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Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

ABSTRACT: Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation.SCD was defined as witnessed death ?60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient-years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P<0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29-1.86] and 1.56 [95% CI 1.14-2.11], respectively; Pinteraction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year).SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

SUBMITTER: Eisen A

PROVIDER: S-EPMC5015407 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

Eisen Alon A Ruff Christian T CT Braunwald Eugene E Nordio Francesco F Corbalán Ramón R Dalby Anthony A Dorobantu Maria M Mercuri Michele M Lanz Hans H Rutman Howard H Wiviott Stephen D SD Antman Elliott M EM Giugliano Robert P RP

Journal of the American Heart Association 20160708 7

<h4>Background</h4>Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation.<h4>Methods and results</h4>SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risk ...[more]

PMID: 27402235

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Project description:BackgroundAtrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status.MethodsPost hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding.ResultsA fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19-1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27-1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty.ConclusionsEdoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population.Trial registrationClinicalTrials.gov NCT00781391 . First registered on 28 October 2008.

Project description:Atrial fibrillation (AF) is associated with increased risk for thromboembolism and death; however, the relationships between cardiac structure and function and adverse outcomes among individuals with AF are incompletely understood.The Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 study tested the once-daily oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke (ischemic or hemorrhagic) or systemic embolism in 21,105 subjects with nonvalvular AF and increased risk for thromboembolic events (CHADS2 score ? 2). In a prospective substudy of 971 subjects who underwent transthoracic echocardiography at baseline, Cox proportional hazards models were used to evaluate associations between cardiac structure and function and the risks for death and thromboembolism (ischemic stroke, transient ischemic attack, or systemic embolism).Over a median follow-up period of 2.5 years, 89 deaths (9.2%) and 48 incident thromboembolic events (4.9%) occurred in 971 subjects. In models adjusted for CHADS2 score, aspirin use, and randomized treatment, larger left ventricular (LV) end-diastolic volume index (hazard ratio per 1 SD [12.9 mL/m(2)], 1.49; 95% CI, 1.16-1.91) and higher LV filling pressures measured by E/e' ratio (hazard ratio per 1 SD [4.6], 1.32; 95% CI, 1.08-1.61) were independently associated with increased risks for death. E/e' ratio > 13 significantly improved the prediction of death beyond clinical factors alone. No features of cardiac structure and function were independently associated with thromboembolism in this population. Findings were similar when adjusted for CHA2DS2-VASc score in place of CHADS2 score.In a contemporary population of patients with AF at increased risk for thromboembolic events, larger LV size and higher filling pressures were significantly associated with increased risk for death, but neither left atrial nor LV measures were associated with thromboembolic risk. LV size and filling pressures may help identify patients with AF at increased risk for death.

Project description:The impact of different types of extracranial bleeding events on health-related quality of life and health-state utility among patients with atrial fibrillation is not well understood. The ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol-5D (EQ-5D-3L) questionnaire, prospectively collected at 3-month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health-state utility over 12 months following the event. Longitudinal mixed-effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (-0.029 [-0.044 to -0.014; P<0.001] and -0.029 [-0.046 to -0.012; P=0.001], respectively). These effects decreased in magnitude over time, and were no longer significant for major nongastrointestinal bleeds at 9 months, but remained borderline significant for major gastrointestinal bleeds at 12 months. Clinically relevant nonmajor and minor bleeds were associated with smaller but measurable immediate impacts on utility (-0.010 [-0.016 to -0.005] and -0.016 [-0.024 to -0.008]; P<0.001 for both), which remained relatively constant and statistically significant over the 12 months following the bleeding event. All categories of bleeding events were associated with negative impacts on health-state utility in patients with atrial fibrillation. Major bleeds were associated with relatively large immediate decreases in utility scores that gradually diminished over 12 months; clinically relevant nonmajor and minor bleeds were associated with smaller immediate decreases in utility that persisted over 12 months. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Project description:Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). In the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow-up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10-2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36-2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all-cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction. In this observational analysis of patients with atrial fibrillation without investigator-reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Project description:BACKGROUND:The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain. METHODS:ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ?2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores. RESULTS:Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin. CONCLUSIONS:The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Project description:BackgroundFemale sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men.MethodsThe ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis-defined major bleeding (safety).ResultsIn comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P<0.001). Treatment with edoxaban in women resulted in greater peak edoxaban concentration and inhibition of endogenous factor Xa in comparison with men, resulting in similar endogenous factor Xa activity between the sexes 2 to 4 hours after dose. Treatment with higher-dose edoxaban regimen (versus warfarin) resulted in similar reduction in the risk of stroke/systemic embolic events (women: hazard ratio [HR], 0.87 [0.69-1.11], men: HR, 0.87 [0.71-1.06]; P-interaction=0.97) and major bleeding (women: HR, 0.74 [0.59-0.92], men: HR, 0.84 [0.72-0.99]; P-interaction=0.34) in women and men. However, women assigned to higher-dose edoxaban regimen experienced greater reductions in hemorrhagic stroke (HR, 0.30 [95% CI, 0.15-0.59] versus HR, 0.70 [95% CI, 0.46-1.06]), intracranial bleeding (HR, 0.20 [95% CI, 0.10-0.39] versus HR, 0.63 [95% CI, 0.44-0.89]), and life-threatening or fatal bleeding (HR, 0.25 [95% CI, 0.15-0.42] versus HR, 0.72 [95% CI, 0.54-0.96]) than men (each P-interaction<0.05).ConclusionsDespite many differences in baseline characteristics between women and men and higher baseline endogenous factor Xa levels in women, the intensity of anticoagulation achieved with edoxaban between the sexes was similar. Treatment with higher-dose edoxaban regimen resulted in an even greater reduction in hemorrhagic stroke and several serious bleeding outcomes in women than in men, whereas the efficacy profile was similar between sexes.

Dataset Information

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

Publications

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

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