Are the results of the RATE-AF trial reproducible in daily practice? Clinical outcomes with digoxin vs beta-blocker for heart rate control in permanent atrial fibrillation

Background There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation (AF), in particular those with coexisting heart failure. In the recent RATE-AF trial that included patients with permanent AF and symptoms of heart failure, treatment with low-dose digoxin or bisoprolol did not result in statistically significant difference in quality of life at 6 months. The purpose of the study was to analyse whether the clinical outcomes may differ among unselected patients with permanent AF treated with digoxin or beta-blocker seen in daily practice. Methods All patients with atrial fibrillation (AF) seen in an academic institution were identified in a database. We examined the clinical course of 8962 consecutive patients with AF seen over a 10-year period. The adverse outcomes were investigated during follow-up and we identified the causes of death. Among them 1,787 patients had the RATE-AF criteria of inclusion (permanent AF, age ≥60 and NYHA ≥2), of whom 512 patients (29%) were treated with beta-blocker alone, 425 (24%) were treated with digoxin alone and 237 (13%) were treated with both a beta-blocker and digoxin. Outcomes in patients treated with beta-blocker alone or digoxin alone were compared after 1:1 propensity-score matching. Results After propensity score matching, 270 patients treated with beta-blocker were matched 1:1 with 270 patients treated with digoxin. In these patients (age 79±8 years, CHA2DS2VASc score 4.0±1.3), 125 deaths were recorded during a follow-up of 2.2±2.7 years (median 1.1, interquartile 0.1–3.5 years, yearly rate of death 10.4%) including 72 cardiovascular deaths (yearly rate 6.0%). Major clinical events (all-cause death, myocardial infarction, ischemic stroke or major bleeding) were recorded in 192 patients (yearly rate 19.1%). In this matched analysis, risk was not statistically significant in the 2 groups for all-cause death (HR 0.95, 95% CI 0.67–1.35 for beta-blocker use vs digoxin use), cardiovascular death (HR 1.23, 95% CI 0.77–1.96 for beta-blocker use vs digoxin use) or major clinical events (HR 0.98, 95% CI 0.74–1.31 for beta-blocker use vs digoxin use). Conclusion Our analysis included more patients and had a longer follow-up than in the RATE-AF trial, resulting in a 10-fold higher number of clinical events. We found that among patients with permanent AF and symptoms of HF, there was no statistically significant difference in the risk of all-cause death, cardiovascular mortality and major clinical events between those treated with digoxin or beta-blocker. Concerns regarding the use of digoxin, such as the narrow therapeutic window and drug interactions, were not issues resulting in worse clinically relevant cardiovascular outcomes with the approach used in the current study. FUNDunding Acknowledgement Type of funding sources: None.

A “Proof of Concept” Randomized Controlled Trial of a Video Game Requiring Emotional Regulation to Augment Anger Control Training

Emotional dysregulation leading to clinically significant anger and aggression is a common and substantial concern for youth and their families. While psychotropic medications and cognitive behavioral therapies can be effective, these modalities suffer from drawbacks such as significant side effects, high rates of attrition, and lack of real-world skill translation. Regulate and Gain Emotional Control (RAGE-Control) is a video game designed as an engaging augment to existing treatments. The game facilitates emotional regulation skill building through practice modulating physiological arousal while completing a challenging inhibitory task. We compared reduction in anger, aggression, oppositionality, and global severity between two treatment conditions: Anger Control Training (ACT) augmented with RAGE-Control and ACT with a sham version of the game, in a pilot double-blind randomized controlled trial. To begin to understand mechanisms of change, we examined heart rate during game play over the course of the study and explored associations between symptom changes and heart rate changes.Materials and Methods: Forty youth with clinically significant anger dyscontrol (age 10–17) were randomly assigned to 10 sessions of ACT with RAGE-Control or ACT with sham video game.Results: Both treatments similarly reduced self-reported anger. However, ACT with RAGE-Control led to larger improvements in aggression (CI: −17 to −1.0, ES: 0.55, p = 0.015); oppositionality (CI: −9.0 to −7e-6, ES: 0.48, p = 0.032); and global severity (CI: −1.0 to −5e-6, ES: 0.51, p = 0.023) relative to sham. Participants in the RAGE-Control group saw a decrease in median heart rate during game play (β = 1.2, p < 0.001). Larger pre to post decreases in heart rate were significantly associated with larger pre to post decreases in aggression and oppositional behaviors.Discussion: Augmenting ACT with RAGE-Control reduced behavioral expression of anger, but not the experience of angry feelings, as compared to ACT with a sham version of the game. Increased heart rate control, demonstrated by reduction in median heart rate during gameplay, was associated with decreased aggression and oppositional behavior. Together these findings support that augmenting traditional treatment with technology facilitating heart rate control through skill practice translates to enhancements in real-life behavioral change. Therefore, further exploration into engaging skill-focused games such as RAGE-Control is warranted.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01551732.

Effects of Esmolol on Vascular Waterfall Phenomenon in Septic Shock Patients by Bedside Measurement of Critical Closure Pressure and Mean Systemic Filling Pressure: A Prospective Observational Study

Background To explore the effect of esmolol on the vascular waterfall phenomenon and body oxygen supply and demand in septic shock patients by bedside measurements of critical closure pressure (Pcc) and mean systemic circulation filling pressure (Pmsf). Methods Enrolled in the Intensive Care Medicine Unit (ICU) of the Third People's Hospital of Chengdu City/Southwest Jiaotong University Hospital from August 2019 to January 2021, admitted to our department for infectious shock. Adults with endotracheal intubation, invasive ventilator-assisted ventilation, pulse-indicated continuous cardiac output monitoring (PiCCO) catheters and deep venous catheters placed for medical reasons. Results After 24 hours of initial hemodynamic optimization, 56 patients were finally enrolled. After heart rate control with esmolol, patients had a significant decrease in cardiac index (CI) (4.0 vs. 3.3 L/min/m2, p < 0.001), a significant increase in stroke index (SI) (34.1 vs. 36.6 ml/m2, p < 0.01), and a significant decrease in heart rate (HR) (116.8 vs. 90.6 beats/min, p < 0.001). After 1 hour of treatment with esmolol, patients had a significant increase in Pcc (31.4 vs 36.7 mmHg, p < 0.01). The difference between Pcc and Pmsf before and after treatment was statistically different (4.0 vs 10.0 mmHg, p < 0.01). After heart rate control with esmolol, the patients had a significant increase in the body circulation vascular resistance indices (RIs) (15.14 vs 18.25 mmHg/min/m2-L-1, p < 0.001). There was an increase in ScvO2 in patients after treatment with esmolol, but the difference was not statistically significant (68.4% vs 69.8%, p > 0.05), while Pcv-aCO2 was significantly lower (6.3 vs 4.9 mmHg, p < 0.001) and patients had a significant decrease in blood lactate levels (4.0 vs 3.6 mmol/L, p < 0.05) . Conclusion Patients with septic shock whose heart rate was still greater than 95 beats/min after hemodynamic optimization were treated with esmolol, which could effectively control heart rate and reduce CI, as well as improve Pcc and increase the difference between Pcc and Pmsf, without affecting MAP, CVP, Pmsf and arteriovenous vascular resistance, and improve the balance of oxygen supply and demand in the body.

Comparative Study between Ivabradine Versus Bisoprolol Effects for Heart Rate Control on Hemodynamics and Clinical Outcomes in Patients with Septic Shock

Background: Septic shock is associated with excessive sympathetic outflow, high plasma catecholamine levels, myocardial depression, vascular hypo-reactivity, and autonomic dysfunction. Typically, patients have a low resistance, high cardiac output circulation with tachycardia and arterial hypotension that may be poorly or even nonresponsive to exogenous catecholamine vasopressors. The aim of the present study was to compare the effect of ivabradine vs bisoprolol for heart rate control on the hemodynamics and clinical outcomes in patients with septic shock. Methods: The study was carried out on 90 patients, aging from 18 to 60 years of both sex presented with septic shock in ICU. Patients were randomly classified into 3 equal groups each of 30 patients. Group I (Control group) received conventional therapy. Group II (Bisoprolol group) received conventional therapy plus bisoprolol 5 mg once daily & one placebo pill on 12 hrs interval via nasogastric tube for 7 days. Group III (Ivabradine group) received conventional therapy plus ivabradine 5 mg twice daily on 12 hrs interval via nasogastric tube for 7 days. Results: Both bisoprolol and ivabradine effectively lowered heart rate in septic shock patients but ivabradine was more effective than bisoprolol. Both bisoprolol and ivabradine did not affect mean blood pressure, with ivabradine being more effective in maintaining blood pressure than bisoprolol. Noradrenaline dose was lower in ivabradine group in comparison with the other two groups. As regard to stroke volume & cardiac output, there was improvement in ivabradine group in comparison with bisoprolol and control groups. As regard to serum lactate level, there was improvement in ivabradine group in comparison with the other two groups. Both bisoprolol & ivabradine resulted in reduction in LOS & 28-day mortality with no significant difference between both groups. Conclusions: Controlling heart rate in septic shock patients with either bisoprolol or ivabradine improves outcomes. Ivabradine is better than bisoprolol in maintaining hemodynamics and improving tissue perfusion parameters.

Advances in Physiological Cardiac Stimulation

Advances in cardiac stimulation demonstrate that bradyarrhythmia treatments go beyond heart rate control. The concern with the ventricular stimulation site and, consequently, with the maintenance of intraventricular synchrony has become routine in most services. Techniques of physiological cardiac stimulation, such as stimulation of the bundle of His and the left branch, have been improved. Despite the indisputable benefits of these therapeutic modalities, there are technical difficulties that limit systematic use. In this sense, to make physiological cardiac stimulation more practical and reproducible, the concept of parahissian stimulation was expanded and studied. The technique, simpler and reproducible, contemplates a conventional approach of the right ventricle. The big difference is the use of QRS spatial variance analysis technology (Synchromax®, Exo S.A., Argentina) to confirm the maintenance of ventricular synchrony according to the implanted site.