Predicting Myocardial Infarction Risk in ACS Survivors Using Pharmacogenetics
Overview
A prediction index incorporating 18 baseline variables effectively stratifies future myocardial infarction (MI) risk in acute coronary syndrome (ACS) survivors. In patients with the AA genotype at rs1967309 in the ADCY9 gene, dalcetrapib significantly reduces MI risk independent of traditional risk factors.
Background
Despite advances in ACS management and secondary prevention, survivors remain at high risk for recurrent cardiovascular events, particularly MI. Traditional risk factors and biomarkers such as LDL-cholesterol, blood pressure, glycated hemoglobin (A1c), and high-sensitivity C-reactive protein (hs-CRP) continue to influence risk. Pharmacogenetics offers a precision medicine approach to identify patients who may benefit from targeted therapies like dalcetrapib, especially those with specific genetic profiles.
Data Highlights
Variable
Contribution to Prediction Index
Number of baseline variables considered
36
Variables included in prediction index
18
Harrell C-index (dal-Outcomes placebo patients)
0.72 (95% CI, 0.69–0.75)
Hazard ratio for MI per SD increase in prediction score (dal-GenE AA genotype)
1.92 (95% CI, 1.78–2.08)
Hazard ratio for dalcetrapib vs. placebo (adjusted for prediction index)
0.77 (95% CI, 0.63–0.94)
Sample size dal-Outcomes placebo patients
7086
Sample size dal-GenE participants
5989
Key Findings
Eighteen baseline variables, including prior coronary events, LDL-C, blood pressure, A1c, hs-CRP, smoking, and age, significantly contributed to predicting future MI risk.
The prediction index demonstrated good discrimination with a Harrell C-index of 0.72 in dal-Outcomes placebo patients.
In dal-GenE patients with the AA genotype at rs1967309 in ADCY9, the prediction index strongly predicted MI risk (HR 1.92 per SD increase).
Dalcetrapib reduced MI risk by 23% compared to placebo in AA genotype patients, independent of the prediction index variables (HR 0.77).
Traditional risk factors and biomarkers remain relevant determinants of MI risk despite guideline-directed therapy.
The dal-GenE 2 trial is planned to confirm the pharmacogenetic benefit of dalcetrapib in this genetically defined population.
Clinical Implications
Clinicians should continue to monitor and manage traditional risk factors such as LDL-C, blood pressure, glycemic control, and inflammation markers in ACS survivors to mitigate future MI risk. Pharmacogenetic testing for the ADCY9 rs1967309 genotype may identify patients who could benefit from dalcetrapib therapy as an adjunct to standard secondary prevention. This precision medicine approach could optimize individualized treatment strategies post-ACS.
Conclusion
A validated prediction index incorporating clinical and biomarker data effectively stratifies MI risk in ACS survivors. Dalcetrapib offers a significant MI risk reduction in patients with the AA genotype at rs1967309 in ADCY9, independent of established risk factors, supporting a precision medicine approach in secondary prevention.
References
DalCor Pharmaceuticals/2024 -- Predicting Future Myocardial Infarction Risk in Acute Coronary Syndrome Survivors: Insights from Pharmacogenetic Responses to Dalcetrapib
by Jean-Claude Tardif, Marc A Pfeffer, Simon Kouz, Wolfgang Koenig, Aldo P Maggioni, John J V McMurray, David D Waters, J Wouter Jukema, Harvey D White, Therese Heinonen, David Kallend, Fouzia Laghrissi-Thode, Valtteri Muroke, Annik Fortier, Marie-Claude Guertin, Marie-Pierre Dubé, for the dal-GenE Investigators
