Combined clinical and pharmacogenetic risk scoring model determines ACE-inhibitor treatment benefit in patients with stable coronary artery disease
Rohit M. Oemrawsingh, K. Martijn Akkerhuis, Laura C. van Vark, Kim Fox, Roberto Ferrari, A.H. Jan Danser, Moniek P.M. de Maat, Maarten L. Simoons, Jasper Jan Brugts, Eric H. Boersma, PERGENE investigators · European Heart Journal · 2013
Purpose: To integrate phenotypical and genetic factors that determine the effect of the ACE-inhibitor perindopril in stable coronary artery disease (CAD). Methods: Phenotypical, genetic and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril (8mg daily) versus placebo. The primary endpoint was a composite of cardiovascular death, myocardial infarction and cardiac arrest during 4-year follow-up. Multivariable analysis of phenotype data resulted in a clinical risk score (range: 0-21 points). Patients were classified as low (4.6%), intermediate (8.8%) or high risk (16.2%) of the primary endpoint (P<0.001). Three SNPs determined perindopril treatment effect (rs275651 and rs5182 in the angiotensin-II type I receptor gene and rs12050217 in the bradykinin type I receptor gene). Patients were classified according to the number of "unfavorable" alleles (pharmacogenetic score range: 0-6 points). Results: 785 patients (9.0%) experienced the primary endpoint. Combining phenotypical and pharmacogenetic profiling (in a combined statistical model) revealed large gradients in perindopril treatment effect. Absolute risk reductions ranged from 1.2% to 7.5% in the 74% of patients with 0-2 "unfavorable" alleles. As a consequence, the annual number needed to treat (NNT) to prevent 1 endpoint ranged from as low as 29 (high clinical risk score and 0 unfavorable alleles) to 521 (low clinical risk score and 2 unfavorable alleles) (figure). Non-significant risk increase (and negative NNTs) was seen in the remaining 26% of patients (with ≥ 3 unfavorable alleles). NNT according to pheno-and genotype risk Conclusion: Integration of phenotypical and pharmacogenetic characteristics demonstrated a wide of gradients of absolute treatment benefit by the ACE-inhibitor perindopril in stable CAD patients.