Montreal, QC - New research suggests there is a much higher increased risk for GI bleeding when antithrombotic therapy is combined with ASA or nonsteroidal anti-inflammatory drugs (NSAIDs) [1].

The population-based, retrospective, case-control study found a four- to sixfold increased risk for GI bleeds among patients who took warfarin or clopidogrel with ASA or NSAIDs.

"Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of GI bleeding beyond that associated with each drug used alone. Physicians should be aware of these risks to better assess their patients' therapeutic risk/benefit profiles," the authors write.

Conducted by Dr James Brophy (McGill University Health Centre, Montreal, QC) and colleagues, the study is published online August 14, 2007 in the Canadian Medical Association Journal.

To assess whether coprescribing these drugs or prescribing them with other medications such as NSAIDs increases the risk of GI bleeding, investigators used records from more than 400 general practices included in the United Kingdom General Practice Research Database from 2000 to 2005. They identified 4028 patients over the age of 18 years presenting with their first-ever diagnosis of GI bleeding. These subjects were then matched with 40 171 controls from the same database.

To facilitate a full assessment of patient comorbidity and lifestyle information, all patients had to have medical records with at least three years of data recorded before their first GI bleed.

For the purposes of the study, current drug exposure was defined as a prescription in the 90 days before diagnosis of the first GI bleed.

The average age of study subjects—cases and controls—was 69 years. According to the study results, known risk factors for GI bleeding, including male sex, heavy alcohol use, smoking, acetaminophen use, and liver failure, were important predictors of risk even in the multivariate analysis.

However, they found the combined prescription of ASA with either clopidogrel or warfarin was associated with a greater risk for GI bleeding than with either drug alone.

For example, the authors note a prescription of ASA alone or warfarin alone was associated with an adjusted relative risk for GI bleeding of 1.39 and 1.94, respectively. However, when the two drugs were prescribed in combination, the adjusted effect, or total risk, for GI bleeding was 6.48.

The authors note that similar effects were seen among patients prescribed any NSAID (either a conventional one or a COX-2-selective inhibitor) with either clopidogrel or warfarin.

"Our results indicate that physicians need to be aware of and weight the potential risk for gastrointestinal bleeding due to drug-drug interactions with antithrombotic agents against the known therapeutic benefits of these drug combinations," they write.

In an accompanying editorial [2], Dr David Juurlink (Sunnybrook Health Sciences Centre, Toronto, ON) points out that that the science of potential drug interactions is an ongoing and "daunting" challenge for physicians.

In part, writes Juurlink, this is because there have been few controlled population-based studies that have explored drug interactions.

However, he notes, the approach taken by the investigators in the current study provides clinicians with data from a "real-world" study that links outpatient prescription data with clinical outcomes.

This research, he notes, provides clinicians with an estimate of the excess risk associated with combinations of antiplatelet agents and warfarin. It also "reminds clinicians that, if we opt to prescribe these drugs in combination, especially for an extended period, we had better have good reasons to do so and inform the patient appropriately."

Finally, Juurlink writes, the "thoughtful" and "sophisticated" approach taken by the McGill investigators "contributes to our understanding of these drug interactions in ways uncontrolled observations cannot."