Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment

Abstract

IMPORTANCEThe association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of individual, rather than composite, outcomes, such as all-cause mortality, myocardial infarction, or stroke, is unclear.OBJECTIVE To assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy.DATA SOURCES PubMed and Embase were searched to identify eligible trials from January 1987 to June 2021.STUDY SELECTION Large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes with a planned duration of 2 or more years and that reported absolute changes in LDL-C levels. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care. Participants were men and women older than 18 years.DATA EXTRACTION AND SYNTHESIS Three independent reviewers extracted data and/or assessed the methodological quality and certainty of the evidence using the risk of bias 2 tool and Grading of Recommendations, Assessment, Development and Evaluation. Any differences in opinion were resolved by consensus. Meta-analyses and a meta-regression were undertaken. MAIN OUTCOMES AND MEASURESPrimary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke.FINDINGS Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 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 those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive. CONCLUSIONS AND RELEVANCEThe results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Absolute and relative benefits of statins

“…A systematic review and meta-analysis analysed outcomes from 21 trials that examined the effect of statins on total mortality, cardiovascular outcomes and stroke in adults compared with placebo or usual care 1. Eligible studies had to include >1000 participants, last longer than 2 years and report absolute changes in low-density lipoprotein cholesterol (LDL-C) levels.…”

“…Based on combined data from primary and secondary prevention studies, the ARR was 0.8% and the RRR was 9% for all-cause mortality (19 trials, 132 763 participants; moderate to low certainty) 1. For MI (18 trials, 121 190 participants; moderate certainty), the ARR was 1.3% and the RRR was 29%.…”

“…A meta-regression analysis to determine the association of LDL reduction with these outcomes was inconclusive 1. However, when this analysis was adjusted for event rates, study population or follow-up time, there were some associations seen, but they were inconsistent.…”

“…Healthcare professionals are advised to use absolute reductions in risk and baseline risk in discussions with patients about the risks and benefits of long-term statin treatment 1…”

Study questions relationship between statins and cardiovascular outcomes

“…The relationship between the amount that statins reduce low density lipoprotein cholesterol (LDL-C) levels—sometimes referred to as bad cholesterol—and the risk of death, heart attack, and stroke is “weak or inconsistent,” a review has suggested 1…”