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Genetic Risk, CHD Events, and Statin Benefit: Analysis of Prevention Trials | Journal Scan
Study Questions:
Will a composite of genetic variants ascertain the risk of both incident and recurrent coronary heart disease (CHD) events and identify those individuals who derive greater clinical benefit from statin therapy?
Methods:
The study was conducted in a community-based cohort study (the Malmo Diet and Cancer Study) and four randomized controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy. A total of 48,421 individuals and 3,477 events were included in these analyses. Data were combined from the different studies using a meta-analysis. A genetic risk score was developed based on 27 genetic variants with incident or recurrent CHD, adjusting for traditional clinical risk factors. The primary endpoint was the relative and absolute risk reductions in CHD events with statin therapy stratified by genetic risk.
Results:
When individuals were divided into low, intermediate, and high genetic risk, a significant gradient in risk for incident or recurrent CHD was shown. Compared with low genetic risk, the multivariable-adjusted hazard ratio for CHD for the intermediate genetic risk category was 1.34, and that for the high genetic risk category was 1.72 (both p < 0.0001). In terms of the benefit of statin therapy in the four randomized trials, there was a significant gradient of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, there were greater absolute risk reductions in those individuals in higher genetic risk categories (p = 0.0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one CHD event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in the JUPITER trial, and 57, 47, and 20, respectively, in the ASCOT trial.
Conclusions:
A genetic risk score identified individuals at increased risk for both incident and recurrent CHD events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy.
Perspective:
While genetic variants, lifestyle, and their interaction account for a great deal of the variation in CHD risk, the findings have not yet shown to be clinically useful. This remarkable and important study was gleaned from unique cooperation between the authors who are geneticists, epidemiologists, and clinical trialists. Genetics might provide additional power to standard clinical, biochemical, and imaging for selection of populations for lipid and other strategies for CHD, particularly the high-cost novel agents such as the PCSK9 inhibitors.
Keywords: Cohort Studies, Coronary Disease, Coronary Artery Disease, Genes, Neoplasm, Genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Life Style, Numbers Needed To Treat, Primary Prevention, Risk, Risk Factors, Secondary Prevention
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