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

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Acute coronary syndrome (ACS) survivors face a significant risk of recurrent cardiovascular events.
• Despite current therapies, identifying high-risk individuals for targeted interventions remains crucial.

Purpose of the Study:

• To develop and validate a prediction index for myocardial infarction (MI) in ACS survivors.
• To assess whether dalcetrapib's benefit in reducing MI is independent of established risk markers in patients with the ADCY9 gene AA genotype.

Main Methods:

• A prediction index for MI was developed using Cox proportional hazards modeling in 7086 ACS patients from the Dal-Outcomes trial.
• The index, incorporating 18 baseline variables including prior events, LDL-C, and blood pressure, was applied to 5989 ACS patients from the Dal-GenE trial.
• The effect of dalcetrapib versus placebo on MI was evaluated, adjusting for the prediction index in Dal-GenE participants with the AA genotype at rs1967309.

Main Results:

• The prediction index demonstrated good predictive performance (C-index 0.72) in Dal-Outcomes placebo patients.
• In Dal-GenE AA genotype patients, the index strongly predicted MI (HR 1.92 per SD increase).
• Dalcetrapib significantly reduced MI risk (HR 0.77) compared to placebo, independent of the prediction index.

Conclusions:

• Traditional risk factors like prior coronary events, LDL-C, blood pressure, A1c, and hs-CRP remain important predictors of future MI post-ACS.
• Dalcetrapib demonstrated a significant reduction in MI rates in a specific patient subgroup (Dal-GenE AA genotype), independent of these risk factors.
• The findings support a pharmacogenetic hypothesis, with the Dal-GenE 2 trial designed for confirmation.