Risk of Stroke or Systemic Embolism According to Baseline Frequency and Duration of Subclinical Atrial Fibrillation: Insights From the ARTESiA Trial.

BACKGROUND: In the ARTESiA trial (Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation), apixaban, compared with aspirin, reduced stroke or systemic embolism in patients with device-detected subclinical atrial fibrillation (SCAF). Clinical guidelines recommend considering SCAF episode duration when deciding whether to prescribe oral anticoagulation for this population. METHODS: We performed a retrospective cohort study in ARTESiA. Using Cox regression adjusted for CHA2DS2-VASc score and treatment allocation (apixaban or aspirin), we assessed frequency of SCAF episodes and duration of the longest SCAF episode in the 6 months before randomization as predictors of stroke risk and of apixaban treatment effect. RESULTS: Among 3986 patients with complete baseline SCAF data, 703 (17.6%) had no SCAF episode ≥6 minutes in the 6 months before enrollment. Among 3283 patients (82.4%) with ≥1 episode of SCAF ≥6 minutes in the 6 months before enrollment, 2542 (77.4%) had up to 5 episodes, and 741 (22.6%) had ≥6 episodes. The longest episode lasted <1 hour in 1030 patients (31.4%), 1 to <6 hours in 1421 patients (43.3%), and >6 hours in 832 patients (25.3%). Higher baseline SCAF frequency was not associated with increased risk of stroke or systemic embolism: 1.1% for 1 to 5 episodes versus 1.2%/patient-year for ≥6 episodes (adjusted hazard ratio, 0.89 [95% CI, 0.59-1.34]). In an exploratory analysis, patients with previous SCAF but no episode ≥6 minutes in the 6 months before enrollment had a lower risk of stroke or systemic embolism than patients with at least one episode during that period (0.5% versus 1.1%/patient-year; adjusted hazard ratio, 0.48 [95% CI, 0.27-0.85]). The frequency of SCAF did not modify the reduction in stroke or systemic embolism with apixaban (Pinteraction=0.1). The duration of the longest SCAF episode in the 6 months before enrollment was not associated with the risk of stroke or systemic embolism during follow-up (<1 hour: 1.0%/patient-year [reference]; 1-6 hours: 1.2%/patient-year [adjusted hazard ratio, 1.27 (95% CI, 0.85-1.90)]; >6 hours: 1.0%/patient-year [adjusted hazard ratio, 1.02 (95% CI, 0.63-1.66)]). SCAF duration did not modify the reduction in stroke or systemic embolism with apixaban (Ptrend=0.1). CONCLUSIONS: In ARTESiA, baseline SCAF frequency and longest episode duration were not associated with risk of stroke or systemic embolism and did not modify the effect of apixaban on reduction of stroke or systemic embolism. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01938248.

Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials.

BACKGROUND AND AIMS: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. METHODS: These pre-specified analyses of the NOAH-AFNET 6 (n=2534 patients) and ARTESiA (n=4012 patients) trials compared anticoagulation to no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. RESULTS: In patients with vascular disease (NOAH-AFNET 6 56%, ARTESiA 46.0%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6 2.7%/patient-year, ARTESiA 2.3%/patient-year in both randomised groups). Meta-analysis found consistent results across both trials (I2heterogeneity=6%) with a trend for interaction with randomised therapy (pinteraction=0.08). Stroke/SE behaved similarly. Anticoagulation increased major bleeding in vascular disease patients (edoxaban 2.1%/patient-year, no anticoagulation 1.3%/patient-year; apixaban 1.7%/patient-year; no anticoagulation 1.1%/patient-year; incidence rate ratio 1.55 [1.10-2.20]) and without vascular disease (edoxaban 2.2%/patient-year; no anticoagulation 0.6%/patient-year; apixaban 1.4%/patient-year; no anticoagulation 1.1%/patient-year, incidence rate ratio 1.93 [0.72-5.20]). CONCLUSIONS: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: assessing net clinical benefit.

Subclinical, device-detected atrial fibrillation (AF) is frequently recorded by pacemakers and other implanted cardiac rhythm devices. Patients with device-detected AF have an elevated risk of stroke, but a lower risk of stroke than similar patients with clinical AF captured with surface electrocardiogram. Two randomized clinical trials (NOAH-AFNET 6 and ARTESiA) have tested a direct oral anticoagulant (DOAC) against aspirin or placebo. A study-level meta-analysis of the two trials found that treatment with a DOAC resulted in a 32% reduction in ischaemic stroke and a 62% increase in major bleeding; the results of the two trials were consistent. The annualized rate of stroke in the control arms was ∼1%. Several factors point towards overall net benefit from DOAC treatment for patients with device-detected AF. Strokes in ARTESiA were frequently fatal or disabling and bleeds were rarely lethal. The higher absolute rates of major bleeding compared with ischaemic stroke while on treatment with a DOAC in the two trials are consistent with the ratio of bleeds to strokes seen in the pivotal DOAC vs. warfarin trials in patients with clinical AF. Prior research has concluded that patients place a higher emphasis on stroke prevention than on bleeding. Further research is needed to identify the characteristics that will help identify patients with device-detected AF who will receive the greatest benefit from DOAC treatment.

Residual Stroke Risk Among Patients With Atrial Fibrillation Prescribed Oral Anticoagulants: A Patient-Level Meta-Analysis From COMBINE AF.

BACKGROUND: Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk. METHODS AND RESULTS: Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation-treated patients with a CHA2DS2-VASc score≥2, across strata of CHA2DS2-VASc score, stroke history, and AF type, as either paroxysmal or nonparoxysmal. We included 71 794 patients with AF (median age 72 years, interquartile range, 13 years, 61.3% male) randomized to a direct oral anticoagulant or vitamin K antagonist, and followed for a mean of 2.1 (±0.8) years. The median CHA2DS2-VASc score was 4 (interquartile range, 3-5), 18.8% had a prior stroke, and 76.4% had nonparoxysmal AF. The overall rate of stroke/SE was 1.33%/y (95% CI, 1.27-1.39); 1.38%/y (95% CI, 1.31-1.45) for nonparoxysmal AF, and 1.15%/y (95% CI, 1.05-1.27) for paroxysmal AF. The rate of ischemic stroke/SE increased by a rate ratio of 1.36 (95% CI, 1.32-1.41) per 1-point increase in CHA2DS2-VASc, reaching 1.67%/y (95% CI, 1.59-1.75) ≥4 CHA2DS2-VASc points. Patients with both nonparoxysmal AF and CHA2DS2-VASc ≥4 had a stroke/SE rate of 1.75%/y (95% CI, 1.66-1.85). In patients with a prior stroke, the risk was 2.51%/y (95% CI, 2.33-2.71). CONCLUSIONS: AF type, CHA2DS2-VASc score, and stroke history can identify patients with AF, who despite oral anticoagulation have a residual stroke/SE risk of 1.5% to 2.5% per year. Evaluation of additional stroke/SE prevention strategies in high-risk patients is warranted.

Neurofilament Light Chain and Risk of Stroke in Patients With Atrial Fibrillation.

BACKGROUND: Biomarkers reflecting brain injury are not routinely used in risk assessment of stroke in atrial fibrillation (AF). Neurofilament light chain (NFL) is a novel biomarker released into blood after cerebral insults. We investigated the association between plasma concentrations of NFL, other biomarkers, and risk of stroke and death in patients with AF not receiving oral anticoagulation. METHODS: For this observational study, baseline plasma samples were available from 3077 patients with AF randomized to aspirin in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; 2003 to 2008) and AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; 2007 to 2009). Median follow-up was 1.5 years. NFL was analyzed with a Single Molecule Array (Simoa). Associations with outcomes (total stroke or systemic embolism, ischemic stroke, cardiovascular death, and all-cause death) were explored with Cox regression models. RESULTS: In the combined cohort, the median NFL level was 16.9 ng/L (interquartile range, 11.1-26.5 ng/L), the median age was 71 years, 58% were men, and 13% had a history of previous stroke. NFL was associated with older age, higher creatinine, lower body mass index, previous stroke, female sex, and diabetes but not cardiac rhythm. Higher NFL was associated with a higher risk of stroke or systemic embolism (n=206) independently of clinical characteristics (hazard ratio, 1.27 [95% CI, 1.10-1.46] per doubling of NFL) and other biomarkers (hazard ratio, 1.18 [95% CI, 1.01-1.37]) and including in patients without previous stroke (hazard ratio, 1.23 [95% CI, 1.02-1.48]). NFL was also independently associated with cardiovascular (n=219) and all-cause (n=311) death. The C index for stroke using only NFL was 0.642, on par with the currently used clinical risk scores. Addition of information on NFL improved discrimination in a model also including clinical information, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and high-sensitivity cardiac troponin T, yielding a C index of 0.727. CONCLUSIONS: NFL reflects overt and covert episodes of cerebral ischemia and improves risk assessment of stroke and death in patients with AF without oral anticoagulation, including in patients without previous stroke. The combination of NFL with information on age, history of stroke, and other biomarkers should be explored as a future avenue for stroke risk assessments in patients with AF.

Efficacy and safety of the subcutaneous implantable cardioverter-defibrillator in patients with and without obesity: A meta-analysis.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as an alternative to transvenous systems for prevention of sudden cardiac death. However, concerns have been raised regarding its efficacy and safety in obese individuals. OBJECTIVE: The purpose of this study was to perform a meta-analysis to evaluate the efficacy and safety of the S-ICD in patients with obesity by assessing the relationship between body mass index (BMI) and clinical outcomes. METHODS: A comprehensive search of multiple databases was conducted for English-language peer-reviewed studies reporting clinical outcomes in S-ICD recipients with (BMI ≥30 kg/m2) and without obesity (BMI <30 kg/m2). Data on preimplantation screening failure, defibrillation testing, complications, appropriate and inappropriate shocks, and survival were analyzed using standard, random-effects, meta-analytical techniques. RESULTS: Twenty-nine studies involving 20,486 patients were included. There was no statistically significant difference in mean BMI values of patients with failed or successful preimplantation screening (mean difference -0.60 kg/m2; 95% confidence interval [CI] -2.06 to 0.86). Obesity was associated with higher rates of failed defibrillation testing at ≤65 J (odds ratio [OR] 2.16; 95% CI 1.39-3.35), and malpositioning/suboptimal positioning occurred more frequently in obese compared to nonobese patients (OR 3.37; 95% CI 1.76-6.44). Increased BMI as a continuous variable (per increase in 1 kg/m2 BMI) was associated with elevated defibrillation thresholds (OR 1.05; 95% CI 1.03-1.08); higher risk of complications (hazard ratio [HR] 1.04; 95% CI 1.02-1.05); a trend toward an increased number of appropriate shocks (HR 1.02; 95% CI 1.00-1.04); and no significant increase in the risk of inappropriate shocks (HR 1.01; 95% CI 0.99-1.03). CONCLUSION: This meta-analysis underscores the importance of considering obesity in S-ICD implantation decisions. Although S-ICD remains effective in obese patients, attention to potential technical challenges and higher complication rates is warranted.

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.

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).

Mortality and Morbidity in Adults With Rheumatic Heart Disease.

Importance: Rheumatic heart disease (RHD) remains a public health issue in low- and middle-income countries (LMICs). However, there are few large studies enrolling individuals from multiple endemic countries. Objective: To assess the risk and predictors of major patient-important clinical outcomes in patients with clinical RHD. Design, Setting, and Participants: Multicenter, hospital-based, prospective observational study including 138 sites in 24 RHD-endemic LMICs. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were cause-specific mortality, heart failure (HF) hospitalization, stroke, recurrent rheumatic fever, and infective endocarditis. This study analyzed event rates by World Bank country income groups and determined the predictors of mortality using multivariable Cox models. Results: Between August 2016 and May 2022, a total of 13 696 patients were enrolled. The mean age was 43.2 years and 72% were women. Data on vital status were available for 12 967 participants (94.7%) at the end of follow-up. Over a median duration of 3.2 years (41 478 patient-years), 1943 patients died (15% overall; 4.7% per patient-year). Most deaths were due to vascular causes (1312 [67.5%]), mainly HF or sudden cardiac death. The number of patients undergoing valve surgery (604 [4.4%]) and HF hospitalization (2% per year) was low. Strokes were infrequent (0.6% per year) and recurrent rheumatic fever was rare. Markers of severe valve disease, such as congestive HF (HR, 1.58 [95% CI, 1.50-1.87]; P < .001), pulmonary hypertension (HR, 1.52 [95% CI, 1.37-1.69]; P < .001), and atrial fibrillation (HR, 1.30 [95% CI, 1.15-1.46]; P < .001) were associated with increased mortality. Treatment with surgery (HR, 0.23 [95% CI, 0.12-0.44]; P < .001) or valvuloplasty (HR, 0.24 [95% CI, 0.06-0.95]; P = .042) were associated with lower mortality. Higher country income level was associated with lower mortality after adjustment for patient-level factors. Conclusions and Relevance: Mortality in RHD is high and is correlated with the severity of valve disease. Valve surgery and valvuloplasty were associated with substantially lower mortality. Study findings suggest a greater need to improve access to surgical and interventional care, in addition to the current approaches focused on antibiotic prophylaxis and anticoagulation.

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.

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.

Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis of clinical trials.

BACKGROUND AND AIMS: Mineralocorticoid receptor antagonists (MRAs) improve cardiovascular outcomes in a variety of settings. This study aimed to assess whether cardioprotective effects of MRAs are modified by heart failure (HF) and atrial fibrillation (AF) status and to study their impact on AF events. METHODS: MEDLINE, Embase, and Cochrane Central databases were searched to 24 March 2023 for randomized controlled trials evaluating the efficacy of MRAs as compared with placebo or usual care in reducing cardiovascular outcomes and AF events in patients with or at risk for cardiovascular diseases. Random-effects models and interaction analyses were used to test for effect modification. RESULTS: Meta-analysis of seven trials (20 741 participants, mean age: 65.6 years, 32% women) showed that the efficacy of MRAs, as compared with placebo, in reducing a composite of cardiovascular death or HF hospitalization remains consistent across patients with HF [risk ratio = 0.81; 95% confidence interval (CI): 0.67-0.98] and without HF (risk ratio = 0.84; 95% CI: 0.75-0.93; interaction P = .77). Among patients with HF, MRAs reduced cardiovascular death or HF hospitalization in patients with AF (hazard ratio = 0.95; 95% CI: 0.54-1.66) to a similar extent as in those without AF (hazard ratio = 0.82; 95% CI: 0.63-1.07; interaction P = .65). Pooled data from 20 trials (21 791 participants, mean age: 65.2 years, 31.3% women) showed that MRAs reduce AF events (risk ratio = 0.76; 95% CI: 0.67-0.87) in both patients with and without prior AF. CONCLUSIONS: Mineralocorticoid receptor antagonists are similarly effective in preventing cardiovascular events in patients with and without HF and most likely retain their efficacy regardless of AF status. Mineralocorticoid receptor antagonists may also be moderately effective in preventing incident or recurrent AF events.

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.

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.

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.

Risk Scores for Prediction of Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis.

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and is associated with poor clinical outcomes. The objective of this systematic review and meta-analysis was to assess the performance of risk scores to predict POAF in cardiac surgery patients. We searched MEDLINE, Embase, and Cochrane CENTRAL for studies that developed/evaluated a POAF risk prediction model. Pairs of reviewers independently screened studies and extracted data. We pooled area under the receiver operating curves (AUCs), sensitivity and specificity, and adjusted odds ratios from multivariable regression analyses using the generic inverse variance method and random effects models. Forty-three studies (n = 63,847) were included in the quantitative synthesis. Most scores were originally developed for other purposes but evaluated for predicting POAF. Pooled AUC revealed moderate POAF discrimination for the EuroSCORE II (AUC 0.59, 95% confidence interval [CI] 0.54 to 0.65), Society of Thoracic Surgeons (AUC 0.60, 95% CI 0.56 to 0.63), EuroSCORE (AUC 0.63, 95% CI 0.58 to 0.68), CHADS2 (AUC 0.66, 95% CI 0.57 to 0.75), POAF Score (AUC 0.66, 95% CI 0.63 to 0.68), HATCH (AUC 0.67, 95% CI 0.57 to 0.75), CHA2DS2-VASc (AUC 0.68, 95% CI 0.60 to 0.75) and SYNTAX scores (AUC 0.74, 95% CI 0.71 to 0.78). Pooled analyses at specific cutoffs of the CHA2DS2-VASc, CHADS2, HATCH, and POAF scores demonstrated moderate-to-high sensitivity (range 46% to 87%) and low-to-moderate specificity (range 31% to 70%) for POAF prediction. In conclusion, existing clinical risk scores offer at best moderate prediction for POAF after cardiac surgery. Better models are needed to guide POAF risk stratification in cardiac surgery patients.

In DVT, oral DTIs and factor Xa inhibitors reduce major bleeding but not recurrent VTE vs. conventional anticoagulants.

SOURCE CITATION: Wang X, Ma Y, Hui X, et al. Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2023;4:CD010956. 37058421.

Plasma angiopoietin-2 and its association with heart failure in patients with atrial fibrillation.

AIMS: Several biomarkers are associated with clinical outcomes in patients with atrial fibrillation (AF), but a causal relationship has not been established. This study aimed to evaluate angiopoietin-2, a novel candidate biomarker of endothelial inflammation and vascular remodelling, in patients with AF. METHODS AND RESULTS: Angiopoietin-2 was measured in plasma obtained from patients with AF treated with aspirin monotherapy (exploration cohort, n = 2987) or with oral anticoagulation (validation cohort, n = 13 079). Regression models were built to assess the associations between angiopoietin-2, clinical characteristics, and outcomes. In both cohorts, plasma angiopoietin-2 was independently associated with AF on the baseline electrocardiogram and persistent/permanent AF, age, history of heart failure, female sex, tobacco use/smoking, body mass index, renal dysfunction, diabetes, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Angiopoietin-2 was independently associated with subsequent hospitalization for heart failure after adjusting for age, creatinine, and clinical characteristics in the exploration cohort [c-index 0.79, 95% confidence interval (CI) 0.75-0.82; third vs. first quartile, hazard ratio (HR) 1.74, 95% CI 1.26-2.41] and in the validation cohort (c-index 0.76, 95% CI 0.74-0.78; HR 1.58, 95% CI 1.37-1.82). In both cohorts, the association persisted when also adjusting for NT-proBNP (P ≤ 0.001). In full multivariable models also adjusted for NT-proBNP, angiopoietin-2 did not show statistically significant associations with ischaemic stroke, cardiovascular and all-cause death, or major bleeding that were consistent across the two cohorts. CONCLUSIONS: In patients with AF, plasma levels of angiopoietin-2 were independently associated with subsequent hospitalization for heart failure and provided incremental prognostic value to clinical risk factors and NT-proBNP.

Editorial: Developments in cardiac implantable electronic device therapy: how can we improve clinical implementation?

CIED, cardiac implantable electronic devices; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy defibrillator; EA, electroanatomical; ICD, implantable cardioverter defibrillator; LBB, left bundle branch; LBBAP, left bundle branch area pacing; LV, left ventricular; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; MRI, cardiac magnetic resonance imaging; S-ICD, subcutaneous defibrillator.