-Term Intervention with Pravastatin in Ischemic Disease study of patients with past CHD randomized to pravastatin versus placebo, mean cholesterol levels increased about 0.5 percent per year over the 5 years following the initial intervention period.134 However, the short-term biological and analytical variability was about 7 percent, and it took nearly 4 years for the long-term variation to exceed the short-term variation, indicating a weak signal-to-noise ratio and a high likelihood of false-positive increases with frequent retesting of cholesterol levels. A retrospective Japanese study of serial lipid levels over 4 years in persons not taking lipid-lowering therapy found that the signal-to-noise ratio remained below 1 through 3 years for TC, HDL-C, and LDL-C levels but exceeded 1 for the ratio of TC to HDL-C and LDL-C to HDL-C.134

Studies measuring the tracking coefficient, a measure of the tendency of individuals to maintain their rank or position in a group over time (coefficients >0.50 indicate more stable levels), also indicate relative long-term stability of cholesterol levels. In the Tromsø Study, the tracking coefficient over 16 years for HDL-C levels in more than 18,000 Norwegian subjects ages 39 to 61 years at enrollment ranged from 0.53 to 0.62 in men and from 0.66 to 0.69 in women.135 The tracking coefficient for TC levels was somewhat higher in men (0.69 to 0.73) but similar to that for HDL-C levels in women (0.65 to 0.66). TG levels were less stable (tracking coefficient, 0.43 to 0.45 in men and 0.45 to 0.51 in women). Results were similar in the Austrian Vorarlberg Health Monitoring and Promotion Programme study (n=149,650), with tracking coefficients for TC levels of 0.63 to 0.66 in both men and women age 45 years or older, and 0.59 to 0.63 for TG levels.136

Image appdf1
Image appdf2
Image appdf3
Image appdf4
Image appdf5
Image appdf6
Image appdf7
Image appdf11
Image appdf8
Image appdf12
Image appdf13
Image appdf14
Image appdf15
Image appdf16
Image appdf17
Image appdf18
Image appdf19
Image appdf20

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (2.5M)

Recent Activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...