RESUMEN
IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Benzaldehídos/uso terapéutico , Proteínas Sanguíneas/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Oximas/uso terapéutico , Anciano , Benzaldehídos/efectos adversos , Proteínas Sanguíneas/efectos adversos , Enfermedades Cardiovasculares/mortalidad , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/prevención & control , Isquemia Miocárdica/terapia , Oximas/efectos adversos , Prevención SecundariaRESUMEN
BACKGROUND: Vitamin K antagonists have been the standard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism. Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments. Edoxaban is a selective and direct factor Xa inhibitor that may provide effective, safe, and more convenient anticoagulation. STUDY DESIGN: ENGAGE AF-TIMI 48 is a phase 3, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized to edoxaban high exposure (60 mg daily, adjusted for drug clearance), edoxaban low exposure (30 mg daily, adjusted for drug clearance), or warfarin titrated to an international normalized ratio of 2.0 to 3.0. The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure. Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban. Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS(2) score ≥2. Randomization is stratified by CHADS(2) score and anticipated drug exposure. The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism. The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding. Recruitment began in November 2008. The expected median follow-up is 24 months. CONCLUSIONS: ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa , Infarto del Miocardio/tratamiento farmacológico , Piridinas/uso terapéutico , Tiazoles/uso terapéutico , Terapia Trombolítica/métodos , Administración Oral , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Piridinas/administración & dosificación , Estudios Retrospectivos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Tiazoles/administración & dosificación , Resultado del Tratamiento , Warfarina/administración & dosificación , Warfarina/uso terapéuticoRESUMEN
BACKGROUND: We determined the prognostic value of myocardial perfusion imaging (MPI) in patients with atypical clinical presentations and unexpected elevation of cardiac troponin I (cTnI) levels. METHODS AND RESULTS: In 156 consecutive patients with atypical presentations for acute coronary syndromes (ACS) and elevated cTnI levels undergoing MPI within 30 days, rates of all-cause mortality (100% follow-up; median follow-up, 611 days) and 6-month cardiac death and nonfatal myocardial infarction (96% follow-up; median follow-up, 167 days) were determined. The mean age of the patients was 68 +/- 14 years. The majority of the study cohort (96%) was at low to intermediate clinical risk for ACS (Thrombolysis in Myocardial Infarction score for unstable angina/non-ST-segment elevation myocardial infarction <5). The overall event rate was high, with 45 deaths (28.8%). There were 13 cardiac deaths/nonfatal myocardial infarctions in 6 months (8.3%). A normal MPI result was associated with a high event-free survival rate, whereas an abnormal MPI result was associated with a 3-fold and 7-fold higher risk of all-cause mortality and 6-month cardiac events, respectively. An abnormal MPI result was an independent predictor of all-cause death. CONCLUSIONS: In patients with cTnI elevation and a low to intermediate risk for ACS, a normal MPI result portends a good prognosis. Patients with abnormal MPI results have a higher 6-month cardiac event rate and a worse survival rate.
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Angina Inestable/diagnóstico por imagen , Infarto del Miocardio/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Troponina I/sangre , Anciano , Anciano de 80 o más Años , Angina Inestable/sangre , Angina Inestable/diagnóstico , Biomarcadores/sangre , Prueba de Esfuerzo , Femenino , Imagen de Acumulación Sanguínea de Compuerta , Corazón/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Pronóstico , Estudios Prospectivos , Radiofármacos , Análisis de Supervivencia , Tecnecio Tc 99m SestamibiRESUMEN
Extreme obesity is known to be associated with left ventricular (LV) systolic dysfunction. The relation of lesser degrees of obesity and LV systolic function is controversial. This study assessed the relation between body mass index (BMI; weight in kilograms divided by height in meters squared) and the LV ejection fraction (EF) and volumes in 1,806 subjects with normal technetium-99m sestamibi myocardial perfusion imaging results. BMI was evaluated as a continuous and a categorical variable (normal >18.5 and <25, overweight > or =25 and <30, obese > or =30 and <35, and severely obese > or =35 kg/m(2)). The prevalence of an EF < or =50% was similar in normal, overweight, obese, and severely obese subjects. On univariate analysis, only severely obese women had mildly reduced LVEFs. LV end-diastolic and end-systolic volumes increased linearly from normal to obese men and women, respectively (each p <0.01). On multiple linear regression analysis (R = 0.5, p <0.001), BMI (p = 0.03) and diabetes (p <0.001) influenced the EF adversely, whereas age and female gender were protective (p <0.001). However, on gender-stratified analysis, diabetes, not BMI, independently predicted the EF in men and women. BMI remained an independent predictor of greater end-diastolic volumes in men and women (p <0.01) even after accounting for co-morbidities. In conclusion, mild obesity was associated with LV dilatation, but the LVEF was preserved even with severe obesity. Weight control may be recommended to reduce the incidence of obesity-related co-morbidities and their impact on adverse LV remodeling.
Asunto(s)
Índice de Masa Corporal , Hipertrofia Ventricular Izquierda/fisiopatología , Obesidad Mórbida/fisiopatología , Volumen Sistólico , Disfunción Ventricular Izquierda/fisiopatología , Adulto , Anciano , Análisis de Varianza , Peso Corporal , Estudios de Casos y Controles , Prueba de Esfuerzo , Femenino , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/epidemiología , Modelos Lineales , Masculino , Persona de Mediana Edad , Reperfusión Miocárdica , Obesidad Mórbida/diagnóstico , Obesidad Mórbida/epidemiología , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Radiofármacos , Factores Sexuales , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón Único , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/epidemiologíaRESUMEN
BACKGROUND: Slow upsloping ST-segment depression during stress is thought to represent an ischemic response to exercise treadmill testing (ETT). AIM: We used modern single-photon emission computed tomography (SPECT) imaging protocols to determine the incidence of ischemia in patients with slow upsloping ST depression during exercise and whether this response signifies more or less severe coronary artery disease (CAD) and risk in comparison with rapid upsloping ST depression and particularly with horizontal or downsloping ST depression. METHODS: We enrolled 33 patients (group 1) with rapid upsloping ST depression (>1 mm extending <0.08 seconds beyond J point), 32 patients (group 2) with slow upsloping depression (>1.5 mm extending >0.08 seconds beyond J point), and 35 patients (group 3) with horizontal or downsloping depression (>1 mm at 0.08 seconds beyond J point). Summed stress score (SSS), summed difference score (SDS), stress extent percent (SE%) and reversible extent percent (RE%) of perfusion abnormalities, lung-heart ratio (LHR), and transient ischemic dilatation (TID) were calculated. RESULTS: The mean SSS, SDS, SE%, RE%, and LHR were similar between groups 1 and 2 but significantly higher in group 3. Incidence of ischemia was similar in groups 1 and 2 (39% and 25%) but significantly higher in group 3 (77%, P <.001). Evidence of TID was seen in none of the patients in groups 1, in 3% of patients in group 2, and in 23% of patients in group 3. CONCLUSIONS: Slow upsloping ST depression does not signify more severe ischemia, more extensive CAD, or more stress-induced backward left ventricular failure. Thus, it would be reasonable to consider patients with slow upsloping ST depression during exercise as having a very low likelihood of CAD, similar to patients with rapid upsloping ST depression.