Evaluation of Time to Benefit of Statins for the Primary Prevention of Cardiovascular Events in Adults Aged 50 to 75 Years: A Meta-analysis

The American Heart Association (AHA), American College of Cardiology (ACC), and the US Preventive Services Task Force (USPSTF) all recommend hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) for primary prevention of cardiovascular events in adults aged 40 to 75 years who have an elevated risk (most often defined as ≥7.5% risk of major adverse cardiovascular event [MACE] within 10 years).

[..] Although the benefits of statins to decrease cardiovascular events such as myocardial infarction and stroke have been well documented for adults younger than 75 years, when these benefits occur is unclear. In contrast, the burdens of statins appear to occur relatively quickly. The most commonly reported adverse effect of statins is myalgia, which in some observational studies is reported by as many as 30% of patients within weeks of starting therapy.

[..] we only included randomized clinical trials with a mean patient age of older than 55 years. Given our focus on primary prevention, we focused on trials in which less than 15% of participants had known preexisting cardiovascular disease. In addition, we focused on larger trials (>1000 participants) and trials rated as high or moderate quality by Cochrane and USPSTF criteria.

[..] These short-term potential burdens and harms of statins, both perceived and real, highlight the importance of individualizing statin therapy so that it is preferentially targeted to the patients who are most likely to live long enough to also experience its benefits. Lee et al previously proposed a framework for individualizing prevention decisions in older adults that focuses on a patient’s life expectancy and the intervention’s time to benefit (TTB). Older adults with a limited life expectancy (usually defined as less than an intervention’s TTB) should avoid preventive interventions with an extended TTB, because these older adults would be exposed to the up-front harms and burdens of the intervention with little chance that they survive to experience the benefit. Although many indexes to predict life expectancy for older adults have been validated and are available through websites such as ePrognosis (ePrognosis.ucsf.edu), the TTB of statins for the primary prevention of MACEs is unclear.

We identified 8 randomized clinical trials that met our inclusion criteria (65,383 participants; 33.7% women and 66.3% men). The trials ranged in size from 1129 to 17,802 participants.

[..] Follow-up duration ranged from 2 to 6 years, and the ARR of MACE varied from 0.4% (95% CI, −2.4% to 3.1%) in the ASPEN study to 3.9% (95% CI not available) in the CARDS study. One study (JUPITER) reported that statins decreased all-cause mortality; a second study (WOSCOPS) reported that statins decreased cardiovascular mortality. No other study found that statins decreased mortality.

[..] We determined that 2.5 (95% CI, 1.7-3.4) years were needed to prevent 1 MACE per 100 adults aged 50 to 75 years treated with a statin (ARR = 0.010). Similarly, 200 adults aged 50 to 75 years would need to be treated with a statin for 1.3 (95% CI, 1.0-1.7) years to avoid 1 MACE (ARR, 0.005), and 500 adults aged 50 to 75 years would need to be treated with a statin for 0.8 (95% CI, 0.5-1.0) years to avoid 1 MACE (ARR, 0.002).

[..] although the pooled time to prevent 1 MACE for 100 persons treated (ARR = 0.010) was 2.5 (95% CI, 1.7-3.4) years, the TTB for individual trials ranged from 1.4 (95% CI, 0.5-3.4) years in the CARDS study to 6.5 (95% CI, 3.2-11.8) years in the MEGA study. Statistical tests for heterogeneity demonstrated that variation in the effect estimates between different studies at each ARR threshold were likely due to chance (P = .90 at ARR = 0.002, P = .71 at ARR = 0.005, and P = .15 at ARR = 0.010), and our measure of inconsistency showed that the percentage of variability in effect estimates due to heterogeneity was low to moderate (I2 = 0 at ARR = 0.002 and 0.005 and 34.3% at ARR = 0.010).

In this survival meta-analysis, the TTB to prevent 1 MACE for 100 adults aged 50-75 years treated with statins was 2.5 years. These results suggest that statins are most likely to benefit adults aged 50-75 years with a life expectancy of greater than 2.5 years and less likely to benefit those with a life expectancy of less than 2.5 years. In fact, because the potential harms of statins occurs within weeks, whereas the benefits take years, adults aged 50 to 75 years with a life expectancy of less than 2.5 years may be more likely to be harmed than helped by statin therapy.

[..] Holmes and colleagues conducted a systematic review of statin randomized controlled trials, focusing on TTB for all-cause mortality. Similar to our mortality findings, they found only 2 of 8 trials showed all-cause mortality benefit. In the 2 trials that did show benefit, the authors determined the TTB through visual observation of curve separation at 1.5 years for the ACAPS study and 2.5 to 3.0 years for the JUPITER study. Our study’s focus on MACE makes a direct comparison challenging. However, the relative similarity in TTB estimates from the study by Holmes et al31 and our study supports the general conclusion that it takes approximately 1.5 to 3.0 years for the benefits of statin therapy to be seen.”

Full article, Yourman LC, Cenzer IS, Boscardin WJ et al. JAMA Internal Medicine 2020.11.16