LVS-HARMED Risk Score for Incident Heart Failure in Patients With Atrial Fibrillation Who Present to the Emergency Department: Data from a World-Wide Registry.

Background Heart failure (HF) is a common complication to atrial fibrillation (AF), leading to rehospitalization and death. Early identification of patients with AF at risk for HF might improve outcomes. We aimed to derive a score to predict 1-year risk of new-onset HF after an emergency department (ED) visit with AF. Methods and Results The RE-LY AF (Randomized Evaluation of Long-Term Anticoagulant Therapy) registry enrolled patients with AF presenting to an ED in 47 countries, and followed them for a year. The end point was HF hospitalization and/or HF death. Among 15 400 ED patients, 9765 had no prior HF (mean age, 64.9±14.9 years). Within 1 year, new-onset HF developed in 6.8% of patients, of whom 21% died of HF. Independent predictors of HF included left ventricular hypertrophy (odds ratio [OR], 1.47; 95% CI, 1.19-1.82), valvular heart disease (OR, 1.55; 95% CI, 1.18-2.04), smoking (OR, 1.42; 95% CI, 1.12-1.78), height (OR, 0.93; 95% CI, 0.90-0.95 per 3 cm), age (OR, 1.11; 95% CI, 1.07-1.15 per 5 years), rheumatic heart disease (OR, 1.77, 95% CI, 1.24-2.51), prior myocardial infarction (OR, 1.85; 95% CI, 1.45-2.36), remaining in AF at ED discharge (OR, 1.86; 95% CI, 1.46-2.36), and diabetes (OR, 1.33; 95% CI, 1.09-1.64). A continuous risk prediction score (LVS-HARMED [left ventricular, valvular heart disease, smoking or other tobacco use, height, age, rheumatic heart disease, myocardial infarction, emergency department discharge rhythm, and diabetes]) had good discrimination (C statistic, 0.735; 95% CI, 0.716-0.755). Validation was conducted internally using bootstrapping (optimism-corrected C statistic, 0.705) and externally (C statistic, 0.699). The 1-year incidence of HF hospitalization and/or HF death across quartile groups of the score was 1.1%, 4.5%, 6.9%, and 14.4%, respectively. LVS-HARMED also predicted incident stroke (C statistic, 0.753; 95% CI, 0.728-0.778). Conclusions The LVS-HARMED score predicts new-onset HF after an ED visit for AF. Preventative strategies should be considered in patients with high LVS-HARMED HF risk.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke.

BACKGROUND: Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons. METHODS: We conducted a multicenter, randomized trial involving participants with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating greater risk of stroke) who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The participants, research personnel, and primary care physicians (other than the surgeons) were unaware of the trial-group assignments. RESULTS: The primary analysis population included 2379 participants in the occlusion group and 2391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure, and at 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.85; P = 0.001). The incidence of perioperative bleeding, heart failure, or death did not differ significantly between the trial groups. CONCLUSIONS: Among participants with atrial fibrillation who had undergone cardiac surgery, most of whom continued to receive ongoing antithrombotic therapy, the risk of ischemic stroke or systemic embolism was lower with concomitant left atrial appendage occlusion performed during the surgery than without it. (Funded by the Canadian Institutes of Health Research and others; LAAOS III ClinicalTrials.gov number, NCT01561651.).

Complete revascularization with multivessel PCI for myocardial infarction

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS: We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS: At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P=0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P=0.62 and P=0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS: Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.). (AU)

Estimated stroke risk, yield, and number needed to screen for atrial fibrillation detected through single time screening: a multicountry patient-level meta-analysis of 141,220 screened individuals.

BACKGROUND: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata. METHODS AND FINDINGS: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA2DS2-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA2DS2-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (≥85 years); 72% of ≥65 years had ≥1 additional stroke risk factor other than age/sex. All new AF ≥75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ≥65 years, 926 for 60-64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples. CONCLUSIONS: People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ≥1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations.

Complete Revascularization with Multivessel PCI for Myocardial Infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS: We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS: At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS: Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.).

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Diagnostic accuracy and yield of screening tests for atrial fibrillation in the family practice setting: a multicentre cohort study.

BACKGROUND: Detection of undiagnosed or undertreated ("actionable") atrial fibrillation could increase the use of appropriate oral anticoagulant therapy and reduce the risk of stroke. We sought to compare newer screening technologies with a pulse-check for the detection of atrial fibrillation and to determine whether the detection of actionable atrial fibrillation increases the use of oral anticoagulant agents. METHODS: This prospective multicentre cohort study involved 22 primary care clinics. We recruited participants aged 65 years and older who were attending routine appointments. Each participant underwent 3 methods of screening: a 30-second radial pulse-check; single-lead electrocardiogram; and screening by blood pressure machine with atrial fibrillation detection algorithms. Participants who received a positive result on 1 or more test underwent 12-lead electrocardiogram with or withour 24-hour Holter. Screening tests were compared using the McNemar test. Participants with confirmed atrial fibrillation received follow-up at 90 days. RESULTS: The mean age of participants was 73.7 (± 6.9) years, and 53.4% of participants were female. Of 2171 patients, we had data from all 3 screening tests for 2054 patients. Both single-lead electrocardiogram and the blood pressure device showed superior specificity compared with pulse-check (p < 0.001 for each). Fifty-six patients (2.7%) had confirmed atrial fibrillation: 12 patients had newly detected atrial fibrillation (none of the patients were using anticoagulation agents), and 44 patients had previously diagnosed atrial fibrillation (42 patients were receiving anticoagulant therapy, 2 were not). Thus, 14 patients had actionable atrial fibrillation (0.7%). By 90 days, 77% of patients with actionable atrial fibrillation had started anticoagulant therapy. INTERPRETATION: Newer screening technologies showed superior specificity compared with a pulse-check. Screening detected undiagnosed or undertreated atrial fibrillation in 0.7% of participants, and 77% started appropriate anticoagulant therapy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02262351.

Is Screening for Atrial Fibrillation in Canadian Family Practices Cost-Effective in Patients 65 Years and Older?

We present an economic evaluation of a recently completed cohort study in which 2054 seniors were screened for atrial fibrillation (AF) in 22 Canadian family practices. Using a Markov model, trial and literature data were used to project long-term outcomes and costs associated with 4 AF screening strategies for individuals aged 65 years or older: no screening, screen with 30-second radial manual pulse check (pulse check), screen with a blood pressure machine with AF detection (BP-AF), and screen with a single-lead electrocardiogram (SL-ECG). Costs and outcomes were discounted at 1.5% and the model used a lifetime horizon from a public payer perspective. Compared with no screening, screening for AF in Canadian family practice offices using pulse check or screen with a blood pressure machine with AF detection is the dominant strategy whereas screening with SL-ECG is a highly cost-effective strategy with an incremental cost per quality-adjusted life-year (QALY) gained of CAD$4788. When different screening strategies were compared, screening with pulse check had the lowest expected costs ($202) and screening with SL-ECG had the highest expected costs ($222). The no-screening arm resulted in the lowest number of QALYs (8.74195) whereas pulse check and SL-ECG resulted in the highest expected QALYs (8.74362). Probabilistic analysis confirmed that pulse check had the highest probability of being cost-effective (63%) assuming a willingness to pay of $50,000 per QALY gained. Screening for AF in seniors during routine appointments with Canadian family physicians is a cost-effective strategy compared with no screening. Screening with a pulse check is likely to be the most cost-effective strategy.

Effects of dabigatran according to age in atrial fibrillation.

OBJECTIVE: The prevalence of atrial fibrillation (AF) and the risk of stroke and bleeding vary according to age. To estimate effects of dabigatran, compared with warfarin, on stroke, bleeding and mortality in patients with AF in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial according to age, we analysed treatment effects using age as a continuous variable and using age categories. METHODS: RE-LY included 10 855 (59.9%) patients aged <75 years, 4231 patients (23.4%) aged 75-79 years, 2305 (12.7%) aged 80-84 years and 722 (4.0%) aged ≥85 years at baseline. RESULTS: Benefits of dabigatran versus warfarin regarding stroke (HR range 0.63 (95% CI 0.46 to 0.86) to 0.70 (0.31 to 1.57) for dabigatran 150 mg twice daily), HR range 0.52 (0.21 to 1.29) to 1.08 (0.73 to 1.60) for dabigatran 110 mg twice daily) and intracranial bleeding were maintained across all age groups (interaction p values all not significant). There was a highly significant interaction (p value interaction <0.001) between age and treatment for extracranial major bleeding, with lower rates with both doses of dabigatran compared with warfarin in younger patients (HR 0.78 (0.62 to 0.97) for 150 mg twice daily, HR 0.72 (0.57 to 0.90) for 110 mg twice daily) but similar (HR 1.50 (1.03 to 2.18) for 110 mg twice daily) or higher rates (HR 1.68 (1.18 to 2.41) for 150 mg twice daily) in older patients (≥80 years). CONCLUSION: Effects of dabigatran compared with warfarin on stroke prevention and intracranial bleeding are consistent across all age groups. Effects of dabigatran on extracranial major bleeding are age dependent, supporting selection of dabigatran 110 mg twice daily for elderly patients (age ≥80 years). TRIAL REGISTRATION NUMBER: Clinical trial registration number: https://clinicaltrials.gov NCT00262600.

Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study.

BACKGROUND: Atrial fibrillation is an important cause of morbidity and mortality worldwide, but scant data are available for long-term outcomes in individuals outside North America or Europe, especially in primary care settings. METHODS: We did a cohort study using a prospective registry of patients in 47 countries who presented to a hospital emergency department with atrial fibrillation or atrial flutter as a primary or secondary diagnosis. 15 400 individuals were enrolled to determine the occurrence of death and strokes (the primary outcomes) in this cohort over eight geographical regions (North America, western Europe, and Australia; South America; eastern Europe; the Middle East and Mediterranean crescent; sub-Saharan Africa; India; China; and southeast Asia) 1 year after attending the emergency department. Patients from North America, western Europe, and Australia were used as the reference population, and compared with patients from the other seven regions FINDINGS: Between Dec 24, 2007, and Oct 21, 2011, we enrolled 15 400 individuals to the registry. Follow-up was complete for 15 361 (99·7%), of whom 1758 (11%) died within 1 year. Fewer deaths occurred among patients presenting to the emergency department with a primary diagnosis of atrial fibrillation compared with patients who had atrial fibrillation as a secondary diagnosis (377 [6%] of 6825 patients vs 1381 [16%] of 8536, p<0·0001). Twice as many patients had died by 1 year in South America (192 [17%] of 1132) and Africa (225 [20%] of 1137) compared with North America, western Europe, and Australia (366 [10%] of 3800, p<0·0001). Heart failure was the most common cause of death (519 [30%] of 1758); stroke caused 148 (8%) deaths. 604 (4%) of 15361 patients had had a stroke by 1 year; 170 (3%) of 6825 for whom atrial fibrillation was a primary diagnosis and 434 (5%) of 8536 for whom it was a secondary diagnosis (p<0·0001). The highest number of strokes occurred in patients in Africa (89 [8%] of 1137), China (143 [7%] of 2023), and southeast Asia (88 [7%] of 1331) and the lowest occurred in India (20 [<1%] of 2536). 94 (3%) of 3800 patients in North America, western Europe, and Australia had a stroke. INTERPRETATION: Marked unexplained inter-regional variations in the occurrence of stroke and mortality suggest that factors other than clinical variables might be important. Prevention of death from heart failure should be a major priority in the treatment of atrial fibrillation. FUNDING: Boehringer Ingelheim.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study

Background Atrial fi brillation is an important cause of morbidity and mortality worldwide, but scant data are availablefor long-term outcomes in individuals outside North America or Europe, especially in primary care settings. Methods We did a cohort study using a prospective registry of patients in 47 countries who presented to a hospital emergency department with atrial fi brillation or atrial fl utter as a primary or secondary diagnosis. 15 400 individuals were enrolled to determine the occurrence of death and strokes (the primary outcomes) in this cohort over eight geographical regions (North America, western Europe, and Australia; South America; eastern Europe; the Middle Eastand Mediterrane an crescent; sub-Saharan Africa; India; China; and southeast Asia) 1 year after attending the emergency department. Patients from North America, western Europe, and Australia were used as the reference population, and compared with patients from the other seven regions...

Temporal relationship between subclinical atrial fibrillation and embolic events.

BACKGROUND: Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship. METHODS AND RESULTS: The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. In the 14 patients with SCAF detected >30 days before stroke or systemic embolism, the most recent episode occurred at a median interval of 339 days (25th to 75th percentile, 211-619) earlier. Eight patients (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days (25th to 75th percentile, 202-719) before their event. CONCLUSIONS: Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00256152.

Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: the RE-LY Atrial Fibrillation Registry.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries. METHODS AND RESULTS: This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15,400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America, P<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe, P<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India, P<0.001. The use of oral anticoagulation among patients with a CHADS2 score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China, P<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa, P<0.001. CONCLUSIONS: There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.

Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

BACKGROUND: The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets. METHODS AND RESULTS: All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin. CONCLUSIONS: Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00262600.