Aspirin’s GI Bleeding Risk Increased by Concomitant Use of Gastrotoxic Drugs

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In the general patient population, low-dose aspirin almost doubles the likelihood of upper gastrointestinal (GI) bleeding, and adding drugs such as clopidogrel or high-dose corticosteroids raises the risk even more. The findings were published online February 28, 2011, ahead of print in Circulation.

According to Luis A. García Rodríguez, MD, MS, of the Spanish Centre for Pharmacoepidemiological Research (Madrid, Spain), and colleagues, theirs is one of the first studies to quantify the risk of upper GI bleeding associated with specific combination therapies in the general population.

For the study, the researchers used the Health Improvement Network UK primary care database to identify individuals who were diagnosed with upper GI bleeding from 2000 to 2007. All subjects were enrolled with a primary care physician and were between 40 and 84 years of age at the time of diagnosis (n = 2,049). They were compared with 20,000 controls from the same database who were matched for age, sex, and calendar year. Multivariate logistic regression analysis assessed the effects of different gastrotoxic medications on upper GI bleeding.

The risk of upper GI bleeding was significantly higher in those with a history of the condition. However, there was no association between such bleeding and cardiovascular disease. Only a minority of subjects were taking low-dose aspirin (30.8%), clopidogrel (3.3%), or dual antiplatelet therapy (1.6%) at the time of a confirmed GI bleeding event.

An Additive Effect

Compared with patients who did not take aspirin, the risk of upper GI bleeding was higher in current users of low-dose aspirin (75-300 mg), regardless of whether they were simultaneously receiving clopidogrel (adjusted RR 1.80; 95% CI 1.59-2.03). The effect was consistent across all daily doses studied. Similarly, patients who were on clopidogrel therapy with or without low-dose aspirin also experienced higher bleeding risk than those not currently receiving the thienopyridine (adjusted RR 1.67; 95% CI 1.24-2.24). Treatment duration of more or less than 1 year made no difference in risk for either drug.

Dual antiplatelet therapy, meanwhile, raised the risk of bleeding even higher compared with nonuse of aspirin and clopidogrel (adjusted RR 3.71; 95% CI 2.38-5.76).

Concomitant use of several medications augmented the bleeding risk beyond that imparted by low-dose aspirin alone. However, statins did not add to aspirin’s risk, nor did oral corticosteroids when given at a low dose (table 1).

Table 1. Bleeding Risk: Aspirin + Concomitant Medications vs. Aspirin Monotherapy


Adjusted RR

95% CI




Oral Anticoagulants



Low-/Medium-Dose NSAIDs



High-Dose NSAIDs



Low-Dose Oral Corticosteroids



High-Dose Oral Corticosteroids






Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

The incidence of upper GI bleeding has been estimated to be 0.5 to 1 case per 1,000 person-years. Thus, the relative risk associated with dual antiplatelet therapy over no clopidogrel/aspirin use translates to an excess risk of 1.4 to 2.7 cases per 1,000 patients exposed to the drugs annually.

Notably, however, low-dose aspirin or clopidogrel monotherapy each “increased the risk of [upper GI bleeding] by a similar extent, which suggests that neither therapy is superior” at preventing the complication when given alone, the paper notes.

Previous studies on aspirin use “have tended to conclude that the cardiovascular benefits of [aspirin] definitely outweigh its gastrointestinal risks when used in secondary prevention but not necessarily when it is used in primary prevention, particularly not if individuals are already taking statins,” the investigators write, noting that such studies typically take only patient age into account when calculating risk. “However, our results suggest that they should also take into account the other gastrotoxic agents that may be coadministered to these patients.”

Study Details

Over 95% of patients taking clopidogrel received 75 mg daily, so results were not stratified according to dose.

High-dose NSAIDs were defined as a daily dose greater than: 200 mg for aceclofenac, 120 mg for acemetacin, 600 mg for azapropazone, 200 mg forcelecoxib, 100 mg for diclofenac, 1,500 mg for diflunisal, 400 mg for etodolac, 90 mg for etoricoxib, 900 mg for fenbufen, 1,200 mg for fenprofen, 150 mg for flurbiprofen, 1,200 mg for ibuprofen, 75 mg for indomethacin, 150 mg for ketoprofen, 30 mg for ketorolac, 1,000 mg for mefenamic acid, 7.5 mg for meloxican, 1,000 mg for nabumetone, 750 mg for naproxen, 10 mg for piroxicam, 25 mg for rofecoxib, 200 mg for sulindac, 10 mg for tenoxicam, 600 mg for tiaprofenac, and 20 mg for valdecoxib.

A high dose of corticosteroids was defined as greater than 10 mg/day prednisolone or the equivalent dose for other corticosteroids.


García Rodríguez LA, Lin KJ, Hernández-Díaz S, Johansson S. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone or in combination with clopidogrel and other medications. Circulation. 2011;123:1108-1115.



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Caitlin E. Cox is News Editor of TCTMD and Associate Director, Editorial Content at the Cardiovascular Research Foundation. She produces the…

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  • The study was funded by an unrestricted research grant to the Spanish Centre for Pharmacoepidemiological Research from Astra Zeneca.
  • Catherine Hill, PhD, of Oxford PharmaGenesis, provided writing assistance that was funded by AstraZeneca.
  • Dr. García Rodríguez reports that his institution has received research funding and consulting fees from AstraZeneca.