Outcomes of Oral Anticoagulation with Concomitant NSAID Use: A Registry Based Cohort Study
Authors: Schaefer Jordan K , Errickson Josh , Kong Xiaowen , Ali Mona A , Chipalkatti Naina , Dorby Paul , Giuliano Christopher , Haymart Brian , Kaatz Scott , Kurlander Jacob E , Krol Gregory D , Shankar Sahana , Sood Suman L , Froehlich James , Barnes Geoffrey D. 
Published: December 2023

Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs), available without a prescription, are some of the most commonly used drugs in the United States. For patients on oral anticoagulation (OAC), concomitant NSAID use can increase the risk of bleeding. Patients are often advised to avoid this drug combination, or else consider adding a proton pump inhibitor (PPI) or H2 receptor antagonists (H2RA) for gastroprotection when both NSAIDs and OAC are used. However, there are limited data on how NSAID use impacts thrombotic and hemorrhagic outcomes. Available data may be biased due to selection bias, confounding, misclassification, and variable NSAID exposure. We sought to determine the frequency of NSAID use among patients on OAC, the impact on clinical outcomes, and if gastroprotection may mitigate bleeding risk. We hypothesized that NSAIDs would increase bleeding risk without impacting thrombotic risk. We did not anticipate gastroprotection would mitigate this risk.
Methods
We conducted a retrospective registry-based cohort study of adults starting a direct oral anticoagulant (DOAC) or warfarin therapy for the indications of venous thromboembolism and/or non-valvular atrial fibrillation between June 2011 and June 2023. As part of the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2), warfarin-treated patients were followed by six anticoagulation clinics, and four of the six clinics contributed data for patients on DOACs. Patients were excluded if they had a history of valvular AF, less than 3 months of follow-up, or on more than one antiplatelet drug. Two propensity matched cohorts (OAC alone vs. OAC+NSAID) of patients were analyzed based on NSAID use at the time of study enrollment, using a 4:1 matching ratio. Both prescribed and over the counter NSAIDs were included, potentially with the former being more frequently captured in the study registry. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression.
Results
Of 12,083 patients on OAC, 449 (3.7%) were on concomitant NSAIDs. After propensity matching, we compared 1,796 patients on OAC to 449 patients on OAC+NSAIDs. Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for an average of 30 months (standard deviation 34.2 months). For patients on OAC alone vs. OAC+NSAIDs, bleeding event rates were similar: 25.1 (95% confidence interval [CI] 23.7-26.6) versus 24.3 (95% CI 21.4-27.3) bleeds per 100 patient years ( P=0.56). Rates of non-major, major, life-threatening, central nervous system, and fatal bleeding were also similar. Furthermore, rates of thrombosis, emergency room visits, hospitalizations, transfusion, and death were similar. A pre-defined subgroup analysis comparing patients on OAC+NSAIDs with gastrointestinal prophylaxis (PPIs or H2RAs, N=179) to patients on OAC+NSAIDs without gastrointestinal prophylaxis (N=270) also showed similar rates of bleeding and healthcare utilization.
Conclusions
Nearly 4% of patients were taking NSAIDs with OAC and outcomes were similar to patients on OAC alone. Study limitations include NSAIDs and gastroprotection were only reliably known at time of enrollment. In addition, the potential for unmeasured or unadjusted confounding inherent to observational studies. Further research is needed to determine if there is a “safe” level of NSAID use for patients on OAC and to better define the role of gastrointestinal prophylaxis.