New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding

A Systematic Review and Meta-analysis

I. Lisanne Holster; Vera E. Valkhoff; Ernst J. Kuipers; Eric T. T. L. Tjwa


Gastroenterology. 2013;145(1):105-112. 

In This Article

Materials and Methods

Study Definitions

The exposure of interest was defined as the (approximated) indication-specific recommended daily dose of the nOAC either by the European Medicines Agency[12] or the Food and Drug Administration[13] for registered nOAC. When nOAC was not registered for the indication for which it was studied, the indication-specific daily dose was defined according to the pharmaceutical manufacturer.

Standard care was defined as either low-molecular-weight heparin, vitamin K antagonist, antiplatelet therapy, or no (additional) therapy/placebo, depending on the (inter)national guidelines regarding antithrombotic therapy for the concerning indication.

The primary outcome of this systematic review was the risk of GIB. GIB was considered as at least one episode of clinically apparent hematemesis (frank blood or coffee-ground material that tested positive for blood), melena, or spontaneous rectal bleeding (if more than a few spots) or endoscopically confirmed bleeding, and was judged as major or clinically relevant nonmajor depending on the severity.[14]

The secondary outcome was the risk of clinically relevant bleeding (encompassing both major bleeding and clinically relevant nonmajor bleeding). Major bleeding and clinically relevant nonmajor bleeding in the included studies were defined by the following: (1) the International Society on Thrombosis and Haemostasis, [15,16] (2) the Thrombolysis In Myocardial Infarction,[17] or (3) an adjustment of the International Society on Thrombosis and Haemostasis definition (see Table 1 for exact definitions).

Data Sources and Searches

A comprehensive literature search was conducted to identify RCTs reporting GIB or clinically relevant bleeding in patients receiving nOAC compared with standard treatment. Medline with PubMed as interface, EMbase, and the Cochrane Central Register of Controlled Trials were searched from inception to July 2012. Medical subject heading terms and keywords used to identify RCTs included "apixaban," "rivaroxaban," "dabigatran," "edoxaban," "betrixaban," "humans," and "randomized controlled trial." No language restrictions were applied. The electronic search strategy was complemented by a manual review of reference lists of included articles. References of recent reviews on nOAC also were examined.[11,18,19,20,21,22,23]

Study Selection

Search results were combined and duplicates were removed. Studies were first screened based on title and abstract for relevance, after which the full text was reviewed. This was performed independently by 2 reviewers (I.L.H. and V.E.V.). Inter-rater agreement was assessed using the k statistic. Any discrepancies were resolved by consensus, contacting a third author (E.T.T.L.T.). Studies had to meet the following inclusion criteria: (1) the study compared nOAC with the current standard care in a randomized setting; (2) results included bleeding events as a safety outcome; (3) the study was conducted in the target population of the drug and not in healthy volunteers; and (4) it was published as a full-text article. If any of the 4 criteria were not met, the study was excluded. If data from the same study were published in multiple languages, data from the English article were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication were extracted.

Data Extraction

The included studies were divided by clinical indication of anticoagulant therapy into the following indication groups: (1) prevention of stroke and systemic embolism in patients with atrial fibrillation (AF); (2) prevention of venous thromboembolism after orthopedic surgery (OS); (3) prevention of venous thromboembolism in medically ill patients; (4) treatment of acute deep vein thrombosis (DVT) or pulmonary embolism (PE); and (5) treatment of acute coronary syndrome (ACS). For each included study, we recorded the number of trial participants, follow-up period, and the number of patients who developed the primary safety end points for both treatment arms. The mean age at baseline and the percentage of males were assessed, as well as other characteristics of the study population such as relevant concomitant medications that may affect bleeding risk. This was performed independently by 2 authors (I.L.H. and V.E.V.). Finally, we contacted the main investigator for missing data. Furthermore, given the heterogeneity of the studies, an individual patient data analysis was attempted. All authors were contacted and requested to provide individual patient data. We received responses from 7 of 23 authors (covering 12 of 43 studies). Unfortunately, no one agreed to share this information.

Quality Assessment

The quality of included studies was assessed according to the Cochrane Reviewers' Handbook.[24] Both manuscript and protocol, if available online, were scanned for relevant information on quality.

Data Synthesis and Analysis

Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for each RCT and were the bases for the meta-analyses. To include studies with null events in either the active treatment arm or the standard care arm, 0.5 events were added to all cells with study results. In case of null events in both arms, no OR was calculated. To quantify how many patients needed to be exposed to nOAC therapy to cause one additional GIB compared with standard care the number needed to harm (NNH) was assessed.

To explore between-study variability the Cochran Q test and the Higgins I2 test for heterogeneity were used. Significant heterogeneity was assumed when the Cochran Q P value was less than .10 and the I2 was greater than 50%. To reduce the impact of heterogeneity, we used a random-effects model in these cases.

To account for possible sources of heterogeneity, we performed prespecified subgroup analyses according to type of nOAC and indication. Heterogeneity between subgroups was evaluated further by a post hoc meta-regression analysis by indication, type of nOAC, and comparator. Comprehensive meta-analysis v2.0 (Biostat, Englewood, NJ) was used to perform the meta-analysis. Meta-regression was performed using PASW statistics 20.0 for Windows (SPSS, IBM, Armonk, New York).

Sensitivity analysis was performed to exclude studies that compared the bleeding risk of nOAC use with the use of placebo as standard care because this intervention is unlikely to increase bleeding risk. Because we only included published data, publication bias was quantified with the Egger regression test, with the results considered to indicate publication bias when the P value was less than .10. In addition, funnel plots were examined for asymmetry.