Gastroenterology

Gastroenterology

Volume 147, Issue 4, October 2014, Pages 784-792.e9
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Risk of Upper Gastrointestinal Bleeding From Different Drug Combinations

https://doi.org/10.1053/j.gastro.2014.06.007Get rights and content

Background & Aims

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs.

Methods

We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]).

Results

Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9.

Conclusions

Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

Section snippets

Data Sources

Data were obtained from a network of 7 electronic health record (EHR) databases from 3 countries. The EU-ADR Project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) has successfully established a platform that integrates data from various repositories of European EHRs for evaluation of drug safety.11

We analyzed data from 3 primary care databases (Integrated Primary Care Information [IPCI, The Netherlands]; Health Search/CSD

Risk of UGIB With Drug Monotherapy

In total, 114,835 patients with UGIB (cases) with corresponding follow-up of 930,888 person-years were included in the analysis (Table 1). For all drugs of interest, monotherapy showed a significantly increased relative risk compared with no use of any of the drugs of interest. Monotherapy with nsNSAIDs was associated with an IRRp of 4.3 (95% CI, 4.1–4.4), which is higher than monotherapy with either COX-2 inhibitors (IRRp, 2.9; 95% CI, 2.7–3.2) or low-dose aspirin (IRRp, 3.1; 95% CI, 2.9–3.2) (

Discussion

We determined the magnitude of increased risk of diagnosed UGIB when nsNSAIDs, COX-2 inhibitors, and low-dose aspirin were combined with specific drug classes that may be independently associated with diagnosed UGIB. Although it may seem reasonable to assume synergistic effects with concurrent use of drugs that independently increase risk, these effects have rarely been investigated. To study the risk of diagnosed UGIB during use of specific drug combinations, it is essential to have a large

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    This article has an accompanying continuing medical education activity on page e13. Learning Objective: Upon completion of these exercises, successful learners will be able to recognize, differentiate and apply the risk and excess risk of upper gastrointestinal bleeding associated with use of non-steroidal anti-inflammatory drugs and low-dose aspirin combined with other drugs.

    Conflicts of interest The authors disclose the following: V.E.V., as an employee of Erasmus University Medical Center, has conducted research for AstraZeneca. M.J.S. has accepted a full-time position at Janssen R&D since completion of this research. R.H. is scientific director of PHARMO Institute, which performs studies for various pharmaceutical companies. G.M. has started working for the European Medicines Agency since completion of this research. M.C.J.M.S is coordinating a research group that has unconditional research grants from Pfizer, Novartis, and Lilly, none of which are related to this research. The remaining authors disclose no conflicts.

    Funding EU-ADR is a research and development project funded by the European Commission Seventh Framework Programme (FP7/2007–2013) under grant no. 215847–The EU-ADR Project. The funding agency had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

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