Bleeding Risk and Mortality of Edoxaban: A Pooled Meta-Analysis of Randomized Controlled Trials

Abstract

Objective(s)Edoxaban, a factor Xa inhibitor, is a new oral anticoagulant that has been developed as an alternative to vitamin K antagonists. However, its safety remains unexplored.MethodsMedline, Embase and Web of Science were searched to March 8, 2014 for prospective, randomized controlled trials (RCTs) that assessed the safety profile of edoxaban with warfarin. Safety outcomes examined included bleeding risk and mortality.ResultsFive trials including 31,262 patients that met the inclusion criteria were pooled. Overall, edoxaban was associated with a significant decrease in major or clinically relevant nonmajor bleeding events [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.74 to 0.82, p<0.001] and any bleeding events [RR 0.82, 95% CI 0.79 to 0.85, p<0.001]. Edoxaban also showed superiority to warfarin both in all-cause mortality [RR 0.92, 95% CI0.85 to0.99, p = 0.02] and cardiovascular mortality [RR 0.87, 95% CI0.79 to 0.96, p = 0.004]. Subgroup analyses indicated that RRs of edoxaban 30, 60 or 120 mg/d were 0.67 (p<0.001), 0.87 (p<0.001) and 3.3 (p = 0.004) respectively in major or clinically relevant nonmajor bleeding; 0.71 (p<0.001), 0.89 (p<0.001) and 2.29 (p = 0.002) respectively in any bleeding; as well as 0.86 (p = 0.01), 0.87 (p = 0.01) and 0.28 (p = 0.41) respectively in cardiovascular death… Meanwhile, paramount to note that pooled results other than the largest trial showed edoxaban was still associated with a decrease in the rate of major or clinically relevant nonmajor bleeding event (p = 0.02) and any bleeding (p = 0.002), but neither in all-cause death (p = 0.66) nor cardiovascular death (p = 0.70).ConclusionsEdoxaban, a novel orally available direct factor Xa inhibitor, seems to have a favorable safety profiles with respect to bleeding risk and non-inferior in mortality when compared to warfarin. Further prospective RCTs are urgently needed to confirm the results of this meta-analysis.

Efficacy and Safety of Edoxaban in Nonvalvular Atrial Fibrillation: A Meta-analysis of Randomized Controlled Trials

“…The RRs of edoxaban at 30, 60, or 120 mg/day gradually increased with regard to bleeding; at the 120 mg/day dose, the bleeding risk was higher than warfarin. 30 This was similar to our results. We also found a significant decrease in allcause mortality, major bleeding, CRNM bleeding, and minor bleeding when edoxaban was compared with warfarin, although they were not significantly different in terms of all bleeding categories.…”

Factors related to inappropriate edoxaban use

“…Major gastrointestinal bleeding was shown to occur more frequently with 60 mg edoxaban than well‐managed warfarin in 21 105 patients with NVAF . On the other hand, a subgroup analysis of pooled meta‐analysis of randomized controlled trials (RCTs) with 31 262 patients indicated that the rates of bleeding with edoxaban 30, 60 or 120 mg/d were significantly lower than those for warfarin . Because the results of these studies are conflicting, bleeding safety remains to be explored.…”

“…Because the results of these studies are conflicting, bleeding safety remains to be explored. Moreover, the previous studies analysed the data from RCTs, which may not have included enough patients with bleeding risks such as renal insufficiency and low body weight . Therefore, an individualized approach should be adopted in some patients to decide the appropriate anticoagulation regimen after weighing the overall risks and benefits of therapy .…”

“…6,7 On the other hand, a subgroup analysis of pooled meta-analysis of randomized controlled trials (RCTs) with 31 262 patients indicated that the rates of bleeding with edoxaban 30, 60 or 120 mg/d were significantly lower than those for warfarin. 8 Because the results of these studies are conflicting, bleeding safety remains to be explored. Moreover, the previous studies analysed the data from RCTs, which may not have included enough patients with bleeding risks such as renal insufficiency and low body weight.…”

“…Moreover, the previous studies analysed the data from RCTs, which may not have included enough patients with bleeding risks such as renal insufficiency and low body weight. 6,8 Therefore, an individualized approach should be adopted in some patients to decide the appropriate anticoagulation regimen after weighing the overall risks and benefits of therapy. 9 Moreover, with the growth of the older population, an increase in the diagnosis of NVAF and thromboembolic diseases is expected; thus, a number of risk factors for bleeding such as the presence of comorbid medical conditions, renal insufficiency and drug interactions from polypharmacy need to be considered before prescribing anticoagulants.…”