Can we still consider treatment with colchicine effective in SARS-COV-2 infection? Systematic review, meta-analysis, and trial sequential analysis.

OBJECTIVE: To assess the effectiveness of colchicine, compared with standard of care, for reducing mortality, admission to intensive care, and use of mechanical ventilation. MATERIALS AND METHODS: We performed a systematic review, meta-analysis, and sequential trial analysis. The terms (SARS-CoV-2 OR COVID-19 OR coronavirus) AND (colchicine) were searched in MEDLINE, Scopus, Embase, Cochrane Central Register of Controlled Trials, and preprint repositories (February 2020 to April 2021, extended to June 2021). Risk of bias for randomised controlled trials and observational studies were assessed using the tools RoB 2.0 and ROBINS-I, respectively. We performed subgroup analyses based on study design and sensitivity analyses based on time of colchicine administration. RESULTS: We included six observational studies (1329 patients) and five clinical trials (16,048 patients). All studies but one were conducted in the hospital setting. Colchicine treatment was not associated with a significant decrease in mortality (RR 0.93, 95% CI 0.87 to 1; p=0.06, I2=72%) with a significant subgroup effect (p<0.001) depending on the design of the studies. The drug was effective in observational studies (RR 0.57, 95% CI 0.46 to 0.70, p<0.001, I2=50%) but not in clinical trials (RR 0.99, 95% CI 0.92 to 1.07, p=0.89, I2=21%). The effect of colchicine on intensive care admissions and the need for mechanical ventilation could not be confirmed. Trial sequential boundaries for cumulative meta-analyses of randomised controlled trials suggested no significant effect on mortality (p=0.182) beyond the optimal information size (13,107 patients). CONCLUSIONS: Our results suggest that colchicine treatment has no effect on mortality in hospitalised patients with SARS-CoV-2 infection, and that no further confirmatory clinical trials are needed owing to futility.

Investigación en el enfermo crítico. Dificultades y perspectivas / Clinical research in critical care. Difficulties and perspectives

En el ámbito de la medicina intensiva, el aumento de la supervivencia ha venido de la mano de la mejora de los cuidados, la detección precoz del deterioro clínico y la prevención de la iatrogenia, mientras que la investigación de nuevos tratamientos se ha seguido de una abrumadora serie de decepciones. Las raíces de estos fracasos hay que buscarlas en la conjunción de problemas metodológicos -comunes a otras disciplinas- y las particularidades de los pacientes críticos. En este artículo se exploran ambos aspectos y se sugieren algunas vías de progreso

In the field of Intensive Care Medicine, improved survival has resulted from better patient care, the early detection of clinical deterioration, and the prevention of iatrogenic complications, while research on new treatments has been followed by an overwhelming number of disappointments. The origins of these fiascos must be sought in the conjunction of methodological problems - common to other disciplines - and the particularities of critically ill patients. The present article discusses both aspects and suggests some options for progress

Clinical research in critical care. Difficulties and perspectives. / Investigación en el enfermo crítico. Dificultades y perspectivas.

In the field of Intensive Care Medicine, improved survival has resulted from better patient care, the early detection of clinical deterioration, and the prevention of iatrogenic complications, while research on new treatments has been followed by an overwhelming number of disappointments. The origins of these fiascos must be sought in the conjunction of methodological problems - common to other disciplines - and the particularities of critically ill patients. The present article discusses both aspects and suggests some options for progress.

Respuesta de los autores: Accesibilidad al sistema sanitario de los pacientes diabéticos con síndrome coronario agudo con elevación del segmento ST / Author's reply: Accessibility to healthcare of diabetic patients with acute coronary syndrome with ST-segment elevation

No disponible

Respuesta de los autores: Educación y concienciación en el paciente diabético con síndrome coronario agudo con elevación del ST / Author's reply: Education and awareness in the diabetic patient with ST-segment elevation acute coronary syndrome

No disponible

Estrategia invasiva de rutina en el síndrome coronario agudo sin elevación del segmento ST con disfunción renal. Resultados del registro ARIAM-SEMICYUC / Routine invasive strategy in acute coronary syndrome patients with renal dysfunction. Results of the ARIAM-SEMICYUC registry

OBJETIVO: Evaluar la utilización y efectividad de la estrategia invasiva de rutina (EIR) en pacientes con síndrome coronario agudo sin elevación de ST con disfunción renal en el mundo real. MÉTODOS: Estudio de cohortes retrospectivo basado en el registro ARIAM-SEMICYUC (años 2011-2014). Se consideró que había disfunción renal cuando el GFR (Cockroft-Gault) era menor de 60 ml/min (disfunción moderada) o de 30 ml/min (disfunción grave). Se excluyeron los pacientes en los que la coronariografía precoz (< 72 h) se debió a shock cardiogénico o isquemia recurrente. El desenlace primario fue la mortalidad hospitalaria. El control del confounding se realizó mediante un análisis de propensión. RESULTADOS: Se analizan 4.279 pacientes, de los cuales un 26% tenía disfunción renal moderada y un 5% disfunción grave. Los pacientes con disfunción renal presentaron una mayor gravedad y comorbilidad, una mayor mortalidad hospitalaria (8,6 frente a 1,8%) y una menor utilización de la EIR (40 frente a 52%). Las OR ajustadas mediante emparejamiento para pacientes sin/con disfunción renal fueron de 0,38 (intervalo de confianza al 95% [IC 95%] de 0,17 a 0,81) y 0,52 (IC 95% de 0,32 a 0,87), respectivamente (p de interacción 0,4779). El impacto de la EIR (diferencia de riesgos ajustada) fue mayor en el grupo con disfunción renal (-5,1%, IC 95% entre -8,1 y -2,1, frente a --1,6%, IC 95% entre -2,6 y -0,6, p de interacción = 0,0335). Tampoco se detectó interacción significativa respecto a los demás enlaces considerados (mortalidad en UCI o a los 30 días, riesgo combinado de muerte o infarto, fracaso renal agudo o hemorragias moderadas/graves) . CONCLUSIONES: Los resultados evidencian que la efectividad de la EIR es similar en pacientes con función renal normal o reducida y alertan sobre una infrautilización de esta estrategia en estos últimos

OBJECTIVE: To evaluate the use and effectiveness of a routine invasive strategy (RIS) in patients with acute coronary syndrome without persistent ST-segment elevation with renal dysfunction in the real world scenario. METHODS: A retrospective cohort study based on the ARIAM-SEMICYUC Registry (2011-2014) was carried out. Renal dysfunction was defined as GFR (Cockroft-Gault) < 60 ml/min (moderate dysfunction) or < 30 ml/min (severe dysfunction). Patients in which early angiography (< 72h) was performed due to cardiogenic shock or recurrent myocardial ischemia were excluded. The primary endpoint was hospital mortality. Confounding factors were controlled using propensity score analysis. RESULTS: A total of 4,279 patients were analyzed, of which 26% had moderate renal dysfunction and 5% severe dysfunction. Patients with renal dysfunction had greater severity and comorbidity, higher hospital mortality (8.6 vs. 1.8%), and lesser use of the RIS (40 vs. 52%). The adjusted OR for mortality in patients without/with renal dysfunction were 0.38 (95% confidence interval [95% CI] 0.17 to 0.81) and 0.52 (95% CI 0.32 to 0.87), respectively (interaction P-value = .4779). The impact (adjusted risk difference) of RIS was higher in the group with renal dysfunction (-5.1%, 95% CI -8.1 to -2.1 vs. -1.6%, 95% CI -2.6 to -0.6; interaction P-value = .0335). No significant interaction was detected for the other endpoints considered (ICU mortality, 30-day mortality, myocardial infarction, acute renal failure or moderate/severe bleeding). CONCLUSIONS: The results suggest that the effectiveness of IRS is similar in patients with normal or abnormal renal function, and alert to the under-utilization of this strategy in such patients

Accesibilidad al sistema sanitario de los pacientes diabéticos con síndrome coronario agudo con elevación del segmento ST / Accessibility to health care of diabetic patients with acute coronary syndrome ST-segment elevation

OBJETIVOS: El objetivo de este estudio es medir la accesibilidad al sistema sanitario de los pacientes diabéticos y analizar si las posibles diferencias en la accesibilidad explican la mayor mortalidad conocida en aquellos. MÉTODOS: Estudio de cohortes retrospectivo, realizado en pacientes diabéticos con síndrome coronario agudo con elevación del segmento ST incluidos en los años 2010 al 2013 del registro ARIAM-SEMICYUC. Se realiza análisis crudo y ajustado mediante regresión logística no condicional. RESULTADOS: Se han analizado 4817 pacientes, de los cuales 1070 (22,2%) son diabéticos. Los pacientes diabéticos contactan con el sistema sanitario de la misma forma que los pacientes no diabéticos aunque con mayor retraso (retraso atribuible al paciente 90 min vs. 75 min con p = 0,004 y retraso prehospitalario 150 min vs. 130 min con p = 0,002). Una vez dentro del sistema sanitario, estos pacientes tienen menor tasa de reperfusión (50 vs. 57,7%; p < 0,001) pero sin objetivar mayor retraso en el tratamiento. Como ya es conocido, los pacientes diabéticos presentan una mayor mortalidad hospitalaria (12,5 vs. 6%; p < 0,001); sin embargo, no se identifican como variables predictoras independientes de la mortalidad ni el retraso atribuible al paciente ni el retraso prehospitalario. CONCLUSIONES: Los pacientes diabéticos tienen una mayor demora en el acceso al sistema sanitario, sin embargo no hemos podido objetivar que esta demora se relacione de forma independiente con la mayor mortalidad

OBJECTIVES: To measure accessibility to health care among diabetic patients and analyze whether differences in delay explain differences in hospital mortality. METHODS: A retrospective cohort study was conducted in diabetic patients with acute coronary syndrome with ST-segment elevation included in the ARIAM-SEMICYUC registry (2010-2013). Crude and adjusted analyses were performed using unconditional logistic regression. RESULTS: A total of 4817 patients were analyzed, of whom 1070 (22.2%) were diabetics. No differences were found in access to health care between diabetic and non-diabetic patients. Diabetic patients presented with longer patient delay (90 min vs. 75 min; p = .004) and prehospital delay (150min vs. 130 min; p = .002). Once the health system was contacted, diabetic patients had a lower reperfusion rate (50% vs. 57.7%; p < .001), but no longer delay in treatment was observed compared with the non-diabetic individuals. Diabetic patients have greater in-hospital mortality (12.5 vs. 6%; p < .001), though neither patient delay nor prehospital delay were identified as independent predictors of in-hospital mortality. CONCLUSIONS: Diabetic patients had a longer delay in access to health care, though such delay was not independently related to increased mortality

Routine invasive strategy in acute coronary syndrome patients with renal dysfunction. Results of the ARIAM-SEMICYUC registry. / Estrategia invasiva de rutina en el síndrome coronario agudo sin elevación del segmento ST con disfunción renal. Resultados del registro ARIAM-SEMICYUC.

OBJECTIVE: To evaluate the use and effectiveness of a routine invasive strategy (RIS) in patients with acute coronary syndrome without persistent ST-segment elevation with renal dysfunction in the real world scenario. METHODS: A retrospective cohort study based on the ARIAM-SEMICYUC Registry (2011-2014) was carried out. Renal dysfunction was defined as GFR (Cockroft-Gault)<60ml/min (moderate dysfunction) or<30ml/min (severe dysfunction). Patients in which early angiography (<72h) was performed due to cardiogenic shock or recurrent myocardial ischemia were excluded. The primary endpoint was hospital mortality. Confounding factors were controlled using propensity score analysis. RESULTS: A total of 4,279 patients were analyzed, of which 26% had moderate renal dysfunction and 5% severe dysfunction. Patients with renal dysfunction had greater severity and comorbidity, higher hospital mortality (8.6 vs. 1.8%), and lesser use of the RIS (40 vs. 52%). The adjusted OR for mortality in patients without/with renal dysfunction were 0.38 (95% confidence interval [95%CI] 0.17 to 0.81) and 0.52 (95%CI 0.32 to 0.87), respectively (interaction P-value=.4779). The impact (adjusted risk difference) of RIS was higher in the group with renal dysfunction (-5.1%, 95%CI -8.1 to -2.1 vs. -1.6%, 95%CI -2.6 to -0.6; interaction P-value=.0335). No significant interaction was detected for the other endpoints considered (ICU mortality, 30-day mortality, myocardial infarction, acute renal failure or moderate/severe bleeding). CONCLUSIONS: The results suggest that the effectiveness of IRS is similar in patients with normal or abnormal renal function, and alert to the under-utilization of this strategy in such patients.

[Accessibility to health care of diabetic patients with acute coronary syndrome ST-segment elevation]. / Accesibilidad al sistema sanitario de los pacientes diabéticos con síndrome coronario agudo con elevación del segmento ST.

OBJECTIVES: To measure accessibility to health care among diabetic patients and analyze whether differences in delay explain differences in hospital mortality. METHODS: A retrospective cohort study was conducted in diabetic patients with acute coronary syndrome with ST-segment elevation included in the ARIAM-SEMICYUC registry (2010-2013). Crude and adjusted analyses were performed using unconditional logistic regression. RESULTS: A total of 4817 patients were analyzed, of whom 1070 (22.2%) were diabetics. No differences were found in access to health care between diabetic and non-diabetic patients. Diabetic patients presented with longer patient delay (90 min vs. 75 min; p=.004) and prehospital delay (150 min vs. 130 min; p=.002). Once the health system was contacted, diabetic patients had a lower reperfusion rate (50% vs. 57.7%; p<.001), but no longer delay in treatment was observed compared with the non-diabetic individuals. Diabetic patients have greater in-hospital mortality (12.5 vs. 6%; p <.001), though neither patient delay nor prehospital delay were identified as independent predictors of in-hospital mortality. CONCLUSIONS: Diabetic patients had a longer delay in access to health care, though such delay was not independently related to increased mortality.

Respuesta de los autores: Predictores del uso de la estrategia invasiva precoz en mujeres con síndrome coronario agudo sin elevación de ST / Author's reply: Predictors of the use of the early invasive strategy in women with non-ST-elevation acute coronary syndrome

No disponible

[Predictors of the use of the early invasive strategy in women with non-ST-elevation acute coronary syndrome]. / Predictores del uso de la estrategia invasiva precoz en mujeres con síndrome coronario agudo sin elevación de ST.

OBJECTIVE: To identify determinants associated to an early invasive strategy in women with acute coronary syndromes without ST elevation (NSTE-ACS). DESIGN: A retrospective cohort study was made. Crude and adjusted analysis of the performance of the early invasive strategy using logistic regression. SETTING: Coronary Units enrolled in 2010 - 2011 in the ARIAM-SEMICYUC registry. PATIENTS: A total of 440 women with NSTE-ACS were studied. Sixteen patients were excluded due to insufficient data, together with 58 patients subjected to elective coronary angiography (> 72 h). VARIABLES ANALYZED: Demographic parameters, coronary risk factors, previous medication, comorbidity. Clinical, laboratory, hemodynamic and electrocardiographic data of the episode. RESULTS: Women treated conservatively were of older age, had oral anticoagulation, diabetes, previous coronary lesions, and heart failure (p<0.005), increased baseline bleeding and ischemic risk (p=0.05) and a higher heart rate upon admission (p<0.05). After adjustment, only age > 80 years (OR 0.48, 95% CI 0.27 to 0.82, p=0.009), known coronary lesions (OR 0.47, 95% CI 0.26-0.84, p=0.011), and heart rate (OR 0.98, 95% CI 0.97-0.99, p=0.003) were independently associated to conservative treatment. Smoking (OR 2.50, 95% CI 1.20 to 5.19, p=0.013) and high-risk electrocardiogram (OR 2.96, 95% CI 1.72 to 4.97, p<0.001) were associated to the early invasive strategy. The exclusion of early deaths (<24 h) did not alter these results. CONCLUSIONS: In women with NSTE ACS, smoking and a high-risk electrocardiogram upon admission were independent factors associated to the early invasive strategy. Previous coronary lesions, age > 80 years and increased heart rate were independent factors associated to conservative treatment.

Nuevas recomendaciones sobre la utilización de soluciones de albúmina humana en pacientes con sepsis grave y shock séptico. Una evaluación crítica de la literatura / New recommendations on the use of human albumin solutions in patients with severe sepsis and septic shock. A critical evaluation of the literature

La tercera edición de las guías de la Surviving Sepsis Campaign de 2012 abre las puertas a la utilización de albúmina en el soporte hemodinámico de los pacientes con sepsis grave y shock séptico. Estas recomendaciones se apoyan en un reciente metaanálisis que incluye estudios con indicios de una insuficiente expansión plasmática en el grupo control y estudios realizados en niños con malaria con clara heterogeneidad estadística (p de interacción=0,02). Al excluir estos últimos, el intervalo de confianza del estimador de efecto fue compatible con un exceso de mortalidad en el grupo tratado con albúmina (OR=0,87 [IC95%: 0,71-1,07]). Tras la publicación del metaanálisis se han comunicado los resultados de nuevos estudios aleatorizados que no han encontrado beneficio en los pacientes tratados con albúmina. Dada la incertidumbre acerca del verdadero efecto de la albúmina (debido a la existencia de datos indirectos y a imprecisión) y el coste de la albúmina, se sugiere no utilizar albúmina en la reanimación inicial de pacientes con sepsis grave y shock séptico (GRADE2C) (AU)

The third edition of the Surviving Sepsis Campaign guidelines opens the door to the use of albumin for fluid resuscitation in patients with severe sepsis and septic shock. This recommendation is based on a recent meta-analysis that included studies with evidence of insufficient plasma expansion in the control group and studies performed in children with malaria with clear statistical heterogeneity (P for interaction=.02). After excluding pediatric studies, the confidence interval of the effect estimate was consistent with a mortality excess in the group treated with albumin (OR=.87 [95%CI: .71 to 1.07]). Two new randomized studies reported after publication of the meta-analysis found no benefit in patients treated with albumin. Given the uncertainty about the true effect of albumin (due to the existence of indirectness and imprecision) and its cost considerations, it is suggested not to use albumin in the initial resuscitation of patients with severe sepsis and septic shock (GRADE2C) (AU)

[New recommendations on the use of human albumin solutions in patients with severe sepsis and septic shock. A critical evaluation of the literature]. / Nuevas recomendaciones sobre la utilización de soluciones de albúmina humana en pacientes con sepsis grave y shock séptico. Una evaluación crítica de la literatura.

The third edition of the Surviving Sepsis Campaign guidelines opens the door to the use of albumin for fluid resuscitation in patients with severe sepsis and septic shock. This recommendation is based on a recent meta-analysis that included studies with evidence of insufficient plasma expansion in the control group and studies performed in children with malaria with clear statistical heterogeneity (P for interaction=.02). After excluding pediatric studies, the confidence interval of the effect estimate was consistent with a mortality excess in the group treated with albumin (OR=.87 [95%CI: .71 to 1.07]). Two new randomized studies reported after publication of the meta-analysis found no benefit in patients treated with albumin. Given the uncertainty about the true effect of albumin (due to the existence of indirectness and imprecision) and its cost considerations, it is suggested not to use albumin in the initial resuscitation of patients with severe sepsis and septic shock (GRADE2C).

Trombolisis en el ictus isquémico agudo en centros sin unidad de ictus: ¿derivación a centro de referencia o tratamiento in situ? / Thrombolysis in acute ischemic stroke in centers lacking a stroke unit: referral to reference center or on-site treatment?

Objetivo: Cuantificar los resultados clínicos de la trombolisis in situ frente a la trombolisis diferida en un hospital de referencia en pacientes con ictus isquémico atendidos en un hospital sin unidad de ictus. Diseño: Análisis de decisiones de valor esperado y simulación de Monte Carlo. Pacientes y ámbito: Simulación basada en un estudio de cohortes (SIT-MOST) y un meta-análisis de ensayos aleatorizados de trombolisis contra placebo en pacientes con ictus isquémico agudo. Intervenciones: Trombolisis in situ frente a la trombolisis diferida en un centro dotado de unidad de ictus. Variables principales: Resultados neurológicos (escala de Rankin modificada) a los 3 meses del ingreso en función de la demora en la aplicación de la trombolisis. Resultados: En las condiciones basales del estudio SIT-MOST (demora inicial de 135min, tiempo de transporte de 60min) el tratamiento in situ fue más efectivo que la derivación a otro hospital (número de pacientes con resultado neurológico favorable de 45,3 frente al 41,3%). En los pacientes atendidos a los 45 minutos, de cada 10 pacientes trasladados se produce un caso adicional con resultado neurológico desfavorable, que se hubiera evitado con el tratamiento trombolítico in situ. En el análisis de Monte Carlo, sesgado en contra del tratamiento in situ mediante una reducción de la efectividad del 30%, el tratamiento in situ fue superior a la derivación de los enfermos en el 77,2% de los casos. Conclusiones: La evidencia disponible no apoya las recomendaciones de la estrategia nacional del ictus y de los diversos planes autonómicos que desaconsejan la realización de trombolisis en hospitales sin unidades de ictus (AU)

Objective: To assess the clinical impact of on-site thrombolysis versus referral to another hospital in patients with ischemic stroke attended in a hospital lacking a stroke unit. Design: Expected value decision analysis and Monte Carlo simulation. Patients and setting: Decision analysis based on a cohort study (SIT-MOST) and a meta-analysis of randomized trials of thrombolysis versus placebo in patients with acute ischemic stroke. Interventions: On-site thrombolysis (in hospitals lacking a stroke unit) versus delayed thrombolysis in a reference hospital. Main outcomes: Neurological outcome (modified Rankin scale) three months after admission according to the delay in the administration of thrombolysis. Results: At baseline (initial delay of 135min, travel time 60minutes), on-site treatment was more effective than referral to another hospital (number of patients with favorable neurological outcome 45.3% versus 41.3%). In patients seen within 45minutes of the onset of symptoms, for every 10 patients transferred there was an additional case with an unfavorable neurological outcome that could have been avoided with on-site thrombolysis. In the Monte Carlo analysis, biased against on-site treatment by a reduction in effectiveness of 30%, on-site treatment was superior to patient referral in 77.2% of the cases. Conclusions: The available evidence does not support the recommendations of the national stroke strategy or some regional plans that discourage the administration of thrombolysis in hospitals without stroke units (AU)

[Thrombolysis in acute ischemic stroke in centers lacking a stroke unit: referral to reference center or on-site treatment?]. / Trombolisis en el ictus isquémico agudo en centros sin unidad de ictus: ¿derivación a centro de referencia o tratamiento in situ?

OBJECTIVE: To assess the clinical impact of on-site thrombolysis versus referral to another hospital in patients with ischemic stroke attended in a hospital lacking a stroke unit. DESIGN: Expected value decision analysis and Monte Carlo simulation. PATIENTS AND SETTING: Decision analysis based on a cohort study (SIT-MOST) and a meta-analysis of randomized trials of thrombolysis versus placebo in patients with acute ischemic stroke. INTERVENTIONS: On-site thrombolysis (in hospitals lacking a stroke unit) versus delayed thrombolysis in a reference hospital. MAIN OUTCOMES: Neurological outcome (modified Rankin scale) three months after admission according to the delay in the administration of thrombolysis. RESULTS: At baseline (initial delay of 135 min, travel time 60 minutes), on-site treatment was more effective than referral to another hospital (number of patients with favorable neurological outcome 45.3% versus 41.3%). In patients seen within 45 minutes of the onset of symptoms, for every 10 patients transferred there was an additional case with an unfavorable neurological outcome that could have been avoided with on-site thrombolysis. In the Monte Carlo analysis, biased against on-site treatment by a reduction in effectiveness of 30%, on-site treatment was superior to patient referral in 77.2% of the cases. CONCLUSIONS: The available evidence does not support the recommendations of the national stroke strategy or some regional plans that discourage the administration of thrombolysis in hospitals without stroke units.