Clinical Review

Selecting a Direct Oral Anticoagulant for the Geriatric Patient with Nonvalvular Atrial Fibrillation

Journal of Clinical Outcomes Management. 2015 December;22(12)

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Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C _max were not influenced by age.

Clinical Evaluations

Although DOACs offer advantages over warfarin [41], there is still no assurance regarding the promise of reduced or similar risk of bleeding with DOACs compared with warfarin in the geriatric population. Generalizability of bleeding rates reported in landmark studies leads to underestimating the risk of bleeding in geriatric patients [42]. For example, in one case series 67% of the bleeding complications with dabigatran were in patients ≥ 80 years old [43]. Furthermore, although subgroup analyses were performed evaluating geriatric patients in the landmark studies, these analyses are inherently biased. First, they represent post-hoc analyses and are not adequately powered. Second, geriatric patients included in landmark studies may have lower CHADS2 scores compared to those seen in clinical practice. Third, patients with severe renal dysfunction (ie, CrCl < 25–30 mL/min) were excluded from many landmark studies. However, several large observational studies have found that the DOACs pose no disproportionate risk of bleeding the geriatric population versus warfarin [44–46]. A review of major bleeding complications reported from landmark clinical trials are summarized Table 3 [29–31, 47–50]. Figure 1