Impacto de un Heart Team en pacientes con estenosis aórtica candidatos a reemplazo percutáneo / Impact of a Heart Team in patients with aortic stenosis who are candidates for transcatheter aortic valve replacement

RESUMEN La difusión del reemplazo valvular aórtico percutáneo (TAVI) en la estenosis aórtica (EAo) generó la creación de un Heart Team (HT), para elegir el mejor tratamiento. Existen pocos reportes sobre su utilidad. Objetivos: analizar los resultados del tratamiento de los pacientes con EAo evaluados por un HT durante 10 años Material y métodos: Inclusión consecutiva de todos los pacientes con EAo candidatos a TAVI entre enero del 2012 y julio del 2021 para seleccionar el mejor tratamiento, incluyendo además Cirugía de reemplazo valvular aórtico (CRVA) y Tratamiento médico conservador (TMC). Resultados: De 841 pacientes, se asignaron a TAVI 455 (53%), CRVA 213 (24%) y TMC 183 (23%). El porcentaje asignado a TAVI aumentó con el tiempo de 48 a 62% (p < 0,05). Los pacientes que fueron a TAVI, con respecto a los enviados a CRVA, eran mayores (86 ± 7 vs 83 ± 7 años), con mayor EUROSCORE II (6,2, IC95% 5,7-6,6 vs 5,6, IC95% 4,4-6,5) y más frágiles (1,62 ± 1 vs 0,91 ± 1), en todos los casos p <0,01. La sobrevida actuarial (IC 95%) a 1 y a 2 años fue, para TAVI 88% (84-91%) y 82% (77-86%), para CRVA 83% (76-88%) y 78% (70-84%) y para TMC 70% (60-87%) y 59% (48-68%) respectivamente (p <0,001). Conclusiones: Durante los primeros 10 años de establecido un Heart Team para la toma de decisiones en EAo, se asignaron a TAVI aproximadamente la mitad y el resto se asignó por mitades a cirugía u observación. La sobrevida de los pacientes intervenidos fue similar a 2 años y mayor que la de los no intervenidos.

ABSTRACT As transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) became widespread, the need for a Heart Team (HT) arose to choose the best treatment. There are few reports regarding its usefulness. Objectives: To analyze treatment outcomes in patients with AS evaluated by a HT for 10 years. Methods: Consecutive enrollment of all patients with AS who were candidates for TAVI between January 2012 and July 2021 to choose the best treatment, including surgical aortic valve replacement (SAVR) and conservative medical management (CMM). Results: Out of 841 patients, 455 were assigned to TAVI (53%), 213 to SAVR (24%), and 183 to CMM (23%). The percentage assigned to TAVI has increased from 48% to 62% over time (p <0.05). Patients who underwent TAVI versus those who underwent SAVR were older (86 ± 7 vs. 83 ± 7 years), had a higher EUROSCORE II (6.2, 95% CI 5.7-6.6 vs. 5.6; 95% CI 4.4-6.5) and were frailer (1.62 ± 1 vs. 0.91 ± 1), in all cases p <0.01. Actuarial survival (95% CI) at 1 and 2 years was 88% (84-91%) and 82% (77-86%) for TAVI, 83% (76-88%) and 78% (70-84%) for SAVR, and 70% (60-87%) and 59% (48-68%) for CMM, respectively (p <0.001). Conclusions: For the first 10 years after a Heart Team was established for AS decision-making, approximately half of the patients were assigned to TAVI, and the rest were equally assigned in halves to either surgery or observation. Survival for patients who received interventions was similar at 2 years and higher than in those who did not.

[Role of polypills in cardiovascular risk reduction in primary prevention]. / Rol de las polipíldoras en la reducción del riesgo cardiovascular en prevención primaria.

Unlike medications that contain fixed-dose combinations, such as those recommended by clinical guidelines for treating high blood pressure, the so-called polypills contain several drugs that simultaneously treat two or more cardiovascular conditions or risk factors. They were proposed 2 decades ago, both for primary and secondary prevention with the hypothesis that they could have wide dissemination and population penetration, improving the use of therapeutics with proven benefits individually, thanks to an increase in patient adherence by reducing the number of daily tablets and also by having an equal or lower cost. In this simple review, we present a look at risk stratification different from that posed by clinical scores and summarize the benefits of polypills in the treatment of risk factors and in the reduction of major cardiovascular events. Additionally, we review the clinical messages of the HOPE-3 trial, which aim to control two of the most prevalent conditions, such as high blood pressure and high cholesterol, through a combination of candesartan, hydrochlorothiazide and rosuvastatin. Finally, we propose its potential indication in a heterogeneous health system such as that of our country, both at the population level based on intermediate or low risk, determined intuitively or using a risk calculator, as well as in the personalized care that is practiced in many health scenarios.

A diferencia de los medicamentos que contienen combinaciones de dosis fijas, como los recomendados por las guías clínicas para tratar la hipertensión arterial, las llamadas polipíldoras contienen varios fármacos que tratan simultáneamente dos o más afecciones cardiovasculares o factores de riesgo. Se propusieron hace 2 décadas, tanto para prevención primaria como secundaria, con la hipótesis de que tengan amplia difusión y penetración poblacional, es decir, que mejoren el uso de terapéuticas con probados beneficios en forma individual, gracias a un incremento en la adherencia de los pacientes al reducir el número de comprimidos diarios y también al tener un costo igual o menor. En esta revisión simple, planteamos una mirada de la estratificación del riesgo distinta a la planteada por los puntajes clínicos y resumimos los beneficios de las polipíldoras en el tratamiento de los factores de riesgo y en la reducción de eventos cardiovasculares mayores. Adicionalmente, repasamos los mensajes clínicos del ensayo HOPE-3, que apuntan a controlar dos de las condiciones más prevalentes, como son la hipertensión arterial y el colesterol elevado, mediante una combinación de candesartán, hidroclorotiazida y rosuvastatina. Finalmente, proponemos su potencial indicación en un sistema sanitario heterogéneo como el de nuestro país, tanto a nivel poblacional basado en el riesgo intermedio o bajo, determinado intuitivamente o usando un calculador de riesgo, así como también en la atención personalizada que se practica en muchos escenarios sanitarios.

Rol de las polipíldoras en la reducción del riesgo cardiovascular en prevención primaria / Role of polypills in cardiovascular risk reduction in primary prevention

Resumen A diferencia de los medicamentos que contienen combinaciones de dosis fijas, como los recomendados por las guías clínicas para tratar la hipertensión arterial, las llamadas polipíldoras contienen varios fármacos que tratan simultáneamente dos o más afecciones cardiovasculares o factores de riesgo. Se propusieron hace 2 décadas, tanto para prevención primaria como secundaria, con la hipótesis de que tengan amplia difusión y penetración poblacional, es decir, que mejoren el uso de terapéuticas con probados beneficios en forma individual, gracias a un incremento en la adherencia de los pacientes al reducir el número de com primidos diarios y también al tener un costo igual o menor. En esta revisión simple, planteamos una mirada de la estratificación del riesgo distinta a la planteada por los puntajes clínicos y resumimos los beneficios de las polipíldoras en el tratamiento de los factores de riesgo y en la reducción de eventos cardiovasculares mayores. Adicionalmente, repasamos los mensajes clínicos del ensayo HOPE-3, que apuntan a controlar dos de las con diciones más prevalentes, como son la hipertensión arterial y el colesterol elevado, mediante una combinación de candesartán, hidroclorotiazida y rosuvastatina. Finalmente, proponemos su potencial indicación en un sistema sanitario heterogéneo como el de nuestro país, tanto a nivel poblacional basado en el riesgo intermedio o bajo, determinado intuitivamente o usando un calculador de riesgo, así como también en la atención personalizada que se practica en muchos escenarios sanitarios.

Abstract Unlike medications that contain fixed-dose combinations, such as those recommended by clinical guidelines for treating high blood pressure, the so-called polypills contain several drugs that simultaneously treat two or more cardiovascular conditions or risk factors. They were proposed 2 decades ago, both for primary and secondary prevention with the hypothesis that they could have wide dissemination and population penetration, improving the use of therapeutics with proven benefits individually, thanks to an increase in patient adherence by reducing the number of daily tablets and also by having an equal or lower cost. In this simple review, we present a look at risk stratification different from that posed by clinical scores and summarize the benefits of polypills in the treatment of risk factors and in the reduction of major cardiovascular events. Additionally, we review the clinical messages of the HOPE-3 trial, which aim to control two of the most prevalent conditions, such as high blood pressure and high cholesterol, through a combination of candesartan, hydrochlorothiazide and rosuvastatin. Finally, we propose its potential indication in a heterogeneous health system such as that of our country, both at the population level based on intermediate or low risk, determined intuitively or using a risk calculator, as well as in the personalized care that is practiced in many health scenarios.

Recomendaciones de manejo de los anticoagulantes orales directos (DOACs) anti Xa y anti IIa / Recommendations for the practical management of the direct oral anticoagulants anti Xa and anti IIa

Resumen Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas pro piedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Abstract Direct oral anticoagulants have emerged as the drugs that have changed the man agement of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagu lants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

Uso de agentes hipolipemiantes y cumplimiento de metas terapéuticas en pacientes de alto riesgo cardiovascular en la República Argentina / Use of Lipid-Lowering Agents and Therapeutic Goal Achievement in Cardiovascular High-Risk Patients in Argentina

RESUMEN Introducción: Uno de los pilares fundamentales para la reducción del riesgo cardiovascular en pacientes en prevención secundaria es el correcto manejo del tratamiento hipolipemiante. Las estatinas en altas dosis, el ezetimibe, y más recientemente los inhibidores de PCSK9 (iPCSK9) son las principales herramientas farmacológicas con las que contamos para que estos pacientes cumplan metas terapéuticas de colesterol LDL (C-LDL). A pesar de la contundente evidencia a favor de estas terapéuticas, existe una gran subutilización de las mismas a nivel mundial, con bajos niveles de adherencia e inercia terapéutica. En Argentina existe escasa evidencia sobre la calidad del tratamiento hipolipemiante, y qué porcentaje de pacientes en prevención secundaria se encuentran con un perfil lipídico controlado acorde a guías nacionales e internacionales. Material y métodos: Diseñamos un estudio de corte transversal en pacientes en prevención secundaria de eventos cardiovasculares incluidos de forma prospectiva, consecutiva y multicéntrica en hospitales de la República Argentina que poseen sistema de Residencia Médica afiliados al Consejo Argentino de Residentes de Cardiología (CONAREC). Se realizó la recolección de datos durante los meses de marzo a agosto del año 2020. Se relevó el tratamiento hipolipemiante que recibían, los motivos detrás de la no utilización de estatinas en dosis adecuadas, y los valores de perfil lipídico en caso de contar con un registro en los últimos 6 meses previos a la inclusión. Resultados: Se incluyeron 1000 pacientes consecutivos de 24 centros, correspondientes a 11 provincias. Un 85,9% se encontraba bajo tratamiento con estatinas; un 4,8%, con ezetimibe; un 2,4% con fibratos; y un 13%, sin tratamiento. De aquellos pacientes en tratamiento con estatinas, un 67% recibía estatinas en altas dosis (58% del total de pacientes). Un total de 509 pacientes presentaban medición del C-LDL dentro de los últimos 6 meses. El valor promedio de C-LDL fue de 94 (90,6-97,8) mg/dL; el de C-LDL, 41 (40,7-42,6) mg/dL; y el de triglicéridos, 151 (142,9-159,8) mg/dL. Un 30% se encontraba con valores por debajo del corte de 70 mg/dL. Un 16% se encontraba con valores por debajo de 55 mg/dL. Un 37% de los pacientes presentaba C-LDL >100 mg/dL. Conclusiones: En este estudio multicéntrico de pacientes en prevención secundaria desarrollado en la República Argentina, poco más de la mitad presentaba tratamiento con estatinas en altas dosis, con una escasa utilización de ezetimibe. El subtratamiento se reflejó en los valores de C-LDL, con más de dos tercios de los pacientes fuera de rango terapéutico y, por lo tanto, lejos de las recomendaciones de las guías clínicas.

ABSTRACT Background: The correct management of lipid-lowering treatment is one of the key factors for the reduction of cardiovascular risk in secondary prevention patients. High-dose statins, ezetimibe, and more recently PCSK9 inhibitors (PCSK9i) are the main tools available to meet LDL cholesterol (LDL-C) therapeutic goals in these patients. Despite the overwhelming evidence in their favor, these therapies are greatly underutilized worldwide, with low levels of adherence and therapeutic inertia. In Argentina, there is scarce evidence on the quality of lipid-lowering treatment and the rate of patients in secondary prevention with a controlled lipid profile according to national and international guidelines. Methods: A prospective, multicenter, cross-sectional study including consecutive patients in secondary prevention for cardiovascular events from hospitals of Argentina with a Medical Residency system affiliated to CONAREC, was carried out from March to August 2020. Data was collected on the lipid-lowering treatment received, the reasons behind the non-use of statins in adequate doses and the lipid profile levels in case of having a record from the last 6 months prior to inclusion. Results: Among 1000 consecutive patients included from 24 centers corresponding to 11 provinces, 85.9% was treated with statins, 4.8% with ezetimibe, 2.4% with fibrates, and 13% was without treatment. In the case of patients treated with statin therapy, 67% was receiving high-dose statins (58% of the total number of patients). A total of 509 patients presented LDL-C assessment within the last 6 months. Mean LDL-C was 94 (90.6-97.8) mg/dl, HDL cholesterol 41 (40.7-42.6) mg/dl, and triglycerides 151 (142.9-159.8) mg/dl. In 30% of cases, LDL-C was below the cut-off value of 70 mg/dl and in 16% below 55 mg/ dl. In 37% of patients, LDL-C was >100 mg/dl. Conclusions: In this multicenter secondary prevention study performed in Argentina, just over half of the patients presented high-dose statin treatment, with scarce use of ezetimibe. Undertreatment was reflected in LDL-C values, with more than two-thirds of patients outside the therapeutic range, and therefore far from clinical guideline recommendations.

Injuria miocárdica luego de cirugía no cardíaca / Myocardial injury after non-cardiac surgery

Resumen Las complicaciones cardiovasculares mayores en el postoperatorio son frecuentes y el principal factor contribuyente es la injuria miocárdica o infarto (MINS, Myocardial Injury after Noncardiac Surgery) asociado a cirugía no cardíaca. El riesgo de mortalidad a 30 días de los pacientes con injuria miocárdica es 4-5 veces mayor que los pacientes que no lo presentan. Se estima que 85% de los pacientes con MINS no presentan síntomas, por lo que la única manera de detectarlos es mediante screening sistemático de troponinas. Si bien no existen intervenciones de aplicación sistemática que permitan prevenir esta complicación, existen alternativas de tratamiento y manejo, por lo que la pesquisa activa es costo-efectiva y relevante desde el punto de visto clínico.

Major cardiovascular complications in the postoperative period are frequent and the main contributing factor is myocardial injury or infarction (MINS, Myocardial Injury after Noncardiac Surgery) associated with non-cardiac surgery. The 30-day mortality risk in patients with myocardial injury is 4-5 times higher than in patients without this complication. It is estimated that 85% of patients with MINS/infarction are asymptomatic, hence the only way to detect them is through systematic screening of troponins. Although there are no systematic interventions to prevent this complication, there are treatment and management alternatives, so the active early diagnosis is cost effective and relevant from a clinical point of view.

Enfermedad cardiovascular en tiempos de COVID-19 / Cardiovascular disease in times of COVID-19

Existen crecientes informes sobre una drástica caída en consultas y realización de procedimientos cardiovasculares (incluyendo urgencias y emergencias) en regiones afectadas por la pandemia de COVID-19, con el consecuente incremento marcado de la mortalidad total que no se explica totalmente por las defunciones atribuidas a COVID-19. En Argentina, la enfermedad cardiovascular lidera el ranking de muertes en adultos con 280 muertes por día, y en las últimas décadas hemos reducido su mortalidad entre 20 y 30% mediante diversas intervenciones basadas en la evidencia. En el presente trabajo realizamos análisis predictivos para entender cuáles podrían ser las consecuencias de una peor implementación de dichas intervenciones. Estimamos que un menor control de los factores de riesgo cardiovascular de abril a octubre de 2020 podría causar hasta 10 500 nuevos casos prevenibles de enfermedad cardiovascular. En términos de infarto de miocardio, una caída del 40% al 60% del tratamiento de reperfusión podría incrementar la mortalidad del 3% al 5%. Un incremento marginal de riesgo relativo de 10% a 15% de muerte cardiovascular equivaldría a un exceso de 6000 a 9000 muertes evitables. En conclusión, dada la alta prevalencia y fatalidad de la enfermedad cardiovascular, incluso un pequeño impacto negativo en la eficacia de su cuidado se traducirá en grandes cantidades de afectados en Argentina. Es necesario informar a las autoridades y educar al público para que sigan controlando enfermedades cardiovasculares y sus factores de riesgo, siempre que existan recursos y minimizando el riesgo de contagio y propagación del virus.

There are increasing reports of a drastic drop in consultations and cardiovascular procedures (including urgencies and emergencies) in regions affected by the COVID-19 pandemic, with a consequent marked increase in total mortality that is not fully explained by COVID-19. Cardiovascular disease leads the ranking in deaths in adults in Argentina with 280 deaths per day, and in recent decades we have reduced its mortality by 20-30% through various evidence-based interventions. Herein we conducted predictive analyses to understand what could be the consequences of a worse implementation of those interventions. We estimate that less control of cardiovascular risk factors from April to October 2020 could cause up to 10 500 new preventable cases of cardiovascular disease. In terms of myocardial infarction, a drop from 40% to 60% of the reperfusion treatment could increase mortality by 3% to 5%. A marginal 10% to 15% increase in relative risk of cardiovascular death would be equivalent to an excess of 6000 to 9000 preventable deaths. In conclusion, given the high prevalence and fatality of cardiovascular disease, even a small negative impact on the efficacy of its care will translate into large numbers of people affected in Argentina. It is necessary to inform the authorities and educate the public so cardiovascular diseases and their risk factors remain a health priority, as long as resources exist and minimizing the risk of contagion and spread of the virus.

Improved identification of secondary hypertension: use of a systematic protocol.

BACKGROUND: The accurate identification and diagnosis of secondary hypertension is critical, especially while atherosclerotic cardiovascular heart disease continues to be the leading cause of death in the industrialized world. Nevertheless, despite the existence of diagnostic tools, there are significant variations of the estimated prevalence of secondary hypertension, due to multiple etiologies and suboptimal recognition. This study demonstrates the results of using a systematic and protocolled approach to improve recognition of the presence of secondary hypertension. In the future, this questionnaire can be a quick and effective tool to unveil secondary hypertension in a broad array of clinical settings. METHODS: A total of 28,633 consecutive patients from January 1, 2007 to January 1, 2017 were diagnosed as having primary or secondary hypertension, utilizing the International Code of Diseases. Patients were located at the Center of Hypertension, Institute of Cardiology at Austral University Hospital, Buenos Aires, Argentina and were then further classified as having TRH, or non-resistant hypertension, to which a systematic protocol was employed in search for secondary hypertension. The confirmation of secondary hypertension was subsequently confirmed by diagnostic laboratory and imaging techniques in a hospital setting. RESULTS: A final population of 12,284 patients with treatment resistant hypertension (TRH) and non-treatment resistant hypertension (NTRH) were included in this study, where an etiology of secondary hypertension was identified in 50.9% and 36% of patients in each treatment group, respectively. Physicians used confirmatory laboratory testing and imaging of patients who were identified as having a cause for their secondary hypertension, with no significant differences in sex, age and body mass index (BMI) among study groups. CONCLUSIONS: These results illustrate the prevalence and distribution of the causes of secondary hypertension using a systematic, protocolled approach, which revealed a higher percentage of secondary hypertension than previously reported. This tool may be used by healthcare providers to ensure the appropriate recognition of secondary causes of hypertension in a wider range of patients with high blood pressure beyond resistant hypertension, changing the diagnostic paradigm of this condition.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. METHODS: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. FINDINGS: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76). INTERPRETATION: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]. FUNDING: Boehringer Ingelheim and Canadian Institutes of Health Research.

Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE).

BACKGROUND: Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS. METHODS: The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients. RESULTS: The trial randomized 1754 patients between January 2013 and July 2017. Patients' mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants. CONCLUSION: MANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS.

Frequency of early vascular aging and associated risk factors among an adult population in Latin America: the OPTIMO study.

The main objective was to estimate the frequency of early vascular aging (EVA) in a sample of subjects from Latin America, with emphasis in young adults. We included 1416 subjects from 12 countries in Latin America who provided information about lifestyle, cardiovascular risk factors (CVRF), and anthropometrics. We measured pulse wave velocity (PWV) as a marker of arterial stiffness, and blood pressure (BP) using an oscillometric device (Mobil-O-Graph). To determine the frequency of EVA, we used multiple linear regression to estimate each subject's PWV expected for his/her age and systolic BP, and compared with observed values to obtain standardized residuals (z-scores). We defined EVA when z-score was ≥1.96. Finally, a multivariable logistic regression analysis was performed to determine baseline characteristics associated with EVA. Mean age was 49.9 ± 15.5 years, male gender was 50.3%. Mean PWV was 7.52 m/s (SD 1.97), mean systolic BP was 125.3 mmHg (SD 16.7) and mean diastolic BP was 78.9 mmHg (SD 12.2). The frequency of EVA was 5.7% in the total population, 9.8% in adults of 40 years or less and 18.7% in those 30 years or less. In these young adults, multiple logistic regression analyses demonstrated that dyslipidemia and hypertension showed an independent association with EVA, and smoking a borderline association (p = 0.07). In conclusion, the frequency of EVA in a sample from Latin America was around 6%, with higher rates in young adults. These results would support the search of CVRF and EVA during early adulthood.

Period-dependent Associations between Hypotension during and for Four Days after Noncardiac Surgery and a Composite of Myocardial Infarction and Death: A Substudy of the POISE-2 Trial.

BACKGROUND: The relative contributions of intraoperative and postoperative hypotension to perioperative morbidity remain unclear. We determined the association between hypotension and a composite of 30-day myocardial infarction and death over three periods: (1) intraoperative, (2) remaining day of surgery, and (3) during the initial four postoperative days. METHODS: This was a substudy of POISE-2, a 10,010-patient factorial-randomized trial of aspirin and clonidine for prevention of myocardial infarction. Clinically important hypotension was defined as systolic blood pressure less than 90 mmHg requiring treatment. Minutes of hypotension was the exposure variable intraoperatively and for the remaining day of surgery, whereas hypotension status was treated as binary variable for postoperative days 1 to 4. We estimated the average relative effect of hypotension across components of the composite using a distinct effect generalized estimating model, adjusting for hypotension during earlier periods. RESULTS: Among 9,765 patients, 42% experienced hypotension, 590 (6.0%) had an infarction, and 116 (1.2%) died within 30 days of surgery. Intraoperatively, the estimated average relative effect across myocardial infarction and mortality was 1.08 (98.3% CI, 1.03, 1.12; P < 0.001) per 10-min increase in hypotension duration. For the remaining day of surgery, the odds ratio was 1.03 (98.3% CI, 1.01, 1.05; P < 0.001) per 10-min increase in hypotension duration. The average relative effect odds ratio was 2.83 (98.3% CI, 1.26, 6.35; P = 0.002) in patients with hypotension during the subsequent four days of hospitalization. CONCLUSIONS: Clinically important hypotension-a potentially modifiable exposure-was significantly associated with a composite of myocardial infarction and death during each of three perioperative periods, even after adjustment for previous hypotension.

Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery.

IMPORTANCE: Little is known about the relationship between perioperative high-sensitivity troponin T (hsTnT) measurements and 30-day mortality and myocardial injury after noncardiac surgery (MINS). OBJECTIVE: To determine the association between perioperative hsTnT measurements and 30-day mortality and potential diagnostic criteria for MINS (ie, myocardial injury due to ischemia associated with 30-day mortality). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of patients aged 45 years or older who underwent inpatient noncardiac surgery and had a postoperative hsTnT measurement. Starting in October 2008, participants were recruited at 23 centers in 13 countries; follow-up finished in December 2013. EXPOSURES: Patients had hsTnT measurements 6 to 12 hours after surgery and daily for 3 days; 40.4% had a preoperative hsTnT measurement. MAIN OUTCOMES AND MEASURES: A modified Mazumdar approach (an iterative process) was used to determine if there were hsTnT thresholds associated with risk of death and had an adjusted hazard ratio (HR) of 3.0 or higher and a risk of 30-day mortality of 3% or higher. To determine potential diagnostic criteria for MINS, regression analyses ascertained if postoperative hsTnT elevations required an ischemic feature (eg, ischemic symptom or electrocardiography finding) to be associated with 30-day mortality. RESULTS: Among 21 842 participants, the mean age was 63.1 (SD, 10.7) years and 49.1% were female. Death within 30 days after surgery occurred in 266 patients (1.2%; 95% CI, 1.1%-1.4%). Multivariable analysis demonstrated that compared with the reference group (peak hsTnT <5 ng/L), peak postoperative hsTnT levels of 20 to less than 65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0% (123/4049; 95% CI, 2.6%-3.6%), 9.1% (102/1118; 95% CI, 7.6%-11.0%), and 29.6% (16/54; 95% CI, 19.1%-42.8%), with corresponding adjusted HRs of 23.63 (95% CI, 10.32-54.09), 70.34 (95% CI, 30.60-161.71), and 227.01 (95% CI, 87.35-589.92), respectively. An absolute hsTnT change of 5 ng/L or higher was associated with an increased risk of 30-day mortality (adjusted HR, 4.69; 95% CI, 3.52-6.25). An elevated postoperative hsTnT (ie, 20 to <65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) without an ischemic feature was associated with 30-day mortality (adjusted HR, 3.20; 95% CI, 2.37-4.32). Among the 3904 patients (17.9%; 95% CI, 17.4%-18.4%) with MINS, 3633 (93.1%; 95% CI, 92.2%-93.8%) did not experience an ischemic symptom. CONCLUSIONS AND RELEVANCE: Among patients undergoing noncardiac surgery, peak postoperative hsTnT during the first 3 days after surgery was significantly associated with 30-day mortality. Elevated postoperative hsTnT without an ischemic feature was also associated with 30-day mortality.

Clonidine in patients undergoing noncardiac surgery.

BACKGROUND: Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent perioperative myocardial infarction and death without inducing hemodynamic instability. METHODS: We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. RESULTS: Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02). CONCLUSIONS: Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Aspirin in patients undergoing noncardiac surgery.

BACKGROUND: There is substantial variability in the perioperative administration of aspirin in patients undergoing noncardiac surgery, both among patients who are already on an aspirin regimen and among those who are not. METHODS: Using a 2-by-2 factorial trial design, we randomly assigned 10,010 patients who were preparing to undergo noncardiac surgery and were at risk for vascular complications to receive aspirin or placebo and clonidine or placebo. The results of the aspirin trial are reported here. The patients were stratified according to whether they had not been taking aspirin before the study (initiation stratum, with 5628 patients) or they were already on an aspirin regimen (continuation stratum, with 4382 patients). Patients started taking aspirin (at a dose of 200 mg) or placebo just before surgery and continued it daily (at a dose of 100 mg) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin regimen. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. RESULTS: The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P=0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P=0.04). The primary and secondary outcome results were similar in the two aspirin strata. CONCLUSIONS: Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. METHODS: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. RESULTS: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. CONCLUSION: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Recuento de glóbulos blancos como predictor de hallazgos angiográficos y eventos clínicos en los síndromes coronarios agudos sin supradesnivel del segmento ST.: Subanálisis del estudio PACS angiográfico / Leukocyte Count as Predictor of Angiographic Findings and Clinical Events in Non-ST-Segment Elevation Acute Coronary Syndromes.: Sub-analysis of the PACS Angiographic Study

Introducción La relación entre los marcadores inflamatorios y los síndromes coronarios agudos se ha estudiado previamente. PACS (Prognosis in Acute Coronary Syndromes) fue un estudio prospectivo multicéntrico que se desarrolló entre enero de 2000 y mayo de 2002 en 11 unidades coronarias de la Argentina e incluyó pacientes con síndrome coronario agudo sin elevación del segmento ST (SCASEST) con el objetivo de determinar el valor pronóstico de los diferentes biomarcadores, solos o en combinación en la estratificación de riesgo. Sin embargo, la relación de la elevación de leucocitos con los hallazgos angiográficos y los eventos a mediano plazo se ha estudiado escasamente. Objetivo Determinar si el nivel de leucocitos al ingreso se relaciona con lesiones coronarias complejas y pronóstico adverso a los 6 meses en pacientes internados con SCASEST. Material y métodos El subestudio PACS angiográfico comprendió un subgrupo de 1.253 pacientes de la cohorte del estudio PACS central (cuya población total fue de 1.500 pacientes) e incluyó centros con disponibilidad de cinecoronariografía (CCG). De los 1.253 pacientes del subestudio, se realizó una CCG (media de tiempo 48 horas del ingreso, percentiles 25-75, 24-72 horas) en 633 (50,5%). Para el presente subanálisis se obtuvieron datos completos de 580 pacientes (46,2%). En estos, además de lo establecido en el protocolo PACS de biomarcadores, se analizó el recuento de leucocitos en sangre dentro de las 24 horas de la admisión. La población se dividió en percentiles según el recuento leucocitario al ingreso. En el percentil inferior se incluyeron los pacientes con un recuento inicial de glóbulos blancos < 7.700/mm³, en el percentil intermedio los pacientes con un recuento de entre 7.700 y 11.500/mm³ y en el percentil superior aquellos con > 11.500/mm³. Resultados De los 580 pacientes, la mayoría eran hombres (72,9%), edad media de 66 años (± 12). Tenían antecedentes de hipertensión el 64,4%, de diabetes el 17,9%, historia de infarto previo el 22,2%, riesgo clínico alto (ACC/AHA) el 60% y el electrocardiograma de ingreso mostró alteración del segmento ST o T en el 61,1%. El recuento de leucocitos superior a 11.500/mm³ se asoció con una tasa mayor de trombo visible, presencia de placa complicada y mayor extensión de enfermedad coronaria (p = 0,019, 0,033 y 0,07, respectivamente). En el seguimiento a 6 meses, los pacientes del percentil superior tuvieron mayor tendencia a muerte o infarto que los pacientes del percentil inferior (14,2% vs. 7,5%; p = 0,026). Conclusión En los pacientes con SCASEST, un recuento elevado de leucocitos al ingreso se asocia con lesiones coronarias complejas y peor pronóstico a los 6 meses.

Background Previous studies have analyzed the relationship between inflammatory markers and acute coronary syndromes. Prognosis in Acute Coronary Syndromes (PACS) is a prospective, multicentric study conducted between January 2000 and May 2002 in 11 coronary care units of Argentina. It determined the prognostic value of different biomarkers, alone or in combination, to stratify risk in patients with non-ST-segment elevation acute coronary syndromes (NSTEACS). However, there are few studies on the relationship of increased leuko-cyte levels with angiographic findings and mid-term events. Objective The aim of the study was to establish whether leukocyte count at admission is associated with complex coronary disease and adverse prognosis at 6-month follow-up in patients with NSTEACS. Methods The angiographic PACS substudy was conducted in 1253 patients from the PACS study core group (with a population of 1500 patients) and it included centers with coronary angiography (CA). Out of the 1253 substudy patients, CA was performed in 633 (50.5%) (mean of 48 hours after admission, percentiles 25-75, 24-72 hours). To perform the sub-analysis, complete data were obtained from 580 patients (46.2%). In this group, leukocyte count within 24 hours of admission was analyzed in addition to tests performed in the biomarkers PACS protocol. The population was divided in percentiles according to admission leukocyte count. Patients with initial leukocytes < 7700/ mm³ were included in the lower percentile, patients with leukocyte count between 7700 and 11500/mm³ in the middle percentile and those with leukocyte count > 11500/mm³ in the higher percentile. Results Most of the 580 patients were men (72.9%), and mean age was 66±12 years. Among these patients, 64.4% had history of hypertension, 17.9% of diabetes, 22.2% of previous infarction, 60% presented high clinical risk (ACC/AHA) and 61.1% had ECG at admission with ST-segment or T wave alterations. Leukocyte count > 11500/mm³ was associated with higher rate of visible thrombus, presence of complicated plaque and more extensive coronary disease (p = 0.019, 0.033 and 0.07, respectively). At the 6-month follow-up, patients in the higher percentile had greater tendency of death or infarction than patients in the lower percentile (14.2% vs. 7.5%; p = 0.026). Conclusion In patients with NSTEACS, a high leukocyte count at admission is associated with complex coronary disease and worse prognosis at 6 month-follow-up.

Revisiting sample size: are big trials the answer?

The superiority of the evidence generated in randomized controlled trials over observational data is not only conditional to randomization. Randomized controlled trials require proper design and implementation to provide a reliable effect estimate. Adequate random sequence generation, allocation implementation, analyses based on the intention-to-treat principle, and sufficient power are crucial to the quality of a randomized controlled trial. Power, or the probability of the trial to detect a difference when a real difference between treatments exists, strongly depends on sample size. The quality of orthopaedic randomized controlled trials is frequently threatened by a limited sample size. This paper reviews basic concepts and pitfalls in sample-size estimation and focuses on the importance of large trials in the generation of valid evidence.

Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery.

CONTEXT: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE: To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS: A total of 15,133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT ≤ 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSION: Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study.

OBJECTIVES: To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay. DESIGN AND METHODS: We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults. RESULTS: Postoperatively 45% (95% CI: 39-50%) of patients had hs-TnT≥14ng/L and 22% (95% CI:17-26%) had an elevation (≥14ng/L) and change (>85%) in hs-TnT. CONCLUSION: Further research is needed to inform the optimal hs-TnT threshold and change in this setting.