Efficacy and Safety of Direct Oral Anticoagulants in Elderly Patients With Atrial Fibrillation: A Network Meta-Analysis

Abstract

Background: Direct oral anticoagulants (DOACs) have been widely used in patients with atrial fibrillation (AF) for antithrombotic prophylaxis, which were shown to have a favorable risk-benefit profile. However, there are no guidelines for the use of DOACs in elderly patients (aged ≥75 years) with AF, which creates uncertainty about the optimal antithrombotic treatment in these patients. Methods: After comprehensively searching Embase, PubMed, and Cochrane databases, five phase III randomized controlled trials involving 28,137 elderly participants were included in this study. The efficacy outcome was stroke or systemic embolism, and the safety outcome was major bleeding. We conducted a network meta-analysis by using a Bayesian random-effect model for the first time to evaluate the efficacy and safety of main DOACs (apixaban, edoxaban, rivaroxaban, and dabigatran) and warfarin in elderly patients with AF. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were used to assess the effect of drugs on efficacy and safety. The rank probabilities were used to reflect the hierarchy of drugs, and a larger rank probability value symbolized a better rank of drugs. Results: In the prophylaxis of stroke or systemic embolism, apixaban was found to be the best among DOACs compared to warfarin (HR, 0.71; 95% CI: 0.33-1.50), though this finding was not statistically significant. Apixaban ranked the best (rank probabilities, 41.2%) in efficacy of drugs, followed by rivaroxaban, edoxaban, dabigatran, and warfarin (rank probabilities, 31.8, 15.9, 10.9, and 0.2%, respectively). In reducing the risk of major bleeding, apixaban was found to be the best among DOACs too, compared to warfarin (HR, 0.64; 95% CI: 0.33-1.30), though this finding was not statistically significant. In safety, apixaban ranked the best (rank probabilities, 71.4%), followed by edoxaban, dabigatran, warfarin, and rivaroxaban (rank probabilities, 21.0, 5.8, 0.9, and 0.8%, respectively). Conclusions: DOACs showed a lower incidence of stroke/systemic embolism and major bleeding compared with warfarin in antithrombotic therapy in elderly patients (aged ≥75 years), with apixaban being the best of those interventions. Therefore, apixaban should be given priority as an anticoagulant in stroke prevention for elderly patients with AF.

Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

“…In conclusion, these post hoc analyses and meta-analyses of RCTs have shown that apixaban is associated with the best efficacy and safety profile of all OACs in older AF patients, followed by edoxaban (Lin et al, 2015;Sadlon and Tsakiris, 2016;Malik et al, 2019;Deng et al, 2020).…”

“…The risk of stroke in older AF patients varies across studies, documenting similar to significantly lower stroke/SE risks for NOACs as compared to warfarin. This may be due to the VKA-associated increase in vascular calcification ( Weijs et al., 2011 ; Deng et al., 2020 ; Millenaar et al., 2020 ). However, it should be mentioned that not all stroke events in AF patients are necessarily cardio-embolic in origin, which may affect stroke incidence rates of individual OACs in different studies by chance ( Paciaroni et al., 2019 ).…”

“…Based on the abovementioned results, network meta-analyses have specifically compared the efficacy and safety of NOACs in AF patients ≥75 years old (Lin et al, 2015;Sadlon and Tsakiris, 2016;Malik et al, 2019;Deng et al, 2020). Despite a similar stroke/SE risk (Lin et al, 2015;Sadlon and Tsakiris, 2016;Malik et al, 2019), these indirect head-to-head comparisons between NOACs have highlighted significantly lower major bleeding risks for apixaban and edoxaban as compared to dabigatran (both doses) and rivaroxaban, except for a similar risk between edoxaban and dabigatran 110 mg (Lin et al, 2015;Sadlon and Tsakiris, 2016;Malik et al, 2019).…”

“…Importantly, rivaroxaban was associated with a significantly higher risk for intracranial bleeding as compared to other NOACs (Lin et al, 2015;Malik et al, 2019). Moreover, a network meta-analysis that estimated the rank probability of OACs in AF patients ≥75 years old, which reflects the hierarchy of drugs on efficacy and safety, showed that apixaban ranked best on both stroke/SE prophylaxis (followed by rivaroxaban, edoxaban, dabigatran 110 mg and warfarin) and major bleeding risk (followed by edoxaban, dabigatran 110 mg, warfarin, and rivaroxaban) (Deng et al, 2020). In another network meta-analysis, although dabigatran 150 mg ranked best on efficacy outcomes followed by apixaban, apixaban also ranked best on safety measures while dabigatran 150 mg the worst (Malik et al, 2019).…”

“…Overall, across characteristics typical for vulnerable geriatric AF patients, apixaban was consistently associated with the best efficacy and safety profile and appears to be therefore preferred in geriatric patients. Although edoxaban ranked second on safety endpoints and third on efficacy outcomes in AF patients ≥75 years old (Deng et al, 2020), data are lacking on the impact of other geriatric patient characteristics, limiting the generalizability of the reassuring edoxaban results in older patients to all multimorbid, frail AF patients with polypharmacy. Dabigatran appears to have a more intermediate place in geriatric AF patients, especially due to the frequently noted higher gastrointestinal bleeding risks.…”