Apixaban vs Aspirin According to CHA2DS2-VASc Score in Subclinical Atrial Fibrillation: Insights From ARTESiA.

BACKGROUND: ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) demonstrated that apixaban, compared with aspirin, significantly reduced stroke and systemic embolism (SE) but increased major bleeding in patients with subclinical atrial fibrillation. OBJECTIVES: To help inform decision making, the authors evaluated the efficacy and safety of apixaban according to baseline CHA2DS2-VASc score. METHODS: We performed a subgroup analysis according to baseline CHA2DS2-VASc score and assessed both the relative and absolute differences in stroke/SE and major bleeding. RESULTS: Baseline CHA2DS2-VASc scores were <4 in 1,578 (39.4%) patients, 4 in 1,349 (33.6%), and >4 in 1,085 (27.0%). For patients with CHA2DS2-VASc >4, the rate of stroke was 0.98%/year with apixaban and 2.25%/year with aspirin; compared with aspirin, apixaban prevented 1.28 (95% CI: 0.43-2.12) strokes/SE per 100 patient-years and caused 0.68 (95% CI: -0.23 to 1.57) major bleeds. For CHA2DS2-VASc <4, the stroke/SE rate was 0.85%/year with apixaban and 0.97%/year with aspirin. Apixaban prevented 0.12 (95% CI: -0.38 to 0.62) strokes/SE per 100 patient-years and caused 0.33 (95% CI: -0.27 to 0.92) major bleeds. For patients with CHA2DS2-VASc =4, apixaban prevented 0.32 (95% CI: -0.16 to 0.79) strokes/SE per 100 patient-years and caused 0.28 (95% CI: -0.30 to 0.86) major bleeds. CONCLUSIONS: One in 4 patients in ARTESiA with subclinical atrial fibrillation had a CHA2DS2-VASc score >4 and a stroke/SE risk of 2.2% per year. For these patients, the benefits of treatment with apixaban in preventing stroke/SE are greater than the risks. The opposite is true for patients with CHA2DS2-VASc score <4. A substantial intermediate group (CHA2DS2-VASc =4) exists in which patient preferences will inform treatment decisions. (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; NCT01938248).

Results of the COMPASS Trial Analyzed Using Win Ratio Compared With Conventional Analytic Approaches.

BACKGROUND: Win ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches. METHODS: We used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points. We compared the WR results with those obtained using the Cox proportional hazards regression model for first events and Anderson-Gill method for total events. We calculated the win difference to estimate absolute treatment effects. RESULTS: The WR approach produced results consistent with those obtained using conventional statistical methods for the primary composite end point (first event: WR, 1.32 [95% confidence interval (CI), 1.14-1.52]; 1/Cox hazard ratio, 1.32 [95% CI, 1.16-1.52]; total [first plus recurrent] events: WR, 1.32 [95% CI, 1.14-1.52]; 1/Anderson-Gill hazard ratio, 1.32 [95% CI, 1.16-1.54]) as well as for main safety and net clinical benefit end points. The absolute benefits of the combination of rivaroxaban and aspirin compared with aspirin alone calculated using the win difference were greatest in those with multiple high-risk features. CONCLUSIONS: Reanalysis of the COMPASS trial results using WR produced results that were consistent with those obtained using conventional statistical approaches. CLINICAL TRIAL REGISTRATION: NCT01776424.

Sodium Intake and Incident Atrial Fibrillation in Individuals With Vascular Disease.

Importance: Numerous prospective cohort studies have reported a J-shaped association of urinary sodium excretion with cardiovascular events and mortality. Objective: To study the association between sodium intake and incident atrial fibrillation (AF). Design, Setting, and Participants: This cohort study included participants in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) multicenter, randomized clinical trials comparing the effect of ramipril 10 mg daily with telmisartan 80 mg daily, or their combination (ONTARGET) or 80 mg telmisartan daily with placebo (TRANSCEND) for the outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. ONTARGET and TRANSCEND included 31 546 participants with vascular disease or high-risk diabetes, and this study excluded participants without a urine sample for sodium measurement, missing data for key covariates, a history of AF, or AF detected in the first year after enrollment. Analyses were performed in July 2023 to May 2024. Exposure: Estimated sodium intake from a morning fasting urine sample (Kawasaki formula). Main Outcomes and Measures: The main outcome was incident AF. The association between estimated sodium intake and incident AF was modeled using multivariable adjusted Cox regression and cubic splines. Results: A total of 27 391 participants (mean [SD] age, 66.3 [7.2] years; 19 310 [70.5%] male) were included. Mean (SD) estimated sodium intake was 4.8 (1.6) g/d. During a mean (SD) follow-up of 4.6 (1.0) years, 1562 participants (5.7%) had incident AF. After multivariable adjustment, a J-shaped association between sodium intake and AF risk was observed (P for nonlinearity = .03). Sodium intake of 8 g/d or greater (3% of participants) was associated with incident AF (hazard ratio, 1.32; 95% CI, 1.01-1.74) compared with sodium intake of 4 to 5.99 g/d. Cubic splines showed that sodium intake greater than 6 g/d (19% of participants) was associated with a 10% increased AF risk per additional 1-g/d sodium intake (hazard ratio, 1.10; 95% CI, 1.03-1.18), but with no further lowering of AF risk at lower levels of sodium intake. Conclusions and Relevance: In this cohort study of sodium intake and AF risk, there was a J-shaped association between sodium intakes and AF risk in patients with cardiovascular disease or diabetes. Lowering sodium intake for AF prevention is best targeted at individuals who consume high sodium diets.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

BACKGROUND: In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). METHODS: This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. RESULTS: Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. CONCLUSIONS: About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Atrial Fibrillation Ablation in Heart Failure With Reduced vs Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Importance: Catheter ablation is associated with reduced heart failure (HF) hospitalization and death in select patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF). However, the benefit in patients with HF with preserved ejection fraction (HFpEF) is uncertain. Objective: To investigate whether catheter ablation for AF is associated with reduced HF-related outcomes according to HF phenotype. Data Source: A systematic search of MEDLINE, Embase, and Cochrane Central was conducted among studies published from inception to September 2023. Study Selection: Parallel-group randomized clinical trials (RCTs) comparing catheter ablation with conventional rate or rhythm control therapies in patients with HF, New York Heart Association functional class II or greater, and a history of paroxysmal or persistent AF were included. Pairs of independent reviewers screened 7531 titles and abstracts, of which 12 RCTs and 4 substudies met selection criteria. Data Extraction and Synthesis: Data were abstracted in duplicate according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Pooled effect estimates were calculated using random-effects Mantel-Haenszel models. Interaction P values were used to test for subgroup differences. Main Outcomes and Measures: The primary outcome was HF events, defined as HF hospitalization, clinically significant worsening of HF, or unscheduled visits to a clinician for treatment intensification. Secondary outcomes included cardiovascular and all-cause mortality. Results: A total of 12 RCTs with 2465 participants (mean [SD] age, 65.3 [9.7] years; 658 females [26.7%]) were included; there were 1552 participants with HFrEF and 913 participants with HFpEF. Compared with conventional rate or rhythm control, catheter ablation was associated with reduced risk of HF events in HFrEF (risk ratio [RR], 0.59; 95% CI, 0.48-0.72), while there was no benefit in patients with HFpEF (RR, 0.93; 95% CI, 0.65-1.32) (P for interaction = .03). Catheter ablation was associated with reduced risk of cardiovascular death compared with conventional therapies in HFrEF (RR, 0.49; 95% CI, 0.34-0.70) but a differential association was not detected in HFpEF (RR, 0.91; 95% CI, 0.46-1.79) (P for interaction = .12). Similarly, no difference in the association of catheter ablation with all-cause mortality was found between HFrEF (RR vs conventional therapies, 0.63; 95% CI, 0.47-0.86) and HFpEF (RR vs conventional therapies, 0.95; 95% CI, 0.39-2.30) groups (P for interaction = .39). Conclusions and Relevance: This study found that catheter ablation for AF was associated with reduced risk of HF events in patients with HFrEF but had limited or no benefit in HFpEF. Results from ongoing trials may further elucidate the role of catheter ablation for AF in HFpEF.

Estimating Vitamin K Antagonist Anticoagulation Benefit in People With Atrial Fibrillation Accounting for Competing Risks: Evidence From 12 Randomized Trials.

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 differences in estimated benefit and whether the differences varied by life expectancy. RESULTS: A total of 7933 participants (median age, 73 years, 36% women) had a median life expectancy of 8 years (interquartile range, 6-12), determined by comorbidity-adjusted life tables and 43% were randomized to VKAs. The CHA2DS2-VASc model estimated a larger ARR than the competing risk model (median ARR at 3 years, 6.9% [interquartile range, 4.7%-10.0%] versus 5.2% [interquartile range, 3.5%-7.4%]; P<0.001). 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 -1.3% (95% CI, -1.3% to -1.2%); for those with life expectancies in the lowest decile, 3-year ARR difference was 4.7% (95% CI, 4.5%-5.0%). CONCLUSIONS: VKA anticoagulants were exceptionally effective at reducing stroke risk. However, VKA benefits were misestimated with CHA2DS2-VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced when life expectancy was low and when the benefit was estimated over a multiyear horizon.

Optimizing warfarin dosing for patients with atrial fibrillation using machine learning.

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 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

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 bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

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 those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.

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 therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.

Colchicine to Prevent Atrial Fibrillation Recurrence After Catheter Ablation: A Randomized, Placebo-Controlled Trial.

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 at 2 weeks (31% versus 32%; hazard ratio [HR], 0.98 [95% CI, 0.59-1.61]; P=0.92) or at 3 months following ablation (14% versus 15%; HR, 0.95 [95% CI, 0.45-2.02]; P=0.89). Postablation chest pain consistent with pericarditis was reduced with colchicine (4% versus 15%; HR, 0.26 [95% CI, 0.09-0.77]; P=0.02) and colchicine increased diarrhea (26% versus 7%; HR, 4.74 [95% CI, 1.95-11.53]; P<0.001). During a median follow-up of 1.3 years, colchicine did not reduce a composite of emergency department visit, cardiovascular hospitalization, cardioversion, or repeat ablation (29 versus 25 per 100 patient-years; HR, 1.18 [95% CI, 0.69-1.99]; P=0.55). CONCLUSIONS: Colchicine administered for 10 days following catheter ablation did not reduce atrial arrhythmia recurrence or AF-associated clinical events, but did reduce postablation chest pain and increase diarrhea.

Outcomes of Patients with a Mechanical Heart Valve and Poor Anticoagulation Control on Warfarin.

BACKGROUND: Patients with a mechanical heart valve (MHV) require oral anticoagulation. Poor anticoagulation control is thought to be associated with adverse outcomes, but data are limited. OBJECTIVE: To assess the risks of clinical outcomes in patients with a MHV and poor anticoagulation control on warfarin. METHODS: We conducted a retrospective study of consecutive patients undergoing MHV implantation at a tertiary care center (2010-2019). Primary outcome was a composite of ischemic stroke, systemic embolism, or prosthetic valve thrombosis. Major bleeding and death were key secondary outcomes. We constructed multivariable regression models to assess the association between time in therapeutic range (TTR) on warfarin beyond 90 days after surgery with outcomes. RESULTS: We included 671 patients with a MHV (80.6% in aortic, 14.6% in mitral position; mean age 61 years, 30.3% female). Median follow-up was 4.9 years, mean TTR was 62.5% (14.5% TTR <40%, 24.6% TTR 40-60%, and 61.0% TTR >60%). Overall rates of the primary outcome, major bleeding, and death were 0.73, 1.41, and 1.44 per 100 patient-years. Corresponding rates for patients with TTR <40% were 1.31, 2.77, and 3.22 per 100 patient-years. In adjusted analyses, every 10% decrement in TTR was associated with a 31% increase in hazard for the primary outcome (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.13-1.52), 34% increase in major bleeding (HR: 1.34, 95% CI: 1.17-1.52), and 32% increase in death (HR: 1.32, 95% CI: 1.11-1.57). CONCLUSION: In contemporary patients with a MHV, poor anticoagulation control on warfarin was associated with increased risks of thrombotic events, bleeding, and death.