LAUSR

In the US, more than 126 million adults have been diagnosed with cardiovascular disease (CVD).1 Reducing the morbidity and mortality associated with CVD is a public health imperative. Accordingly, considerable resources and effort have been invested in determining not only how to effectively treat symptomatic coronary artery disease or ischemic stroke, but also on prevention of clinical CVD. Although elevated lowdensity lipoprotein (LDL) is associated with higher rates of CVD,2 there is uncertainty regarding the net benefit to risk ratio of using statins to reduce LDL among persons without CVD (primary prevention). This contrasts with the established role of LDL reduction for persons with established CVD (secondary prevention). The US Preventive Services Task Force (USPSTF) has updated its 2016 recommendations on the use of statins for the primary prevention of clinical CVD.3 Two of us (M.H.K. and R.F.R.) wrote about the 2016 recommendations,4 and in this Editorial we update our comments for the 2022 recommendations.5 The 2022 recommendations seem largely unchanged from the 2016 recommendations.3,5 For individuals aged 40 to 75 years without clinical CVD, with LDL lower than 190 mg/dL, and without known familial hypercholesterolemia, the USPSTF makes 3 recommendations. First, the Task Force concludes with moderate certainty that those with an estimated 10-year CVD event risk of 10% or higher based on the American College of Cardiology/American Heart Association pooled cohort equations (PCEs) and at least 1 risk factor— dyslipidemia (LDL of >130 mg/dL or high-density lipoprotein of <40 mg/dL), diabetes, hypertension, and/or smoking—are likely to derive moderate benefit (B recommendation) from initiation of a moderate-intensity statin (lowers LDL by 30%49% on average). Second, the Task Force concludes with moderate certainty that those with an estimated 10-year CVD event risk of 7.5% to less than 10% and at least 1 risk factor are likely to experience small net benefit (C recommendation) from initiation of a moderate-intensity statin, and thus clinicians should engage patients in shared decision-making. Third, the Task Force concludes that there is insufficient evidence (I statement) to fully assess the net harms and benefits of initiating statins in adults 76 years and older, regardless of estimated 10-year CVD event risk or presence of risk factors. The details of the updated recommendations merit further consideration.5 The systematic review6 that accompanies the 2022 USPSTF recommendations examined 22 randomized clinical trials (RCTs; n = 90 624 participants) that compared statin therapy vs placebo or no statin, with a mean follow-up duration of 3 years. The systematic review examined the clinical end points of all-cause mortality, CVD mortality, fatal/nonfatal myocardial infarction, and fatal/ nonfatal stroke among those with a mean age of 52 to 66 years, except for 1 trial that only enrolled older individuals between 70 and 82 years of age (Table6,7). The updated evidence synthesis6 found that statins yielded a slightly smaller, but still statistically significant, reduction in all-cause mortality (pooled relative risk, 0.92; 95% CI, 0.870.98), as well as for myocardial infarction and stroke (Table). The USPSTF recommendations should be considered in the context of a meta-analysis, published in 2010,8 which included only trials that enrolled patients receiving high-risk primary prevention; this study showed no benefit on all-cause mortality with statins. The benefit for CVD mortality was not statistically significant (pooled relative risk, 0.91; 95% CI, 0.811.02). Notably, there was no significant statistical heterogeneity (I2 = 0) across the 12 trials (n = 75 138) examined. The null result was robust in sensitivity analyses that excluded trials that stopped early, trials that included patients receiving secondary prevention, good-quality trials, trials with at least 3 years of follow-up, and trials with participants with a median baseline LDL lower than 160 mg/dL.6 The lack of benefit on CVD mortality found in the 2022 evidence review6 and the lack of benefit on all-cause mortality in the purely high-risk primary prevention meta-analysis8 call into question the reliability of the all-cause mortality benefit reported in the sys-