Risk of Major Adverse Cardiovascular Events Associated with Concomitant Use of Antidepressants and Non-steroidal Anti-inflammatory Drugs: A Retrospective Cohort Study

Background: Both antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to affect platelet aggregation, blood pressure and heart rate. Despite the high prevalence of the combined use of antidepressants and NSAIDs, there is limited evidence on the potential risk of major adverse cardiovascular events (MACE) associated with their use. Objective: The objective of this study was to assess the association between concomitant antidepressant and NSAID use and MACE. Methods: We conducted a retrospective cohort study using South Korea's nationwide healthcare database. The study cohort was defined as those with new prescriptions for antidepressants and NSAIDs between 2004 and 2015. Exposure was assessed as time varying into four discrete periods: non-use, antidepressant use, NSAID use and concomitant use. Our primary outcome was MACE, a composite of haemorrhagic and thromboembolic events; secondary outcomes were the individual events of MACE. A multivariable Cox proportional hazards model was used to estimate hazards ratios with 95% confidence intervals. We also performed subgroup analyses by class of antidepressant/type of NSAIDs, age and sex. Results: From 240,982 patients, 235,080, 4393 and 1509 patients were users of NSAIDs, antidepressants or both drugs at cohort entry, respectively. The cohort generated 2.1 million person-years of follow-up with 22,453 events of MACE (incidence rate 1.07 per 100 person-years). Compared with non-use, concomitant use (hazard ratio 1.13, 95% confidence interval 1.01-1.26) and NSAID-only use (1.05, 1.001-1.10) were positively associated with MACE, while antidepressant-only use showed a negative association (0.91, 0.83-0.99). Concomitant use increased the individual risk of haemorrhagic stroke (1.46, 1.06-2.00), ischaemic stroke (1.22, 1.07-1.38) and heart failure (1.19, 1.02-1.38), but showed a protective effect on cardiovascular deaths (0.36, 0.21-0.62). Of the six possible combinations of antidepressants and NSAIDs by their classes, only concomitant use of tricyclic antidepressants and non-selective NSAIDs was positively associated with MACE (1.26, 1.09-1.47). The risk of MACE remained elevated with concomitant use among those aged ≥ 45 years (1.14, 1.01-1.29) and male patients (1.19, 1.01-1.42). Conclusions: Concomitant use of antidepressants and NSAIDs moderately elevated the risk of MACE, of which the observed risk appears to be driven by the concomitant use of tricyclic antidepressants and non-selective NSAIDs. Thus, healthcare providers should take precaution when co-prescribing these drugs, weighing the potential benefits and risks associated with their use.restrictio