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Individualized Angiotensin-Converting Enzyme (ACE)-Inhibitor Therapy in Stable Coronary Artery Disease Based on
Rohit M Oemrawsingh1, K Martijn Akkerhuis2, Laura C Van Vark2
1Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands Netherlands Heart Institute, Utrecht, The Netherlands.
Insights
Angiotensin-converting enzyme (ACE) inhibitor therapy benefits vary in stable coronary artery disease (CAD). Combining clinical and genetic factors predicts individual patient response to ACE inhibitors, optimizing treatment for CAD patients.
Area of Science:
- Cardiology
- Pharmacogenetics
- Clinical Risk Prediction
Background:
- Stable coronary artery disease (CAD) patients exhibit heterogeneous responses to angiotensin-converting enzyme (ACE)-inhibitor therapy.
- Predicting individual treatment benefits remains a challenge in managing stable CAD.
Purpose of the Study:
- To develop a combined risk prediction model integrating clinical and pharmacogenetic factors for ACE-inhibitor therapy in stable CAD.
- To identify patient subgroups with varying absolute treatment benefits from ACE inhibitors.
Main Methods:
- Utilized data from 8726 stable CAD patients in the EUROPA/PERGENE trial (perindopril vs. placebo).
- Developed a clinical risk score based on phenotype data (0-21 points).
- Constructed a pharmacogenetic risk score (PGXscore) using three single-nucleotide polymorphisms (0-6 points).
Main Results:
- The primary endpoint (cardiovascular mortality, myocardial infarction, cardiac arrest) occurred in 9.0% of patients over 4.2 years.
- Absolute risk reductions ranged from 1.2% to 7.5% in patients with a PGXscore of 0-2.
- Identified a wide range of treatment benefits, with estimated annual numbers needed to treat varying from 29 to 521.
Conclusions:
- Both clinical phenotype and genotype influence the efficacy of ACE inhibition in stable CAD.
- A combined clinical and pharmacogenetic risk model reveals significant gradients in absolute treatment benefit.
- Suggests cost-effectiveness of long-term perindopril in patients with a PGXscore of 0-2.
Background:
Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model.
Methods And Results:
Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective.
Conclusions:
Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit.
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