Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study

Abstract Aims Non-vitamin K antagonist oral anticoagulants (NOACs) are displacing vitamin K antagonists (VKAs) for stroke prophylaxis in patients with atrial fibrillation (AF). Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) could increase gastrointestinal bleeding (GIB) risks among these patients. The aim of this study was to examine the risk of GIB among Danish AF patients taking oral anticoagulants (OACs) and NSAIDs. Methods and results Using nationwide administrative registries, we determined concomitant NSAID use among anticoagulant-naïve patients with AF initiating OACs between August 2011 and June 2017. We calculated short-term absolute risks differences and hazard ratios (HRs) for GIB based on multiple adjusted cause-specific Cox regressions with time-dependent NSAID treatment. Among 41 183 patients [median age 70 years (interquartile range 64–78); 55% men], 21% of patients on NOACs and 18% on VKA were co-prescribed NSAIDs. The differences in absolute risk [95% confidence interval (CI)] of GIB within 14 days of commencing concomitant NSAID therapy (vs. no concomitant NSAID therapy) were 0.10% (0.04–0.18%) for NOACs and 0.13% (0.03–0.24%) for VKA. NOACs overall were associated with less GIB than VKA [HR 0.77 (95% CI 0.69–0.85)]. Compared with OACs alone, concomitant NSAIDs doubled the GIB risk associated with NOACs overall [HR 2.01 (95% CI 1.40–2.61)] and with VKA [HR 1.95 (95% CI 1.21–2.69)]. Conclusion Among this nationwide AF population taking OACs, concomitant NSAID therapy increased the short-term absolute risk of GIB. Non-vitamin K antagonist oral anticoagulants alone were associated with lower GIB risks than VKA but concomitant NSAIDs abolished this advantage. The findings align with post hoc analyses from randomized studies. Physicians should exercise appropriate caution when prescribing NSAIDs for patients with AF taking NOACs or VKA.

Download Full-text

The Risk of Gastrointestinal Bleeding between Non-Vitamin K Antagonist Oral Anticoagulants and Vitamin K Antagonists in the Asian Atrial Fibrillation Patients: A Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010137 ◽

2020 ◽

Vol 18 (1) ◽

pp. 137

Author(s):

Kuang-Tsu Yang ◽

Wei-Chih Sun ◽

Tzung-Jiun Tsai ◽

Feng-Woei Tsay ◽

Wen-Chi Chen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Vitamin K ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Cochrane Library ◽

Secondary Outcome ◽

Optimal Dosage

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are more commonly used to prevent atrial fibrillation (AF) patients from thromboembolic events than vitamin K antagonists (VKAs). However, the gastrointestinal bleeding (GIB) risk in the Asian AF patients associated with NOACs in comparison with VKAs remained unaddressed. Materials and Methods: A systematic search of studies on NOACs and VKAs in the Asian AF patients was conducted in PubMed, Cochrane Library, and ClinicalTrials.gov. The primary outcome was the hazard ratio (HR) of any GIB associated with NOACs versus VKAs. The secondary outcome was the GIB risks in different kinds of NOACs compared with VKAs. Results: This meta-analysis included two randomized controlled trials (RCTs) and four retrospective studies, comprising at least 200,000 patients in total. A significantly lower HR of GIB risks was found in all kinds of NOACs than VKAs in the Asian AF patients (HR: 0.633; 95% confidence interval: 0.535–0.748; p < 0.001). Additionally, the GIB risks of different NOACs were apixaban (HR: 0.392), edoxaban (HR: 0.603), dabigatran (HR: 0.685), and rivaroxaban (HR: 0.794), respectively. Conclusions: NOACs significantly reduced the risk of GIB in the Asian AF patients compared with VKAs. In the four NOACs compared with VKAs, apixaban probably had a trend of the least GIB risk. We need further head-to-head studies of different NOACs to confirm which NOAC is the most suitable for Asian AF patients and to know the optimal dosage regimen of different NOACs.

Download Full-text

Gastrointestinal bleeding risk following concomitant treatment with oral glucocorticoids in patients on non-vitamin K oral anticoagulants

Heart ◽

10.1136/heartjnl-2021-319503 ◽

2021 ◽

pp. heartjnl-2021-319503

Author(s):

Anders Holt ◽

Paul Blanche ◽

Bochra Zareini ◽

Peter Vibe Rasmussen ◽

Jarl Emanuel Strange ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Vitamin K ◽

Absolute Risk ◽

Oral Anticoagulants ◽

Concomitant Treatment ◽

Short Term ◽

Oral Glucocorticoid ◽

Risk Increase ◽

Daily Dose ◽

Oral Glucocorticoids

ObjectiveGastrointestinal bleeding (GIB) risk in relation to concomitant treatment with non-vitamin K oral anticoagulants (NOAC) and oral glucocorticoids is insufficiently explored. We aimed to investigate the short-term risk following coexposure.MethodsThis is a register-based, nationwide Danish study including patients with atrial fibrillation on NOACs during 2012–2018. Patients were defined as exposed to oral glucocorticoids if they claimed a prescription within 60 days prior to GIB. We investigated the associations between GIB and oral glucocorticoid exposure, reporting HRs via a nested case–control design and absolute risk via a cohort design. Matching terms were age, sex, calendar year, follow-up time and NOAC agent.Results98 376 patients on NOACs (median age: 75 years (IQR: 68–82), 44% female) were included, and 16% redeemed at least one oral glucocorticoid prescription within 3 years. HRs of GIB were increased comparing exposed with non-exposed patients (<20 mg daily dose, HR 1.54 (95% CI 1.29 to 1.84); ≥20 mg daily dose, HR 2.19 (95% CI 1.81 to 2.65)). 60-day standardised absolute risk of GIB following first claimed oral glucocorticoid prescription increased compared with non-exposed: 60-day absolute risk: 0.71% (95% CI 0.58% to 0.85%) vs 0.38% (95% CI 0.32% to 0.43%). The relative risk was elevated as well: risk ratio of 1.89 (95% CI 1.43 to 2.36).ConclusionsConcomitant treatment with NOACs and oral glucocorticoids was associated with a short-term rate and risk increase of GIB compared with patients only on NOACs. This could have implications for clinical management, necessitating closer monitoring or other risk mitigation strategies during episodes of cotreatment with oral glucocorticoids.

Download Full-text

Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial

Circulation ◽

10.1161/circulationaha.119.041296 ◽

2020 ◽

Vol 141 (1) ◽

pp. 10-20 ◽

Cited By ~ 3

Author(s):

Frederik Dalgaard ◽

Hillary Mulder ◽

Daniel M. Wojdyla ◽

Renato D. Lopes ◽

Claes Held ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Clinical Trial Registration ◽

Risk Of Bleeding ◽

Number Of Patients ◽

Increased Risk ◽

Inflammatory Drugs ◽

Anti Inflammatory

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin. Methods: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models. Results: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11–2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16–2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. Conclusions: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Download Full-text

Off-Label Underdosing or Overdosing of Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.724301 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xiaojuan Wu ◽

Linyan Hu ◽

Jinjin Liu ◽

Qiuping Gu

Keyword(s):

Myocardial Infarction ◽

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Vitamin K ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Systemic Embolism ◽

Off Label ◽

Label Dose

Background: Several studies have investigated the role of off-label non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). We aimed to compare the effectiveness and safety outcomes between off-label underdose or overdose vs. on-label dose of NOACs in AF patients.Methods: The PubMed database was systematically searched until August 2021. Observational cohorts were included if they compared the outcomes of off-label underdose or overdose with on-label dose of NOACs in AF patients. The risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a fixed-effects model (I2 ≤ 50%) or a random-effects model (I2 > 50%).Results: A total of 15 observational studies were included. Compared with on-label dose of NOACs, off-label underdose of NOACs was associated with increased risks of stroke or systemic embolism (RR = 1.09, 95% CI 1.02–1.16), and all-cause death (RR = 1.29, 95% CI 1.10–1.52) but not ischemic stroke (RR = 1.34, 95% CI 0.76–2.36), myocardial infarction (RR = 1.08, 95% CI 0.92–1.28), major bleeding (RR = 0.97, 95% CI 0.89–1.05), intracranial hemorrhage (RR = 1.12, 95% CI 0.90–1.40), and gastrointestinal bleeding (RR = 0.96, 95% CI 0.85–1.07), whereas off-label overdose of NOACs was associated with increased risks of SSE (RR = 1.20, 95% CI 1.05–1.36), all-cause death (RR = 1.22, 95% CI 1.06–1.39), and major bleeding (RR = 1.33, 95% CI 1.16–1.52) but not gastrointestinal bleeding (RR = 1.18, 95% CI 0.99–1.42) and myocardial infarction (RR = 0.98, 95% CI 0.75–1.30).Conclusion: Compared with on-label dose of NOACs, off-label underdose was associated with increased risks of stroke or systemic embolism and all-cause death, whereas off-label overdose of NOACs was associated with increased risks of stroke or systemic embolism, all-cause death, and major bleeding.

Download Full-text

Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Atrial Fibrillation Patients With Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.118.023797 ◽

2019 ◽

Vol 50 (4) ◽

pp. 939-946 ◽

Cited By ~ 7

Author(s):

Peter Brønnum Nielsen ◽

Flemming Skjøth ◽

Mette Søgaard ◽

Jette Nordstrøm Kjældgaard ◽

Gregory Y.H. Lip ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Risk Reduction ◽

Vitamin K ◽

Risk Ratio ◽

Absolute Risk ◽

Oral Anticoagulants ◽

Absolute Risk Reduction ◽

Vitamin K Antagonist

Background and Purpose— Recurrent bleeding associated with oral anticoagulants (OACs) causes a dilemma in patients with atrial fibrillation (AF) sustaining an intracerebral hemorrhage. Treatment recommendations guiding clinical practice on optimal OAC agent selection in this population are lacking. This study aimed to investigate the comparative effectiveness and safety of non–vitamin K antagonist OAC (NOAC) versus warfarin in patients with AF sustaining an intracerebral hemorrhage. Methods— We conducted a nationwide observational cohort study including patients with AF sustaining an intracerebral hemorrhage and who subsequently claimed an OAC prescription. Contrasts of 1-year risks for ischemic stroke and intracerebral hemorrhage risks were obtained and evaluated by inverse probability treatment weighted absolute risk reduction and risk ratios. Results— Among 622 AF patients with intracerebral hemorrhage, 274 claimed a warfarin prescription and 348 a NOAC prescription. Mean age was 76 years (39% females); 72% had an index nonsevere event and 28% moderate to severe index event according to the Scandinavian Stroke Severity scale. The 1-year ischemic stroke risk was 7.85% for warfarin and 4.01% for NOACs, with a weighted absolute risk reduction of 3.78% (95% CI, −0.15% to 7.71%); the weighted risk ratio was 0.52 (0.27–1.00). For recurrent intracerebral hemorrhage, the risk was 7.00% for warfarin and 5.07% for NOACs. The absolute risk reduction was 1.93% (−2.02% to 5.87%), with an a weighted risk ratio of 0.72 (0.38–1.38). Conclusions— NOACs were associated with a nonsignificant lower risk of ischemic stroke and recurrent intracerebral hemorrhage compared with warfarin. The results add to current recommendations of selecting a NOAC agent for stroke prophylaxis treatment in patients with AF, including those with sustaining an intracerebral hemorrhage.

Download Full-text