stuart J. Connolly

BACKGROUND Inflammation may promote atrial fibrillation (AF) recurrence after catheter ablation. This study aimed to evaluate a short-term anti-inflammatory treatment with colchicine following ablation of AF. METHODS Patients scheduled for ablation were randomized to receive colchicine 0.6 mg twice daily or placebo for 10 days. The first dose of the study drug was administered within 4 hours before ablation. Atrial arrhythmia recurrence was defined as AF, atrial flutter, or atrial tachycardia >30 s on two 14-day Holters performed immediately and at 3 months following ablation. RESULTS The modified intention-to-treat population included 199 patients (median age, 61 years; 22% female; 70% first procedure) who underwent radiofrequency (79%) or cryoballoon ablation (21%) of AF. Antiarrhythmic drugs were prescribed at discharge in 149 (75%) patients. Colchicine did not prevent atrial arrhythmia recurrence …

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0–3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 …

BackgroundFrail pts with AF are at increased risk of death, ischemic and bleeding complications. Prior analyses with DOACs in frail pts were underpowered and/or had other limitations.MethodsTo compare outcomes in pts stratified by frailty status, we used individual pt data from the COMBINE AF database, which includes all pts randomized in 4 pivotal AF trials comparing DOACs to warfarin. Frailty was assessed with 5 domains: 1) Gencer high-risk features (AHJ 2022; 247: 24-32), 2) CHADS-VASc 3) Polypharmacy, 4) Charlson Comorbidity Index (CCI), 5) High fall risk. The number of these domains was also used as a surrogate. Outcomes of interest were stroke or systemic embolism (SEE), major bleeding, mortality, and the net clinical outcome (NCO). We also evaluated heterogeneity in treatment effect across trials.ResultsOf 58,634 pts (median age 72 [65-77] yrs, 37% female), the median [IQR] values were: 1 …

Background Andexanet alfa, a specific reversal agent for factor Xa inhibitors, resulted in effective hemostasis in 79% of patients with intracranial bleeding in the ANNEXA‐4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial (NCT02329327). However, little is known about predictors associated with hematoma expansion in patients with factor Xa inhibitor–associated intracranial hemorrhage (ICrH) receiving andexanet alfa. Methods The ANNEXA‐4 trial was a prospective, single‐arm, open‐label study of andexanet alfa in patients with acute major bleeding within 18 hours after taking a factor Xa inhibitor. Hematoma volumes at baseline and 12 hours after andexanet alfa treatment were measured using a computerized‐assisted volumetric method. Univariable and multivariable logistic regression analyses of clinical and nonclinical parameters were performed to identify factors …

Background Phase II trials of asundexian were underpowered to detect important differences in bleeding. Objectives The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. Methods We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. Results In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all …

BackgroundPatients with ASCVD and AF are at high risk for AF-related outcomes. The efficacy and safety of DOACs vs warfarin (W) in pts with overt ASCVD, stratified by arterial bed and including pts with prior MI/stroke, has not been well described.MethodsWe conducted an individual patient data meta-analysis of 4 pivotal RCTs testing standard-dose DOACs vs W in AF. Pts were grouped by presence and subtype of ASCVD at baseline (CAD, cerebrovascular disease, or PAD). Endpoints were stroke/systemic embolism (SSE), major bleeding, death, and the primary net outcome (SSE, major bleeding, or death). Cox models, stratified by trial, were used to compare DOACs vs W.ResultsWe included 58,634 pts (median 72 yrs; 63% male), of which 54% had ASCVD at baseline (of these, 58% CAD; 56% CVD; 9% PAD). Pts with ASCVD (vs no ASCVD) had comparable rates of diabetes (30.5% vs 31.5%) and active …

BACKGROUND Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334—Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet …

BACKGROUND Patients with atrial fibrillation have a high mortality rate that is only partially attributable to vascular outcomes. The competing risk of death may affect the expected anticoagulant benefit. We determined if competing risks materially affect the guideline-endorsed estimate of anticoagulant benefit. METHODS We conducted a secondary analysis of 12 randomized controlled trials that randomized patients with atrial fibrillation to vitamin K antagonists (VKAs) or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of VKAs to prevent stroke or systemic embolism using 2 methods—first using a guideline-endorsed model (CHA2DS2-VASc) and then again using a competing risk model that uses the same inputs as CHA2DS2-VASc but accounts for the competing risk of death and allows for nonlinear growth in benefit. We compared the absolute and relative …

Background and purposeThe ANNEXA‐4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume.MethodsThirty patients were randomly selected from the ANNEXA‐4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty‐eight different ANNEXA‐4 subjects were …

Background Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. Methods We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the …

BACKGROUND Device-detected atrial fibrillation (also known as subclinical atrial fibrillation or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear. METHODS We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation with antiplatelet or no antithrombotic therapy in adults with device-detected atrial fibrillation recorded by a pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy device, or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). The review was preregistered …

Atrial fibrillation (AF) and heart failure (HF) are increasing in prevalence worldwide [1]. Atrial fibrillation can be a cause or a consequence of HF and cardiomyopathy [1]. Data from the Framingham study shows that approximately 40% of patients with either HF or AF will develop the other condition [2]. In patients with HF with reduced ejection fraction (HFrEF), the prevalence of AF increases with worsening New York Heart Association (NYHA) class with AF occurring in approximately half of the patients with NYHA class IV HF [3, 4]. Atrial fibrillation with HF portends a worse prognosis, with a 10-year mortality of 79% in HFrEF and 83% mortality in HF with preserved EF [5]. Rhythm control in HFrEF, especially by catheter ablation, has been shown to improve survival [5 e7]. The CASTLE-AF study showed that catheter ablation of AF in patients with HFrEF improved the primary composite endpoint of allcause mortality or HF …

BackgroundRivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know.MethodsUS direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate.ResultsThe costs of events …

BACKGROUND The efficacy and safety of non–vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to …

BackgroundThe open-label FRAIL-AF trial of 1330 elderly frail pts with AF on VKA randomized to continued VKA vs DOAC (median f/u 1 yr) showed that switching to DOAC increased bleeding and did not reduce thromboembolism. Limitations to the study design have been raised.MethodsWe conducted a pt-level metanalysis in frail, elderly VKA-experienced pts from 4 landmark DOAC vs warfarin AF trials (COMBINE-AF). Frail pts were identified in 5 ways: 1) CHADS-VASc 5+(N= 5523), 2) 4+ Gencer high-risk factors (AHJ 2022; 247: 24-32)(N= 4054), 3) 5+ comedications (N= 2306), 4) Charlson Comorbidity Index 3+(n= 1266), 5) High fall risk (N= 909). Sensitivity analyses were performed restricted to pts: 1) 80+ yrs, 2) data from apixaban and edoxaban trials only.Results10,905 pts age 75+ yrs in COMBINE-AF (median f/u 2.2 yrs) were VKA-experienced. In frail pts, DOACs tended to reduce stroke/systemic embolism …

IntroductionIn clinical trials, event adjudication is a process to review and confirm the accuracy of outcomes reported by site investigators. Despite efforts to automate the communication between a clinical-data-and-coordination center and an event adjudication committee, the review and confirmation of outcomes, as the core function of the process, still fully rely on human labor. To address this issue, we present an automated event adjudication system and its application in two randomized controlled trials.MethodsCentrally executed by a clinical-data-and-coordination center, the automated event adjudication system automatedly assessed and classified outcomes in a clinical data management system. By checking clinically predefined criteria, the automated event adjudication system either confirmed or unconfirmed an outcome and automatedly updated its status in the database. It also served as a management …

ImportancePatients with atrial fibrillation have a high rate of all-cause mortality that is only partially attributable to vascular outcomes. While the competing risk of death affects expected anticoagulant benefit, guidelines do not account for the competing risk of death.ObjectiveCompare anticoagulant benefit for patients with atrial fibrillation estimated with the CHA2DS2-VASc model vs. a Competing Risk Model that accounts for the competing risk of death and does not assume a consistent growth in treatment benefit over timeDesignSecondary analysis of randomized controlled trials (RCTs).Setting12 RCTs randomizing patients with atrial fibrillation to oral anticoagulants or either placebo or antiplatelets.Participants7933 adults with non-valvular atrial fibrillation.ExposurePredicted anticoagulant absolute risk reduction (ARR) by guideline-endorsed model (CHA2DS2-VASc) vs. a Competing Risk Model that uses the same inputs as CHA2DS2-VASc but accounts for the competing risk of death and allows for non-linear growth in benefit over time.Main outcome measuresIschemic stroke or systemic embolismResults7933 participants had a median life expectancy of 8 years (IQR 6, 12), determined by comorbidity-adjusted life tables. 43% were randomized to oral anticoagulation (median age 73 years, 36% women). The guideline-endorsed CHA2DS2-VASc model estimated a larger ARR than the Competing Risk Model (median ARR at 3 years, 6.9% vs. 5.2%). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA2DS2-VASc model – Competing Risk Model 3-year risk) was -1.2% (42 …

Background The LAAOS III (Left Atrial Appendage Occlusion Study) clinical trial demonstrated that concomitant left atrial appendage (LAA) occlusion leads to a lower risk of ischemic stroke or systemic embolism compared with no occlusion in participants with atrial fibrillation and a CHA2DS2‐VASc score of≥ 2 undergoing cardiac surgery for another indication. We report the cost implications of concomitant LAA occlusion during cardiac surgery. Methods and Results Using LAAOS III data, we compared the costs (in US dollars) associated with LAA occlusion to no occlusion from the perspective of the Centers for Medicare and Medicaid Services. We calculated the average cost per participant during the trial by applying Medicare reimbursement costs to cardiovascular events for all trial participants. We conducted sensitivity analyses, varying the cost of stroke±25% and occlusion technique use. Cost neutrality was …

Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group …

Introduction: Despite oral anticoagulation treatment atrial fibrillation (AF) patients have residual risk of ischemic stroke and systemic embolism (SE) which could potentially be mitigated. Methods: Harmonized individual patient data from five landmark trials testing direct oral anticoagulants (DOAC) were pooled in the COMBINE-AF dataset, which we used to calculate annual rate of ischemic stroke/SE according to CHA2DS2-Vasc score, history of stroke, and AF type. Results: We included 71,794 subjects (median age 72 IQR 65-78 years 61.3% male) with CHA2DS2-Vasc scores≥2 randomized to either standard- or lower-dose DOAC or warfarin, and followed for a median of 2.1 (IQR 1.5-2.7) years. The median CHA2DS2-VASc score was 4 (IQR 3-5), and 18.8% had a history of stroke and 76.4% had non-paroxysmal AF. The overall annual stroke/SE rate was 1.33%/year (95%CI 1.27-1.39%). Subjects with non …