Combining nonsteroidal anti-inflammatory drugs with selective serotonin reuptake inhibitors increased the risk of upper gastrointestinal bleeding by up to 190% beyond the baseline risk found for NSAID monotherapy, researchers reported in the October issue of Gastroenterology.
Patients also faced excess risks of upper GI bleeding when they took corticosteroids, aldosterone antagonists, or anticoagulants together with low-dose aspirin or nonselective NSAIDs, although the effect was not seen for COX-2 inhibitors, said Dr. Gwen Masclee at Erasmus Medical Center in Rotterdam, the Netherlands and her associates.
Source: American Gastroenterological Association
The findings should help clinicians tailor treatments to minimize chances of upper gastrointestinal bleeding, particularly for elderly patients who often take multiple drugs, the investigators said (Gastroenterology 2014 [doi:10.1053/j.gastro.2014.06.007]).
The researchers analyzed 114,835 cases of upper gastrointestinal bleeding, including all gastroduodenal ulcers and hemorrhages extracted from seven electronic health record databases from the Netherlands, Italy, and Denmark. Three databases included primary care data, and four were administrative claims data, the investigators said. Cases served as their own controls, they noted.
Monotherapy with prescription nonselective NSAIDs increased the chances of an upper gastrointestinal bleed by 4.3 times, compared with not using any of the drugs studied (95% confidence interval, 4.1-4.4), the researchers said. Notably, bleeding risk from taking either nonselective NSAIDs or corticosteroids was the same, they said, adding that previous studies have yielded inconsistent findings on the topic. The incidence ratios for monotherapy with low-dose aspirin and COX-2 inhibitors were slightly lower at 3.1 (95% CI, 2.9-3.2) and 2.9 (95% CI, 2.7-3.2), respectively, they added.
Combining nonselective NSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs led to excess risks of upper gastrointestinal bleeding of 1.6 (95% CI, 0.5-2.6), 1.9 (95% CI, 0.2-3.4), and 0.49 (–0.05-1.03), respectively, the researchers reported. "From a biological point of view, this interaction seems plausible because SSRIs decrease the serotonin level, resulting in impaired thrombocyte aggregation and an increased risk of bleeding in general," they said.
Corticosteroids combined with nonselective NSAIDs led to the greatest increases in bleeding risk, with an incidence ratio of 12.8 (95% CI, 11.1-14.7), compared with nonuse of any drug studied, and an excess risk of 5.5 (3.7-7.3), compared with NSAID use alone, said the researchers. Adding aldosterone antagonists to nonselective NSAIDs led to an excess risk of 4.46, compared with using nonselective NSAIDs alone, they reported (95% CI, 1.79-7.13).
Because the study did not capture over-the-counter NSAID prescriptions, it could have underestimated use of these drugs, the investigators said. Also, changes in health or NSAID use during the study could have created residual confounding, although sensitivity analyses did not reveal problems, they reported. They added that misclassification of some data could have led them to underestimate risks. "Finally, we did not take any carryover effect or dose of drug exposure into account, which potentially limits the generalizability concerning causality of the associations," they concluded.
Five authors reported employment or other financial support from Erasmus University Medical Center, AstraZeneca, Janssen, PHARMO Institute, and the European Medicines Agency. The other authors reported no relevant conflicts of interests.