Key result
High genetic risk score linked to ~71% higher CHD risk, with greatest benefit from statins.
Why the study?
Genetic variants have been associated with CHD risk, but their ability to identify risk and predict statin therapy benefit for incident and recurrent CHD events was unclear.
Does the clinical benefit of statin therapy vary by genetic risk score in individuals undergoing primary and secondary prevention for coronary heart disease?
Meta-Analysis (n=48,421)
Yes
Does the clinical benefit of statin therapy vary by genetic risk score in individuals undergoing primary and secondary prevention for coronary heart disease?
Hazard Ratio: 1.71 (95% CI 1.54–1.91)
p-value: p=<0.0001
A multilocus genetic risk score can help identify individuals at heightened risk for CHD who will derive substantially greater absolute and relative clinical benefit from statin therapy, which could refine primary prevention strategies.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We need more research to confirm these results. Regardless, we can at least say that patients with a high genetic-risk score appear to benefit more from statin therapy because they're starting at a higher baseline risk, even controlling for all the clinical measures we routinely examine.”
Supports genetic risk stratification to prioritize statin therapy; extends RCT evidence by quantifying greater benefit in high-risk groups.
Genetic variants have been associated with the risk of coronary heart disease (CHD). We tested whether a composite of these variants could identify the risk of both incident as well as recurrent CHD events and distinguish individuals who derived greater clinical benefit from statin therapy. A community-based cohort and four randomized controlled trials of both primary (JUPITER and ASCOT) and secondary (CARE and PROVE IT-TIMI 22) prevention with statin therapy totaling 48,421 individuals and 3,477 events were included in these analyses. We examined the association of a genetic risk score based on 27 genetic variants with incident or recurrent CHD, adjusting for established clinical predictors. We then investigated the relative and absolute risk reductions in CHD events with statin therapy stratified by genetic risk. Data from studies were combined using meta-analysis. When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient of risk for incident or recurrent CHD was demonstrated with the multivariable-adjusted HRs (95% CI) for CHD for the intermediate and high genetic risk categories vs. low genetic risk category being 1.32 (1.20-1.46, P<0.0001) and 1.71 (1.54-1.91, P<0.0001), respectively. In terms of the benefit of statin therapy in the four randomized trials, there was a significant gradient of increasing relative risk reduction across the low, intermediate, and high genetic risk categories (13%, 29%, and 48%, P=0.0277). Similarly, greater absolute risk reductions were seen in those individuals in higher genetic risk categories (P=0.0101), resulting in an approximate three-fold gradient in the number needed to treat (NNT) in the primary prevention trials. Specifically, in the primary prevention trials, the NNT to prevent one MACE over 10 years for the low, intermediate, and high GRS individuals was 66, 42, and 25 in JUPITER and 57, 47, and 20 in ASCOT. A genetic risk score identified individuals at increased risk for both incident and recurrent CHD events. Individuals with the highest burden of genetic risk derived the largest relative and absolute clinical benefit with statin therapy.
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Mega et al. (2015) conducted a meta-analysis in Coronary Heart Disease (Primary and Secondary Prevention) (n=48,421). High genetic risk score (quintile 5) vs. Low genetic risk score (quintile 1) was evaluated on Incident or recurrent coronary heart disease (composite of coronary heart death, MI, unstable angina, CABG, or PCI depending on the included study) (HR 1.71, 95% CI 1.54-1.91, p=<0.0001). A high genetic risk score was associated with increased risk of incident or recurrent CHD (HR 1.71) compared to low risk, and individuals in the highest risk category derived a 48% relative risk reduction from statin therapy.
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