Background: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in the United States. A 2016 review for the US Preventive Services Task Force (USPSTF) found statin therapy associated with decreased risk of all-cause and cardiovascular mortality and CVD events in adults at increased CVD risk but without prior CVD events.
Purpose: To update the 2016 review on statins for primary prevention in adults to inform an updated USPSTF recommendation.
Data Sources: We searched the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE, from May, 2016 to November 12 2021, and reference lists; with surveillance through May 20, 2022.
Study Selection: Randomized controlled trials (RCTs) on the benefits and harms of statin therapy versus placebo or no statin and large cohort studies on harms of statin therapy in adults without prior cardiovascular events.
Data Extraction: One investigator abstracted data and a second investigator checked data abstraction for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF.
Data Synthesis (Results): 22 trials (N=90,624) with followup from 6 months to 6 years compared statin therapy versus placebo or no statin, one additional trial compared statins of different intensities (N=5,144) and three cohort studies (N=417,523) cohort study reported harms. Compared to the 2016 USPSTF review, additional data were available from three trials (1 new trial and 2 older trials that reported results for the primary prevention population) and one large cohort study (n=261,032). Statin therapy was associated with decreased risk of all-cause mortality (relative risk [RR] 0.92, 95% confidence interval [CI], 0.87 to 0.98; absolute risk difference [ARD], −0.35%; number needed to treat [NNT] 286), stroke (RR 0.78, 95% CI, 0.68 to 0.90; ARD −0.39%; NNT 256), myocardial infarction (RR 0.67, 95% CI, 0.60 to 0.75; ARD −0.85%; NNT 118), and composite cardiovascular outcomes (RR 0.72, 95% CI, 0.64 to 0.81; ARD −1.28%; NNT 78); though the estimate for all-cause mortality was mildly attenuated compared to the 2016 USPSTF review. With the inclusion of additional data, the estimate for cardiovascular mortality was no longer statistically significant (RR 0.91, 95% CI, 0.81 to 1.02; ARD −0.13%; NNT 769). Overall, relative benefits appeared to be consistent in groups defined by demographic and clinical characteristics, including populations with cardiovascular risk factors without marked dyslipidemia. Data for older persons remains sparse and imprecise, particularly for persons >75 years of age. Statin therapy was not associated with significantly increased risk of serious adverse events (RR 0.97, 95% CI, 0.93 to 1.01), myalgia (RR 0.98, 95% CI, 0.86 to 1.11), or liver-related harms (RR 0.94, 95% CI, 0.78 to 1.13). Statin therapy was not associated with increased risk of diabetes (RR 1.04, 95% CI, 0.92 to 1.19), though statistical heterogeneity was present (I2=52%), and one trial found that high-intensity statins were associated with increased risk (RR 1.25, 95% CI, 1.05 to 1.49). Otherwise, there were no clear differences in benefits or harms based on intensity of statin therapy.
Limitations: Restricted to English language, statistical heterogeneity in some pooled analyses, methodological limitations in some trials, and limited ability to assess for publication bias.
Conclusions: In adults at increased CVD risk but without prior CVD events, statin therapy is associated with reduced risk of all-cause mortality and CVD events; with the inclusion of additional data, effects on cardiovascular mortality are not statistically significant. Benefits of statin therapy appear to be present across diverse demographic and clinical populations, with greater absolute benefits in patients at higher baseline risk, and do not appear to be restricted to patients with marked dyslipidemia.