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You are here: HomeRecommendations for Primary Care PracticePublished RecommendationsRecommendation SummaryOther Supporting Document : Evidence Summary: Statins for Prevention of Cardiovascular Disease in Adults

Evidence Summary: Statins for Prevention of Cardiovascular Disease in Adults

Other Supporting Document for Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication

Roger Chou, MD; Tracy Dana, MLS; Ian Blazina, MPH; Monica Daeges, BA; Thomas L. Jeanne, MD


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in JAMA on November 13, 2016.

Abstract

Importance: Cardiovascular disease (CVD), the leading cause of mortality and morbidity in the United States, may be potentially preventable with statin therapy.

Objective: To systematically review benefits and harms of statins for prevention of CVD to inform the US Preventive Services Task Force.

Data Sources: Ovid MEDLINE (from 1946), Cochrane Central Register of Controlled Trials (from 1991), and Cochrane Database of Systematic Reviews (from 2005) to June 2016.

Study Selection: Randomized clinical trials of statins vs placebo, fixed-dose vs titrated statins, and higher- vs lower-intensity statins in adults without prior cardiovascular events.

Data Extraction and Synthesis: One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Data were pooled using random-effects meta-analysis.

Main Outcomes and Measures: All-cause mortality, CVD-related morbidity or mortality, and harms.

Results: Nineteen trials (n = 71,344 participants [range, 95-17,802]; mean age, 51-66 years) compared statins vs placebo or no statin. Statin therapy was associated with decreased risk of all-cause mortality (risk ratio [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%]), cardiovascular mortality (RR, 0.69 [95% CI, 0.54 to 0.88]; I2 = 54%; ARD, −0.43% [95% CI, −0.75% to −0.11%]), stroke (RR, 0.71 [95% CI, 0.62 to 0.82]; I2 = 0; ARD, −0.38% [95% CI, −0.53% to −0.23%]), myocardial infarction (RR, 0.64 [95% CI, 0.57 to 0.71]; I2 = 0%; ARD, −0.81% [95% CI, −1.19 to −0.43%]), and composite cardiovascular outcomes (RR, 0.70 [95% CI, 0.63 to 0.78]; I2 = 36%; ARD,−1.39% [95% CI, −1.79 to −0.99%]). Relative benefits appeared consistent in demographic and clinical subgroups, including populations without marked hyperlipidemia (total cholesterol level <200 mg/dL); absolute benefits were higher in subgroups at higher baseline risk. Statins were not associated with increased risk of serious adverse events (RR, 0.99 [95% CI, 0.94 to 1.04]), myalgias (RR, 0.96 [95% CI, 0.79 to 1.16]), or liver-related harms (RR, 1.10 [95% CI, 0.90 to 1.35]). In pooled analysis, statins were not associated with increased risk of diabetes (RR, 1.05 [95% CI, 0.91 to 1.20]), although statistical heterogeneity was present (I2 = 52%), and 1 trial found high-intensity statins associated with increased risk (RR, 1.25 [95% CI, 1.05 to 1.49]). No trial directly compared titrated vs fixed-dose statins, and there were no clear differences based on statin intensity.

Conclusions and Relevance: In adults at increased CVD risk but without prior CVD events, statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and CVD events, with greater absolute benefits in patients at greater baseline risk.

Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States.1 A challenge in reducing adverse outcomes of CVD is that the first clinical manifestation can be catastrophic, including sudden cardiac death, acute myocardial infarction, or stroke.2, 3

Statins reduce the risk of CVD-associated morbidity and mortality through their effects on lipids and are also thought to have anti-inflammatory and other plaque-stabilization effects.4 Seven statins are available in the United States (Table 1). Although statin therapy for patients with prior cardiovascular events is widely supported, use in patients without prior cardiovascular events is controversial.5 Recent guidelines on statins for prevention of CVD4 differ from previous guidelines6 in terms of the recommended instrument to estimate cardiovascular risk, the target populations for statin therapy, and treatment strategies (eg, treat to target lipid levels vs fixed-dose statin therapy; choice of statin intensity).7, 8

The United States Preventive Services Task Force (USPSTF) commissioned this review9 to inform the development of recommendations on statin therapy for prevention of CVD in adults 40 years and older without prior cardiovascular events.10 Although previous USPSTF recommendations11 addressed screening for lipid disorders, the USPSTF has not addressed selection of patients for preventive therapy or statin selection and treatment strategies.

Methods

Scope of the Review

Using established methods,12 the USPSTF determined the scope and key questions for this review (Figure 1). This review was conducted as a subcategory of the lipid disorders in adults topic. The final research plan was posted on the USPSTF website prior to conducting the review.13 Detailed methods are available in the full evidence report available at http://www.uspreventiveservicestaskforce.org/Page/Document/final-evidence-review149/statin-use-in-adults-preventive-medication1.

Data Sources and Searches

A research librarian searched the Cochrane Central Register of Controlled Trials (from 1991), the Cochrane Database of Systematic Reviews (from 2005), and Ovid MEDLINE (from 1946) to June 2016 for English-language publications (eAppendix 1 in the Supplement), and reference lists. After the draft report was posted for public comment and peer review, the search was updated in June 2016 and 1 additional trial was added.14

Study Selection

Two reviewers independently evaluated each study on the basis of predefined criteria at the abstract and full-text review levels (eTable 1 in the Supplement). The population of interest was adults 40 years and older without prior CVD events. Studies were limited to those in which fewer than 10% of the participants had prior CVD events to include only trials that predominantly enrolled the population of interest. We included randomized trials of statin therapy vs placebo or no statin and assessed all-cause mortality, coronary heart disease, stroke-related morbidity or mortality, or harms of treatment (including muscle injury, cognitive loss, incident diabetes, and hepatic injury). We also included studies of statin treatment adjusted to achieve target low-density lipoprotein cholesterol (LDL-C) levels vs fixed-dose or other treatment strategies and studies that evaluated effects of statin therapy intensity on benefits and harms. For diabetes incidence, large cohort and case-control studies of statin use vs nonuse were also included. The selection of literature is summarized in Figure 2.

Data Abstraction and Quality Assessment

One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, and results, and a second investigator checked the abstracted data. Two investigators independently applied criteria developed by the USPSTF12 to rate the quality of each study as good, fair, or poor (eTable 2 in the Supplement). Discrepancies were resolved through consensus.

Data Synthesis and Analysis

Meta-analyses were conducted to calculate risk ratios (RRs) for statins vs placebo using the Dersimonian–Laird random-effects model with Review Manager version 5.2 (Cochrane Collaboration Nordic Cochrane Centre). Statistical heterogeneity was assessed with the I2 statistic.15 When statistical heterogeneity was present (defined as I2 >30%), sensitivity analysis was performed with the profile likelihood method using Stata version 10.1 (StataCorp).16 Additional sensitivity and stratified analyses were performed based on study quality, exclusion of trials that enrolled patients with prior CVD events, duration of follow-up, intensity of statin therapy,4 mean total cholesterol and LDL-C levels at baseline, and whether the trial was stopped early. For analyses with 10 or more trials, funnel plots were constructed to detect small sample effects.17

The aggregate internal validity (quality) of the body of evidence was assessed for each key question using methods developed by the USPSTF (eTable 3 in the Supplement),12 based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence.

Results

Study Characteristics

Nineteen randomized trials (Table 2) assessed the effects of statins vs placebo or no statin on health outcomes in adults without prior CVD events (full list of primary and secondary publications, including study acronyms, are reported in eAppendix 2 in the Supplement).14, 18-35 The trials enrolled between 95 and 17,802 study participants (total sample, 71,344 participants). Mean ages ranged from 51 to 66 years. Duration of follow-up ranged from 6 months to 6 years.

All trials enrolled patients at increased cardiovascular risk. In 6 trials, the main criterion for enrollment was presence of dyslipidemia;19, 24, 30, 31, 33, 35 in 3 trials, early cerebrovascular disease;18, 25, 32 in 4 trials, diabetes;21, 23, 26, 27 in 2 trials, hypertension;20, 28 and in 1 trial each, mild to moderate aortic stenosis,22 microalbuminuria, and elevated C-reactive protein (CRP) level (>20 mg/L [to convert CRP values to nmol/L, multiply by 9.524]).29 One trial enrolled patients with at least 1 of a number of risk factors, including elevated waist-to-hip ratio, dyslipidemia, dysglycemia, and mild renal dysfunction, among others.14

Patients with severe dyslipidemia at baseline were excluded in the 3 diabetes trials21, 23, 26 (mean total cholesterol levels, 195-217 mg/dL; mean LDL-C levels, 114-139 mg/dL [to convert total cholesterol and LDL-C values to mmol/L, multiply by 0.0259]). In the 2 hypertension trials,20, 28 mean total cholesterol levels were 212 to 232 mg/dL and mean LDL-C levels were 131 to 151 mg/dL; in the aortic stenosis trial,22 the mean total cholesterol level was 205 mg/dL and mean LDL-C levels were 120-124 mg/dL. The elevated CRP trial restricted inclusion to patients with LDL-C levels less than 130 mg/dL.29 In the other trials, mean lipid levels at baseline ranged from 201 to 272 mg/dL for total cholesterol and from 128 to 192 mg/dL for LDL-C. Three trials enrolled some patients (<10%) with a history of clinical CVD.20, 30, 34

Six trials were rated as of good quality,14, 22, 26, 29, 30, 35 1 trial as of poor quality,27 and 12 trials as of fair quality (eTable 2 in the Supplement).18-21, 23-25, 28, 31-34 Methodological limitations in the fair-quality trials included unclear randomization and allocation concealment methods and unclear blinding status. The poor-quality trial also did not report attrition. Two trials18, 33 reported no industry funding; the rest were fully or partially industry funded. The trials were judged to have high applicability to general US primary care settings based on the characteristics of the patients enrolled, the statin therapies evaluated, and study settings.

Benefits of Statin Treatment

Key Question 1a. What are the benefits of statins in reducing the incidence of CVD-related morbidity or mortality or all-cause mortality in asymptomatic adults 40 years or older without prior CVD events?

Statins were associated with reduced risk vs placebo of all-cause mortality (15 trials; RR, 0.86 after 1-6 years [95% CI, 0.80 to 0.93]; I2 = 0%; absolute risk difference [ARD], −0.40% [95% CI, −0.64% to −0.17%]) (Figure 3),14, 18-21, 23, 24, 26, 28-32, 34, 35 cardiovascular mortality (10 trials; RR, 0.69 after 2-6 years [95% CI, 0.54 to 0.88]; I2 = 54%; ARD, −0.43% [95% CI, −0.75% to −0.11%]) (Figure 3),14, 18-20, 22, 29-31, 34, 35 fatal or nonfatal stroke (13 trials; RR, 0.71 after 6 months to 6 years [95% CI, 0.62 to 0.82]; I2 = 0%; ARD, −0.38% [95% CI, −0.53% to −0.23%]) (eFigure 1 in the Supplement),14, 18, 20-22, 26, 27, 29-31, 33-35 fatal or nonfatal myocardial infarction (12 trials; RR, 0.64 after 2-6 years [95% CI, 0.57 to 0.71]; I2 = 0%; ARD, −0.81% [95% CI, −1.19% to −0.43%]) (eFigure 2 in the Supplement),14, 18-22, 25, 26, 29-31, 35 revascularization (7 trials; RR, 0.63 after 2-6 years [95% CI, 0.56 to 0.72]; I2 = 0%; ARD, −0.66% [95% CI, −0.87% to −0.45%]) (eFigure 3 in the Supplement),14, 19, 26, 29-31, 35 and composite cardiovascular outcomes (13 trials; RR after 1-6 years, 0.70 [95% CI, 0.63 to 0.78]; I2 = 36%; ARD, −1.39% [95% CI, −1.79% to −0.99%]) (eFigure 4 in the Supplement).14, 18-21, 23, 26-29, 31, 34, 35 Results from individual trials are summarized in eTable 4 in the Supplement.

Seven trials reported similar estimates for fatal myocardial infarction (RR, 0.70 [95% CI, 0.50 to 0.99]; I2 = 0%; ARD, −0.16% [95% CI, −0.42% to 0.11%]) and nonfatal myocardial infarction (RR, 0.64 [95% CI, 0.46 to 0.91], I2 = 50%; ARD, −0.46% [95% CI, −0.90% to −0.02%]).18, 19, 25, 29-31, 35 Statins were associated with decreased risk of nonfatal stroke (3 trials; RR, 0.57 [95% CI, 0.41 to 0.81]; I2 = 0%; ARD, −0.32% [95% CI, −0.52% to −0.12%])26, 29, 33 but not significantly associated with 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%]).26, 29 Three trials of patients with mild cerebrovascular disease at baseline either did not report strokes23, 25 or reported few events.18

For cardiovascular mortality, statistical heterogeneity was present (I2 = 54%), but the estimate was similar using the profile likelihood method (RR, 0.71 [95% CI, 0.55 to 0.88]). Among trials that reported at least 10 cardiovascular mortality events, the smallest effects of statin therapy were reported by the HOPE-3 trial (n = 12,705),14 which enrolled patients with at least 1 CVD risk factor (2.4% vs 2.7% after 6 years; RR, 0.90 [95% CI, 0.72 to 1.11]), and the ASCOT-LLA trial (n = 10,305),20 which enrolled patients with hypertension and at least 3 other risk factors (1.4% vs 1.6% after 3 years; RR, 0.90 [95% CI, 0.66 to 1.23]); RR estimates ranged from 0.53 to 0.68 in the others.

Excluding JUPITER29 and ASCOT-LLA,20 which were both stopped early and together accounted for approximately 40% of the total sample and events for several outcomes, resulted in similar pooled estimates (eTable 5 in the Supplement). Results were also similar in sensitivity analyses restricted to good-quality studies,14, 22, 26, 29, 30, 35 studies with duration of follow-up greater than 3 years,14, 19, 21, 22, 26, 28, 31, 34, 35 studies in which participants had baseline mean LDL-C levels less than 160 mg/dL,14, 18-24, 26, 28, 29, 31, 32, 34 or when trials that included patients with prior CVD events20, 30, 34 were excluded (eTable 5 in the Supplement).

Funnel plot asymmetry was not observed for outcomes reported in at least 10 trials (eFigures 5-9 in the Supplement).

Key Question 1b. What are the benefits of statin treatment to achieve target LDL-C levels vs other treatment strategies?

No trial directly compared statin treatment titrated to attain target cholesterol levels vs fixed-dose treatment. There were no clear differences in estimates between 3 trials18, 19, 31 of statins vs placebo that permitted limited dose titration (RR for cardiovascular mortality, 0.61 [95% CI, 0.37 to 1.02]; I2 = 9%; ARD, −0.30% [95% CI, −0.66% to 0.06%] and RR for composite cardiovascular outcomes, 0.63 [95% CI, 0.53 to 0.76]; I2 = 0%; ARD, −1.47% [95% CI, −2.43% to −0.51%]) and the 16 fixed-dose trials (RR for cardiovascular mortality, 0.71 [95% CI, 0.53 to 0.94]; I2 = 58%; ARD, −0.47% [95% CI, −0.93% to −0.01%] and RR for composite cardiovascular outcomes, 0.72 [95% CI, 0.63 to 0.81]; I2 = 43%; ARD, −1.40% [95% CI, −1.90 to −0.91%]).

Key Question 1c. Do the benefits vary in subgroups defined by demographic or clinical characteristics?

Seven trials reported results stratified according to various subgroups, primarily focusing on composite cardiovascular events (eTables 6 and 7 in the Supplement).14, 19, 20, 26, 29, 31, 35 There were no clear differences in relative risk estimates based on sex (6 trials),14, 19, 20, 26, 29, 31 age (7 trials),14, 19, 20, 26, 29, 31, 35 race/ethnicity (2 trials),14, 29, 36 baseline lipid levels (6 trials),14, 19, 20, 26, 31, 37 cardiovascular risk score (3 trials),14, 19, 29 presence of hypertension (3 trials),14, 29, 31 renal dysfunction (2 trials),19, 20 diabetes (2 trials),20, 31 or the metabolic syndrome (2 trials).20, 29

Sex and age were the most commonly reported subgroups. For composite cardiovascular outcomes, relative risk estimates were very similar for men and women in 5 trials (eTable 6 in the Supplement).14, 19, 26, 29, 31 In the ASCOT-LLA trial, the hazard ratio (HR) for nonfatal myocardial infarction plus fatal coronary heart disease was 0.59 (95% CI, 0.44 to 0.77) in men and 1.10 (95% CI, 0.57 to 2.12) in women.20 In addition to composite cardiovascular outcomes, JUPITER reported subgroup effects for specific outcomes.29 Effects of statins vs placebo on composite cardiovascular outcomes were similar in men and women (HR, 0.58 [95% CI, 0.45 to 0.73] and HR, 0.54 [95% CI, 0.37 to 0.80], respectively), but statins were associated with lower risk of nonfatal stroke in men (HR, 0.33 [95% CI, 0.17 to 0.63]) compared with women (HR, 0.84 [95% CI, 0.45 to 1.58]; P = 0.04 for interaction), with an opposite pattern observed for risk of revascularization or hospitalization (HR, 0.63 [95% CI, 0.46 to 0.86] vs 0.24 [95% CI, 0.11 to 0.51]; P = 0.01 for interaction).29

There were also no clear differences in the association between statin use and outcomes in analyses stratified by age older or younger than 55, 60, 65, or 70 years, with very similar estimates from 7 trials (eTable 6 in the Supplement).14, 19, 20, 26, 29, 31, 35 None of the trials that enrolled patients older than 75 years18, 20, 22, 23, 27, 29 reported results in this subgroup.

Although relative risk estimates across subgroups were similar, absolute benefits were greater in subgroups at higher risk for events. For example, in the JUPITER trial, for composite cardiovascular events the ARD for statins vs placebo was −0.0106 (number needed to treat [NNT], 94) in people younger than 70 years and −0.0162 (NNT, 62) in those 70 years and older,29 and in the HOPE-3 trial the ARD was −0.0088 (NNT, 114) in people 65 years and younger and −0.0183 (NNT, 55) in those older than 65 years.14 Similar trends for CHD events were observed in the CARDS and ASCOT-LLA trials, with ARDs of −1.77% (NNT, 56) and −2.13% (NNT, 47) in people younger than 65 years and 65 years and older, respectively, and −0.78% (NNT, 128) and −1.22% (NNT, 82) in those 60 years and younger and older than 60 years, respectively.20, 26 Two trials of patients with hypertension20, 28 reported effects on most cardiovascular outcomes that were generally consistent with other statin trials, although 1 of the trials (ASCOT-LLA) found small, statistically nonsignificant effects of statins vs placebo on cardiovascular mortality (RR, 0.90 [95% CI, 0.66 to 1.23]).20

Pooled estimates were similar in trials restricted to patients with diabetes21, 23, 26, 27 or that excluded patients with diabetes.19, 24, 29, 32, 33 For composite cardiovascular outcomes, the RR in trials restricted to patients with diabetes was 0.63 (95% CI, 0.38 to 1.05; I2 = 70%; ARD, −3.18% [95% CI, −6.68% to 0.33%]); the RR in 2 trials that excluded patients with diabetes and reported this outcome was 0.61 (95% CI, 0.52 to 0.71; I2 = 0%; ARD, −1.48% [95% CI, −2.35% to −0.62%]).

The AFCAPS/TexCAPS trial stratified results according to baseline LDL-C and CRP levels in a post hoc analysis.38 In patients with LDL-C levels less than 149.1 mg/dL, statin therapy was associated with decreased risk of acute major coronary events in participants with CRP levels of 0.16 mg/dL or greater (RR, 0.58 [95% CI, 0.34 to 0.98]) but not in those with CRP levels 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). Subsequently, the JUPITER trial, which focused on patients with elevated CRP levels (>2.0 mg/L) and LDL-C levels less than 130 mg/dL at baseline (mean, 108 mg/dL), found statin therapy 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 vs placebo.29 However, the HOPE-3 trial (mean baseline LDL-C level, 128 mg/dL) found similar effects of statins on risk of composite cardiovascular outcomes among persons with CRP levels greater than 2.0 mg/L (HR, 0.77 [95% CI, 0.60 to 0.98]) or 2.0 mg/L or less (HR, 0.82 [95% CI, 0.64 to 1.06]) at baseline.14

Harms of Statin Treatment

Key Question 2. What are the harms of statin treatment?

Compared with placebo, 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%]) (eFigure 10 in the Supplement),14, 18, 19, 30-34, 39 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%]) (eFigure 11 in the Supplement),14, 19, 22, 24, 28, 29, 32, 39 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%]) (eFigure 12 in the Supplement),14, 19, 22, 23, 25, 29-31, 37, 39 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%]),14, 18, 19, 26, 29 myalgias (7 trials; RR, 0.96 [95% CI, 0.79 to 1.16]; I2 = 42%; ARD, 0.03% [95% CI, −0.53% to 0.60%]) (eFigure 13 in the Supplement),19, 23, 24, 30, 32, 37, 39 or elevated aminotransferase levels (11 trials; RR, 1.10 [95% CI, 0.90 to 1.35]; I2 = 0%; ARD, 0.08% [95% CI, −0.04% to 0.19%]) (eFigure 14 and eTable 8 in the Supplement).18, 19, 22-24, 26, 29-32, 37 Statin therapy was also not associated with increased risk of rhabdomyolysis (4 trials; RR, 1.57 [95% CI, 0.41 to 5.99]; I2 = 0%; ARD, 0.01% [95% CI, −0.02% to 0.03%])14, 19, 29, 40 or myopathy (3 trials; RR, 1.09 [95% CI, 0.48 to 2.47]; I2 = 0%; ARD, 0.01% [95% CI, −0.05% to 0.06%]),14, 19, 39 but estimates were imprecise. Evidence on renal dysfunction20, 29 and cognitive harms33 was sparse but showed no clear associations. One trial reported increased risk of cataract surgery after 6 years with statin use relative to placebo (3.8% vs 3.1%; RR, 1.24 [95% CI, 1.03 to 1.49]; ARD, 0.73% [95% CI, 0.10% to 1.36%]);14 no other trial reported this outcome. Few serious adverse events were reported.

Four trials reported risk of new-onset diabetes following initiation of statin therapy (eTable 8 in the Supplement),14, 20, 29, 41, 42 and unpublished diabetes risk data from 2 other trials (MEGA and AFCAPS/TexCAPS) were available from a systematic review.43 Statins were not associated with increased risk of diabetes vs placebo (6 trials; RR, 1.05 [95% CI, 0.91 to 1.20]; I2 = 52%; ARD, 0.19% [95% CI, −0.16% to 0.53%]) (Figure 3). Results using the profile likelihood method were similar (RR, 1.06 [95% CI, 0.93 to 1.18]). JUPITER, the only trial to evaluate a high-potency statin, was also the only trial to find increased risk (3.0% vs 2.4%; RR, 1.25 [95% CI, 1.05 to 1.49]).29 In JUPITER, only participants with 1 or more diabetes risk factors (including the metabolic syndrome, impaired fasting glucose, body mass index >30 [calculated as weight in kilograms divided by height in meters squared], and hemoglobin A1c level >6.0%) were at higher risk for incident diabetes (HR, 1.28 [95% CI, 1.07 to 1.54] vs 0.99 [95% CI, 0.45 to 2.21] in persons with no risk factors).41 The other trials found no clear association between statin use and increased risk of diabetes, with 1 trial (WOSCOPS) reporting reduced risk (1.9% vs 2.8%; HR, 0.70 [95% CI, 0.50 to 0.98]).42 Definitions for incident diabetes varied. The pooled estimate was similar in a sensitivity analysis in which WOSCOPS diabetes incidence was based on less stringent diabetes criteria (RR, 1.07 [95% CI, 0.95 to 1.19]; I2 = 33%).43

A matched case-control study (588 cases) based on the United Kingdom General Practice Research Database found no association between statin use vs nonuse and increase in diabetes risk (adjusted odds ratio [OR], 1.01 [95% CI, 0.80 to 1.40]),44 although an analysis from the Women’s Health Initiative (n = 10,834) found statin use associated with increased risk (adjusted HR, 1.48 [95% CI, 1.38 to 1.59]).45

Benefits, Harms, and Statin Potency

Key Question 3. How do benefits and harms vary according to statin treatment potency?

Two trials of statin therapy at different intensities were underpowered to evaluate clinical outcomes.24, 33 For all-cause mortality, risk estimates for statins vs placebo for all-cause mortality were similar in trials of low-intensity statins (2 trials; RR, 0.72 [95% CI, 0.52 to 1.00]; I2 = 0%; ARD, −0.55% [95% CI, −1.10% to 0.00%]),28, 31 moderate-intensity statins (8 trials; RR, 0.88 [95% CI, 0.80 to 0.97]; I2 = 0%; ARD, −0.55% [95% CI, −0.97% to −0.13%),14, 20, 21, 23, 26, 30, 34, 35 and high-intensity statins (2 trials; RR, 0.80 [95% CI, 0.67 to 0.97]; I2 = 0%; ARD, −0.44% [95% CI, −0.70% to −0.18%]).29, 32 As noted above, JUPITER, the only trial to find statin therapy associated with increased risk of diabetes, evaluated high-intensity statin therapy (rosuvastatin [20 mg/d]).29, 41

Discussion

In adults at increased cardiovascular risk but without prior cardiovascular events, statin therapy was associated with reduced risk of clinical outcomes vs placebo, based on 19 trials with 6 months to 6 years of follow-up (summarized in Table 3). Although the trials evaluated diverse populations, findings were generally consistent for all-cause mortality (15 trials; RR, 0.86 after 1-6 years [95% CI, 0.80 to 0.93]; I2 = 0%; ARD, −0.40% [95% CI, −0.64% to −0.17%]), cardiovascular mortality (10 trials; RR, 0.69 after 2-6 years [95% CI, 0.54 to 0.88]; I2 = 54%; ARD, −0.43% [95% CI, −0.75 to −0.11%]), and other individual and composite cardiovascular outcomes. Findings were generally robust in sensitivity and stratified analyses based on trial quality, follow-up duration, baseline lipid levels, exclusion of trials stopped early, and exclusion of trials with some (<10% of sample) patients with prior cardiovascular events. Adding the large HOPE-3 trial,14 which was identified when the search was updated, also had little effect on findings. Based on pooled estimates, the NNT to prevent 1 death from any cause was 250 after 1 to 6 years, and to prevent 1 cardiovascular death was 233 after 2 to 6 years. However, the NNT varied in individual trials depending on factors such as the baseline risk of the population (eTable 7 in the Supplement) and the duration of follow-up (eTable 5 in the Supplement).

These findings regarding benefits associated with statin therapy were generally consistent with findings from recent systematic reviews46-49 that primarily focused on patients without prior cardiovascular events, despite variability in inclusion criteria, use of individual-patient data,46 and analytic methods. For all-cause mortality, the point estimate was very similar to those from recent systematic reviews,46-48 although in 1 review the difference was not statistically significant (RR, 0.91 [95% CI, 0.83 to 1.01]).46

Outcomes associated with statin use appeared to be similar in patient subgroups defined according to demographic and clinical characteristics. Few trials enrolled patients older than 75 years, and no trial reported results in this subgroup. Benefits of statins did not appear to be restricted to patients with severely elevated lipid levels, because similar effects were observed in subgroups stratified according to baseline levels.21, 23, 26, 29 In a population without markedly elevated lipid levels (mean LDL-C, 128 mg/dL), the HOPE-3 trial found similar effects of statins among persons with and without elevated CRP levels.14 Similarly, trials reported similar relative risk estimates in persons classified as having higher and lower assessed cardiovascular risk.19, 29 Given similar relative risk estimates, the absolute benefits of statin therapy will be greater in populations at higher baseline risk. For example, in the JUPITER trial, the NNT to prevent 1 cardiovascular event was 94 in people younger than 70 years and 62 in those 70 years and older.29 In the AFCAPS/TexCAPS trial, the absolute risk reduction for major cardiovascular events was 6.64 per 1000 person-years in persons with a 10-year risk greater than 20% and 3.29 per 1000 person-years in those with 10-year risk less than 20%.50

This review found no evidence that statins were associated with increased risk of withdrawal because of adverse events, serious adverse events, cancer, or elevated liver enzyme levels vs placebo or no statin therapy. These findings are generally consistent with those from recent systematic reviews, some of which also included trials of statins for secondary prevention.47, 51-53 Similar to other meta-analyses of primary and secondary prevention trials,54, 55 this review found no association between use of statins and increased risk of muscle-related harms, although some observational studies and randomized rechallenge trials found statins associated with increased risk of myopathy or joint-related symptoms.56-58 The large HOPE-3 trial found statins associated with increased risk of cataract surgery, an unanticipated finding.14 No other trial of statins for primary prevention evaluated risk of cataracts or cataract surgery. A systematic review that included non–primary prevention trials and observational studies reported discordant findings, with statins associated with decreased risk of cataracts (OR, 0.81 [95% CI, 0.71 to 0.93]).59

In contrast with systematic reviews of primary and secondary prevention trials that reported a slightly increased risk of diabetes with statin therapy (OR, 1.09 [95% CI, 1.02 to 1.17]43, 60 and RR, 1.13 [95% CI, 1.03 to 1.23]61), this review found no increased risk of diabetes in 6 primary prevention trials (RR, 1.05 [95% CI, 0.91 to 1.20]; I2 = 52%). Another systematic review limited to primary prevention trials also found no association with increased risk of diabetes (4 trials; RR, 1.05 [95% CI, 0.84 to 1.32]).48 However, individual trials were inconsistent, with 1 large trial (JUPITER) reporting an increased risk (3.0% vs 2.4%; RR, 1.25 [95% CI, 1.05 to 1.49]).29 The JUPITER study was the only primary prevention trial reporting diabetes risk that evaluated high-potency statin therapy. Other analyses that included secondary prevention trials also suggested an association between higher statin intensity and diabetes risk.48, 60, 62, 63 In the JUPITER study, among patients with diabetes risk factors, 134 cardiovascular events were prevented for every 54 incident cases of diabetes, while among persons without diabetes risk factors, 86 cardiovascular events were prevented, with no incident diabetes.41 Evidence for the association between statin use and cognitive harms was sparse but indicated no clear increase in risk. These findings are consistent with those from a recent systematic review of randomized trials and observational studies that found no adverse associations of statins with incidence of Alzheimer disease, dementia, or decreased scores on tests of cognitive performance.52

No trial directly compared treatment with statins titrated to attain target cholesterol levels vs fixed-dose therapy, and only 318, 19, 31 of 18 trials permitted limited dose titration, with no clear differences compared with fixed-dose trials. There was also little direct evidence to determine effects of statin therapy intensity on outcomes, although there were no clear differences in effect estimates when placebo-controlled trials of statins were stratified according to the intensity of therapy. A meta-analysis of individual-patient data from 22 trials, including trials of patients with prior cardiovascular events, found an association between the degree of LDL-C lowering and reduced risk of clinical outcomes, potentially providing indirect evidence regarding the effects of statin intensity.64

This review had limitations. The meta-analysis used the Dersimonian-Laird random-effects model to pool studies, which can result in overly narrow confidence intervals when heterogeneity is present, particularly when there are few studies.16 However, when statistical heterogeneity was present, analyses were repeated using the profile likelihood method, which resulted in similar findings. We did not have access to individual-patient data. An individual-patient data meta-analysis found that the association between use of statins for primary prevention and all-cause mortality did not reach statistical significance (RR, 0.91 [95% CI, 0.83 to 1.01])46 but did not include the recently published, large HOPE-3 trial,14 which reported results consistent with the pooled estimates in this review. Because that meta-analysis had access to individual-patient data, the authors were able to include some trials that we excluded because more than 10% of the population had prior cardiovascular events.65, 66 For trials in which less than 10% of patients had prior cardiovascular events,20, 30, 34 it was also able to separately analyze the patients with no prior cardiovascular events. Excluding these trials from our analyses did not affect the findings. Direct evidence was unavailable or limited on effects of dose titration vs fixed-dose therapy or statin intensity on clinical outcomes. Therefore, this review primarily relied on analyses of placebo-controlled trials stratified according to the use of dose titration or statin intensity. The review also excluded non–English-language articles67, 68 and formally assessed for publication bias only when there were at least 10 studies. Graphical and statistical tests for publication bias are not recommended when there are fewer than 10 studies, because they can be misleading.17 Drugs in the proprotein convertase subtilisin kexin 9 class were outside the scope of this review.

Additional research is needed to directly compare effects of statin therapy to target lipid levels vs fixed-dose therapy and higher- vs lower-intensity statin therapy; to more definitively determine whether statin therapy is associated with increased diabetes or cataract risk; and to determine how statin intensity affects risk. Research is needed to understand benefits and harms of statins in older persons and to compare effects of selection of patients for statin therapy based on global risk assessment scores vs presence of defined cardiovascular risk factors. The validation of cardiovascular risk assessment instruments (with some studies showing overestimation of risk) and research on effects of using newer risk factors to supplement traditional cardiovascular risk assessment is ongoing.7, 69-72

Conclusions

In adults at increased CVD risk but without prior CVD events, statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and CVD events, with greater absolute benefits in patients at greater baseline risk.

Copyright and Source Information

Source: This article was first published in JAMA on November 13, 2016.

Disclaimer: The investigators are solely responsible for the content and the decision to submit the manuscript for publication. The views expressed here do not represent and should not be construed to represent a determination or policy of AHRQ or the U.S. Department of Health and Human Services.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This research was funded under contract No. HHSA2902012000015I from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight; reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

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Table 1. Statin Dosing and American College of Cardiology/American Heart Association Classification of Intensitya

Statin Total Daily Dosage, mg
Low Intensity
(LDL-C Lowering <30%)
Moderate Intensity
(LDL-C Lowering 30% to <50%)
High Intensity
(LDL-C Lowering ≥50%)
Atorvastatin NA 10-20 40-80
Fluvastatin 20-40 Twice daily: 40
Extended release: 80
NA
Lovastatin 20 40 NA
Pitavastatin 1 2-4 NA
Pravastatin 10-20 40-80 NA
Rosuvastatin NA 5-10 20-40
Simvastatin 10 20-40 NA

Abbreviations: LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
a Source: American College of Cardiology/American Heart Association, 2013.4

Figure 1. Analytic Framework and Key Questions

Text Description is below the image.

Text Description.

This figure depicts the analytic framework, which outlines the evidence areas covered in the review, including the population, interventions and related harms, and outcomes. The population includes adults age 40 years and older without prior cardiovascular disease events. An arrow from the population leads to risk assessment, including cardiovascular risk factors and 10-year or lifetime individualized cardiovascular disease risk level. A line representing statin treatment then proceeds from risk assessment to the outcomes examined in the review, which include morbidity or mortality related to coronary heart disease or cerebrovascular accident (stroke) and all-cause mortality. A subsequent arrow from the intervention assesses resulting harms.

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. Further details are available from the USPSTF procedure manual.

CHD indicates coronary heart disease; CVA, cerebrovascular accident (stroke); CVD, cardiovascular disease; KQ, key question.

Figure 2. Literature Flow Diagram

Text Description is below the image.

Text Description.

This figure is a literature flow diagram depicting the search and selection of articles for the review. The diagram shows that 3007 abstracts of potentially relevant articles were identified through MEDLINE and Cochrane databases, while 346 articles were reviewed at the full-text level after excluding 2661 nonrelevant abstracts and background articles. From the 346 articles reviewed for inclusion, 291 were excluded. Articles were excluded due to wrong population (34), wrong population due to >10% history of cardiovascular disease at baseline (38), wrong intervention (8), wrong outcomes (46), wrong study design for key question (39), wrong publication type (45), not English language but possibly relevant (3), in systematic review but not directly used (2), wrong comparison (18), abstract only (2), or using original studies instead (56). After excluding these studies, 21 studies in 55 publications were included that provide evidence for the key questions, as follows: 19 trials for Key Question 1a, 0 trials (direct evidence) for Key Question 1b, 7 trials for Key Question 1c, 17 trials and 2 observational studies for Key Question 2, and 3 trials (direct evidence) for Key Question 3.

CVD indicates cardiovascular disease; KQ, key question.

a Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
b More than 10% of participants with history of CVD at baseline.
c For example, symptomatic prior cardiovascular events; wrong age.
d For example, meta-analysis; compiled study data; data from another publication.
e For example, nonsystematic reviews; letters.
f Studies may be included for more than 1 key question.

Table 2. Study Characteristics of Randomized Clinical Trials of Statins vs Placebo or No Statin

Source Study Quality Inclusion Criteria Duration of Follow-up Statin Intensity Intervention and Comparator
ACAPS
Furberg et al,18 1994
Fair Age 40-79 y
Early carotid atherosclerosis (LDL-C 160-189 mg/dL with 0 or 1 risk factor or LDL-C 130-159 mg/dL with >1 risk factor at baseline or after intensive dietary treatment)
Triglycerides ≤400 mg/dL
3 y Low (20 mg) and moderate (40 mg) Lovastatin (20 mg/d, titrated to 40 mg/d for target LDL-C 90-110 mg/dL) (n = 460)
Placebo (n = 459)
AFCAPS/TexCAPS
Downs et al,19 1998
Fair Age 45-73 y (men) or 55-73 y (women)
TC 180-264 mg/dL
LDL-C 130-190 mg/dL
HDL-C ≤45 mg/dL (men) or ≤47 mg/dL (women) Triglycerides ≤400 mg/dL
Also included patients with LDL-C 125-129 mg/dL if TC:HDL-C ratio >6.0
5 y Low (20 mg) and moderate (40 mg) Lovastatin (20 mg/d, titrated to 20-40 mg/d for target LDL-C ≤110 mg/dL) (n = 3304)
Placebo (n = 3301)
ASCOT-LLA
Sever et al,20 2003
Fair Age 40-79 y
Untreated or treated hypertension
TC ≤251 mg/dL
No current fibrate or statin use
≥3 CVD risk factors
Triglycerides <399 mg/dL
3 y Moderate Atorvastatin (10 mg/d) (n = 5168)
Placebo (n = 5137)
ASPEN
Knopp et al,21 2006
Fair Age 40-75 y
Diabetes
LDL-C <160 mg/dL
4 y Moderate Atorvastatin (10 mg/d) (n = 959b)
Placebo (n = 946b)
ASTRONOMER
Chan et al,22 2010
Good Age 18-82 y
Asymptomatic mild or moderate aortic stenosis (aortic valve velocity, 2.5 to 4.0 m/s)
No clinical indications for statin use (CAD, cerebrovascular disease, peripheral vascular disease, diabetes)
Lipids within target levels for respective risk categories according to Canadian guidelines
4 y High Rosuvastatin (40 mg/d) (n=136)
Placebo (n = 135)
Beishuizen et al,23
2004
Fair Age 30-80 y
Type 2 diabetes duration ≥1 y
No history of CVD
TC 155-267 mg/dL
Triglycerides ≤531 mg/dL
2 y Moderate Cerivastatin (0.4 mg/d; after mean 15 mo, switched to simvastatin [20 mg/d]) (n = 125)
Placebo (n = 125)
Bone et al,24 2007 Fair Women age 40-75 y
LDL-C ≥130 mg/dL and <190 mg/dL
No history of diabetes or CHD
Criteria modified during trial to women with LDL-C ≥160 mg/dL and ≥2 CVD risk factors
1 y Moderate (10-20 mg) and high (40-80 mg) Atorvastatin (10 mg/d)
(n = 118)
Atorvastatin (20 mg/d)
(n = 121)
Atorvastatin (40 mg/d)
(n = 124)
Atorvastatin (80 mg/d)
(n = 122)
Placebo (n = 119)
CAIUS
Mercuri et al,25 1996
Fair Age 45-65 y
LDL-C 150-250 mg/dL
Triglycerides <250 mg/dL
No symptomatic CAD
≥1 carotid artery lesion
3 y Moderate Pravastatin (40 mg/d) (n = 151)
Placebo (n = 154)
CARDS
Colhoun et al,26 2004
Good Age 40-75 y
Diabetes and ≥1 additional risk factor for CHD
No previous CVD events
BMI <35a
HbA1c <12%
SBP <200 mm Hg
DBP <110 mm Hg
Not receiving any other lipid-lowering medication
LDL-C ≤160 mg/dL
Triglycerides ≤600 mg/dL
4 y Moderate Atorvastatin (10 mg/d) (n = 1428)
Placebo (n = 14010)
Heljić et al,27 2009 Poor Obese patients with diabetes, without preexisting CHD
Triglycerides ≤266 mg/dL
States LDL-C used as entry criterion, but values not reported
1 y Moderate Simvastatin (40 mg/d) (n = 45)
Placebo (n = 50)
HOPE-3
Yusuf et al,14 2016
  Men age ≥55 y and women age ≥65 y with ≥1 CV risk factor (elevated waist-hip ratio, low HDL-C, current or recent tobacco use, dysglycemia, family history of premature coronary heart disease, or mild renal dysfunction) or women aged ≥60 y with ≥2 CV risk factors 6 y Moderate Rosuvastatin (10 mg/d)
(n = 6361)
Placebo (n = 6344)
HYRIM
Anderssen et al,28
2005
Fair Men age 40-74 y
Receiving drug treatment for hypertension
TC 174-309 mg/dL
Triglycerides <399 mg/dL
BMI 25-35a
<1 h/wk regular exercise
4 y Low Fluvastatin (40 mg/d) (n = 142)
Fluvastatin (40 mg/d + lifestyle intervention [physical activity plus dietary intervention])
(n = 141)
Placebo (n = 143)
Placebo + lifestyle intervention (n = 142)
JUPITER
Ridker et al,29 2008
Good Men age ≥50 y or women age ≥60 y
No history of CVD
LDL-C <130 mg/dL
CRP ≥2.0 mg/L
Triglycerides <500 mg/dL
2 y Rosuvastatin (20 mg/d) (n = 8901)
Placebo (n = 8901)
High
KAPS
Salonen et al,30 1995
Good Men age 42, 48, 54, or 60 y
LDL-C ≥164 mg/dL
TC <308 mg/dL
BMI <32a
ALT <1.5 ULN
3 y Moderate Pravastatin (40 mg/d)
(n = 224)
Placebo (n = 223)
MEGA
Nakamura et al,31
2006
Fair Age 40-70 y
TC 220-270 mg/dL
No history of CHD or stroke
5 y Low Intensive lipid control with diet + pravastatin (10 mg/d, titrated up to 20 mg/d for target TC <220 mg/dL) (n = 3866)
Standard lipid control with diet only (n = 3966)
METEOR
Crouse et al,32 2007
Fair Men age 45-70 y or women age 55-70 y
LDL-C 120 to <190 mg/dL if age only risk factor, or LDL-C 120 to <160 mg/dL with ≥2 CHD risk factors and 10-y risk of CHD events <10%
HDL-C ≤60 mg/dL
Triglycerides <500 mg/dL
Maximum CIMT 1.2 to <3.5 mm
2 y High Rosuvastatin (40 mg/d)
(n = 702)
Placebo (n = 282)
Muldoon et al,33 2004 Fair Generally healthy men and women age 35 to 70 y
LDL-C 160 and 220 mg/dL

 

6 mo Low (10 mg) and moderate (40 mg) Simvastatin (40 mg/d) (n = 103)
Simvastatin (10 mg/d) (n = 103)
Placebo (n = 102)
PREVEND-IT
Asselbergs et al,34
2004
Fair Age 28-75 y
Persistent microalbuminuria (urine albumin >10 mg/L in 1 early-morning spot sample and 15 to 300 mg/24 h in two 24-h samples)
Blood pressure <160/100 mm Hg and no antihypertensive medication
TC <309 mg/dL or <193 mg/dL if previous MI
No lipid lowering medication
4 y Moderate Pravastatin (40 mg) (n = 433)
Placebo (n = 431)
WOSCOPS
Shepherd et al,35
1995
Good Men age 45 to 64 y
At risk for CAD
TC >251 mg/dL
LDL-C >155 mg/dL with ≥1 value 173-232 mg/dL
No significant CAD
5 y Moderate Pravastatin (40 mg/d) (n = 3302)
Placebo (n = 3293)

Table 2 (continued)

Source Patient Population
Mean Age, y Women, % Race, % Mean Baseline Lipids, mg/dL Risk Factors
ACAPS
Furberg et al,18 1994
62 50 White, 93 LDL-C: 156
HDL-C: 45.8 (men), 58.3 (women)
TC: 235
Triglycerides: 138
Diabetes: 2%
Smoker: 12%
Hypertension: 31%
Mean BMI: 25.9 (men), 25.7 (women)a
AFCAPS/TexCAPS
Downs et al,19 1998
58 15 White, 89 LDL-C: 150
HDL-C: 36
TC: 221
Triglycerides: 158
Diabetes: 3%
Smoker: 12.5%
Mean SBP: 138 mm Hg
Mean DBP: 78 mm Hg
Mean BMI: 27 (men), 26 (women)a
Daily aspirin use: 17%
ASCOT-LLA
Sever et al,20
2003
63 19 White, 95 LDL-C: 131
HDL-C: 50
TC: 212
Triglycerides: 147
LVH: 14%
Other ECG abnormalities: 14%
PVD: 5%
Other CVD: 4%
Diabetes: 25%
Smoker: 33%
Mean BMI: 28.6a
History of stroke or TIA: 10%
Mean risk factors: 4
ASPEN
Knopp et al,21 2006
60 38 White, 84
Black, 7.5
LDL-C: 114
HDL-C: 48
TC: 195
Triglycerides: 145
Diabetes: 100% (duration, 8 y)
Smoker: 13%
Mean SBP: 133 mm Hg
Mean DBP: 77 mm Hg
Mean BMI: 29a
ASTRONOMER
Chan et al,22
2010
58 38 White, 99 LDL-C: 122
HDL-C: 62
TC: 205
Triglycerides: 111
Smoker: 11%
Mean BP: 129/71 mm Hg
Mean BMI: 28a
Beishuizen et al,23 2004 59 53 White, 68
Asian, 19
Other, 13
LDL-C: 135
HDL-C: 48
TC: 215
Triglycerides: 164
Diabetes: 100%
Current smoker: 24%
Hypertension: 51%
Mean BMI: 31.0a
Bone et al,24 2007 59 100 overall White, 88 LDL-C: 157
HDL-C: 54
TC: 243
Triglycerides: 141
Current or former smoker: 47%
CAIUS
Mercuri et al,25 1996
55 47 NR LDL-C: 181
HDL-C: 53
TC: 262
Triglycerides: 138
Smoker: 24%
Mean SBP: 134 mm Hg
Mean DBP: 82 mm Hg
Mean BMI: 25a
Family history of CVD: 45%
CARDS
Colhoun et al,26 2004
62 32 White, 95 LDL-C: 118
HDL-C: 55
TC: 207
Triglycerides: 150 (median)
Diabetes: 100% (mean duration, 8 y)
Smoker: 23%
Mean SBP: 144 mm Hg
Mean DBP: 83 mm Hg
Mean BMI: 29a
Heljić et al,27
2009
61 58 NR LDL-C: 170
HDL-C: 41
TC: 239
Triglycerides: 217
Mean BP: <140/90 mm Hg
Mean BMI: 31.6a
HOPE-3
Yusuf et al,14
2016
66 46 Chinese, 29
Latin, 28
Asian, 21
White, 20
Black, 2
Other, 2
LDL-C: 128
HDL-C: 45
TC: 201
Triglycerides: 128
Diabetes: 6%
IFG or IGT: 13%
Smoker: 28%
Mean SBP: 138 mm Hg
Mean DBP: 82 mm Hg
Hypertension: 38%
Mean BMI: 27a
Family history of early CHD: 26%
Early renal dysfunction: 3%
Elevated waist-hip ratio: 87%
Low HDL-C: 36%
HYRIM
Anderssen et al,28 2005
57 0 NR LDL-C: 150
HDL-C: 49
TC: 230
Triglycerides: 158
Smoker: 16%
Mean SBP: 141 mm Hg
Mean DBP: 88 mm Hg
Mean BMI: 29a
Median CRP: 2.0 mg/L
JUPITER
Ridker et al,29 2008
66 (median, each group) 39 White, 71
Black, 13
Hispanic, 13
Other, 4
LDL-C: 108 (median, each group)
HDL-C: 49 (median, each group)
TC: 186 (median, intervention group); 185 (median, placebo group)
Triglycerides: 118 (median, each group)
HbA1c: 5.7% (median, each group)
Smoker: 16%
BP: 134/80 mm Hg (median, each group)
BMI: 28 (median, each group)a
CRP: 4.2 mg/L (median, intervention group); 4.3 mg/L (median, placebo group)
Family history of CHD: 12%
Metabolic syndrome: 42%
Daily aspirin use: 17%
KAPS
Salonen et al,30 1995
58 0 NR LDL-C: 189
HDL-C: 46
TC: 259
Triglycerides: 151
Prior MI: 7.5%
Diabetes: 2.5%
Current smoker: 27%
Hypertension: 33%
MEGA
Nakamura et al,31 2006
58 69 NR LDL-C: 157
HDL-C: 58
TC: 242
Triglycerides: 128
Diabetes: 21%
Smoker: 21%
Hypertension: 42%
Mean BMI: 24a
METEOR
Crouse et al,32 2007
57 40 White, 60 LDL-C: 155
HDL-C: 50
TC: 229
Triglycerides: 128
Smoker: 3.9%
Hypertension: 20%
BMI >30a: 20%
Family history of CHD: 9.6%
Metabolic syndrome: 15%
≥2 Risk factors: 34%
Muldoon et al,33 2004 54 52 White, 86 LDL-C: 181
HDL-C: 51
TC: 263
Triglycerides: 151
NR
PREVEND-IT
Asselbergs et al,34 2004
52 35 White, 96 LDL-C: 157
HDL-C: 39
TC: 224
Triglycerides: 120
Prior CVD event: 3% (MI, 0.4%)
Diabetes: 3%
Smoker: 40%
Mean SBP: 131 mm Hg
Mean DBP: 77 mm Hg
Mean BMI: 26a
Use of aspirin and antiplatelet agents: 2.5%
WOSCOPS
Shepherd et al,35 1995
55 0 NR LDL-C: 192
HDL-C: 44
TC: 272
Triglycerides: 163
Smoker: 44%
Mean SBP: 136 mm Hg
Mean DBP: 84 mm Hg
Mean BMI: 26a

Abbreviations: ACAPS, Asymptomatic Carotid Artery Progression Study; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALT, alanine aminotransferase; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non–insulin Dependent Diabetes Mellitus; ASTRONOMER, Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CAIUS, Carotid Atherosclerosis Italian Ultrasound Study; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, coronary heart disease; CIMT, carotid intima-media thickness; CRP, C-reactive protein; CVD, cardiovascular disease; DBP, diastolic blood pressure; ECG, electrocardiogram; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOPE, Heart Outcomes Prevention Evaluation; HYRIM, Hypertension High Risk Management; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; KAPS, Kuopio Atherosclerosis Prevention Study; LDL-C, low-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; METEOR, Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin; MI, myocardial infarction; PREVEND-IT, Prevention of Renal and Vascular Endstage Disease Intervention Trial; PVD, peripheral vascular disease; SBP, systolic blood pressure; TC, total cholesterol; TIA, transient ischemic attack; ULN, upper limit of normal; WOSCOPS, West of Scotland Coronary Prevention Study Group.

SI conversion factors: To convert HDL-C, LDL-C, and total cholesterol values to mmol/L, multiply by 0.0259; to convert triglyceride values to mmol/L, multiply by 0.0113.

a Calculated as weight in kilograms divided by height in meters squared.
b Primary prevention patients only.

Figure 3. Meta-Analysis: Statins vs Placebo and All-Cause Mortality, Cardiovascular Mortality, and Incident Diabetes

A. All-cause mortality

Study Follow-up, y Statins Control Risk Ratio (95% CI) Weight in Analysis, %
Patients With Events, No. / Total (%) Patients With Events, No. / Total (%)
ACAPS,18 1994 3 1/460 (0.22) 8/459 (1.7) 0.12 (0.02-0.99) Figure is is a forest plot for Meta-Analysis: Statins Versus Placebo on All-Cause Mortality. Risk ratios were reported or calculated for 15 studies, with a pooled risk ratio of 0.86 (95% confidence interval, 0.80 to 0.93) and an overall I-squared value of 0%. 0.2
AFCAPS/TexCAPS,19 1998 5 80/3304 (2.4) 77/3301 (2.3) 1.04 (0.76-1.41) 9.5
ASCOT-LLA,20 2003 3 185/5168 (3.6) 212/5137 (4.1) 0.87 (0.71-1.05) 24.3
ASPEN,21 2006 4 44/959 (4.6) 41/946 (4.3) 1.06 (0.70-1.60) 5.3
Beishuizen et al,23 2004 2 3/103 (2.9) 4/79 (5.1) 0.58 (0.13-2.50) 0.4
Bone et al,24 2007 1 0/485 (0) 0/119 (0) Not estimable  
CARDS,26 2004 4 61/1428 (4.3) 82/1410 (5.8) 0.73 (0.53-1.01) 8.7
HOPE-3,14 2016 6 334/6361 (5.3) 357/6344 (5.6) 0.93 (0.81-1.08) 30.2
HYRIM,28 2005 4 4/283 (1.4) 5/285 (1.8) 0.81 (0.22-2.97) 0.5
JUPITER,29 2008 2 198/8901 (2.2) 247/8901 (2.8) 0.80 (0.67-0.96) 26.7
KAPS,30 1995 3 4/214 (1.9) 3/212 (1.4) 1.32 (0.30-5.83) 0.4
MEGA,31 2006 5 55/3866 (1.4) 79/3966 (2.0) 0.71 (0.51-1.00) 7.8
METEOR,32 2007 2 1/700 (0.14) 0/281 (0) 1.21 (0.05-29.5) 0.1
Prevend-IT,34 2004 4 13/433 (3.0) 12/431 (2.8) 1.08 (0.50-2.34) 1.5
WOSCOPS,35 1995 5 106/3302 (3.2) 135/3293 (4.1) 0.78 (0.61-1.01) 14.6
Total (95% CI)   1089/35 967 (3.0) 1262/35 164 (3.6) 0.86 (0.80-0.93) 100.0

Heterogeneity: τ2 = 0.00; χ213 = 11.07 (P = 0.60); I2 = 0.
Test for overall effect: Z = 3.63 (P <0.003)

B. Cardiovascular mortality

Study Follow-up, y Statins Control Risk Ratio (95% CI) Weight in Analysis, %
Patients With Events, No. / Total (%) Patients With Events, No. / Total (%)
ACAPS,18 1994 3 0/460 (0) 6/459 (1.3) 0.08 (0.004-1.36) is a forest plot for Meta-Analysis: Statins Versus Placebo on Cardiovascular mortality. Risk ratios were reported or calculated for 10 studies, with a pooled risk ratio of 0.69 (95% confidence interval, 0.54 to 0.88) and an overall I-squared value of 0%. 0.8
AFCAPS/TexCAPS,19 1998 5 17/3304 (0.51) 25/3301 (0.76) 0.68 (0.37-1.26) 12.1
ASCOT-LLA,20 2003 3 74/5168 (1.4) 82/5137 (1.6) 0.90 (0.66-1.23) 23.1
ASTRONOMER,22 2010 4 2/103 (1.9) 12/79 (15.2) 0.13 (0.03-0.55) 3.0
HOPE-3,14 2016 6 154/6361 (2.4) 171/6344 (2.7) 0.90 (0.72-1.11) 21.3
JUPITER,29 2008 2 83/8901 (0.93) 157/8901 (1.8) 0.53 (0.41-0.69) 25.4
KAPS,30 1995 3 2/214 (0.93) 2/212 (0.94) 0.99 (0.14-6.97) 1.8
MEGA,31 2006 5 11/3866 (0.28) 18/3966 (0.45) 0.63 (0.30-1.33) 9.3
Prevend-IT,34 2004 4 4/433 (0.92) 4/431 (0.93) 1.00 (0.25-3.95) 3.4
WOSCOPS,35 1995 5 50/3302 (1.5) 73/3293 (2.2) 0.68 (0.48-0.98) 21.1
Total (95% CI)   397/32 112 (1.2) 550/32 123 (1.7) 0.69 (0.54-0.88) 100.0

Heterogeneity: τ2 = 0.06; χ29 = 19.46 (P = 0.02); I2 = 54%.
Test for overall effect: Z = 3.00 (P = 0.003)

C. Incident diabetes

Study Follow-up, y Statins Control Risk Ratio (95% CI) Weight in Analysis, %
Patients With Events, No. / Total (%) Patients With Events, No. / Total (%)
AFCAPS/TexCAPS,19 1998 5 72/3094 (2.3) 74/3117 (2.4) 0.98 (0.71-1.35) is a forest plot titled Meta-Analysis: Statins Versus Placebo on Incident diabetes. Risk ratios were reported or calculated for 6 studies, with a pooled risk ratio of 1.05 (95% confidence interval, 0.91 to 1.20) and an overall I-squared value of 0%. 15.7
ASCOT-LLA,20 2003 3 154/5168 (3.0) 134/5137 (2.6) 1.14 (0.91-1.44) 21.4
HOPE-3,14 2016 6 232/6361 (3.6) 226/6344 (3.6) 1.02 (0.86-1.23) 20.9
JUPITER,29 2008 2 270/8901 (3.0) 216/8901 (2.4) 1.25 (1.05-1.49) 25.2
MEGA,31 2006 5 172/3013 (5.7) 164/3073 (5.3) 1.07 (0.87-1.32) 22.8
WOSCOPS,35 1995 5 57/2999 (1.9) 82/2975 (2.8) 0.69 (0.49-0.96) 15.0
Total (95% CI)   957/29 536 (3.2) 896/29 547 (3.0) 1.05 (0.91-1.20) 100.0

Heterogeneity: τ2 = 0.02; χ2 = 10.46 (P = 0.06); I2 = 52%.
Test for overall effect: Z = 0.64 (P = 0.52)

Size of data markers indicates weight of study in the pooled analysis.

Table 3. Summary of Evidence, Adults Aged ≥40 Years Without Prior CVD Events

No. of Studies and Study Design Sample Size Summary of Findings Consistencya Applicability Limitations Overall Quality
Key Question 1a: Benefits
19 RCTs Total: n = 71,344
All-cause mortality: n = 71,131
CV mortality: n = 65,235
Stroke: n = 62,863
MI: n = 68,537
Revascularization: n = 54,803
Composite CV outcomes: n = 69,215
In adults at increased CV risk but without prior CVD events, statins were associated with reduced risk of: All-cause mortality (15 trials; RR, 0.86 [0.80-0.93]; I2 = 0%; ARD, −0.40%; NNT, 250)
CV mortality (10 trials; RR, 0.69 [95% CI, 0.54-0.88]; I2 = 54%; ARD, −0.43%; NNT, 233)
Stroke (13 trials; RR, 0.71 [95% CI, 0.62-0.82]; I2 = 0%; ARD, −0.38%; NNT, 263)
MI (12 trials; RR, 0.64 [95% CI, 0.57-0.71]; I2 = 0%; ARD, −0.81%; NNT, 123)
Revascularization (7 trials; RR, 0.63 [95% CI, 0.56-0.72]; I2 = 0%; ARD, −0.66%; NNT, 152)
Composite CV outcomes (13 trials; RR, 0.70 [95% CI, 0.63-0.78]; I2 = 36%; ARD, −1.39%; NNT, 72)
Findings were robust in sensitivity analysis based on quality, duration of follow-up, mean lipid levels at baseline, and other factors.
Consistent High applicability to US primary care settings
All studies enrolled participants with ≥1 CVD risk factor; 3 studies included <10% of study participants with prior CVD events
Only 1 study with duration >5 y; variability in inclusion criteria, statins therapy, and outcomes assessed
Quality: 6 good-quality trials, 12 fair-quality trials, 1 poor-quality trial
Estimates precise
Good
Key Question 1b: Treating to Target vs Fixed-Dose Statin Therapy
No studies (direct)
19 RCTs (indirect)
n = 71,344 No study directly compared treatment with statins titrated to attain target cholesterol levels vs other treatment strategies.
There were no clear differences in risk of all-cause or cardiovascular mortality, MI, or stroke between 3 trials of statins vs placebo or no statin that permitted limited dose titration of statins and 16 trials of fixed-dose statin therapy.
Consistent High applicability to US primary care settings No direct evidence
Limited indirect evidence from 3 trials of statin vs placebo that permitted dose titration.
Quality: See key question 1a
Estimates precise
Poor
Key Question 1c: Subgroups
7 RCTs Total: n = 64,682
Sex: n = 58,087
Age: n = 64,682
Race: n = 30,507
Baseline lipids: n = 46,880
CV risk score: n = 37,112
Baseline hypertension: n = 38,339
Renal dysfunction: n = 16,910
Diabetes: n = 18,137
Metabolic syndrome: n = 28,107
7 trials found no clear differences in relative risk estimates associated with statin therapy vs placebo or no statin in subgroups defined by demographic and clinical factors, although absolute benefits were greater in higher-risk groups. Consistent High applicability to US primary care settings
Study participants were primarily white race with little age variation (range, 51 y to 66 y)
Limited evidence on specific clinical outcomes in subgroups
Quality: 4 good-quality trials, 3 fair-quality trials
Estimates precise
Fair
Key Question 2: Harms
17 RCTs and 2 observational studies Total: n = 81,765 (n = 69,755 in RCTs)
Withdrawal due to adverse events: n = 33,589
Serious adverse events: n = 41,804
Any cancer: n = 55,554
Myalgia: n = 35,607
Elevated aminotransferase: n= 44,936
Diabetes: n = 59,083
Evidence from trials found statin therapy was not associated with increased risk of:
Withdrawal due to adverse events (9 trials; RR, 0.95 [95% CI, 0.75-1.21]; I2 = 86%)
Serious adverse events (7 trials; RR, 0.99 [95% CI, 0.94-1.04]; I2 = 0%)
Cancer (10 trials; RR, 1.02 [95% CI, 0.90-1.16]; I2 = 43%)
Diabetes (6 trials; RR, 1.05 [95% CI, 0.91-1.20]; I2 = 52%)
Myalgia (7 trials; RR, 0.96 [95% CI, 0.79-1.16]; I2 = 42%)
Elevated transaminases (11 trials; RR, 1.10 [95% CI, 0.90-1.35]; I2 = 0%)
Evidence on the association between statins and renal or cognitive harms was sparse but did not clearly indicate increased risk.
Evidence from observational studies was mixed on risk of incident diabetes with statin use (adjusted OR, 1.01 [95% CI, 0.80-1.4] and adjusted HR, 1.48 [95% CI, 1.38-1.59]).
Consistent High applicability to US primary care settings
All studies enrolled participants with ≥2 CVD risk factors; most trials assessed moderate-potency statins
Harms are often inconsistently reported; only one study with duration >5 y
Quality: 6 good-quality trials, 11 fair-quality trials
Estimates precise
Good
Key Question 3: Statin Potency
2 RCTs (direct); 12 RCTs (indirect) n = 912 (direct)
n = 59,050 (indirect)
Two trials of statin therapy at different intensities were underpowered to evaluated clinical outcomes.
Based on trials of statins vs placebo or no statin, risk estimates for all-cause mortality were similar in trials of low-intensity (2 trials; RR, 0.72 [95% CI, 0.52-1.00]; I2 = 0%), moderate-intensity (8 trials; RR, 0.88 [95% CI, 0.80-0.97]; I2 = 0%), and high-intensity (2 trials; RR, 0.80 [95% CI, 0.67-0.97]; I2 = 0) statins.
For other clinical outcomes, there were too few trials of low- and high-intensity statins to conduct meaningful comparisons.
Consistent High applicability to US primary care settings
Of 2 trials providing direct evidence, 1 was conducted in women and the other in people with early CVA at baseline.
Two trials that directly compared different intensities of statin therapy were underpowered and only reported incidence of CVA.
Too few trials of low- and high-intensity statins to evaluate differences in most clinical outcomes based on indirect evidence.
Quality: 5 good-quality trials, 8 fair-quality trials, 1 poor-quality trial
Estimates precise
Fair

Abbreviations: CHD, coronary heart disease; CV, cardiovascular; CVA, cerebrovascular accident (stroke); CVD, cardiovascular disease; HR, hazard ratio; MI, myocardial infarction; NA, not applicable; NNT, number needed to treat; OR, odds ratio; RCT, randomized clinical trial; RR, relative risk.

a Studies were considered consistent if the I2 value was less than 30% or was 30% to 60% but more than 75% of studies reported estimates in the same direction.

Current as of: November 2016

Internet Citation: Evidence Summary: Statins for Prevention of Cardiovascular Disease in Adults: Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication. U.S. Preventive Services Task Force. November 2016.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary-statins/statin-use-in-adults-preventive-medication1

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