Impacto de la evaluación de la reactividad plaquetar y de la presencia de polimorfismos del citocromo P450, 2C19 y paraoxonasa 1 en pacientes remitidos para intervencionismo percutáneo sometidos doble antiagregación

Abstract

ABSTRACT Background and objectives. Previous studies have shown that the metabolism of P2Y12 receptor blockers is influenced not only by CYP2C19*2 but also by PON1-Q192R alelles. We aimed to evaluate the impact of CYP2C19*2 and PON1-Q192R polymorphisms carriage in platelet reactivity and clinical outcome in patients with ischemic heart disease undergoing cardiac catheterization. In addition, intending to evaluate the clinical utility of the devices "bedside " measuring platelet aggregation , we conducted a sub-study comparison between the two main measurement devices platelet aggregability: VerifyNow and Multiplate Methods. We recruited prospectively patients with acute coronary syndrome undergoing cardiac catheterization (n=247). We evaluated the genotype (CYP2C19*2, CYP2C19*17, PON1-Q192R) with TaqMan assay and platelet aggregometry in all patients. We assessed both in and out-of-hospital events (unstable angina, periprocedural and spontaneous myocardial infarction, myocardial infarction, all-cause death, stent thrombosis and stroke) during follow-up. For the substudy 168 patients of our hospital and 83 patients in the San Juan Hospital (Alicante) were enrolled with acute coronary syndrome or stable angina who underwent platelet activity measured by the VerifyNow and Multiplate systems. Monitoring and adverse events recorded during the same were similar to those of the main study. Results. Carriers of CYP2C19*2 alleles showed a significant higher residual platelet reactivity (PRU, mean [SD], 252[76] vs. 287[74], p=0.002). Carriers of PON1-Q192R CT (RQ) and TT(QQ) alleles and CYP2C19*17 did not present a different response to clopidogrel. In a multivariable setting for the prediction of platelet reactivity, the contribution of CYP2C19*2 was modest (Wald=7.5; OR para ? 1 alelo *2 = 2.786, 95% CI 1.337-5.808). Independent predictors were baseline hemoglobine levels (g/dL, OR 0.666, 95% CI 0.555-0.801) and the use of statins (OR=0.376, 95% CI 0.162-0.873). Body mass index was a risk factor (OR=1.074, CI 95% 1.005-1.148). Studied polymorphisms did not predict an adverse outcome. In the case of comparative sub-study, we identified as poor responders to 173 (68.9%) patients with PRU> 235 U and 147 (58.6%) percent inhibition with <15% by VerifyNow¿; while with Multiplate¿, we identified 48 (19.1%) with ABC ADP test> 53 and 89 (35.5%) with ABC test ADPhs> 31. The proportion of patients was not inhibited significantly and substantially higher with respect to VerifyNow¿ the comparator (p <0.05). In the case of aspirin, they were identified 38 (15.3%) patients not inhibited by ARU> 550 and only 6 (2.4%) by ABC Aspi Test> 74. Regarding tests response to clopidogrel, as agreement was the percent inhibition (VerifyNow¿) and ADPhs Test (Multiplate¿) being ? of -0266 (p <0.001). In other comparisons ? value was less than 0.2. To salicylates, the observed agreement between the two analyzers was also low (? = 0.194, p = 0.001). As for the combined event, just PRU base and TRAP test they showed significantly different ABC 0.5 ROC (AUC ROC = 0.66, 95% CI 0.55 to 0.76 and 0.66, 95% CI from 0.54 to 0.77 respectively) Conclusions. CYP2C19*2 polymorphism influenced moderately platelet reactivity but did not show an impact on clinical outcome in patients with acute coronary syndrome. CYP2C19*17 nor PON1-Q192R polymorphisms showed an impact upon platelet reactivity or outcome. As for the comparative substudy, the degree of agreement in the diagnosis of poor response to aspirin and clopidogrel among VerifyNow¿ and Multiplate¿ systems was generally poor. Most platelet reactivity "basal" was associated with an increased occurrence of adverse events.