Severity of Ischemic Stroke After Left Atrial Appendage Closure vs Nonwarfarin Oral Anticoagulants.

BACKGROUND: Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis-thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS). OBJECTIVES: The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC. METHODS: A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (ISLAAC) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (ISDOAC). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later. RESULTS: Compared with ISDOAC patients (n = 322), ISLAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years; P = 0.002), with higher HAS-BLED scores (3.0 vs 2.0; P = 0.004) and more frequent prior bleeding events (54.4% vs 23.6%; P < 0.001), but similar CHA2DS2-VASc scores (5.0 vs 5.0; P = 0.28). Strokes were less frequently disabling/fatal with ISLAAC than ISDOAC at both hospital discharge (38.3% vs 70.3%; P < 0.001) and 3 months later (33.3% vs 56.2%; P < 0.001). Differences in stroke severity persisted after propensity score matching. By multivariate regression analysis, ISLAAC was independently associated with fewer disabling/fatal strokes at discharge (OR: 0.22; 95% CI: 0.13-0.39; P < 0.001) and 3 months (OR: 0.25; 95% CI: 0.12-0.50; P < 0.001), and fewer deaths at 3 months (OR: 0.28; 95% CI: 0.12-0.64; P < 0.001). CONCLUSIONS: Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis.

Interatrial Block Association With Adverse Cardiovascular Outcomes in Patients Without a History of Atrial Fibrillation.

BACKGROUND: Interatrial block (IAB) is associated with thromboembolism and atrial arrhythmias. However, prior studies included small patient cohorts so it remains unclear whether IAB predicts adverse outcomes particularly in context of atrial fibrillation (AF)/atrial flutter (AFL). OBJECTIVES: This study sought to determine whether IAB portends increased stroke risk in a large cohort in the presence or absence of AFAF/AFL. METHODS: We performed a 5-center retrospective analysis of 4,837,989 electrocardiograms (ECGs) from 1,228,291 patients. IAB was defined as P-wave duration ≥120 ms in leads II, III, or aVF. Measurements were extracted as .XML files. After excluding patients with prior AF/AFL, 1,825,958 ECGs from 458,994 patients remained. Outcomes were analyzed using restricted mean survival time analysis and restricted mean time lost. RESULTS: There were 86,317 patients with IAB and 355,032 patients without IAB. IAB prevalence in the cohort was 19.6% and was most common in Black (26.1%), White (20.9%), and Hispanic (18.5%) patients and least prevalent in Native Americans (9.2%). IAB was independently associated with increased stroke probability (restricted mean time lost ratio coefficient [RMTLRC]: 1.43; 95% CI: 1.35-1.51; tau = 1,895), mortality (RMTLRC: 1.14; 95% CI: 1.07-1.21; tau = 1,924), heart failure (RMTLRC: 1.94; 95% CI: 1.83-2.04; tau = 1,921), systemic thromboembolism (RMTLRC: 1.62; 95% CI: 1.53-1.71; tau = 1,897), and incident AF/AFL (RMTLRC: 1.16; 95% CI: 1.10-1.22; tau = 1,888). IAB was not associated with stroke in patients with pre-existing AF/AFL. CONCLUSIONS: IAB is independently associated with stroke in patients with no history of AF/AFL even after adjustment for incident AF/AFL and CHA2DS2-VASc score. Patients are at increased risk of stroke even when AF/AFL is not identified.

Association Between Stable Coronary Artery Disease and Hospital Readmissions Following Catheter Ablation for Atrial Fibrillation.

OBJECTIVE: To evaluate the association of stable coronary artery disease (CAD) with readmission following hospitalization for catheter ablation (CA) for atrial fibrillation (AF). PATIENTS AND METHODS: Using the Nationwide Readmissions Database, we identified all hospitalizations from the last quarter of 2015 through 2019 with a Medicare Severity-Diagnosis Related Group designation for a percutaneous intracardiac procedure, a procedure code for CA, and a primary discharge diagnosis of AF. Cases of acute coronary syndrome (ACS) at index hospitalization were excluded to define stable CAD. The primary outcome was all-cause 90-day hospital readmission; secondary end points included readmissions for AF, repeated CA, ACS, and heart failure (HF). RESULTS: Among 28,466 hospitalizations for CA for AF identified, 3171 (11.1%) involved patients with stable CAD. No hospitalizations included patients with HF diagnosis codes. The incidence of 90-day all-cause readmission was higher in patients with stable CAD (18.4% [400 of 2172] vs 14.4% [2549 of 17,667]; P=.006), as was the incidence of subsequent hospitalization with ACS (5.3% [21] vs 1.1% [28]; P<.001) or HF (17.0% [68] vs 10.2% [260]; P=.007). The incidence of readmission within 90 days with recurrent AF did not differ for those with or without stable CAD (21.9% [88] vs 26.5% [675]; P=.217). Pooled analysis of 90-day HF readmissions revealed a higher incidence among older patients, those with chronic kidney or pulmonary disease, and those with persistent and chronic AF subtypes. CONCLUSION: Results of this large-scale analysis suggest that among patients hospitalized for CA for AF, stable CAD is associated with hospital readmissions within 90 days, including admissions for ACS and decompensated HF.

Predicting Malignant Ventricular Arrhythmias Using Real-Time Remote Monitoring.

BACKGROUND: Although implantable cardioverter-defibrillator (ICD) therapies are associated with increased morbidity and mortality, the prediction of malignant ventricular arrhythmias has remained elusive. OBJECTIVES: The purpose of this study was to evaluate whether daily remote-monitoring data may predict appropriate ICD therapies for ventricular tachycardia or ventricular fibrillation. METHODS: This was a post hoc analysis of IMPACT (Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices), a multicenter, randomized, controlled trial of 2,718 patients evaluating atrial tachyarrhythmias and anticoagulation for patients with heart failure and ICD or cardiac resynchronization therapy with defibrillator devices. All device therapies were adjudicated as either appropriate (to treat ventricular tachycardia or ventricular fibrillation) or inappropriate (all others). Remote monitoring data in the 30 days before device therapy were utilized to develop separate multivariable logistic regression and neural network models to predict appropriate device therapies. RESULTS: A total of 59,807 device transmissions were available for 2,413 patients (age 64 ± 11 years, 26% women, 64% ICD). Appropriate device therapies (141 shocks, 10 antitachycardia pacing) were delivered to 151 patients. Logistic regression identified shock lead impedance and ventricular ectopy as significantly associated with increased risk of appropriate device therapy (sensitivity 39%, specificity 91%, AUC: 0.72). Neural network modeling yielded significantly better (P < 0.01 for comparison) predictive performance (sensitivity 54%, specificity 96%, AUC: 0.90), and also identified patterns of change in atrial lead impedance, mean heart rate, and patient activity as predictors of appropriate therapies. CONCLUSIONS: Daily remote monitoring data may be utilized to predict malignant ventricular arrhythmias in the 30 days before device therapies. Neural networks complement and enhance conventional approaches to risk stratification.

Pathophysiology, Echocardiographic Diagnosis, and Treatment of Atrial Functional Mitral Regurgitation: JACC State-of-the-Art Review.

The conventional view holds that functional mitral regurgitation (MR) is caused by restriction of leaflet motion resulting from displacement of the papillary muscle-bearing segments of the left ventricle. In the past decade, evidence has accrued suggesting functional MR can also be caused by left atrial enlargement. This underrecognized cause of secondary MR-atrial functional MR (AF-MR)-is mechanistically linked to annular enlargement, perturbations of annular contraction, and atriogenic leaflet tethering. AF-MR has been described in patients with atrial fibrillation and heart failure with preserved ejection fraction. Preliminary data suggest rhythm control may decrease MR severity in patients with atrial fibrillation. Additionally, several studies have reported reductions in MR and symptomatic improvement with restrictive annuloplasty and transcatheter edge-to-edge repair. This review discusses the pathophysiology, echocardiographic diagnosis, and treatment of AF-MR. AF-tricuspid regurgitation is also discussed.

Benefit-Risk Assessment of Rivaroxaban for Extended Thromboprophylaxis After Hospitalization for Medical Illness.

Background Venous thromboembolism (VTE) often occurs after hospitalization in medically ill patients, but the population benefit-risk of extended thromboprophylaxis remains uncertain. Methods and Results The MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) study (NCT02111564) was a randomized double-blind trial that compared thromboprophylaxis with rivaroxaban 10 mg daily versus placebo for 45 days after hospital discharge in medically ill patients with a creatinine clearance ≥50 mL/min. The benefit-risk balance in this population was quantified by calculating the between-treatment rate differences in efficacy and safety end points per 10 000 patients treated. Clinical characteristics of the study population were consistent with a hospitalized medical population at risk for VTE. Treating 10 000 patients with rivaroxaban resulted in 32.5 fewer symptomatic VTE and VTE-related deaths but was associated with 8 additional major bleeding events. The treatment benefit was driven by the prevention of nonfatal symptomatic VTE (26 fewer events). There was no between-treatment difference in the composite of critical site or fatal bleeding. Conclusions Extending thromboprophylaxis with rivaroxaban for 45 days after hospitalization provides a positive benefit-risk balance in medically ill patients at risk for VTE who are not at high risk for bleeding. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02111564.

Evolution of antithrombotic therapy for patients with atrial fibrillation: The prospective global GLORIA-AF registry program.

OBJECTIVE: To assess baseline characteristics and antithrombotic treatment (ATT) prescription patterns in patients enrolled in the third phase of the GLORIA-AF Registry Program, evaluate predictors of treatment prescription, and compare results with phase II. METHODS: GLORIA-AF is a large, global, prospective registry program, enrolling patients with newly diagnosed nonvalvular atrial fibrillation (AF) at risk of stroke. Patients receiving dabigatran were followed for two years in phase II, and all patients were followed for 3 years in phase III. Phase II started when dabigatran became available; phase III started when the characteristics of patients receiving dabigatran became roughly comparable with those receiving vitamin K antagonists (VKAs). RESULTS: Between 2014 and 2016, 21,241 patients were enrolled in phase III. In total, 82% of patients were prescribed oral anticoagulation ([OAC]; 59.5% novel/nonvitamin K oral anticoagulants [NOACs], 22.7% VKAs). A further 11% of patients were prescribed antiplatelets without OAC and 7% were prescribed no ATT. A high stroke risk was the main driver of OAC prescription. Factors associated with prescription of VKA over NOAC included type of site, region, physician specialty, and impaired kidney function. CONCLUSION: Over the past few years, data from phase III of GLORIA-AF show that OACs have become the standard treatment option, with most newly diagnosed AF patients prescribed a NOAC. However, in some regions a remarkable proportion of patients remain undertreated. In comparison with phase II, more patients received NOACs in phase III while the prescription of VKA decreased. VKAs were preferred over NOACs in patients with impaired kidney function.

Rivaroxaban Plus Aspirin for Extended Thromboprophylaxis in Acutely Ill Medical Patients: Insights from the MARINER Trial.

Background The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N = 3,159); (2) rivaroxaban alone ( N = 2,848); (3) aspirin alone ( N = 3,046); and (4) no TP ( N = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p = 0.005) and all-cause mortality alone ( p = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p = 0.009). Limitations Aspirin use was not randomized. Conclusion Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials.

BACKGROUND: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). METHODS: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. RESULTS: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P=0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P=0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. CONCLUSIONS: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www. CLINICALTRIALS: gov; Unique identifier: MARINER, NCT02111564.

Dabigatran versus vitamin K antagonists for atrial fibrillation in clinical practice: final outcomes from Phase III of the GLORIA-AF registry.

BACKGROUND: Prospectively collected, routine clinical practice-based data on antithrombotic therapy in non-valvular atrial fibrillation (AF) patients are important for assessing real-world comparative outcomes. The objective was to compare the safety and effectiveness of dabigatran versus vitamin K antagonists (VKAs) in patients with newly diagnosed AF. METHODS AND RESULTS: GLORIA-AF is a large, prospective, global registry program. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc scores ≥ 1 were included and followed for 3 years. To control for differences in patient characteristics, the comparative analysis for dabigatran versus VKA was performed on a propensity score (PS)-matched patient set. Missing data were multiply imputed. Proportional-hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Between 2014 and 2016, 21,300 eligible patients were included worldwide: 3839 patients were prescribed dabigatran and 4836 VKA with a median age of 71.0 and 72.0 years, respectively; > 85% in each group had a CHA2DS2-VASc-score ≥ 2. The PS-matched comparative analysis for dabigatran and VKA included on average 3326 pairs of matched initiators. For dabigatran versus VKAs, adjusted HRs (95% confidence intervals) were: stroke 0.89 (0.59-1.34), major bleeding 0.61 (0.42-0.88), all-cause death 0.78 (0.63-0.97), and myocardial infarction 0.89 (0.53-1.48). Further analyses stratified by PS and region provided similar results. CONCLUSIONS: Dabigatran was associated with a 39% reduced risk of major bleeding and 22% reduced risk for all-cause death compared with VKA. Stroke and myocardial infarction risks were similar, confirming a more favorable benefit-risk profile for dabigatran compared with VKA in clinical practice. Clinical trial registration https://www. CLINICALTRIALS: gov . NCT01468701, NCT01671007.

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry.

BACKGROUND AND PURPOSE: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). METHODS: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. RESULTS: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79-2.03), major bleeding 0.59 (0.40-0.88), myocardial infarction 0.68 (0.40-1.16), and all-cause death 0.86 (0.67-1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76-1.78), myocardial infarction 0.84 (0.48-1.46), major bleeding 0.98 (0.63-1.52) and all-cause death 1.01 (0.79-1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52-1.19), myocardial infarction 0.96 (0.63-1.45), major bleeding 1.54 (1.14-2.08), and all-cause death 0.97 (0.80-1.19). CONCLUSIONS: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013.

Left Ventricular Thrombus Following Acute Myocardial Infarction: JACC State-of-the-Art Review.

The incidence of left ventricular (LV) thrombus following acute myocardial infarction has markedly declined in recent decades caused by advancements in reperfusion and antithrombotic therapies. Despite this, embolic events remain the most feared complication of LV thrombus necessitating systemic anticoagulation. Mechanistically, LV thrombus development depends on Virchow's triad (ie, endothelial injury from myocardial infarction, blood stasis from LV dysfunction, and hypercoagulability triggered by inflammation, with each of these elements representing potential therapeutic targets). Diagnostic modalities include transthoracic echocardiography with or without ultrasound-enhancing agents and cardiac magnetic resonance. Most LV thrombi develop within the first 2 weeks post-acute myocardial infarction, and the role of surveillance imaging appears limited. Vitamin K antagonists remain the mainstay of therapy because the efficacy of direct oral anticoagulants is less well established. Only meager data support the routine use of prophylactic anticoagulation, even in high-risk patients.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data. METHODS: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. RESULTS: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin. CONCLUSIONS: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.

Characteristics of patients with atrial high rate episodes detected by implanted defibrillator and resynchronization devices.

AIMS: Atrial high rate episodes (AHREs) are associated with increased risks of thromboembolism and cardiovascular mortality. However, the clinical characteristics of patients developing AHRE of various durations are not well studied. METHODS AND RESULTS: This was an ancillary analysis of the multicentre, randomized IMPACT trial. In the present analysis, we classified patients according to the duration of AHRE ≤6 min, >6 min to ≤6 h, >6 to ≤24 h and >24 h, and investigated the association between clinical factors and the development of each duration of AHRE. Of 2718 patients included in the trial, 945 (34.8%) developed AHRE. The incidence rates of each AHRE duration category were 5.4/100, 12.0/100, 6.8/100, and 3.3/100 patient-years, respectively. The incidence rates of AHRE >6 h were significantly higher in patients at high risk of thromboembolism (CHADS2 score ≥3) compared to those at low risk (CHADS2 score 1 or 2). Using Cox regression analysis, age ≥65 years and history of atrial fibrillation (AF) and/or atrial flutter (AFL) were risk factors for AHRE >6 min. In addition, hypertension was associated with AHRE >24 h (hazard ratio 2.13, 95% confidence interval 1.24-3.65, P = 0.006). CONCLUSION: Atrial high rate episode >6 min to ≤6 h were most prevalent among all AHRE duration categories. Longer AHREs were more common in patients at risk of thromboembolism. Age and history of AF/AFL were risk factors for AHRE >6 min. Furthermore, hypertension showed a strong impact on the development of AHRE >24 h rather than age.

Ischaemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full- and half-dose edoxaban vs. warfarin: insights from ENGAGE AF-TIMI 48.

AIMS: In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30 mg) and lower dose edoxaban (30/15 mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described. METHODS AND RESULTS: Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg, or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P < 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30 mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15 mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039). CONCLUSION: Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.

Artificial Intelligence-Powered Blockchains for Cardiovascular Medicine.

Clinical databases, particularly those composed of big data, face growing security challenges. Blockchain, the open, decentralized, distributed public ledger technology powering cryptocurrency, records transactions securely without the need for third-party verification. In the health care setting, decentralized blockchain networks offer a secure interoperable gateway for clinical research and practice data. Here, we discuss recent advances and potential future directions for the application of blockchain and its integration with artificial intelligence (AI) in cardiovascular medicine. We first review the basic underlying concepts of this technology and contextualise it within the spectrum of current, well known applications. We then consider specific applications for cardiovascular medicine and research in areas such as high-throughput gene sequencing, wearable technologies, and clinical trials. We then evaluate current challenges to effective implementation and future directions. We also summarise the health care applications that can be realised by combining decentralized blockchain computing platforms (for data security) and AI computing (for data analytics). By leveraging high-performance computing and AI capable of securely managing large and rapidly expanding medical databases, blockchain incorporation can provide clinically meaningful predictions, help advance research methodology (eg, via robust AI-blockchain decentralized clinical trials), and provide virtual tools in clinical practice (eg, telehealth, sensory-based technologies, wearable medical devices). Integrating AI and blockchain approaches synergistically amplifies the strengths of both technologies to create novel solutions to serve the objective of providing precision cardiovascular medicine.