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A genetic model of ivabradine recapitulates results from randomized clinical trials

By Marc-Andre Legault, Johanna Sandoval, Sylvie Provost, Amina Barhdadi, Louis-Philippe Lemieux Perreault, Sonia Shah, Tom Lumbers, Simon de Denus, Benoit Tyl, Jean-Claude Tardif, Marie-Pierre Dube

Posted 03 Feb 2020
medRxiv DOI: 10.1101/2020.01.29.20019521

BackgroundNaturally 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 mutation in HCN4, ivabradines drug target, on safety and efficacy endpoints. MethodsWe used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. ResultsUsing 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 ivabradines 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 x10-9) 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). ConclusionGenetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction. CONDENSED ABSTRACTThe effects of drugs can sometimes be predicted from the effects of mutations in genes encoding drug targets. We tested the effect of a heart rate reducing allele at the HCN4 locus encoding ivabradines drug target and found results coherent with the SHIFT and SIGNIFY clinical trials of ivabradine. The genetic variant increased the risk of atrial fibrillation and cardioembolic stroke and protected against heart failure in a competing risk model accounting for the increased risk of atrial fibrillation. The variant had a neutral effect on a composite of myocardial infarction and cardiovascular death.

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