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.

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.

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.

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

BACKGROUND: Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS: In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).

Rivaroxaban versus warfarin in patients with atrial fibrillation enrolled in Latin America: Insights from ROCKET AF.

BACKGROUND: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW). METHODS: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region. RESULTS: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77). CONCLUSIONS: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted.

Use of the HAVOC Score to Identify Patients at Highest Risk of Developing Atrial Fibrillation.

BACKGROUND: Recent studies using insertable cardiac monitors (ICMs) show a high incidence of atrial fibrillation (AF). Further identifying subsets of patients who could benefit most from ICMs is desirable. We evaluated whether the HAVOC risk score which predicts AF in patients with cryptogenic stroke also predicts AF detection by ICMs in those without recent stroke. METHODS: Participants were included from the prospective, industry-sponsored REVEAL AF study assessing AF incidence in patients with CHADS2 scores ≥3 or =2 with 1 or more additional AF risk factors, who had ICM data and were not receiving anti-arrhythmic drugs. Ischemic stroke occurring less than 1 year prior to enrollment or documented AF were exclusion criteria. AF was defined as an adjudicated ICM-detected episode ≥6 min in duration. HAVOC scores were calculated by assigning 4 points for congestive heart failure, 2 points for each of hypertension, age ≥75 years, valvular disease, and coronary artery disease, and 1 point for each of peripheral vascular disease and obesity (body mass index >30). Scores classified risk as low (0-4), intermediate (5-9), or high (10-14); corresponding AF detection rates were compared using the log-rank test. AF incidence rates in patients with and without a history of remote stroke at baseline were also compared. RESULTS: Among 391 participants, the mean age was 71.5 ± 9.8 years and 186 (47.6%) were women. In total, 130 (33.2%) developed AF over 18 months. Stratification by HAVOC risk score was: 95 (24%) low, 241 (62%) intermediate, and 55 (14%) high. At 18 months, AF incidence in patients with low HAVOC scores (19.5%) was lower than in those with intermediate (32.1%) or high (34.2%) scores. AF incidence was similar among those with (n = 78) versus without (n = 313) remote stroke (27.3% vs. 29.8%; median time from stroke to ICM insertion was 4.2 [2.2-8.2] years). CONCLUSIONS: The HAVOC risk score identified a subset of individuals at greatest risk of developing AF, while AF incidence rates were similar among those with and without remote stroke. The use of the HAVOC score could help identify those at greatest likelihood of manifesting AF during long-term monitoring.

Rhythm monitoring strategies in patients at high risk for atrial fibrillation and stroke: A comparative analysis from the REVEAL AF study.

BACKGROUND: Reducing atrial fibrillation (AF)-related stroke requires timely AF diagnosis, but the optimal monitoring strategy is unknown. OBJECTIVE: We used insertable cardiac monitor (ICM) data from the REVEAL AF study to compare AF detection rates by various short-term continuous monitoring (STM) strategies. METHODS AND RESULTS: Patients without known AF, but with CHADS2 scores ≥3 (or = 2 with ≥1 additional AF risk factor) received an ICM for AF detection. One-time STM strategies were assessed by computing AF incidence at 1, 2, 7, 14, and 30 days post-ICM insertion. Repeated STM strategies (quarterly 24-hour, 48-hour, 7-day, or monthly 24-hour monitoring) were modeled by randomly selecting day(s) within a 30-day window around each nominal evaluation date over a 1-year period (simulated 10,000 times). Endpoints included AF ≥6 minutes, AF ≥1 hour, and daily AF burden ≥1 and ≥ 5.5 hours. The impact of compliance on AF detection was evaluated using daily compliance rates of 85%, 75%, 65% and 55% during follow-up months 1-3, 4-6, 7-9, and 9-12, respectively. Based on data from 385 patients (71.5 ±â€¯9.9 years; CHADS2 score 3.0 ±â€¯1.0) the incidence of AF ≥6 minutes via ICM at 12 months was 27.1% (95% CI, 22.5-31.5%). This exceeded the range of estimated rates from all modeled one-time and repeated STM strategies (0.8% for 24-hour Holter monitoring to 10.6% for quarterly 7-day monitoring). Findings were similar for all AF endpoints. Modeled non-compliance reduced AF detection by 4.5% to 22.9%. CONCLUSIONS: Most AF episodes detected via ICMs would go undetected via conventional STM strategies, thus preventing optimal prophylaxis for adverse consequences.

Antithrombotic treatment for newly diagnosed atrial fibrillation in relation to patient age: the GLORIA-AF registry programme.

AIMS: To assess antithrombotic therapy choices in relation to patient age in a large, global registry on atrial fibrillation (AF). METHODS AND RESULTS: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international programme involving patients with newly diagnosed AF and ≥1 risk factors for stroke. We used Phase II data (from November 2011 through December 2014), which commenced immediately following first non-vitamin K antagonist oral anticoagulants (NOACs) approval in participating countries. Of 15 092 patients (mean age 70.5 ± 11.0 years), enrolled at 982 centres, 26.9% were aged <65 years, 33.9% 65-74, 30.5% 75-84, and 8.6% ≥85 years old. Oral anticoagulant (OAC) use was 73.5%, 81.4%, 83.3%, and 82.3% (overall NOACs use was 44.4%, 49.7%, 48.7%, and 45.6%) for those aged <65, 65-74, 75-84 and ≥85 years, respectively. Corresponding proportions for antiplatelet monotherapy and no treatment were: 16.2% and 10.2%; 11.2% and 7.3%; 10.0% and 6.5%; 10.5% and 7.0%, respectively. Of those aged 65-74, 75-84, and ≥85 years, respectively, 83.7, 86.8 and 85.4% received OAC unless bleeding risk was high (HAS-BLED ≥3), whereby 64.1%, 63.5%, and 64.5% were anticoagulated, and 31.1%, 30.3%, and 31.3% received antiplatelets only. Of patients ≥85 years, OAC use was 88.1% in Europe (NOAC 45.1%), 79.5% in North America (NOAC 44.8%), and 54.1% in Asia (NOAC 40.2%). CONCLUSION: Despite geographic differences in OAC use, neither OAC nor NOAC uptake was lower for patients ≥85 years old compared with younger patients. Although the majority of patients was prescribed OAC at all ages, nearly one-third received antiplatelet monotherapy when bleeding risk was increased. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01468701.

Deep learning for cardiovascular medicine: a practical primer.

Deep learning (DL) is a branch of machine learning (ML) showing increasing promise in medicine, to assist in data classification, novel disease phenotyping and complex decision making. Deep learning is a form of ML typically implemented via multi-layered neural networks. Deep learning has accelerated by recent advances in computer hardware and algorithms and is increasingly applied in e-commerce, finance, and voice and image recognition to learn and classify complex datasets. The current medical literature shows both strengths and limitations of DL. Strengths of DL include its ability to automate medical image interpretation, enhance clinical decision-making, identify novel phenotypes, and select better treatment pathways in complex diseases. Deep learning may be well-suited to cardiovascular medicine in which haemodynamic and electrophysiological indices are increasingly captured on a continuous basis by wearable devices as well as image segmentation in cardiac imaging. However, DL also has significant weaknesses including difficulties in interpreting its models (the 'black-box' criticism), its need for extensive adjudicated ('labelled') data in training, lack of standardization in design, lack of data-efficiency in training, limited applicability to clinical trials, and other factors. Thus, the optimal clinical application of DL requires careful formulation of solvable problems, selection of most appropriate DL algorithms and data, and balanced interpretation of results. This review synthesizes the current state of DL for cardiovascular clinicians and investigators, and provides technical context to appreciate the promise, pitfalls, near-term challenges, and opportunities for this exciting new area.

Safety and effectiveness of dabigatran at 2 years: Final outcomes from Phase II of the GLORIA-AF registry program.

GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35-0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice.

Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial.

Aim: The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and ≤48 h anticoagulation prior to randomization undergoing cardioversion. Methods: One thousand five hundred patients were randomized. The apixaban dose of 5 mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 133 µmol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding. Results: There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events. Conclusions: Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion. Clinical Trials.gov number: NCT02100228.

Safety and efficacy of non-vitamin K oral anticoagulant for atrial fibrillation patients after percutaneous coronary intervention: A bivariate analysis of the PIONEER AF-PCI and RE-DUAL PCI trial.

BACKGROUND: The tradeoff in safety versus efficacy in substituting a non-vitamin K antagonist oral anticoagulant for a vitamin K antagonist (VKA) in the stented atrial fibrillation patient has not been quantitatively evaluated. METHODS: Based on summary data from the PIONEER AF-PCI and RE-DUAL PCI trials, 4 antithrombotic regimens were compared with VKA-based triple therapy: (1) rivaroxaban (riva) 15 mg daily + P2Y12 inhibitor, (2) riva 2.5 mg twice daily + P2Y12 inhibitor + aspirin, (3) dabigatran (dabi) 110 mg twice daily + P2Y12 inhibitor, and (4) dabi 150 mg twice daily + P2Y12 inhibitor. A bivariate model with a noninferiority margin of 1.38 was used to simultaneously assess safety and efficacy. The safety end point was major or clinically relevant nonmajor bleeding by International Society on Thrombosis and Haemostasis definitions. The efficacy end point was a thromboembolic event (myocardial infarction, stroke, or systemic embolism), death, or urgent revascularization. The bivariate outcome, a measure of risk difference in the net clinical outcome, was compared between antithrombotic regimens. RESULTS: All 4 non-vitamin K antagonist oral anticoagulant regimens were superior in bleeding and noninferior in efficacy compared with triple therapy with VKA. Riva 15 mg daily and 2.5 mg twice daily were associated with bivariate combined risk reductions of 5.6% (2.3%-8.8%) and 5.5% (2.1%-8.7%), respectively, and dabi 110 mg twice daily and 150 mg twice daily reduced the bivariate risk by 3.8% (0.5%-7.0%) and 6.3% (2.4%-9.8%), respectively. CONCLUSIONS: A bivariate analysis that simultaneously characterizes both risk and benefit demonstrates that riva- and dabi-based regimens were both favorable over VKA plus dual antiplatelet therapy among patients with atrial fibrillation undergoing PCI.

Impact of polyvascular disease on patients with atrial fibrillation: Insights from ROCKET AF.

BACKGROUND: We investigated the impact of polyvascular disease in patients enrolled in ROCKET AF. METHODS: Cox regression models were used to assess clinical outcomes and treatment effects of rivaroxaban compared with warfarin in patients with atrial fibrillation and coronary, peripheral, or carotid artery disease, or any combination of the 3. RESULTS: A total of 655 (4.6%) patients had polyvascular disease (≥2 disease locations), and 3,391 (23.8%) had single-arterial bed disease. Patients with polyvascular disease had similar rates of stroke/systemic embolism but higher rates of cardiovascular and bleeding events when compared with those without vascular disease. Use of rivaroxaban compared with warfarin was associated with higher rates of stroke in patients with polyvascular disease (hazard ratio [HR] 2.41, 95% CI 1.05-5.54); however, this was not seen in patients with single-bed (HR 0.90, 95% CI 0.64-1.28) or no vascular disease (HR 0.85, 95% CI 0.69-1.04; interaction P = .058). There was a significant interaction for major or nonmajor clinically relevant bleeding in patients with polyvascular (HR 1.23, 95% CI 0.91-1.65) and single-bed vascular disease (HR 1.30, 95% CI 1.13-1.49) treated with rivaroxaban compared with warfarin when compared with those without vascular disease (HR 0.95, 95% CI 0.87-1.04; interaction P = .0006). Additional antiplatelet therapy in this population did not improve stroke or cardiovascular outcomes. CONCLUSION: The use of rivaroxaban compared with warfarin was associated with a higher risk of stroke and bleeding in patients with polyvascular disease enrolled in ROCKET AF. Further studies are needed to understand the optimal management of this high-risk population.

Two-year follow-up of patients treated with dabigatran for stroke prevention in atrial fibrillation: Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry.

BACKGROUND AND PURPOSE: GLORIA-AF is a large, global, prospective registry program of newly diagnosed atrial fibrillation (AF) patients with ≥1 stroke risk factors. We describe the effectiveness and safety of dabigatran etexilate over 2 years from routine clinical practice in nearly 3000 patients from GLORIA-AF who are newly diagnosed with non-valvular AF and at risk of stroke. METHODS: Consecutive enrollment into phase II of GLORIA-AF was initiated following approval of dabigatran for stroke prevention in non-valvular AF. Within this Phase II, 2937 dabigatran patients completed 2-year follow-up by May 2016 and were eligible for analysis. Patients who took at least 1 dose of dabigatran (n=2932) were used to estimate incidence rates. RESULTS: Overall incidence rates per 100 person-years of 0.63 (95% confidence interval [CI], 0.42-0.92) for stroke, 1.12 (0.83-1.49) for major bleeding, 0.47 (0.29-0.72) for myocardial infarction, and 2.69 (2.22-3.23) for all-cause death were observed. For patients taking 150 mg dabigatran twice daily (BID), corresponding rates (95% CI) were 0.56 (0.30-0.94), 1.00 (0.64-1.47), 0.48 (0.25-0.83), and 2.07 (1.55-2.72), respectively. For patients taking 110 mg dabigatran BID, event rates (95% CI) were 0.67 (0.33-1.20), 1.16 (0.70-1.80), 0.43 (0.17-0.88), and 3.16 (2.36-4.15). CONCLUSIONS: These global data confirm the sustained safety and effectiveness of dabigatran over 2 years of follow-up, consistent with the results from clinical trials as well as contemporary real-world studies. WHAT IS KNOWN: • Non-vitamin K antagonist (VKA) anticoagulants (NOACs) are the preferred therapy for prevention of ischemic stroke based on phase 3 trials, but there is insufficient information on their efficacy and safety in daily practice, based on prospectively collected data. WHAT IS NEW: • This study shows that in non-valvular AF patient population, with up to 2 years of follow-up, the use of dabigatran led to a low incidence of ischemic stroke, major bleeding, and myocardial infarction in routine clinical care, confirming the sustained safety and effectiveness of dabigatran in clinical practice over 2 years of follow-up.

Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention.

Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI).

Three-dimensional echocardiography demonstrates a skewered left ventricular thrombus in a patient with a heart transplant.

A left ventricular (LV) false tendon is a frequently visualized structure in echocardiography with unclear clinical significance. We present the case of a false tendon serving as a nidus for thrombus in a post-orthotopic heart transplantation patient. Three-dimensional transthoracic echocardiography (3DTTE) was utilized to visualize a LV mass and facilitate its identification as a thrombus as well as the surrounding structures. Using datasets from 3DTTE, the lack of ventricular wall attachment and circumferential formation of the thrombus around the false tendon was identified. Serial imaging demonstrated resolution of the thrombus with anticoagulation.

Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1.

Patients with atrial fibrillation (AF) have a high risk of stroke and mortality, which can be considerably reduced by oral anticoagulants (OAC). Recently, four non-vitamin-K oral anticoagulants (NOACs) were compared with warfarin in large randomized trials for the prevention of stroke and systemic embolism. Today's clinician is faced with the difficult task of selecting a suitable OAC for a patient with a particular clinical profile or a particular pattern of risk factors and concomitant diseases. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. NOACs for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In the first of a two-part review, we discuss the choice of NOAC for stroke prevention in the following subgroups of patients with AF: (i) stable coronary artery disease or peripheral artery disease, including percutaneous coronary intervention with stenting and triple therapy; (ii) cardioversion, ablation and anti-arrhythmic drug therapy; (iii) mechanical valves and rheumatic valve disease, (iv) patients with time in therapeutic range of >70% on warfarin; (v) patients with a single stroke risk factor (CHA2DS2VASc score of 1 in males, 2 in females); and (vi) patients with a single first episode of paroxysmal AF. Although there are no major differences in terms of efficacy and safety between the NOACs for some clinical scenarios, in others we are able to suggest that particular drugs and/or doses be prioritized for anticoagulation.

Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2.

The choice of oral anticoagulant (OAC) for patients with atrial fibrillation (AF) may be influenced by individual clinical features or by patterns of risk factors and comorbidities. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. non-vitamin K oral anticoagulants (NOACs) for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In addition, we discuss the timing of initiation of anticoagulation. In the second of a two-part review, we discuss the use of NOAC for stroke prevention in the following subgroups of patients with AF: (vii) secondary stroke prevention in patients after stroke or transient ischaemic attack (TIA), (viii) patients with acute stroke requiring thrombolysis or thrombectomy, (ix) those initiating or restarting OAC treatment after stroke or TIA, (x) those with renal impairment on dialysis, (xi) the elderly, (xii) those at high risk of gastrointestinal bleeding, and (xiii) those with hypertension. In addition, we discuss adherence and compliance. Finally, we present a summary of treatment suggestions. In specific subgroups of patients with AF, evidence supports the use of particular NOACs and/or particular doses of anticoagulant. The appropriate choice of treatment for these subgroups will help to promote optimal clinical outcomes.

Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) often take multiple medications. METHODS AND RESULTS: We examined characteristics and compared adjusted outcomes between rivaroxaban and warfarin according to number of concomitant baseline medications and the presence of combined cytochrome P450 3A4 and P-glycoprotein inhibitors in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study. At baseline, 5101 patients (36%) were on 0 to 4 medications, 7298 (51%) were on 5 to 9, and 1865 (13%) were on ≥ 10. Although polypharmacy was not associated with higher risk of stroke or non-central nervous system embolism (adjusted hazard ratio, 1.02 for ≥ 10 versus 0-4 medications; 95% confidence interval, 0.76-1.38), it was associated with higher risks of the combined end point of stroke, non-central nervous system embolism, vascular death, or myocardial infarction (adjusted hazard ratio, 1.41 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.18-1.68) and nonmajor clinically relevant or major bleeding (adjusted hazard ratio, 1.47 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.31-1.65). There was no significant difference in primary efficacy (adjusted interaction P=0.99) or safety outcomes (adjusted interaction P=0.87) between treatment groups by number of medications. Patients treated with 0 to 4 medications had lower rates of major bleeding with rivaroxaban (adjusted hazard ratio, 0.71; 95% confidence interval, 0.52-0.95; interaction P=0.0074). There was no evidence of differential outcomes in those treated with ≥ 1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors. CONCLUSIONS: In a population of patients with atrial fibrillation, two thirds were on ≥ 5 medications. Increasing medication use was associated with higher risk of bleeding but not stroke. Rivaroxaban was tolerated across complex patients on multiple medications. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.