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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.
Gastrointestinal toxicity is the major issue limiting nonsteroidal anti-inflammatory use. The excess annual risk of upper gastrointestinal bleeding per 1,000 patients is about 1 with low-dose aspirin, about 2 with coxibs, and about 4-6 with traditional NSAIDs (ibuprofen, naproxen). However, the risk of upper gastrointestinal bleeding increases markedly with several factors, including the use of concomitant medications.
Ideally, large randomized trials comparing NSAIDs with and without a concomitant medication would inform our assessment of risk. However, few such trials are available, so we commonly rely on observational database studies, such as that of Masclee et al. These studies have the important benefit of large sample size and "real world" results, but also have potential limitations, including reliability of data (for example, accuracy of diagnostic coding) and potential bias because of unequal distribution of confounding factors between cases and controls.
Masclee et al. report significant synergy (more than additive risk) of traditional NSAIDs with corticosteroids, SSRIs, aldosterone antagonists, and antithrombotic agents other than low-dose aspirin (although risk was increased with traditional NSAIDs plus low-dose aspirin). Low-dose aspirin was synergistic with antithrombotic agents and corticosteroids, while coxibs were synergistic with low-dose aspirin and SSRIs.
The results of Masclee et al. support current North American guidelines, which suggest use of proton pump inhibitors or misoprostol for traditional NSAID users taking concomitant medications such as antithrombotics, corticosteroids, or SSRIs, and use of PPIs for low-dose-aspirin users taking antithrombotics or taking corticosteroids if greater than or equal to 60 years old. Their results also suggest further evaluation of aldosterone antagonists is warranted as another possible risk factor.
Dr. Loren Laine is professor of medicine, department of internal medicine, Yale University, New Haven, Conn. He is on the Data Safety Monitoring Boards of Eisai, BMS, and Bayer; and is a consultant for AstraZeneca.
Gastrointestinal toxicity is the major issue limiting nonsteroidal anti-inflammatory use. The excess annual risk of upper gastrointestinal bleeding per 1,000 patients is about 1 with low-dose aspirin, about 2 with coxibs, and about 4-6 with traditional NSAIDs (ibuprofen, naproxen). However, the risk of upper gastrointestinal bleeding increases markedly with several factors, including the use of concomitant medications.
Ideally, large randomized trials comparing NSAIDs with and without a concomitant medication would inform our assessment of risk. However, few such trials are available, so we commonly rely on observational database studies, such as that of Masclee et al. These studies have the important benefit of large sample size and "real world" results, but also have potential limitations, including reliability of data (for example, accuracy of diagnostic coding) and potential bias because of unequal distribution of confounding factors between cases and controls.
Masclee et al. report significant synergy (more than additive risk) of traditional NSAIDs with corticosteroids, SSRIs, aldosterone antagonists, and antithrombotic agents other than low-dose aspirin (although risk was increased with traditional NSAIDs plus low-dose aspirin). Low-dose aspirin was synergistic with antithrombotic agents and corticosteroids, while coxibs were synergistic with low-dose aspirin and SSRIs.
The results of Masclee et al. support current North American guidelines, which suggest use of proton pump inhibitors or misoprostol for traditional NSAID users taking concomitant medications such as antithrombotics, corticosteroids, or SSRIs, and use of PPIs for low-dose-aspirin users taking antithrombotics or taking corticosteroids if greater than or equal to 60 years old. Their results also suggest further evaluation of aldosterone antagonists is warranted as another possible risk factor.
Dr. Loren Laine is professor of medicine, department of internal medicine, Yale University, New Haven, Conn. He is on the Data Safety Monitoring Boards of Eisai, BMS, and Bayer; and is a consultant for AstraZeneca.
Gastrointestinal toxicity is the major issue limiting nonsteroidal anti-inflammatory use. The excess annual risk of upper gastrointestinal bleeding per 1,000 patients is about 1 with low-dose aspirin, about 2 with coxibs, and about 4-6 with traditional NSAIDs (ibuprofen, naproxen). However, the risk of upper gastrointestinal bleeding increases markedly with several factors, including the use of concomitant medications.
Ideally, large randomized trials comparing NSAIDs with and without a concomitant medication would inform our assessment of risk. However, few such trials are available, so we commonly rely on observational database studies, such as that of Masclee et al. These studies have the important benefit of large sample size and "real world" results, but also have potential limitations, including reliability of data (for example, accuracy of diagnostic coding) and potential bias because of unequal distribution of confounding factors between cases and controls.
Masclee et al. report significant synergy (more than additive risk) of traditional NSAIDs with corticosteroids, SSRIs, aldosterone antagonists, and antithrombotic agents other than low-dose aspirin (although risk was increased with traditional NSAIDs plus low-dose aspirin). Low-dose aspirin was synergistic with antithrombotic agents and corticosteroids, while coxibs were synergistic with low-dose aspirin and SSRIs.
The results of Masclee et al. support current North American guidelines, which suggest use of proton pump inhibitors or misoprostol for traditional NSAID users taking concomitant medications such as antithrombotics, corticosteroids, or SSRIs, and use of PPIs for low-dose-aspirin users taking antithrombotics or taking corticosteroids if greater than or equal to 60 years old. Their results also suggest further evaluation of aldosterone antagonists is warranted as another possible risk factor.
Dr. Loren Laine is professor of medicine, department of internal medicine, Yale University, New Haven, Conn. He is on the Data Safety Monitoring Boards of Eisai, BMS, and Bayer; and is a consultant for AstraZeneca.
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.
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.
FROM GASTROENTEROLOGY
Key clinical point: Excess risk of upper gastrointestinal bleeding occurred with combinations of NSAIDs and selective serotonin reuptake inhibitors, and with combinations of nonselective NSAIDs or low-dose aspirin with corticosteroids, aldosterone antagonists, or anticoagulants.
Major finding: Excess risks from combining SSRIs with nonselective NSAIDs, COX-2 inhibitors, or low-dose aspirin were 1.62 (95% CI, 0.58-2.66), 1.86 (95% CI, 0.28- 3.44), and 0.49 (95% CI, –0.05-1.03), respectively.
Data source: Case series analysis of 114,835 patients with upper gastrointestinal bleeding. Patients were identified from seven electronic health record databases from the Netherlands, Italy, and Denmark, and cases served as their own controls.
Disclosures: 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.
