Bedside testing of CYP2C19 vs. conventional clopidogrel treatment to guide antiplatelet therapy in ST-segment elevation myocardial infarction patients.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) patients are treated with dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor. Clopidogrel is widely used in these patients in several areas worldwide, such as Middle East, but is associated to sub-optimal platelet inhibition in up to 1/3 of treated patients. We investigated a CYP2C19 genotype-guided strategy to select the optimal P2Y12 inhibitor. METHODS: This prospective randomized clinical trial included STEMI patients. The standard-treatment group received clopidogrel, while the genotype-guided group were genotyped for CYP2C19 loss-of-function alleles and carriers were prescribed ticagrelor and noncarriers were prescribed clopidogrel. Primary outcome was a combined ischemic and bleeding outcome, comprising myocardial infarction, non-fatal stroke, cardiovascular death, or Platelet Inhibition and Patient Outcomes major bleeding one year after STEMI. RESULTS: STEMI patients (755) were randomized into a genotype-guided- (383) and standard-treatment group (372). In the genotype-guided group, 31 patients carrying a loss-of-function allele were treated with ticagrelor, while all other patients in both groups were treated with clopidogrel. Patients in the genotype-guided group had a significantly lower risk of primary outcome (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.20-0.59,), recurrent myocardial infarction (OR 0.25, 95%CI 0.11-0.53), cardiovascular death (OR 0.16, 95%CI0.06-0.42) and major bleeding (OR 0.49, 95%CI 0.32-0.74). There was no significant difference in the rate of stent thrombosis (OR 0.85, 95%CI 0.43-1.71). CONCLUSION: A genotype-guided escalation of P2Y12 inhibitor strategy is feasible in STEMI patients treated with clopidogrel and undergoing PCI and is associated with a reduction of primary outcomes compared to conventional antiplatelet therapy.

Bedside testing of CYP2C19 gene for treatment of patients with PCI with antiplatelet therapy.

BACKGROUND: To mitigate the risk of stent thrombosis, patients treated by percutaneous coronary intervention (PCI) are administered dual anti-platelet therapy comprising aspirin and a platelet P2Y12 receptor inhibitor. Clopidogrel is a prodrug requiring activation by the cytochrome P450 enzyme, CYP2C19. In Saudi Arabia, it has been reported that approximately 26% of the population carries CYP2C19*2 and/or *3 loss-of-function polymorphisms in addition to a high prevalence of CVD. METHODS: This prospective (April 2013-December 2020) parallel assignment clinical trial focuses on ST-Elevation Myocardial Infarction (STEMI) patient outcomes. The clinical trial includes 1500 STEMI patients from two hospitals in the Eastern Province of Saudi Arabia. Patients are assigned to one of two groups; the control arm receives conventional therapy with clopidogrel, while in the active arm the Spartan RX CYP2C19 assay is used to determine the *2 genotype. Carriers of a CYP2C19*2 loss-of-function allele receive prasugrel or ticagrelor, while non-carriers are treated with clopidogrel. Follow-up is one year after primary PCI. The primary end point is the number of patients who develop an adverse major cardiovascular event, including recurrent MI, non-fatal stroke, cardiovascular death, or major bleeding one year after PCI. DISCUSSION: The risk of stent thrombosis in PCI patients is usually reduced by dual anti-platelet therapy, comprising aspirin and a P2Y12 inhibitor, such as clopidogrel. However, clopidogrel requires activation by the cytochrome P450 enzyme, CYP2C19. Approximately 20% of the population are unable to activate clopidogrel as they possess the CYP2C19*2 loss-of function (LoF) allele. The primary goal of this trial is to study the benefits of treating only those patients that cannot activate clopidogrel with an alternative that has shown to be a more effective platelet inhibitor and does not require bioactivation by the cytochrome P450 enzyme. We expect an improvement in net clinical benefit outcome in the active arm patients, thus supporting pharmacogenetic testing in PCI patients post STEMI. TRIAL REGISTRATION: Trial registration name is "Bedside Testing of CYP2C19 Gene for Treatment of Patients with PCI with Antiplatelet Therapy" (number NCT01823185) retrospectively registered with clinicaltrials.gov on April 4, 2013. This trial is currently at the patient recruitment stage.