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Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI: Results of the GIANT Study
Jean-Sébastien Hulot1, Bernard Chevalier2, Loic Belle3
1Université de Paris, CIC1418 et DMU CARTE, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Insights
Routine CYP2C19 genotyping in ST-segment elevation myocardial infarction patients guides P2Y12 inhibitor therapy. Optimized treatment based on CYP2C19 genotype ensures similar clinical outcomes for all patients, including loss-of-function allele carriers.
Area of Science:
- Cardiology
- Pharmacogenomics
- Genetics
Background:
- Patient response to clopidogrel varies due to CYP2C19 genetic variations.
- CYP2C19 polymorphisms significantly impact thienopyridine treatment efficacy.
Purpose of the Study:
- To prospectively assess the clinical impact of routine CYP2C19 genotyping in managing ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention.
- To evaluate if genotype-guided antiplatelet therapy improves outcomes in STEMI patients.
Main Methods:
- CYP2C19 genotype was determined centrally for 1,445 STEMI patients within 4.1 days of primary PCI.
- Thienopyridine treatment was adjusted based on predicted CYP2C19 metabolic status.
- The primary endpoint was 12-month death, myocardial infarction, or stent thrombosis, comparing wild-type/gain-of-function vs. loss-of-function allele carriers.
Main Results:
- Genotype-guided treatment adjustment occurred in 85% of patients with loss-of-function alleles, increasing prasugrel or double-dose clopidogrel use.
- No significant difference in the primary endpoint was observed between class 1 and class 2 patients (3.31% vs. 3.04%, p=0.82).
- Carriers of loss-of-function alleles without treatment adjustment showed significantly worse outcomes (15.6%). Bleeding rates were similar across groups.
Conclusions:
- CYP2C19 genotyping is feasible within 7 days from saliva DNA during the in-hospital phase for STEMI patients.
- Genotype-guided therapy optimizes P2Y12 inhibition in loss-of-function allele carriers, leading to clinical outcomes comparable to wild-type carriers.
- This approach, demonstrated in the GIANT trial, supports personalized antiplatelet therapy in STEMI management.
Objectives:
The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention.
Background:
Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms.
Methods:
CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment.
Results:
Detection of LOF alleles resulted in adjustment of P2Y12 inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups.
Conclusions:
In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).
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