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- Title
A genetic model of ivabradine recapitulates results from randomized clinical trials.
- Authors
Legault, Marc-André; Sandoval, Johanna; Provost, Sylvie; Barhdadi, Amina; Lemieux Perreault, Louis-Philippe; Shah, Sonia; Lumbers, R. Thomas; de Denus, Simon; Tyl, Benoit; Tardif, Jean-Claude; Dubé, Marie-Pierre
- Abstract
Background: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints. Methods: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. Results: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06–1.13, P = 9.3 ×10−9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83–0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93–1.04, P = 0.61). Conclusion: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.
- Subjects
UNITED Kingdom; IVABRADINE; CLINICAL trials; GENETIC models; ATRIAL fibrillation; PHARMACOLOGY; CLINICAL drug trials
- Publication
PLoS ONE, 2020, Vol 15, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0236193