The association between non‐vitamin K antagonist oral anticoagulants and gastrointestinal bleeding: a meta‐analysis of observational studies

Abstract

Particular concerns have been raised regarding the association between non-vitamin K antagonist oral anticoagulants (NOACs) and the risk of gastrointestinal bleeding (GIB); however, current findings are still inconclusive. We conducted a systematic review with a meta-analysis to examine the association between NOACs and GIB in real-life settings. We performed a systematic search of PubMed, EMBASE and CINAHL Plus up to September 2015. Observational studies that evaluated exposure to NOACs reporting GIB outcomes were included. The inverse variance method using the random-effects model was used to calculate the pooled estimates. Eight cohort studies were included in the primary meta-analysis, enrolling 1442 GIB cases among 106 626 dabigatran users (49 486 patient-years), and 184 GIB cases among 10 713 rivaroxaban users (4046 patient-years). The pooled incidence rates of GIB were 4.50 [95% confidence interval (CI) 3.17, 5.84] and 7.18 (95% CI 2.42, 12.0) per 100 patient-years among dabigatran and rivaroxaban users, respectively. The summary risk ratio (RR) was 1.21 (95% CI 1.05, 1.39) for dabigatran compared with warfarin, and 1.09 (95% CI 0.92, 1.30) for rivaroxaban. Subgroup analyses showed a dose-related effect of dabigatran, with a significantly higher risk of GIB for 150 mg b.i.d. (RR = 1.51, 95% CI 1.34, 1.70) but not for 75 mg b.i.d. or 110 mg b.i.d.. In addition, the use of proton pump inhibitors (PPIs)/histamine H2-receptor antagonists (H2RAs) influenced the association in dabigatran users, whereas this effect was modest among rivaroxaban users. In conclusion, our meta-analysis suggested a slightly higher risk of GIB with dabigatran use compared with warfarin, whereas no significant difference was found between rivaroxaban and warfarin for GIB risk.

Bleeding‐related hospital admissions and 30‐day readmissions in patients with non‐valvular atrial fibrillation treated with dabigatran versus warfarin

“…In this study, we noted a higher incidence of hospitalization for GIB with dabigatran vs. warfarin, which is consistent with previous meta-analyses of randomized controlled trials [15] and observational studies [58]. Importantly, we observed an increased risk of GIB with dabigatran 110 mg b.i.d.…”

Study of Dabigatran Use in a Brazilian Public Hospital Specialized in Cardiology

“…26 Some show the association between dabigatran and gastroprotective agents, not only proton pump inhibitors, but also histamine H2-receptor antagonists. 27,28 These therapeutic associations were also observed in the present work and may explain the reduction of dyspepsia occurrences. 27,28 However, changes in gastric pH may alter the drug's solubility, and proton pump inhibitors have proven able to decrease serum concentrations of dabigatran, even though the interaction is not considered clinically significant.…”

“…27,28 These therapeutic associations were also observed in the present work and may explain the reduction of dyspepsia occurrences. 27,28 However, changes in gastric pH may alter the drug's solubility, and proton pump inhibitors have proven able to decrease serum concentrations of dabigatran, even though the interaction is not considered clinically significant. 24 Apparently, such associations did not compromise the anticoagulant's effectiveness in the present study because no thromboembolic events were recorded.…”

Long‐term use of proton pump inhibitors and prevalence of disease‐ and drug‐related reasons for gastroprotection—a cross‐sectional population‐based study

“…To investigate if the inclusion of more non‐specific diagnoses, where PPI may be considered, would have an impact on the results, additional diagnoses were included in the disease‐related reasons (K29, gastritis and duodenitis; K92.0, haematemesis; K92.1, melaena; K92.2, gastrointestinal haemorrhage, unspecified; B98.0, helicobacter pylori as the cause of diseases classified to other chapters; E16.4, increased secretion of gastrin; Q40.1, congenital hiatus hernia; R12.9, heartburn; R13.9, dysphagia). Further, additional drug groups associated with an increased risk of gastrointestinal complications were included in the drug‐related reasons: anticoagulants (B01AA, B01AE, and B01AF), selective serotonin reuptake inhibitors (SSRI, N06AB), and glucocorticoids (H02AB) …”

“…Further, additional drug groups associated with an increased risk of gastrointestinal complications were included in the drug-related reasons: anticoagulants (B01AA, B01AE, and B01AF), selective serotonin reuptake inhibitors (SSRI, N06AB), and glucocorticoids (H02AB). [28][29][30] As disease-related reasons occurring in 2010 may justify long-term PPI treatment this year, we also performed a sensitivity analysis including diagnoses up to 2010, that is, 2005-2010. To further explore the robustness of the results, a sensitivity analysis was performed where long-term use of PPI, for individuals outside the multi-dose drug dispensing system, was defined as ≥3 dispensings of PPI, each covering ≥90 days of treatment.…”