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Determinants to optimize response to clopidogrel in acute coronary syndrome.

ABSTRACT: The inhibition of platelet function by antiplatelet therapy determines the improvement of the survival of patients with clinically evident cardiovascular disease. Clopidogrel in combination with aspirin is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention. However, major adverse cardiovascular events including stent thrombosis occur in patients taking clopidogrel and aspirin. A growing body of evidence demonstrates that high post-treatment platelet reactivity on antiplatelet treatment is associated with increased risk of adverse clinical events. Clopidogrel requires conversion to active metabolite by cytochrome P450 isoenzymes. The active metabolite inhibits ADP-stimulated platelet activation by irreversibly binding to P2Y(12) receptors. Recently, the loss-of-function CYP2C19*2 allele has been associated with decreased metabolization of clopidogrel, poor antiaggregant effect, and increased cardiovascular events. In high risk vascular patients, the CYP2C19*2 polymorphism is a strong predictor of adverse cardiovascular events and particularly of stent thrombosis. Prospective studies evaluating if an antiplatelet treatment tailored on individual characteristics of patients, CYP2C19*2 genotypes, platelet phenotype, drug-drug interaction, as well as traditional and procedural risk factors, are now urgently needed for the identification of therapeutic strategies providing the best benefit for the single subject.

SUBMITTER: Giusti B

PROVIDER: S-EPMC3513207 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Determinants to optimize response to clopidogrel in acute coronary syndrome.

Giusti Betti B Gori Anna Maria AM Marcucci Rossella R Saracini Claudia C Vestrini Anna A Abbate Rosanna R

Pharmacogenomics and personalized medicine 20100408

The inhibition of platelet function by antiplatelet therapy determines the improvement of the survival of patients with clinically evident cardiovascular disease. Clopidogrel in combination with aspirin is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention. However, major adverse cardiovascular events including stent thrombosis occur in patients taking clopidogrel and aspiri ...[more]

PMID: 23226041

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Project description:BackgroundIt is still unknown whether diabetes mellitus (DM) affects the relative safety and efficacy of ticagrelor vs clopidogrel in East Asian patients with acute coronary syndrome (ACS).ObjectivesThe authors sought to assess the safety and efficacy of ticagrelor vs clopidogrel according to the diabetic status of East Asian patients with ACS undergoing invasive management.MethodsThis prespecified analysis of the TICA KOREA (Clinically Significant Bleeding With Ticagrelor Versus Clopidogrel in Korean Patients With Acute Coronary Syndromes Intended for Invasive Management) trial included 800 Korean patients. The primary safety endpoint was clinically significant bleeding (PLATO [Platelet Inhibition and Clinical Outcomes] major or minor bleeding) at 12 months; the efficacy endpoint was major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke).ResultsOf 800 patients, 216 (27.0%) had DM. The incidence of clinically significant bleeding within 12 months was significantly higher with ticagrelor than clopidogrel in the nondiabetic group (10.2% vs 4.3%; HR: 2.45; 95% CI: 1.27-4.70; P = 0.007) and tended to be higher in the diabetic group (13.8% vs 8.0%; HR: 1.87; 95% CI: 0.54-4.36; P = 0.15); there was no significant interaction between treatment-arm and DM (P for interaction = 0.64). The incidences of major adverse cardiovascular events were not significantly different after ticagrelor or clopidogrel both in the diabetic group (10.8% vs 6.0%; HR: 1.90; 95% CI: 0.71-5.07; P = 0.20) and in the nondiabetic group (8.5% vs 5.7%; HR: 1.51; 95% CI: 0.81-2.81; P = 0.19) without significant interaction (P-for-interaction = 0.71).ConclusionsIn Korean ACS patients undergoing early invasive management, diabetes status did not affect the relative safety and efficacy of ticagrelor and clopidogrel. (Safety and Efficacy of Ticagrelor Versus Clopidogrel in Asian/Korean Patients With Acute Coronary Syndromes Intended for Invasive Management [TICA KOREA]; NCT02094963).

Project description:ImportanceGuidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary events (MACE) vs clopidogrel but increased bleeding and dyspnea.ObjectiveTo compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE.Design, setting, and participantsPopulation-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018.ExposuresOutpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher.Main outcomes and measuresMajor adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea.ResultsOf 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 [36.4%]) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses.Conclusions and relevanceIn this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.

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Determinants to optimize response to clopidogrel in acute coronary syndrome.

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Determinants to optimize response to clopidogrel in acute coronary syndrome.

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