GI Bleeding Risk of DOACs Versus Warfarin: Is Newer Better?

Abstract

Until recently, warfarin had been the mainstay of anticoagulant treatment for patients with atrial fibrillation. With the approval in 2010 of the first direct-acting non-vitamin K oral anticoagulant (DOAC) dabigatran, the choice of therapies has been rapidly evolving. Recent studies reveal that currently half of the patients receiving anticoagulation for atrial fibrillation are taking DOACs as opposed to warfarin [1]. The reason for the rapid acceptance for these drugs has been the convenience of fixed dosing with no need for laboratory monitoring or dietary discretion, as required with warfarin. Despite these apparent advantages, debate has remained regarding the risk of gastrointestinal (GI) bleeding with these agents as compared to warfarin.The landmark trials that led to the United States Food and Drug Administration (FDA) approval of the currently approved DOACs, including dabigatran, rivaroxaban, apixaban, and edoxaban, reported that the all-cause bleeding rates were similar if not lower with DOACs as compared with warfarin. Nevertheless, the rate of GI bleeding was higher for patients treated with dabigatran [2] (3 vs 2%), rivaroxaban [3] (3.2 vs 2.2%), or edoxaban [4] (1.5 vs 1.2%) as compared with patients taking warfarin. On the other hand, the rates of GI bleeding were similar if not lower for patients treated with apixaban [5] as compared to warfarin (1.2 vs 1.3%). Likewise, an FDA postmarketing study also found the rate of GI bleeding with dabigatran to be higher as compared to warfarin (1.6 versus 1.1 per 100 patient years) [6].Of the DOACs, dabigatran is the only direct thrombin inhibitor, whereas the others are direct factor Xa inhibitors. While the reason for the higher risk of GI bleeding with dabigatran is unclear, a few hypotheses exist. Dabigatran is absorbed principally in the stomach and proximal small bowel as an inactive prodrug that is then metabolized to the active drug by serum and hepatic esterases. Nonetheless, the bioavailability of the drug is low (approximately 3-7%) with the unabsorbed dabigatran being converted to active dabigatran in the distal bowel and then excreted in the feces. This active drug in the distal bowel may promote GI bleeding more than warfarin, which is not activated in the bowel [7]. Secondly, there are reports that dabigatran is associated with esophagitis and gastric ulceration, suggesting the drug may directly injure the gastrointestinal mucosa.In this issue of Digestive Diseases and Sciences, Kolb et al. [8] report a post hoc analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (one of the landmark trials discussed above, this one comparing dabigatran to warfarin) where they re-reviewed the cases of suspected GI bleeding, collecting additional data including the causative lesions and the site and acuity of bleeding within the bowel. They could localize bleeding in approximately two-thirds of the cases, with 47% of those cases detected in the upper GI tract and 39% in the colon. Interestingly, the rate of bleeding in the...

Preventable Cases of Oral Anticoagulant-Induced Bleeding: Data From the Spontaneous Reporting System

“…However, the bioavailability of dabigatran is low (3–7%) with an unabsorbed quota being converted to active dabigatran in the distal bowel and then excreted in the feces. This active quota in the distal bowel may be responsible for the onset of lower gastrointestinal bleeding, with a rate even higher than warfarin, which is not activated in the bowel (Feagins and Weideman, 2018).…”

Gastrointestinal bleeding risk of non-vitamin K antagonist oral anticoagulants versus warfarin in general and after polypectomy: a population-based study with propensity score matching analysis

“…Despite uncertainty, this disparity among studies might be associated with how the therapeutic range of warfarin was controlled, which poses a great challenge in clinical practice. Compared to patients in real-world clinical settings, patients treated with warfarin in the randomized trials were much more likely to be strictly monitored, possibly leading to a lower risk of GIB [ 15 ]. In contrast, patients in retrospective observational studies had high concentrations of warfarin, which is associated with poorly controlled monitoring; the mean international normalized ratio (INR) was over 3 and more than half of the patients showed a supratherapeutic range of INR resulting in increased risk for GIB [ 15 ].…”

Apixaban vs. Warfarin in Atrial Fibrillation Patients With Chronic Kidney Disease

“…The population-based observational study and the meta-analyses of multinational randomized trials suggested that all DOACs can reduce overall major bleeding risk, but only apixaban was superior to warfarin in terms of fewer rates of major bleeding ( 39 ) or gastrointestinal bleeding ( 38 ). The reason for the differences in the risk of gastrointestinal bleeding between DOACs requires further research ( 40 ). In the present study, only patients with standard-dose apixaban (vs. warfarin) revealed statistically significant reduction in overall major bleeding.…”