Dataset Information

Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

ABSTRACT:

Introduction

Clopidogrel is an antiplatelet prodrug primarily prescribed to prevent or treat acute coronary syndrome (ACS) or acute ischemic stroke (IS), polymorphisms of genes encoding cytochrome P-450 (CYP) and P-glycoprotein transporter, could affect the efficiency of clopidogrel absorption and biotransformation, especially during the first critical hours following its administration.

Methods

The present study was designed to investigate the potential association of clopidogrel responsiveness and 14 polymorphisms in the genes encoding the CYPs (CYP2C9, 2C19, 3A4, 3A5, 1A2, and 2B6), the ATP binding cassette subfamily B member 1 (ABCB1). Platelet aggregation activity was measured after 8h of 300mg clopidogrel administration for fifty-five ACS patients.

Results

There was no significant association between polymorphism of the studied CYPs and clopidogrel responsiveness (P>0.05). The frequency of the ABCB1 3435 T allele in clopidogrel non-responders was higher (78.9%) compared to responders (52.8%), but this difference was not significant (P=0.057). Demographic characteristics, comorbidities, concomitant treatments were not associated with clopidogrel response.

Discussion

There was no effect of the studied genetic variations and demographic factors on the platelet activity of clopidogrel in Moroccan ACS patients.

SUBMITTER: Mouhrach I

PROVIDER: S-EPMC10557961 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

Mouhrach Ismail I Bouguenouch Laila L Kamal Adil A Meriame Abbassi A El Khorb Nada N El Azami El Idrissi Mohammed M Akoudad Hafid H Bekkari Hicham H

Pharmacogenomics and personalized medicine 20231002

<h4>Introduction</h4>Clopidogrel is an antiplatelet prodrug primarily prescribed to prevent or treat acute coronary syndrome (ACS) or acute ischemic stroke (IS), polymorphisms of genes encoding cytochrome P-450 (CYP) and P-glycoprotein transporter, could affect the efficiency of clopidogrel absorption and biotransformation, especially during the first critical hours following its administration.<h4>Methods</h4>The present study was designed to investigate the potential association of clopidogrel ...[more]

PMID: 37810546

Similar Datasets

Project description:BackgroundPrior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel ("smoker's paradox"). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear.Methods and resultsWe analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double-dose (600 mg day 1;150 mg days 2-7; then 75 mg daily) versus standard-dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double- versus standard-dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double- versus standard-dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50-0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80-1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48-1.24, P=0.28), whereas in nonsmokers, the double-dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37-2.60, P<0.0001). Double-dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24-0.71) and nonsmokers (HR 0.63, 95% CI, 0.42-0.93; P for interaction=0.19).ConclusionsIn smokers, a double-dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452.

Project description:ImportancePhysician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown.ObjectiveTo investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.Design, setting, and participantsThe GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.InterventionsInvestigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.Main outcomes and measuresReasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.ResultsOf 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.Conclusions and relevancePhysicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.Clinical trial registrationClinicalTrials.gov identifier: NCT02293395.

Project description:ObjectivesThis study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel.BackgroundLittle research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel.MethodsPatients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding.ResultsOf the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001).ConclusionsCYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.

Project description:BackgroundPotent P2Y12 inhibitors such as ticagrelor and prasugrel are superior to clopidogrel in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Whether this benefit extends to a patient population with chronic coronary syndromes (CCS) is unclear.AimsWe sought to compare the safety and efficacy of prasugrel and ticagrelor versus clopidogrel in patients undergoing PCI for CCS.MethodsConsecutive patients undergoing PCI for CCS at a tertiary centre between 2014 and 2019 who were discharged on prasugrel or ticagrelor were compared with those on clopidogrel. The primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularisation at 1 year.ResultsOverall, 11,508 patients were included in the study (ticagrelor/prasugrel n=2,860 [24.9%], clopidogrel n=8,648 [75.1%]) with an increasing frequency of potent P2Y12 inhibitor use over the study period (ptrend<0.001). Clopidogrel was used more frequently in patients with multimorbid risk factors, whereas anatomical or procedural complexity was associated with ticagrelor/prasugrel use (left main PCI, bifurcation PCI, number of lesions, rotational atherectomy). No difference in the incidence of death or MI was noted across the groups (ticagrelor/prasugrel vs clopidogrel: 2.7% vs 3.1%, adjusted hazard ratio [adjHR] 0.86, 95% confidence interval [CI]: 0.62-1.17; p=0.33) or secondary outcomes including bleeding (adjHR 0.75, 95% CI: 0.46-1.21; p=0.23) on propensity score stratification analysis. Additionally, no difference in the primary outcome was observed across subgroups, including those undergoing complex PCI.ConclusionsTicagrelor and prasugrel are increasingly used in patients with CCS undergoing PCI with similar 1-year efficacy and safety when compared to clopidogrel. Whether use of these agents can be beneficial in patients undergoing PCI for CCS with a high thrombotic and low bleeding risk warrants further study.

Dataset Information

Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

Introduction

Methods

Results

Discussion

Publications

Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets