Selecting a Direct Oral Anticoagulant for the Geriatric Patient with Nonvalvular Atrial Fibrillation
Journal of Clinical Outcomes Management. 2015 December;22(12)
References
Due to the lack of head-to-head studies comparing the DOACs, clinicians must cautiously rely on indirect comparisons of these agents. Important considerations include differences in landmark study design, population, and outcomes. Table 2 [14–16,27] highlights some of the study design differences.
Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.
Major Bleeding
Table 3 and Table 4 [28–31,56] provide a summary of major bleeding rates reported in landmark trials for the total and age-specific populations. Both apixaban and edoxaban (60 mg and 30 mg) were associated with significantly fewer major bleeding events compared to warfarin (apixaban: 2.1%/year versus 3.1%/year, P < 0.001; edoxaban: 60 mg 2.75%/year and 30 mg 1.61%/year versus 3.43%/year, P < 0.001) [16,27]. Dabigatran and rivaroxaban had similar major bleeding rates compared to warfarin (3.1%/year versus 3.5%/year, P = 0.31 and 5.6% versus 5.4%, P = 0.58, respectively). A pooled analysis of the DOACs reported that major bleeding in patients ≥ 75 years was at least similar to warfarin (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.74–1.17) [32].
Gastrointestinal Bleeding
Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.
Acute Coronary Syndrome
A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.
Valvular Heart Disease
The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) ( P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].
