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


This systematic review and meta-analysis on 43 trials shows that the nOACs are associated with a modest, but significantly higher, risk of GIB compared with current standard care. This risk is the highest in patients treated for thrombosis (ACS and DVT/PE). In ACS, nOACs were administered on top of other antithrombotic medication, increasing the well-known cumulative risk of GIB.[5] The risk of GIB in patients treated for DVT/PE or receiving thromboprophylaxis for AF is higher than in patients receiving thromboprophylaxis after OS, this might suggest a dose and/or duration effect on top of difference in risk caused by patient characteristics in the different indication groups. However, within the subgroup of AF patients, only patients treated with dabigatran and rivaroxaban carry a higher GIB risk, but not with apixaban. Because head-to-head studies between nOAC in AF have not been performed, it is not possible to determine the drugs with the lowest GIB risk in AF without applying statistically indirect comparisons. A network meta-analysis on overall safety was conducted by others on OS patients and showed no significant differences.[65]

The major strength of this meta-analysis was its focus on GIB. We provide a complete review of 43 trials with a total of 151,578 patients. Given the implementation of nOAC on a large scale, all currently available types of nOAC and all present indications were included because GI physicians will have to deal with GIB complications, irrespective of drug or indication. The data conveyed are corroborated by 2 small meta-analyses with GIB as a secondary safety outcome and in which in total only 3 studies for AF were reviewed. [66,67] For optimal clinical relevance, we included only data obtained with the indication-specific registered/recommended dose per drug, instead of combining all levels of dosages per trial, which was performed in meta-analyses assessing overall risk/benefit of thromboprophylaxis after OS.[8,65]

Two limitations of the current study need to be addressed: (1) study design and GIB report of included studies, and (2) heterogeneity between studies. First, all included studies have been designed for showing noninferior or superior efficacy of nOAC vs current standard care. As a consequence, GIB is not reported as a safety outcome in the majority of studies and will have to be assessed by future studies or by a critical assessment of published studies. A large number of included studies reported only on the composite end point of bleeding outcomes in general. Although the use of this end point has the advantage of increased power, a difference in GIB risk therefore cannot be investigated. However, when studies separately reported on GIB, this was performed for major bleedings, but mostly not for clinically relevant nonmajor bleedings. This led to an underestimation of the risk of all clinically relevant GIBs (ie, composed of both major and clinically relevant nonmajor GIBs). In addition, for GIB there was no standard definition according to a scientific commission, but most trials reported used a uniform definition to identify GIB. Regarding heterogeneity, which is inevitable with current available data, we applied a random-effects model and excluded observational cohorts, healthy volunteer studies, nonregistered drugs, and unpublished data. Furthermore, we addressed all perceived sources of heterogeneity by prespecified subgroup analysis and meta-regression by indication, type of nOAC, and comparator. Analysis by concomitant use of antiplatelet therapy was not feasible owing to lack of stratification of outcome by use of antiplatelet therapy.

Some statistical issues merit clarification. First, we calculated risk estimates per study by means of ORs. Although it would have been preferable to calculate hazard ratios, the rationale to compute ORs was that the mean follow-up time until GIB was not reported per treatment arm for any study. The OR can be interpreted as an estimate of the relative risk because the overall occurrence of GIB is rare (1.5%). Second, for the analysis on GIB, following standard practice, we excluded 2 studies that had no events in both arms. This exclusion was performed because such studies do not provide any indication of either the direction or magnitude of the relative treatment effect, whereas exclusion of the 2 trials would not affect the point estimate. Both studies were of relatively small size (and thus would have had a low weight in the meta-analyses, together equaling approximately 2%).

As evidence of the superior efficacy of nOAC accumulates,[8,65,67] it is important to consider 2 crucial issues. First, most trials used extensive exclusion criteria to enroll only those patients with a presumed low risk of GIB complications attributable to anticoagulants. It is estimated that when these drugs are marketed for daily clinical practice, almost 25%–40% of future users are high-risk patients and the risk of hemorrhage can be as much as 3- to 15-fold increased.[68] It is tempting to speculate that the balance between efficacy and safety will shift unfavorably in these patients because the bleeding risk increases to a much greater extent than the risk of thromboembolism. Second, data on concomitant proton pump inhibitor (PPI) use was not available, except for one trial.[62] A recent consensus guideline states that PPIs should be considered in any person with a risk factor for GIB receiving any type of antithrombotic agent[69] because PPIs have proven to reduce the risk of upper GIB among both traditional NSAID users, low-dose aspirin users, and among patients taking clopidogrel.[70] Future trials, investigating whether gastroprotective agents could increase NNH in patients on nOAC, are warranted. This is of importance because many patients may use nOAC for a considerable duration of time and mostly have significant comorbidity.

In conclusion, we have shown that the gastrointestinal bleeding risk associated with nOAC use might be higher compared with standard care. The current evidence, however, is based on a highly selected patient group with a low bleeding risk, disallowing a true reflection of future patients in daily clinical practice. We recommend that future studies specifically report on the gastrointestinal bleeding risk to further elucidate the true incidence and associated risk. Subsequently, co-administration of gastroprotective agents could be beneficial and warrants further investigations.