Perioperative Management and Outcomes in Patients Receiving Low-dose Rivaroxaban and or Aspirin: A Sub-analysis of the COMPASS Trial.

BACKGROUND: No study has investigated the perioperative management and clinical outcomes in patients who are receiving rivaroxaban 2.5 mg bid and ASA 81-100 mg daily. METHODS: Sub-analysis of the COMPASS trial to assess perioperative management and clinical outcomes in patients with stable coronary or peripheral artery disease who were randomized to receive rivaroxaban 2.5 mg bid plus ASA 100 mg daily, rivaroxaban 5 mg bid, or ASA 100 mg daily. Patients studied required a surgery/procedure during the trial. The study outcomes, which included myocardial infarction, angina, stroke, acute limb ischemia, bleeding, and death, were assessed according to treatment allocation. RESULTS: There were 2,632 patients studied (mean age, 68 years; 80% male) who had a surgery/procedure, comprising percutaneous coronary interventions (∼43%), carotid or other arterial angioplasty (∼15%), pacemaker or internal cardiac defibrillator implantation (∼9%), and coronary artery bypass graft surgery (∼7%). Perioperative study drug management varied, with about one-third of patients not interrupting study drug and the remainder interrupting it between 1 and ≥10 days pre-procedure. The incidences of adverse outcomes across treatment groups were 12.7% to 15.3% for myocardial ischemia, 0.8% to 1.2% for stroke, 0.1% to 0.2% for venous thromboembolism, and 3.1% to 4.2% for any bleeding. There was no statistically significant difference in outcome rates across treatment groups. CONCLUSION: In patients in the COMPASS trial who required a surgery/procedure, there was no significant difference in perioperative adverse outcomes whether patients were receiving rivaroxaban 2.5 mg bid and ASA 100 mg daily, rivaroxaban 5 mg bid or ASA alone.

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.

Total intracranial hemorrhage volume measurement summating all compartments best in traumatic and nontraumatic intracranial bleeding.

BACKGROUND AND PURPOSE: The 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. METHODS: Thirty 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 also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4. RESULTS: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. CONCLUSION: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes.

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.

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.

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.

Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC.

BACKGROUND: Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce. AIM: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH. METHODS: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively. RESULTS: Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641). CONCLUSION: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

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.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

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 patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials.

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 (PROSPERO CRD42023463212). RESULTS: From 785 citations, we identified 2 randomized trials with relevant clinical outcome data: NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes; 2536 participants) evaluated edoxaban, and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; 4012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk [RR], 0.68 [95% CI, 0.50-0.92]; high-quality evidence). The results from the 2 trials were consistent (I2 statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85 [95% CI, 0.73-0.99]; I2=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR, 0.95 [95% CI, 0.76-1.17]; I2=0%; moderate-quality evidence) or all-cause mortality (RR, 1.08 [95% CI, 0.96-1.21]; I2=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR, 1.62 [95% CI, 1.05-2.50]; I²=61%; high-quality evidence). CONCLUSIONS: The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these 2 large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected atrial fibrillation and increases the risk of major bleeding.

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.

The Cost-Effectiveness of Rivaroxaban Plus Aspirin Compared with Aspirin Alone in the COMPASS Trial: A US Perspective.

BACKGROUND: Rivaroxaban 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. METHODS: US 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. RESULTS: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower. CONCLUSION: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424.

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. PATIENTS/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.

Cerebral microbleeds and asundexian in non-cardioembolic ischemic stroke: Secondary analyses of the PACIFIC-STROKE randomized trial.

BACKGROUND AND AIMS: Cerebral microbleeds are magnetic imaging resonance (MRI) markers of hemorrhage-prone cerebral small vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exist concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembolic ischemic stroke. METHODS: This is a secondary analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ⩾ 45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 h of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50 mg daily) versus placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of (1) all pooled asundexian doses and (2) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/transient ischemic attack (TIA) (primary outcome), and ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes). RESULTS: Of 1746 participants (mean age, 67.0 ± 10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n = 122) had ischemic stroke/TIA, 0.5% (n = 8) ICrH, and 2.1% (n = 37) died. New microbleeds developed in 10.3% (n = 155) of participants with adequate follow-up MRIs and HT in 31.4% (n = 345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n = 1507), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR, 0.96; 95% CI, 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction > 0.05). The rates of new microbleeds, HT, and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95% CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95% CI, 3.0-6.3). CONCLUSION: Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04304508.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

Atrial Fibrillation Recurrence in Patients With Transient New-Onset Atrial Fibrillation Detected During Hospitalization for Noncardiac Surgery or Medical Illness : A Matched Cohort Study.

BACKGROUND: Atrial fibrillation (AF) is often detected for the first time in patients who are hospitalized for another reason. Long-term risks for AF recurrence in these patients are unclear. OBJECTIVE: To estimate risk for AF recurrence in patients with new-onset AF during a hospitalization for noncardiac surgery or medical illness compared with a matched population without AF. DESIGN: Matched cohort study. (ClinicalTrials.gov: NCT03221777). SETTING: Three academic hospitals in Hamilton, Ontario, Canada. PARTICIPANTS: The study enrolled patients hospitalized for noncardiac surgery or medical illness who had transient new-onset AF. For each participant, an age- and sex-matched control participant with no history of AF from the same hospital ward was recruited. All participants left the hospital in sinus rhythm. MEASUREMENTS: 14-day electrocardiographic (ECG) monitor at 1 and 6 months and telephone assessment at 1, 6, and 12 months. The primary outcome was AF lasting at least 30 seconds on the monitor or captured by ECG 12-lead during routine care at 12 months. RESULTS: Among 139 participants with transient new-onset AF (70 patients with medical illness and 69 surgical patients) and 139 matched control participants, the mean age was 71 years (SD, 10), the mean CHA2DS2-VASc score was 3.0 (SD, 1.5), and 59% were male. The median duration of AF during the index hospitalization was 15.8 hours (IQR, 6.4 to 49.6 hours). After 1 year, recurrent AF was detected in 33.1% (95% CI, 25.3% to 40.9%) of participants in the transient new-onset AF group and 5.0% (CI, 1.4% to 8.7%) of matched control participants; after adjustment for the number of ECG monitors worn and for baseline clinical differences, the adjusted relative risk was 6.6 (CI, 3.2 to 13.7). After exclusion of participants who had electrical or pharmacologic cardioversion during the index hospitalization (n = 40) and their matched control participants and limiting to AF events detected by the patch ECG monitor, recurrent AF was detected in 32.3% (CI, 23.1% to 41.5%) of participants with transient new-onset AF and 3.0% (CI, 0% to 6.4%) of matched control participants. LIMITATIONS: Generalizability is limited, and the study was underpowered to evaluate subgroups and clinical predictors. CONCLUSION: Among patients who have transient new-onset AF during a hospitalization for noncardiac surgery or medical illness, approximately 1 in 3 will have recurrent AF within 1 year. PRIMARY FUNDING SOURCE: Peer-reviewed grants.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.