Future myocardial infarction after an acute coronary syndrome and pharmacogenetic response to dalcetrapib

Tardif, J.C.; Pfeffer, M.A.; Kouz, S.; Koenig, W.; Maggioni, A.P.; McMurray, J.J.; ... ; GenE Investigators dal (2025)

Article / Letter to editor

Aims

Acute coronary syndrome (ACS) survivors have heightened risk for subsequent cardiovascular events.

Methods and results

All baseline characteristics collected in both the dal-Outcomes and dal-GenE trials were considered as potential risk markers. A prediction index for subsequent fatal and non-fatal myocardial infarction (MI) following ACS was developed using Cox proportional hazards modelling on data from dal-Outcomes placebo patients (n = 7086). This prediction index was then applied in all dal-GenE participants (n = 5989) to determine whether the reduction in MI observed with dalcetrapib (vs. placebo) in patients with the AA genotype at rs1967309 in the ADCY9 gene remained significant, independent of the other markers integrated into the prediction index. Of the 36 baseline variables considered as potential risk markers, 18 contributed to the prediction index with a Harrell C-index of 0.72 [95% confidence interval (CI), 0.69-0.75] in dal-Outcomes placebo patients. Prior history of coronary events, LDL-cholesterol (LDL-C), blood pressure, A1c, high-sensitivity C-reactive protein (hs-C-reactive protein), smoking, and age were contributors. The prediction index was strongly predictive when applied to the 5989 AA genotype patients from dal-GenE, with a hazard ratio (HR) for MI of 1.92 (95% CI, 1.78-2.08) for each standard deviation increase in score. When adjusting for the prediction index, the HR for dalcetrapib vs. placebo was 0.77 (95% CI, 0.63-0.94) in dal-GenE.Conclusion Despite guideline-directed therapy following ACS, a history of prior coronary events and on-treatment LDL-C, A1c, hs-CRP, and blood pressure remain determinants of future MI. In the dal-GenE AA genotype patients, dalcetrapib reduced the rate of MI, independently of those variables. The dal-GenE 2 trial is designed to confirm this pharmacogenetic hypothesis.

Registration

dal-Outcomes ClinicalTrials.gov Identifier: NCT00658515; dal-GenE ClinicalTrials.gov Identifier: NCT02525939Despite guideline-directed therapy following an acute coronary syndrome, a history of prior coronary events, smoking, and values while on treatment for LDL-cholesterol, glycated haemoglobin (as a marker of glucose control), high-sensitivity C-reactive protein (as a marker of inflammation), and blood pressure remain predictive of a future heart attack (myocardial infarction).Of the 36 baseline variables considered as potential risk markers, 18 contributed to the prediction index with a good predictive value [a Harrell C-index of 0.72; 95% confidence interval (CI), 0.69-0.75] in 7086 dal-Outcomes placebo patients.When adjusting for the prediction index, dalcetrapib reduced the risk of heart attack (myocardial infarction) compared with placebo by 23% (hazard ratio 0.77; 95% CI, 0.63-0.94) in dal-GenE.

• Risk model
• Precision medicine
• Myocardial infarction
• CETP
• Adenylate cyclase type 9 (ADCY9)
• Genetics

• All authors: Tardif, J.C.; Pfeffer, M.A.; Kouz, S.; Koenig, W.; Maggioni, A.P.; McMurray, J.J.; Waters, D.D.; Jukema, J.W.; White, H.D.; Heinonen, T.; Kallend, D.; Laghrissi-Thode, F.; Muroke, V.; Fortier, A.; Guertin, M.C.; Dubé, M.P.; GenE Investigators dal
• Date: 2025-11-18
• Journal: European Journal of Preventive Cardiology
• DOI: doi:10.1093/eurjpc/zwaf661