Incidence and Clinical Presentation of Gastrointestinal Bleeding in Atrial Fibrillation Patients Taking Direct Oral Anticoagulants

Background: Patients with active peptic ulcer (PU) were excluded from direct oral anticoagulant (DOAC) trials for stroke prevention in patients with atrial fibrillation (AF). This study evaluated the safety and effectiveness of DOACs in AF patients with active, inactive and no peptic ulcer (PU).Methods: This study accessed electronic medical records from January 1, 2009 to May 31, 2019 at a multi-center healthcare provider in Taiwan and involved 2,955 AF patients who had undergone esophagogastroduodenoscopy ≤ 1 year before anticoagulation. Subjects were classified into 3 groups: active (n = 237), inactive (n = 828) and no-PU (n = 1,890) groups. We compared the risks of major bleeding, gastrointestinal bleeding, and ischemic stroke/systemic embolism (IS/SE) between DOACs and warfarin among the 3 groups.Results: In the active PU group, there were no significant differences in the risks of major bleeding [hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.08–4.98, p = 0.676], gastrointestinal bleeding (HR = 0.65, 95% CI 0.08–4.98, p = 0.676) and IS/SE (HR = 2.58; 95% CI 0.53–12.70, p = 0.243) between DOAC and warfarin (as the reference). In the inactive PU group, there were no significant differences in the risks of major bleeding (HR = 0.36, 95% CI 0.09–1.39, p = 0.138), gastrointestinal bleeding (HR = 0.21, 95% CI 0.02–1.80, p = 0.153), and IS/SE (HR = 1.04, 95% CI 0.39–2.82, p = 0.934) between DOAC and warfarin (as the reference). In the no-PU group, DOACs were associated with lower risk of major bleeding (HR = 0.26, 95% CI 0.12–0.53, p < 0.001), gastrointestinal bleeding (HR = 0.25, 95% CI 0.01–0.59, p = 0.002), and similar risk of IS/SE (HR = 0.92, 95% CI 0.55–1.54, p = 0.757) compared to warfarin.Conclusions: DOACs were as effective as warfarin in preventing IS/SE irrespective of PU status and safer than warfarin in reducing major bleeding in the no-PU group. In patients with active or inactive PUs, DOAC and warfarin were not significantly different in their effects on major bleeding or gastrointestinal bleeding.

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Direct Oral Anticoagulants versus Warfarin in Octogenarians with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10225268 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5268

Author(s):

Clara Bonanad ◽

Sergio García-Blas ◽

Javier Torres Llergo ◽

Rosa Fernández-Olmo ◽

Pablo Díez-Villanueva ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Intracranial Bleeding ◽

Significant Heterogeneity ◽

Nonvalvular Atrial Fibrillation ◽

Warfarin Group

Direct oral anticoagulants (DOACs) have been demonstrated to be more effective and safer than vitamin-K antagonist (VKA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). This meta-analysis aims to assess the effect of DOACS vs. VKA in patients ≥ 80 and AF. Primary endpoints were stroke or systemic embolism and all-cause death. Secondary endpoints included major bleeding, intracranial bleeding, and gastrointestinal bleeding. A random-effects model was selected due to significant heterogeneity. A total of 147,067 patients from 16 studies were included, 71,913 (48.90%) treated with DOACs and 75,154 with VKA (51.10%). The stroke rate was significantly lower in DOACs group compared with warfarin group (Relative risk (RR): 0.72; 95% confidence interval (CI): 0.63–0.82; p < 0.001). All-cause mortality was significantly lower in DOACs group compared with warfarin group (RR: 0.82; 95% CI: 0.70–0.96; p = 0.012). Compared to warfarin, DOACs were not associated with reductions in major bleeding (RR: 0.85, 95% CI 0.69–1.04; p = 0.108) or gastrointestinal bleeding risk (RR: 1.08, 95% CI 0.76–1.53; p = 0.678) but a 43% reduction of intracranial bleeding (RR: 0.47, IC 95% 0.36–0.60; p < 0.001) was observed. Our meta-analysis demonstrates that DOACs are effective and safe with statistical superiority when compared with warfarin in octogenarians with AF.

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Gastrointestinal Bleeding During Direct Oral Anticoagulants Therapy in Patients With Nonvalvular Atrial Fibrillation and Risk of Polypharmacy

10.21203/rs.3.rs-1224400/v1 ◽

2022 ◽

Author(s):

Taku Honda ◽

Koichiro Abe ◽

Minoru Oda ◽

Fumito Harada ◽

Kyohei Maruyama ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Risk ◽

Nonvalvular Atrial Fibrillation ◽

Oral Medications ◽

Cerebrovascular Events ◽

Concomitant Medications ◽

Inverse Probability Weighted

Abstract Although concomitant medications have been raised as a factor affecting hemorrhage during direct oral anticoagulants (DOACs) therapy, details remain unelucidated. This study was conducted to clarify the relationship between concomitant medications with possible pharmacokinetic interactions and number of concomitant medications, and bleeding and embolism in patients with nonvalvular atrial fibrillation on DOACs. The subjects were 1,010 patients prescribed DOACs between April 2011 and June 2018. The study investigated their course between the first prescription and December 2018, including the presence or absence of clinically relevant bleeding, gastrointestinal bleeding (GIB), and major cardiovascular and cerebrovascular events (MACCE). Impacts of medications were evaluated by the general linear model with inverse probability-weighted propensity score. The observation period was 2,272 patient-years. The rate of bleeding was 4.7%/year, GIB was 2.8%/year, and MACCE was 2.0%/year. Taking 10 or more oral medications concurrently was a significant risk for GIB (hazard ratio, 2.046 [1.188–3.526]; p = 0.010). Nonsteroidal anti-inflammatory drugs (NSAIDs) was the only significant risk for GIB. Clinicians should be aware of gastrointestinal bleeding when using DOACs with patients taking more than 10 medications and/or NSAIDs.

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Clinical factors associated with safety and efficacy in patients receiving direct oral anticoagulants for non-valvular atrial fibrillation

Scientific Reports ◽

10.1038/s41598-020-77174-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hiroshi Yamato ◽

Koichiro Abe ◽

Shun Osumi ◽

Daisuke Yanagisawa ◽

Shinya Kodashima ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Oral Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Factors Associated ◽

Cerebrovascular Events ◽

Low Dose Aspirin ◽

Positive Correlations

AbstractAlthough patients suffering from atrial fibrillation have increased worldwide, detailed information about factors associated with bleeding during direct oral anticoagulant therapy remains insufficient. We studied 1086 patients for whom direct oral anticoagulants were initiated for non-valvular atrial fibrillation between April 2011 and June 2017. Endpoints were clinically relevant bleeding or major adverse cardiac and cerebrovascular events until the end of December 2018. Incidences of bleeding and thrombosis were 4.5 per 100 person-years and 4.7 per 100 person-years, respectively. Most bleeding events represented gastrointestinal bleeding. Multivariate analysis revealed initiation of anticoagulants at ≥ 85 years old as significantly associated with bleeding, particularly gastrointestinal bleeding, but not major cardiac and cerebrovascular events. Other significant factors included chronic kidney disease, low-dose aspirin and nonsteroidal anti-inflammatory drugs. For gastrointestinal bleeding alone, histories of gastrointestinal bleeding and malignancy also showed positive correlations, in addition to the above-mentioned factors. Clinicians should pay greater attention to the risk of gastrointestinal bleeding when considering prescription of anticoagulants to patients ≥ 85 years old with atrial fibrillation.

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Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation

PLoS ONE ◽

10.1371/journal.pone.0260585 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0260585

Author(s):

Daisuke Yanagisawa ◽

Koichiro Abe ◽

Hirohito Amano ◽

Shogo Komatsuda ◽

Taku Honda ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Clinical Course ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

The Other ◽

Direct Oral Anticoagulant

Several direct oral anticoagulants have been developed to prevent cardiogenic thrombosis in patients with atrial fibrillation, on the other hand, have the complication of bleeding. Since clinical course after bleeding with direct oral anticoagulant remains unclear, the present retrospective cohort study was to clarify the course after hemorrhage among patients receiving direct oral anticoagulants. Among all 2005 patients prescribed dabigatran, rivaroxaban, apixaban, or edoxaban between April 2011 and June 2017, subjects comprised 96 patients with non-valvular atrial fibrillation who experienced relevant bleeding during direct oral anticoagulant therapy (Bleeding Academic Research Consortium type 2 or above). The clinical course after hemorrhage was reviewed to examine whether rebleeding or thrombotic events occurred up to the end of December 2019. Gastrointestinal bleeding was the most frequent cause of initial bleeding (57 patients, 59%). Rebleeding occurred in 11 patients (4.5%/year), with gastrointestinal bleeding in 10 and subarachnoid hemorrhage in 1. All rebleeding occurred in patients who resumed anticoagulation therapy. Another significant factor related with rebleeding included past history of gastrointestinal bleeding. On the other hand, major adverse cardiac and cerebrovascular events occurred in 6 patients older than 75 years old or more (2.5%/year), with systemic thrombosis in 4 and cardiac death in 2. All 4 patients with systemic thrombosis withheld anticoagulants after index bleeding, although only 10 patients withheld anticoagulation therapy. Rebleeding should be taken care of when anticoagulants are resumed after bleeding, particularly among patients who initially experienced gastrointestinal bleeding. Systemic thrombosis occurred at a high rate when anticoagulant therapy was withheld after bleeding.

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Faculty Opinions recommendation of Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725514028.793512947 ◽

2016 ◽

Author(s):

Nanette Wenger

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Venous Thromboembolism ◽

Secondary Prevention ◽

Stroke Prevention ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

The Elderly

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A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624193938 ◽

2020 ◽

Vol 15 ◽

Author(s):

Veronica Ojetti ◽

Angela Saviano ◽

Mattia Brigida ◽

Luisa Saviano ◽

Alessio Migneco ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Medical Emergency ◽

Management Approach ◽

Emergency Setting ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa

Background : Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and the treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, betrixaban) showed a better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. AIM: This review summarizes the current evidences about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with an active major bleeding or who need urgent surgery to offer physicians indications for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

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A Systematic Review of the Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation Patients with Diabetes Using a Risk Index

Journal of Clinical Medicine ◽

10.3390/jcm10132924 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2924

Author(s):

Domenico Acanfora ◽

Marco Matteo Ciccone ◽

Valentina Carlomagno ◽

Pietro Scicchitano ◽

Chiara Acanfora ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Risk Index ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Efficacy Rate ◽

Cochrane Central Register ◽

Efficacy And Safety

Diabetes mellitus (DM) represents an independent risk factor for chronic AF and is associated with unfavorable outcomes. We aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF), with and without diabetes mellitus (DM), using a new risk index (RI) defined as: RI =Rate of EventsRate of Patients at Risk. In particular, an RI lower than 1 suggests a favorable treatment effect. We searched MEDLINE, MEDLINE In-Process, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The risk index (RI) was calculated in terms of efficacy (rate of stroke/systemic embolism (stroke SEE)/rate of patients with and without DM; rate of cardiovascular death/rate of patients with and without DM) and safety (rate of major bleeding/rate of patients with and without DM) outcomes. AF patients with DM (n = 22,057) and 49,596 without DM were considered from pivotal trials. DM doubles the risk index for stroke/SEE, major bleeding (MB), and cardiovascular (CV) death. The RI for stroke/SEE, MB, and CV death was comparable in patients treated with warfarin or DOACs. The lowest RI was in DM patients treated with Rivaroxaban (stroke/SEE, RI = 0.08; CV death, RI = 0.13). The RIs for bleeding were higher in DM patients treated with Dabigatran (RI110 = 0.32; RI150 = 0.40). Our study is the first to use RI to homogenize the efficacy and safety data reported in the DOACs pivotal studies against warfarin in patients with and without DM. Anticoagulation therapy is effective and safe in DM patients. DOACs appear to have a better efficacy and safety profile than warfarin. The use of DOACs is a reasonable alternative to vitamin-K antagonists in AF patients with DM. The RI can be a reasonable tool to help clinicians choose between DOACs or warfarin in the peculiar set of AF patients with DM.

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