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

Fundamento y objetivos. El valor de los polimorfismos PON1-Q192R, CYP2C19*2 y *17 en la identificación del paciente pobre respondedor a clopidogrel es controvertido. Evaluamos la relación de estos polimorfismos con la reactividad plaquetar y el pronóstico a medio plazo en pacientes con síndrome coronario agudo sometidos a doble antiagregación remitidos para cateterismo cardíaco. Además, con intención de valorar la utilidad clínica de los dispositivos “a pie de cama” de medición de agregabilidad plaquetaria, realizamos un subestudio comparativo entre los dos principales dispositivos de medida de agregabilidad plaquetar: VerifyNow y Multiplate. Material y métodos. Se incluyeron prospectivamente 247 pacientes con síndrome coronario agudo. En todos se dispuso del genotipo (CYP2C19*2, CYP2C19*17, PON1-Q192R). Medimos la reactividad plaquetar con VerifyNow. Se registraron eventos adversos intrahospitalarios (muerte e infarto periprocedimiento) y durante el seguimiento (muerte, infarto miocardio, angina, accidente cerebrovascular y trombosis del stent). Para el subestudio se reclutaron 168 pacientes de nuestro centro y 83 en el Hospital de San Juan (Alicante) con diagnóstico de síndrome coronario agudo o angina estable a los que se les realizó medida de actividad plaquetar mediante los sistemas VerifyNow y Multiplate. El seguimiento y los eventos adversos registrados durante el mismo fueron similares a los del estudio principal. Resultados. Los portadores de alelos *2 de CYP2C19 presentaron una mayor reactividad plaquetar residual (PRU, media [DE], 252[76] vs. 287[74], p=0.002). Los portadores de alelos *17 de CYP2C19*17 o de alelos T (Q) de PON1-Q192R no presentaron una reactividad distinta (p>0.05). En un modelo multivariado para la predicción de pobre respuesta a clopidogrel, la contribución de CYP2C19*2 fue modesta (Wald=7.5; OR para ≥ 1 alelo *2 = 2.786, IC 95% 1.337-5.808). Fueron factores protectores independientes la hemoglobina basal (g/dL, OR 0.666, IC 95% 0.555-0.801) y el uso concomitante de estatinas (OR=0.376, IC95% 0.162-0.873). El índice de masa corporal fue un factor de riesgo (OR=1.074, IC 95% 1.005-1.148). Los polimorfismos estudiados no predijeron eventos adversos. En el caso del subestudio comparativo, identificamos como pobres respondedores a 173 (68.9%) pacientes con PRU > 235 U y 147 (58.6%) con porcentaje de inhibición 53 y 89 (35.5%) con ABC del ADPhs test > 31. La proporción de pacientes no inhibidos fue significativa y sustancialmente más alta con VerifyNow® respecto a su comparador (p 550 y sólo 6 (2.4%) mediante ABC del Aspi Test > 74. Respecto de los tests de respuesta a clopidogrel, la concordancia mayor fue la del porcentaje de inhibición (VerifyNow®) y el ADPhs Test (Multiplate®) siendo κ de -0.266 (p<0.001). En el resto de las comparaciones el valor de κ fue inferior a 0.2. Para los salicilatos, la concordancia observada entre los dos analizadores fue igualmente baja (κ=0.194, p=0.001). En cuanto al evento combinado, tan solo PRU base y TRAP test mostraron un ABC ROC significativamente distinta del 0.5 (ABC ROC = 0.66, IC 95% 0.55-0.76 y 0.66, IC 95% 0.54-0.77 respectivamente). Conclusiones. El polimorfismo de CYP2C19*2 influenció la respuesta a clopidogrel de forma modesta, pero no condicionó un pronóstico distinto en pacientes con síndrome coronario agudo. Los polimorfismos de PON1-Q192R y CYP2C19*17 no influenciaron la reactividad plaquetar ni el pronóstico. En cuanto al subestudio comparativo, el grado de acuerdo en el diagnóstico de pobre respuesta a la aspirina y clopidogrel entre los sistemas VerifyNow® y Multiplate® fue globalmente pobre. La mayor reactividad plaquetar "basal" se asoció con una mayor ocurrencia de eventos adversos. Palabras clave: Isquemia miocárdica, plaquetas, genética, agregometría. 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 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 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 κ of -0266 (p <0.001). In other comparisons κ value was less than 0.2. To salicylates, the observed agreement between the two analyzers was also low (κ = 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. Key words. Ischemic cardiac disease, platelets, genetics, aggregometry

Role of cardiovascular magnetic resonance in the prognosis of patients with myocardial infarction with non-obstructive coronary arteries

Abstract Background It is estimated that 5% to 10% of patients with myocardial infarction (MI) present with no obstructive coronary artery lesions. Until now, most studies have focused on acute coronary syndrome, including different clinical entities with a similar presentation encompassed under the term MINOCA (MI with non-obstructive coronary arteries). The aim of this study is to assess the prognosis of patients diagnosed with true infarction, confirmed by cardiovascular magnetic resonance (CMR), in the absence of significant coronary lesions. Methods Prospective multicenter registry study, including 120 consecutive patients with a CMR-confirmed MI without obstructive coronary artery lesions. The primary clinical outcome was major adverse cardiovascular events (MACE: death, non-fatal infarction, stroke, or cardiac readmission), assessed over three years. Results Seventy-six patients (63.3%) were admitted with a diagnosis of acute coronary syndrome, and 44 (36.6%) for other causes (mainly heart failure); the definitive diagnosis was established by CMR. Most patients (64.2%) were men, and the mean age was 58.8 ± 13.5 years. Patients presented with small infarcts: 83 (69.1%) showed late gadolinium enhancement (LGE) in one or two myocardial segments, mainly transmural (in 77.5% of patients) and with a preserved left ventricular ejection fraction (median 54.8%, interquartile range 37–62). The most frequent infarct location was inferolateral (n = 38, 31.7%). During follow-up, 43 patients (35.8%) experienced a MACE, including 9 (7.5%) who died. In multivariable analysis, LGE in two versus one myocardial segment doubled the risk of adverse cardiac events (hazard ratio [HR] 2.32, 95% confidence interval [CI] 0.97–5.83, p = 0.058). Involvement of three or more myocardial segments almost tripled the risk (HR 2.71, 95% CI 1.04–7.04, p = 0.040 respectively). Conclusions Patients with true MI but without significant coronary artery lesions predominantly had small infarcts. Myocardial 3-segment LGE involvement is associated with a significantly higher risk of adverse cardiac events

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p &lt; 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p &lt; 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p &lt; 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease