Arrhythmias in Patients with Pulmonary Hypertension and Right Ventricular Failure: Importance of Rhythm Control Strategies.

Arrhythmias frequently complicate the course of advanced pulmonary hypertension, often leading to hemodynamic compromise, functional impairment, and mortality. Given the importance of right atrial function in this physiology, the restoration and maintenance of sinus rhythm are of critical importance. In this review, we outline the pathophysiology of arrhythmias and their impact on right heart performance; describe considerations for antiarrhythmic drug selection, anesthetic and periprocedural management; and discuss the results of catheter ablation techniques in this complex and challenging patient population.

No Effect of Continued Antiarrhythmic Drug Treatment on Top of Optimized Pulmonary Vein Isolation in Patients With Persistent Atrial Fibrillation: Results From the POWDER-AF2 Trial.

BACKGROUND: In patients with persistent atrial fibrillation (PersAF), catheter ablation aiming for pulmonary vein isolation (PVI) is associated with moderate clinical effectiveness. We investigated the benefit of continuing previously ineffective class 1C or 3 antiarrhythmic drug therapy (ADT) in the setting of a standardized PVI-only ablation strategy. METHODS: In this multicenter, randomized controlled study, patients with PersAF (≥7 days and <12 months) despite ADT were prospectively randomized 1:1 to PVI with ADT continued versus discontinued beyond the blanking period (ADT ON versus ADT OFF). Standardized catheter ablation was performed aiming for durable isolation with stable, contiguous, and optimized radio frequency applications encircling the pulmonary veins (CLOSE protocol). Clinical visits and 1-to-7-day Holter were performed at 3, 6, and 12 months. The primary end point was any documented atrial tachyarrhythmia lasting >30 seconds beyond 3 months. Prospectively defined secondary end points included repeat ablations, unscheduled arrhythmia-related visits, and quality of life among groups. RESULTS: Of 200 PersAF patients, 98 were assigned to ADT OFF and 102 to ADT ON. The longest atrial fibrillation episode qualifying for PersAF was 28 (10-90) versus 30 (11-90) days. Clinical characteristics and procedural characteristics were similar. Recurrence of atrial tachyarrhythmia was comparable in both groups (20% OFF versus 21.2% ON). No differences were observed in repeat ablations and unscheduled arrhythmia-related visits. Marked improvement in quality of life was observed in both groups. CONCLUSIONS: In patients with PersAF, there is no benefit in continuing previously ineffective ADT beyond the blanking period after catheter ablation. The high success rate of PVI-only might be explained by the high rate of durable isolation after optimized PVI and the early stage of PersAF (POWDER-AF2). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03437356.

Emergency department management of atrial fibrillation: 2023 consensus from the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Thrombosis and Hemostasis (SETH). / Manejo de la fibrilación auricular en los servicios de urgencias hospitalarios: actualización a 2023 del consenso de la Sociedad Española de Medicina de Urgencias (SEMES), la Sociedad Española de Cardiología (SEC) y la Sociedad Española de Trombosis y Hemostasia (SETH).

OBJECTIVES: Atrial fibrillation (AF) is the most prevalent sustained arrhythmia managed in emergency departments, and the already high prevalence of this arrhythmia is increasing in Spain. This serious condition associated with increased mortality and morbidity has a negative impact on patient quality of life and the functioning of the health care system. The management of AF requires consideration of diverse clinical variables and a large number of possible therapeutic approaches, justifying action plans to coordinate the work of several medical specialties in the interest of providing appropriate care and optimizing resources. This consensus statement brings together recommendations for emergency department management of AF based on available evidence adapted to special circumstances. The statement was drafted by a multidisciplinary team of specialists from the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Thrombosis and Hemostasis (SETH). Strategies for stroke prophylaxis, measures to bring heart rate and heart rhythm under control, and related diagnostic and logistic issues are discussed in detail.

OBJETIVO: La fibrilación auricular (FA) es la arritmia sostenida de mayor prevalencia en los servicios de urgencias (SU), y en España presenta una frecuentación elevada y creciente. Esta arritmia es una enfermedad grave, que incrementa la mortalidad y asocia una relevante morbilidad e impacto en la calidad de vida de los pacientes y en el funcionamiento de los servicios sanitarios. La diversidad de aspectos clínicos a considerar y el elevado número de opciones terapéuticas posibles justifican la implementación de estrategias de actuación coordinadas entre los diversos profesionales implicados, con el fin de incrementar la adecuación del tratamiento y optimizar el uso de recursos. Este documento, realizado por un grupo multidisciplinario de expertos en arritmias cardiacas miembros de la Sociedad Española de Medicina de Urgencias y Emergencias, la Sociedad Española de Cardiología y la Sociedad Española de Trombosis y Hemostasia, recoge las recomendaciones para el manejo de la FA en los SU hospitalarios, basadas en la evidencia disponible y adaptadas a las especiales circunstancias de los mismos. En él se analizan con detalle las estrategias de profilaxis tromboembólica, control de frecuencia y control del ritmo, y los aspectos logísticos y diagnósticos relacionados.

Manejo de la fibrilación auricular en los servicios de urgencias hospitalarios: actualización a 2023 del consenso de la Sociedad Española de Medicina de Urgencias (SEMES), la Sociedad Española de Cardiología (SEC) y la Sociedad Española de Trombosis y Hem / Emergency department management of atrial fibrillation: 2023 consensus from the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Thrombosis and Hemostasis (SETH)

La fibrilación auricular (FA) es la arritmia sostenida de mayor prevalencia en los servicios de urgencias (SU), y en España presenta una frecuentación elevada y creciente. Esta arritmia es una enfermedad grave, que incrementa la mortalidad y asocia una relevante morbilidad e impacto en la calidad de vida de los pacientes y en el funcionamiento de los servicios sanitarios. La diversidad de aspectos clínicos a considerar y el elevado número de opciones terapéuticas posibles justifican la implementación de estrategias de actuación coordinadas entre los diversos profesionales implicados, con el fin de incrementar la adecuación del tratamiento y optimizar el uso de recursos. Este documento, realizado por un grupo multidisciplinario de expertos en arritmias cardiacas miembros de la Sociedad Española de Medicina de Urgencias y Emergencias, la Sociedad Española de Cardiología y la Sociedad Española de Trombosis y Hemostasia, recoge las recomendaciones para el manejo de la FA en los SU hospitalarios, basadas en la evidencia disponible y adaptadas a las especiales circunstancias de los mismos. En él se analizan con detalle las estrategias de profilaxis tromboembólica, control de frecuencia y control del ritmo, y los aspectos logísticos y diagnósticos relacionados. (AU)

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia managed in emergency departments, and the already high prevalence of this arrhythmia is increasing in Spain. This serious condition associated with increased mortality and morbidity has a negative impact on patient quality of life and the functioning of the health care system. The management of AF requires consideration of diverse clinical variables and a large number of possible therapeutic approaches, justifying action plans to coordinate the work of several medical specialties in the interest of providing appropriate care and optimizing resources. This consensus statement brings together recommendations for emergency department management of AF based on available evidence adapted to special circumstances. The statement was drafted by a multidisciplinary team of specialists from the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC), and the Spanish Society of Thrombosis and Hemostasis (SETH). Strategies for stroke prophylaxis, measures to bring heart rate and heart rhythm under control, and related diagnostic and logistic issues are discussed in detail. (AU)

[Quality of life in patients with idiopathic ventricular arrhythmias treated at the Instituto Nacional Cardiovascular - INCOR]. / Calidad de vida en pacientes con arritmias ventriculares idiopáticas tratados en el Instituto Nacional Cardiovascular - INCOR.

Objective: To describe the quality of life in patients with idiopathic ventricular arrhythmias treated at the Instituto Nacional Cardiovascular INCOR in Lima -Peru. Materials and methods: . Analytical and cross-sectional study of patients with idiopathic ventricular arrhythmias treated by 3D ablation or antiarrhythmic therapy between July 2017 and December 2019 to whom the SF-36 health questionnaire was applied to assess quality of life related to health. Results: Fifty-two patients with idiopathic ventricular arrhythmias were included (34 underwent 3D ablation, and 18 underwent antiarrhythmic therapy only). The percentage of recurrence (14.7% vs. 50%, p=0.01) and adverse effects (0% vs. 22.2%, p=0.011) were lower in the 3D ablation group compared to the antiarrhythmic group. The mean standardized scores obtained from the Spanish version of the Health Survey SF-36v2, applied to the 3D ablation and antiarrhythmic groups were 85.1 vs 68.4 (p<0.001), respectively. Were found statistically significant differences in 6 of the eight components that evaluate health-related quality of life: physical function (96.0 vs. 76.0, p<0.001), physical role (93.4 vs. 61.1, p<0.001), general health (74.5 vs. 47.4, p<0.001), vitality (69.9 vs 54.7, p=0.008), emotional role (92.2 vs. 77.8, p=0.006) and mental health (73.8 vs. 60, p<0.001). Conclusions: Patients with idiopathic ventricular arrhythmias who underwent 3D ablation have a higher mean standardized score for health-related quality of life.

Propofol in ICU Settings: Understanding and Managing Anti-Arrhythmic, Pro-Arrhythmic Effects, and Propofol Infusion Syndrome.

Propofol has revolutionized anesthesia and intensive care medicine owing to its favorable pharmacokinetic characteristics, fast onset, and short duration of action. This drug has been shown to be remarkably effective in numerous clinical scenarios. In addition, propofol has maintained an overwhelmingly favorable safety profile; however, it has been associated with both antiarrhythmic and proarrhythmic effects. This review concisely summarizes the dual arrhythmic cardiovascular effects of propofol and a rare but serious complication, propofol infusion syndrome (PRIS). We also discuss the need for careful patient evaluation, compliance with recommended infusion rates, and vigilant monitoring.

Encainide, a class Ic anti-arrhythmic agent, blocks voltage-dependent potassium channels in coronary artery smooth muscle cells.

Voltage-dependent K+ (Kv) channels are widely expressed on vascular smooth muscle cells and regulate vascular tone. Here, we explored the inhibitory effect of encainide, a class Ic anti-arrhythmic agent, on Kv channels of vascular smooth muscle from rabbit coronary arteries. Encainide inhibited Kv channels in a concentration-dependent manner with an IC50 value of 8.91 ± 1.75 µM and Hill coefficient of 0.72 ± 0.06. The application of encainide shifted the activation curve toward a more positive potential without modifying the inactivation curve, suggesting that encainide inhibited Kv channels by altering the gating property of channel activation. The inhibition by encainide was not significantly affected by train pulses (1 and 2 Hz), indicating that the inhibition is not use (state)-dependent. The inhibitory effect of encainide was reduced by pretreatment with the Kv1.5 subtype inhibitor. However, pretreatment with the Kv2.1 subtype inhibitor did not alter the inhibitory effects of encainide on Kv currents. Based on these results, encainide inhibits vascular Kv channels in a concentration-dependent and use (state)-independent manner by altering the voltage sensor of the channels. Furthermore, Kv1.5 is the main Kv subtype involved in the effect of encainide.

Pathophysiology and treatment of adults with arrhythmias in the emergency department, part 2: Ventricular and bradyarrhythmias.

PURPOSE: This is the second article in a 2-part series reviewing the pathophysiology and treatment considerations for arrhythmias. Part 1 of the series discussed aspects related to treating atrial arrhythmias. Here in part 2, the pathophysiology of ventricular arrhythmias and bradyarrhythmias and current evidence on treatment approaches are reviewed. SUMMARY: Ventricular arrhythmias can arise suddenly and are a common cause of sudden cardiac death. Several antiarrhythmics may be effective in management of ventricular arrhythmias, but there is robust evidence to support the use of only a few of these agents, and such evidence was largely derived from trials involving patients with out-of-hospital cardiac arrest. Bradyarrhythmias range from asymptomatic mild prolongation of nodal conduction to severe conduction delays and impending cardiac arrest. Vasopressors, chronotropes, and pacing strategies require careful attention and titration to minimize adverse effects and patient harm. CONCLUSION: Ventricular arrhythmias and bradyarrhythmias can be consequential and require acute intervention. As experts in pharmacotherapy, acute care pharmacists can participate in providing high-level intervention by aiding in diagnostic workup and medication selection.

Long-term safety and efficacy of renal sympathetic denervation in atrial fibrillation: 3-year results of the AFFORD study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia which has been associated with increased sympathetic nervous system activity and hypertension. Recent evidence indicated that renal sympathetic denervation (RDN) could safely contribute to an improvement in AF burden. OBJECTIVE: To investigate the long-term safety and efficacy of radiofrequency RDN in hypertensive patients with symptomatic AF. METHODS: This pilot study included patients with symptomatic paroxysmal or persistent AF (European Hearth Rhythm Association class ≥ II) despite optimal medical therapy, office systolic blood pressure (BP) ≥ 140 mmHg and ≥ 2 antihypertensive drugs. AF burden was measured using an implantable cardiac monitor (ICM), implanted 3 months prior to RDN. ICM interrogation and 24-h ambulatory BP monitoring were performed at baseline and at 3/6/12/24/36 months post RDN. The primary efficacy outcome was daily AF burden. Statistical analyses were performed using Poisson and negative binomial models. RESULTS: A total of 20 patients with a median age [25th-75th percentiles] of 66.2 [61.2-70.8] years (55% female) were included. At baseline, office BP ± standard deviation (SD) was 153.8/87.5 ± 15.2/10.4 mmHg, while mean 24-h ambulatory BP was 129.5/77.3 ± 15.5/9.3 mmHg. Baseline daily AF burden was 1.4 [0.0-10.9] minutes/day and throughout a 3-year follow-up period, no significant change was observed (- 15.4%/year; 95% confidence interval (CI) - 50.2%, + 43.7%; p = 0.54). The number of defined daily doses of antiarrhythmic drugs and antihypertensive drugs remained stable over time, while mean 24-h ambulatory systolic BP decreased with - 2.2 (95% CI - 3.9, - 0.6; p = 0.01) mmHg/year. CONCLUSIONS: In patients with hypertension and symptomatic AF, stand-alone RDN reduced BP but did not significantly reduce AF burden up until 3 years of follow-up.

Antiarrhythmic Effect of Artemisinin in an Ex-vivo Model of Brugada Syndrome Induced by NS5806.

BACKGROUND AND OBJECTIVES: Brugada syndrome (BrS) is an inherited arrhythmia syndrome that presents as sudden cardiac death (SCD) without structural heart disease. One of the mechanisms of SCD has been suggested to be related to the uneven dispersion of transient outward potassium current (Ito) channels between the epicardium and endocardium, thus inducing ventricular tachyarrhythmia. Artemisinin is widely used as an antimalarial drug. Its antiarrhythmic effect, which includes suppression of Ito channels, has been previously reported. We investigated the effect of artemisinin on the suppression of electrocardiographic manifestations in a canine experimental model of BrS. METHODS: Transmural pseudo-electrocardiograms and epicardial/endocardial transmembrane action potentials (APs) were recorded from coronary-perfused canine right ventricular wedge preparations (n=8). To mimic the BrS phenotypes, acetylcholine (3 µM), calcium channel blocker verapamil (1 µM), and Ito agonist NS5806 (6-10 µM) were used. Artemisinin (100-150 µM) was then perfused to ameliorate the ventricular tachyarrhythmia in the BrS models. RESULTS: The provocation agents induced prominent J waves in all the models on the pseudo-electrocardiograms. The epicardial AP dome was attenuated. Ventricular tachyarrhythmia was induced in six out of 8 preparations. Artemisinin suppressed ventricular tachyarrhythmia in all 6 of these preparations and recovered the AP dome of the right ventricular epicardium in all preparations (n=8). J wave areas and epicardial notch indexes were also significantly decreased after artemisinin perfusion. CONCLUSIONS: Our findings suggest that artemisinin has an antiarrhythmic effect on wedge preparation models of BrS. It might work by inhibition of potassium channels including Ito channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation.

Prevalence and bleeding risk associated with the concomitant use of direct oral anticoagulants and antiarrhythmic drugs in patients with atrial fibrillation, based on the French healthcare insurance database.

PURPOSE: Pharmacokinetic interactions exist between apixaban or rivaroxaban, and CYP3A4 and P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem. We aimed to estimate the prevalence of exposure to this drug-drug association (DDA) and to assess the bleeding risk associated in patients with atrial fibrillation (AF). METHODS: We conducted a cohort study using a representative 1/97th sample of the French healthcare insurance database between 2014 and 2019. Patients with AF receiving apixaban or rivaroxaban were included and followed-up until hospitalization for bleeding, death, discontinuation of apixaban or rivaroxaban, exposure to strong CYP3A4 inhibitor, or until December 31st 2019, whichever came first. Primary outcome was hospitalization for bleeding registered as primary diagnosis. The association between the exposure to the DDA and hospitalization for bleeding was evaluated as a time-dependent variable in Cox model. RESULTS: Between 2014 and 2019, the AF population under apixaban or rivaroxaban represented 10,392 patients. During the study period, the annual average prevalence of DDA exposure in this population was 38.9%. Among the 10,392 patients, 223 (2.1%) were hospitalized for bleeding, of which 75 (33.6%) received the association and 148 (66.4%) received apixaban or rivaroxaban alone. There was no association between DDA exposure and risk of hospitalization for bleeding (aHR = 1.19, [95% CI: 0.90, 1.58]). Age (HR 1.03 [1.02, 1.05]) and male gender (HR 1.72 [1.28, 2.30]) were associated with an increased risk of hospitalization for bleeding. CONCLUSION: Exposure to antiarrhythmic drugs was not associated with an increased risk of hospitalization for bleeding in patients with AF under rivaroxaban or apixaban.

Pathophysiology and treatment of adults with arrhythmias in the emergency department, part 1: Atrial arrhythmias.

PURPOSE: This article, the first in a 2-part review, aims to reinforce current literature on the pathophysiology of cardiac arrhythmias and various evidence-based treatment approaches and clinical considerations in the acute care setting. Part 1 of this series focuses on atrial arrhythmias. SUMMARY: Arrhythmias are prevalent throughout the world and a common presenting condition in the emergency department (ED) setting. Atrial fibrillation (AF) is the most common arrhythmia worldwide and expected to increase in prevalence. Treatment approaches have evolved over time with advances in catheter-directed ablation. Based on historic trials, heart rate control has been the long-standing accepted outpatient treatment modality for AF, but the use of antiarrhythmics is often still indicated for AF in the acute setting, and ED pharmacists should be prepared and poised to help in AF management. Other atrial arrhythmias include atrial flutter (AFL), atrioventricular nodal reentry tachycardia (AVNRT), and atrioventricular reentrant tachycardia (AVRT), which warrant distinction due to their unique pathophysiology and because each requires a different approach to utilization of antiarrhythmics. Atrial arrhythmias are typically associated with greater hemodynamic stability than ventricular arrhythmias but still require nuanced management according to patient subset and risk factors. Since antiarrhythmics can also be proarrhythmic, they may destabilize the patient due to adverse effects, many of which are the focus of black-box label warnings that can be overreaching and limit treatment options. Electrical cardioversion for atrial arrhythmias is generally successful and, depending on the setting and/or hemodynamics, often indicated. CONCLUSION: Atrial arrhythmias arise from a variety of mechanisms, and appropriate treatment depends on various factors. A firm understanding of physiological and pharmacological concepts serves as a foundation for exploring evidence supporting agents, indications, and adverse effects in order to provide appropriate care for patients.

Comparing the Efficacy of Carvedilol and Flecainide on the Treatment of Idiopathic Premature Ventricular Complexes from Ventricular Outflow Tract: A Multicenter, Randomized, Open-Label Pilot Study.

The mechanism of premature ventricular complexes (PVC) occurring in the ventricular outflow tract (OT) is related to an intracellular calcium overload and delayed afterdepolarizations that lead to triggered activity. The guidelines recommend using beta-blockers and flecainide for idiopathic PVCs, but they also acknowledge the limited evidence supporting this recommendation. We conducted a multicenter, randomized, open-label pilot study comparing the effect of carvedilol and flecainide on OT PVC, which are widely used to treat this arrhythmia. Patients with a 24 h Holter recording a PVC burden ≥ 5%, which showed positive R waves in leads II, III, and aVF, and without structural heart disease were enrolled. They were randomly assigned to the carvedilol or flecainide group, and the maximum tolerated dose was administered for 12 weeks. A total of 103 participants completed the protocol: 51 with carvedilol and 52 with flecainide. After 12 weeks of treatment, the mean PVC burden significantly decreased in both groups: 20.3 ± 11.5 to 14.6 ± 10.8% with carvedilol (p < 0.0001) and 17.1 ± 9.9 to 6.6 ± 9.9% with flecainide (p < 0.0001). Both carvedilol and flecainide effectively suppressed OT PVCs in patients without structural heart disease, with flecainide showing a superior efficacy compared to carvedilol.

Dronedarone versus sotalol in patients with atrial fibrillation: A systematic literature review and network meta-analysis.

BACKGROUND: There are limited comparative data on safety and efficacy within commonly used Vaughan-Williams (VW) class III antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in adults with atrial fibrillation (AF). HYPOTHESIS: We hypothesized that dronedarone and sotalol, two commonly prescribed VW class III AADs with class II properties, have different safety and efficacy effects in patients with nonpermanent AF. METHODS: A systematic literature review was conducted searching MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to June 15, 2021 (NCT05279833). Clinical trials and observational studies that evaluated safety and efficacy of dronedarone or sotalol in adults with AF were included. Bayesian random-effects network meta-analysis (NMA) was used to quantify comparative safety and efficacy. Where feasible, we performed sensitivity analyses by including only randomized controlled trials (RCTs). RESULTS: Of 3581 records identified through database searches, 37 unique studies (23 RCTs, 13 observational studies, and 1 nonrandomized trial) were included in the NMA. Dronedarone was associated with a statistically significantly lower risk of all-cause death versus sotalol (hazard ratio [HR] = 0.38 [95% credible interval, CrI: 0.19, 0.74]). The association was numerically similar in the sensitivity analysis (HR = 0.46 [95% CrI: 0.21, 1.02]). AF recurrence and cardiovascular death results were not significantly different between dronedarone and sotalol in all-studies and sensitivity analyses. CONCLUSION: The NMA findings indicate that, across all clinical trials and observational studies included, dronedarone compared with sotalol was associated with a lower risk of all-cause death, but with no difference in AF recurrence.

GPER limits adverse changes to Ca2+ signalling and arrhythmogenic activity in ovariectomised guinea pig cardiomyocytes.

Background: The increased risk of post-menopausal women developing abnormalities of heart function emphasises the requirement to understand the effect of declining oestrogen levels on cardiac electrophysiology and structure, and investigate possible therapeutic targets, namely the G protein-coupled oestrogen receptor 1 (GPER). Methods: Female guinea pigs underwent sham or ovariectomy (OVx) surgeries. Cardiomyocytes were isolated 150-days post-operatively. Membrane structure was assessed using di-8-ANEPPs staining and scanning ion conductance microscopy. Imunnohistochemistry (IHC) determined the localisation of oestrogen receptors. The effect of GPER activation on excitation-contraction coupling mechanisms were assessed using electrophysiological and fluorescence techniques. Downstream signalling proteins were investigated by western blot. Results: IHC staining confirmed the presence of nuclear oestrogen receptors and GPER, the latter prominently localised to the peri-nuclear region and having a clear striated pattern elsewhere in the cells. Following OVx, GPER expression increased and its activation reduced Ca2+ transient amplitude (by 40%) and sarcomere shortening (by 32%). In these cells, GPER activation reduced abnormal spontaneous Ca2+ activity, shortened action potential duration and limited drug-induced early after-depolarisation formation. Conclusion: In an animal species with comparable steroidogenesis and cardiac physiology to humans, we show the expression and localisation of all three oestrogen receptors in cardiac myocytes. We found that following oestrogen withdrawal, GPER expression increased and its activation limited arrhythmogenic behaviours in this low oestrogen state, indicating a potential cardioprotective role of this receptor in post-menopausal women.

Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden.

BACKGROUND: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known. METHODS: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA2DS2-VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA2DS2-VA score). RESULTS: EAST-AFNET4 randomized 1093 patients with CHA2DS2-VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA2DS2-VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA2DS2-VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA2DS2-VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P=0.56, Pinteraction=0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA2DS2-VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P=0.175), but occurred more often in patients with CHA2DS2-VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P=0.019, Pinteraction=0.008). Life-threatening events or death were not different between groups (CHA2DS2-VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA2DS2-VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA2DS2-VA score), the Pinteraction was not significant for the primary efficacy outcome (P=0.25), but remained significant (P=0.044) for the primary safety outcome. CONCLUSIONS: Patients with recently diagnosed atrial fibrillation and CHA2DS2-VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01288352. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20. URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.