Oral Anticoagulants in Very Elderly Nonvalvular Atrial Fibrillation Patients With High Bleeding Risks

Background Data on the effectiveness and safety of oral anticoagulant (OAC) agents in very elderly nonvalvular atrial fibrillation patients with high bleeding risk are lacking. Objectives This study examined 2-year outcomes and effects of OAC agents among these patients using the ANAFIE (All Nippon Atrial Fibrillation in the Elderly) registry (N = 32,275) data. Methods Patients were classified into high-risk (age: ≥80 years; CHADS2 score: ≥2; and presence of ≥1 bleeding risk factor: creatinine clearance of 15-30 mL/minute, prior bleeding at critical sites, body weight of ≤45 kg, or continuous antiplatelet use) and reference groups. Results In the high-risk (n = 7,104) and reference (n = 25,171) group patients, 89.0% and 93.4%, respectively, used OAC agents. Of these, respectively, 30.1% and 24.2% used warfarin, and 58.9% and 69.1% used direct-acting OAC (DOAC) agents. Compared with the reference group, the high-risk group had higher incidences of stroke/systemic embolism, major bleeding, intracranial hemorrhage, gastrointestinal bleeding, cardiovascular events, and all-cause death. In the high-risk group, DOAC agent use vs nonuse of OAC agents was associated with reduced incidences of stroke/systemic embolism (HR: 0.53; 95% CI: 0.36-0.79) and all-cause death (HR: 0.65; 95% CI: 0.52-0.81) but not with major bleeding (HR: 1.09; 95% CI: 0.63-1.89). DOAC agents were superior to warfarin in effectiveness and safety. For high-risk patients, history of major bleeding, severe liver dysfunction, and falls within 1 year were independent risk factors for major bleeding. Conclusions High-risk elderly nonvalvular atrial fibrillation patients had higher event incidences. DOAC agents were associated with reduced risk of stroke/systemic embolism and all-cause death vs nonuse of OAC agents or warfarin. (Prospective Observational Study in Late-Stage Elderly Patients With Nonvalvular Atrial Fibrillation [ANAFIE registry]; UMIN000024006)

W orldwide, atrial fibrillation (AF) is the most common sustained arrhythmia affecting adults, with more than 33 million affected individuals, 1 and is considered a well established and growing global epidemic. 2 AF is associated with high morbidity and mortality among those affected. Because aging is the most important risk factor for developing AF, 3 AF-related complications, such as cardiac dysfunction and stroke, 4  agents, especially direct-acting OAC (DOAC) agents, to prevent stroke in patients with AF, including elderly patients. 6 It is, however, necessary to rigorously evaluate the current status of OAC agent use and outcomes among very elderly patients, who are generally excluded from most clinical trials. Additionally, treating very elderly patients with AF poses a considerable challenge, not only because of the aging process and its consequences but because of comorbidities, associated complications, 3 and increased risk of bleeding. 7,8 The recent ELDERCARE-AF (Edoxaban Low-Dose

RESULTS
PATIENTS. Figure 1 shows the patient disposition.
Of the patients enrolled in the ANAFIE registry   Values are n (%) or mean AE SD. a Overdose was defined as the standard dose prescribed to patients who met the reduced-dose criteria. b Underdose was defined as the reduced dose prescribed to patients who did not meet the reduced-dose criteria.
2.6%, and 11.6%, respectively, in patients receiving on-label DOAC doses (n ¼ 3,173; standard and reduced doses), whereas the incidences were 2.0%, 2.0%, and 11.5%, respectively, in those receiving inappropriately reduced off-label doses (n ¼ 549; underdoses and off-label low doses) (data not shown).  Table 3 shows the HRs for each event in the Cox proportional hazards model for the high-risk group according to OAC agent use (DOAC agent vs warfarin and vs nonuse of OAC agents) with univariate and multivariate analyses. Stroke/SE, all-cause death, cardiovascular death, and net clinical outcome rates were significantly lower in the DOAC agent-treated group compared with the nonuse-of-OAC-agents group, whereas major bleeding rates did not significantly increase with DOAC agent treatment.
The rate for all bleeding events (major bleeding, clinically relevant bleeding, and minor bleeding) was significantly higher in the DOAC agent-treated group than in the nonuse-of-OAC-agents group. Stroke/SE, major bleeding, intracranial hemorrhage, and net clinical outcome rates were significantly lower in the DOAC agent-treated group compared with the warfarin-treated patients, but no significant differences were observed for gastrointestinal bleeding, all-cause death, or cardiovascular death.

RISK FACTORS ASSOCIATED WITH MAIN OUTCOMES
IN THE HIGH-RISK GROUP. Univariate and multivariate analyses of outcomes in the high-risk group according to baseline variables are shown in Table 4.

Significant independent risk factors for stroke/SE
were type of AF (long-standing AF), systolic blood pressure of $140 mm Hg, diabetes (glycated hemoglobin: $6.0%), cerebrovascular disease, and CrCl of $15 to <30 mL/min. Significant independent risk factors for major bleeding were a history of major  bleeding, severe liver dysfunction, and falls within 1 year. Significant independent risk factors of intracranial hemorrhage were severe liver dysfunction, fall within 1 year, and proton pump inhibitor use.
Additionally, we calculated the HRs for outcomes in the reference group (ie, the non-high-risk group) according to baseline variables (Supplemental Table 1). AF type in stroke/SE, falls in major bleeding, and severe liver dysfunction and falls in intracranial hemorrhage showed a significant difference in HRs, even in the reference group; however, the HR value was larger in the high-risk group. In the high-risk group, cerebrovascular disease was the only factor that was not found to be a specific risk factor for stroke/SE.     year, history of catheter ablation; dyslipidemia; creatinine clearance; gastrointestinal diseases; polypharmacy (5 or more); and use of antiarrhythmic agents, proton pump inhibitors, P-glycoprotein inhibitors, and antiplatelet agents were included as an adjustment factor in the model. b All bleeding events (major bleeding, clinically relevant bleeding, and minor bleeding).

DISCUSSION
Abbreviations as in Table 1.