Person:

Giugliano, Robert

Background: We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation (AF). Methods and Results: ENGAGE AF‐TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high‐dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower‐dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS 2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HR adj]=1.46; 95% CI, 1.27–1.67, P<0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HR adj for HDER)=0.94; (95% CI: 0.77–1.15) with SAPT, HR adj=0.70 (95% CI: 0.50–0.98), P interaction (P int)=0.14. (HR adj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99–1.43) With SAPT, 1.03 (95% CI, 0.76–1.39) P int=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HR adj for HDER=0.80 (95% CI, 0.68–0.95), and with SAPT, HR adj=0.82 (95% CI, 0.65–1.03; P int=0.91). For LDER without SAPT (HR adj=0.56 [95% CI 0.46–0.67]) and with SAPT (HR adj=0.51 [95% CI 0.39–0.66]). Conclusions: Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT. Clinical Trial Registration URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Background: Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. Methods and Results: Twenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (P trend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66–1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70–0.99]). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored edoxaban over warfarin in older patients. Conclusions: Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Background: 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. Methods and Results: 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; P interaction=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). Conclusion: 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. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Background: 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). Methods and Results: 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. Conclusions: 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. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.