Ivabradine for controlling heart rate in permanent atrial fibrillation: A translational clinical trial.

BACKGROUND: Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting. OBJECTIVES: The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation. METHODS: The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite ß-blocker or calcium channel blocker treatment. RESULTS: Ivabradine 1 µM inhibited "funny" current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 µM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (-11.5%) in the ivabradine arm (P = .02) vs 19.6 (-20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = -1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10). CONCLUSION: Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.

Evaluating a continuous medical education program to improve general practitioners awareness and practice on erectile dysfunction as a cardiovascular risk factor.

INTRODUCTION: The clear link between erectile dysfunction (ED) and cardiovascular disease (CVD) together with the increased potential for effectively treating ED with oral pharmacological agents make the primary care setting the ideal place to detect and treat ED and its potential comorbidities. Given the observed shortcomings in knowledge related to ED among primary care physicians, continuous medical education (CME) on this topic stands out as a potentially effective way to improve patient care. AIM: To assess general practitioners' (GPs) knowledge, attitudes, and self-confidence about ED management and the relationship between ED and CVD and to test whether these can be improved by means of a brief training program. METHODS: Eighty GPs completed two similar questionnaires on ED issues, one prior to a CME intervention and one following it. The CME program consisted of reading an annotated set of four review articles and six research articles followed by a live half-day seminar conducted by a GP, a urologist, and a cardiologist. MAIN OUTCOME MEASURES: Changes in the answers to the two questionnaires were evaluated by tests for matched pairs using both statistical significance and effect size estimates, and assessment of different predictors were evaluated by multivariate analysis. RESULTS: A marked improvement was observed in physician knowledge, attitudes, and self-confidence with regard to diagnosing and treating ED following the CME training intervention. CONCLUSIONS: The present study shows that a relatively simple educational procedure can substantially improve the awareness of primary care physicians about the cardiovascular implications of ED and their self confidence in the management of these patients.

Neuron-specific enolase kinetics: an additional tool for neurological prognostication after cardiac arrest.

INTRODUCTION AND OBJECTIVES: To analyze neuron-specific enolase (NSE) kinetics as a prognostic biomarker of neurological outcome in cardiac arrest survivors treated with targeted temperature management. METHODS: We performed a retrospective analysis of patients resuscitated from in- or out-of-hospital cardiac arrest admitted from September 2006 to May 2018 in a single tertiary care center and cooled to 32°C to 34°C for 24 hours. Blood samples for measurement of NSE values were drawn at hospital admission and at 24, 48, and 72hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by means of the Cerebral Performance Category (CPC) score at 3 months and was characterized as good (CPC 1-2) or poor (CPC 3-5). RESULTS: Of 451 patients, 320 fulfilled the inclusion criteria and were analyzed (80.3% male, mean age 61±14.1 years). Among these, 174 patients (54.4%) survived with good neurological status. Poor outcome patients had higher median NSE values at hospital admission and at 24, 48 and 72 hours after ROSC. At 48 and 72 hours after ROSC, NSE predicted poor neurological outcome with areas under the receiver-operating characteristic curves of 0.85 (95%CI, 0.81-0.90) and 0.88 (95%CI, 0.83-0.93), respectively. In addition, delta NSE values between 72hours after ROSC and hospital admission predicted poor neurological outcome with an area under the receiver-operating characteristic curve of 0.90 (95%CI, 0.85-0.95) and was an independent predictor of unfavorable outcome on multivariate analysis (P <.001). CONCLUSIONS: In cardiac arrest survivors treated with targeted temperature management, delta NSE values between 72 hours after ROSC and hospital admission strongly predicted poor neurological outcome.

Influence of the temperature on the moment of awakening in patients treated with therapeutic hypothermia after cardiac arrest.

INTRODUCTION: Target temperature management (TTM) has shown to reduce brain damage after an out-of-hospital cardiac arrest (CA), but the time to neurological recovery is not defined yet. We sought to determine the time these patients need to regain consciousness, as well as factors associated with a late post-arrest awakening. METHODS: We performed a retrospective analysis of patients cooled to 32-34°C during 24h after CA, who regained neurological responsiveness after rewarming. We measured the time until awakening, defined as obedience to verbal commands. RESULTS: We included 163 CA survivors (84.7% male, 60.2 years) who regained consciousness after TTM: target temperature was either 32°C (36.2%), 33°C (56.4%) or 34°C (6.7%). Mean time of awakening was 3.8 days. Thirty-four patients (20.9%) regained neurological responsiveness after 5 days after CA. All of them had been cooled to either 32°C (18 patients) or 33°C (16), and no patient cooled to 34°C awakened after day 5. A lower target temperature was associated with a later awakening (p<0.001). The time to advanced cardiopulmonary resuscitation (CPR) was shorter among the early awakers (p=0.04), but we found no other predictors of an earlier awakening. CONCLUSIONS: A high proportion of CA survivors induced to TTM regained consciousness after 5 days, and cooling to a lower target temperature may influence on a late neurological recovery. Therefore, withdrawal of life supporting treatment should be delayed to more than 5 days in patients cooled to 33°C or less. Time to advanced CPR was found to be a predictor of early awakening.

Cinética de la enolasa neuroespecífica: una herramienta adicional para el pronóstico neurológico después de una parada cardiaca / Neuron-specific enolase kinetics: an additional tool for neurological prognostication after cardiac arrest

INTRODUCCIÓN Y OBJETIVOS: Analizar la cinética de la enolasa neuroespecífica (EN) como biomarcador de pronóstico neurológico de los pacientes que sobreviven a una parada cardiaca tratados con control de temperatura. MÉTODOS: Análisis retrospectivo de pacientes ingresados tras sufrir una parada cardiaca dentro o fuera del hospital entre septiembre de 2006 y mayo de 2018 en un centro terciario y enfriados a 32-34°C durante 24 h. Las muestras de EN se tomaron al ingreso hospitalario y a las 24, 48 y 72 h del retorno a circulación espontánea (RCE). El estado neurológico se evaluó a los 3 meses mediante la escala Cerebral Performance Category (CPC) y se categorizó como favorable (CPC 1-2) o desfavorable (CPC 3-5). RESULTADOS: De los 451 pacientes, 320 cumplían los criterios de inclusión (el 80,3% varones; media de edad, 61+/-14,1 años). De estos, 174 (54,4%) sobrevivieron con una evolución neurológica favorable. Los pacientes con estado neurológico desfavorable tenían valores de EN más altos al ingreso hospitalario y a las 24, 48 y 72 h del RCE. A las 48 y las 72 h, los valores de EN predijeron un estado neurológico desfavorable, con áreas bajo la curva de 0,85 (IC95%, 0,81-0,90) y 0,88 (IC95%, 0,83-0,93). Además, el área bajo la curva de los valores delta de EN entre las 72 h y el ingreso hospitalario fue de 0,90 (IC95%, 0,85-0,95), y en el análisis multivariante resultó predictor independiente (p <0,001). CONCLUSIONES: En pacientes que sobrevivieron a una parada cardiaca tratados con control de la temperatura, se ha demostrado que los valores delta de EN entre las 72 h del RCE y el ingreso hospitalario son un potente predictor de resultado neurológico desfavorable

INTRODUCTION AND OBJECTIVES: To analyze neuron-specific enolase (NSE) kinetics as a prognostic biomarker of neurological outcome in cardiac arrest survivors treated with targeted temperature management. METHODS: We performed a retrospective analysis of patients resuscitated from in- or out-of-hospital cardiac arrest admitted from September 2006 to May 2018 in a single tertiary care center and cooled to 32°C to 34°C for 24 hours. Blood samples for measurement of NSE values were drawn at hospital admission and at 24, 48, and 72hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by means of the Cerebral Performance Category (CPC) score at 3 months and was characterized as good (CPC 1-2) or poor (CPC 3-5). RESULTS: Of 451 patients, 320 fulfilled the inclusion criteria and were analyzed (80.3% male, mean age 61+/-14.1 years). Among these, 174 patients (54.4%) survived with good neurological status. Poor outcome patients had higher median NSE values at hospital admission and at 24, 48 and 72 hours after ROSC. At 48 and 72 hours after ROSC, NSE predicted poor neurological outcome with areas under the receiver-operating characteristic curves of 0.85 (95%CI, 0.81-0.90) and 0.88 (95%CI, 0.83-0.93), respectively. In addition, delta NSE values between 72hours after ROSC and hospital admission predicted poor neurological outcome with an area under the receiver-operating characteristic curve of 0.90 (95%CI, 0.85-0.95) and was an independent predictor of unfavorable outcome on multivariate analysis (P <.001). CONCLUSIONS: In cardiac arrest survivors treated with targeted temperature management, delta NSE values between 72 hours after ROSC and hospital admission strongly predicted poor neurological outcome

Spectral analysis-based risk score enables early prediction of mortality and cerebral performance in patients undergoing therapeutic hypothermia for ventricular fibrillation and comatose status.

BACKGROUND: Early prognosis in comatose survivors after cardiac arrest due to ventricular fibrillation (VF) is unreliable, especially in patients undergoing mild hypothermia. We aimed at developing a reliable risk-score to enable early prediction of cerebral performance and survival. METHODS: Sixty-one out of 239 consecutive patients undergoing mild hypothermia after cardiac arrest, with eventual return of spontaneous circulation (ROSC), and comatose status on admission fulfilled the inclusion criteria. Background clinical variables, VF time and frequency domain fundamental variables were considered. The primary and secondary outcomes were a favorable neurological performance (FNP) during hospitalization and survival to hospital discharge, respectively. The predictive model was developed in a retrospective cohort (n = 32; September 2006-September 2011, 48.5 ± 10.5 months of follow-up) and further validated in a prospective cohort (n = 29; October 2011-July 2013, 5 ± 1.8 months of follow-up). RESULTS: FNP was present in 16 (50.0%) and 21 patients (72.4%) in the retrospective and prospective cohorts, respectively. Seventeen (53.1%) and 21 patients (72.4%), respectively, survived to hospital discharge. Both outcomes were significantly associated (p < 0.001). Retrospective multivariate analysis provided a prediction model (sensitivity = 0.94, specificity = 1) that included spectral dominant frequency, derived power density and peak ratios between high and low frequency bands, and the number of shocks delivered before ROSC. Validation on the prospective cohort showed sensitivity = 0.88 and specificity = 0.91. A model-derived risk-score properly predicted 93% of FNP. Testing the model on follow-up showed a c-statistic ≥ 0.89. CONCLUSIONS: A spectral analysis-based model reliably correlates time-dependent VF spectral changes with acute cerebral injury in comatose survivors undergoing mild hypothermia after cardiac arrest.