Absolute Benefits of Statins Cautioned Due To Significant Heterogeneity

Paula Byrne, PhD

A recent meta-analysis found inconclusive and inconsistent findings in regards to the association between the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction due to treatment with statins and all-cause mortality, myocardial infarction, or stroke.

Data show a modest benefit in the absolute risk reduction of statins compared with the relative risk reductions, with investigators noting the benefits should be interpreted with caution due to the presence of significant heterogeneity.

Led by Paula Byrne, PhD, HRB Centre for Primary Care Research, RCSI University of Medicine and Health Sciences, investigators searched PubMed and EMBASE in September 2020 and updated the search in June 2021 to identify eligible trials for the study.

Any randomized clinical trial examined the efficacy of statins on total mortality and cardiovascular outcomes and stroke in adults, had a planned duration of 2 years or longer, had an enrollment of more than 1000 participants, and reported absolute changes in LDL-C levels.

The study conducted a subgroup meta-analysis for each of the outcomes by study population and used the LDL-C absolute difference as an explanatory variable in a random-effects meta-regression analysis of the treatment effect for each study.

From 275 studies eligible for title and abstract screening, 36 studies (13.1%) were selected for full-text review and 15 (41.7%) were excluded, leaving a total of 21 studies included in the review.

The included trials consisted of an equal distribution between primary prevention trials (n = 7 [33%]), secondary prevention trials (6 [29%]), and trials that included participants from primary and secondary prevention populations (n = 8 [38%]). From those, the meta-analysis was conducted on 19 of 21 trials that reported data on all-cause mortality and 18 trials reporting data on myocardial infarction and stroke.

The absolute risk reduction was 0.8% (95% CI, 0.4% - 1.2%) for all-cause mortality, 1.3% (95% CI, 0.9% - 1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2% - 0.6%) for stroke in patients randomized to statin treatment.

Further, the associated relative risk reduction was 9% (95% CI, 5% - 14%) for all-cause mortality, 29% (95% CI, 22% - 34%) for myocardial infarction, and 14% (95% CI, 5% - 22%) for stroke.

Additionally, a meta-regression explored the potential mediating association of LDL-C reduction with relative and absolute treatment effects. Investigators found the results were inconclusive, with the proportion of between-study variance explained by LDL-C ranging from 0% - 14. This showed little association between the magnitude of LDL-C reduction and size of the treatment effect.

Investigators observed inconsistent associations between the magnitude of LDL-C reduction and size of treatment effects on clinical outcomes in exploratory meta-regression adjusted for controle event rates and length of follow-up.

Some association was found for the relative effects on all-cause mortality and stroke, but not for myocardial infarction. Similarly, some association was found between the magnitude of LDL-C reduction and size of the absolute treatment effect on stroke, but not for all-cause mortality or myocardial infarction.

“The transparent communication of [relative risk reduction] and [absolute risk reduction] by clinicians, as well as the potential for harm, to their patients may lead to more informed decision-making about the true benefits and risks of statins,” wrote Byrne.

The study, “Evaluating the Association between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment,” was published in JAMA Internal Medicine.