Post Marketing Safety Data Analysis Reveals Increased Propensity for Severe Cardiovascular and Cerebrovascular Side Effects in Patients Taking Celecoxib Compared to Other NSAIDs Aarti Patel, PharmD Candidate, Tigran Makunts, PharmD, Ruben Abagyan, Ph.D. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA ABSTRACT RESULTS

Non-steroidal anti-inflammatory medications, NSAIDS, are commonly used Cardiovascular ADR Report Frequencies Cardiovascular ADR Report Frequencies Odds ratios of cardiovascular ADR worldwide for their analgesic and anti-inflammatory properties, and are deemed out of 100,202 NSAID Reports Among Male and Female Celecoxib Users among Celecoxib male users when safe for over the counter access. NSAIDS as a class have been associated with Myocardial Infarction 4.79 compared to female users cardiovascular, CV, cerebrovascular, CVA, and hypertension, side effects, with Cerebrovascular Accident 3.66 Cerebrovascular 9.69 Accident 11.23 rofecoxib being removed from the market due to these toxicities. However, the Chest Pain 0.85 Cerebrovascular Accident 1.18 risks of heart attack and stroke were deemed similar in all currently marketed Hypertension 0.73 Palpitations 0.49 1.77 NSAIDs. The growing concern over the potentially fatal CV and CVA warranted ADR Hypertension Hypertension 1.16 Hypotension 0.46 ADR 2.05 FEMALES further studies to quantify the associations these side effects. Here, we ADR Atrial Fibrillation MALES analyzed over twelve million reports in the FDA Adverse Event Reporting 0.29 Congestive Heart Failure 0.28 12.16 System, FAERS, to evaluate the reporting odds ratios of hypertension, Myocardial Infarction Myocardial Infarction 2.42 Tachycardia 0.25 myocardial infarction, and stroke in patients taking individual NSAIDs and 25.11 0 1 2 3 4 5 acetaminophen as monotherapy. We found that the risk of CV and CVA ADRs 0 0.5 1 1.5 2 2.5 3 FREQUENCY (%) 0 5 10 15 20 25 30 ROR was 10-200 fold higher for celecoxib, when compared to ibuprofen, naproxen, FREQUENCY (%) meloxicam, ketoprofen, diclofenac and acetaminophen. Additionally, male Fig. 1. Top Cardiovascular ADRs in patients taking NSAIDs for pain Fig. 3. Celecoxib ADRs among male and female users. a) Frequencies of CVA, HTN, and MI patients taking celecoxib were at a nearly two-fold higher risk of myocardial were calculated between male and female Celecoxib users. b) Odds ratios were performed among infarction. Odds ratios of myocardial infarction reports of male users when compared to females for the three ADRs. Celecoxib when compared to other NSAIDs Fig. 2. Odds ratios of Celecoxib vs Acetaminophen 34.22 BACKGROUND AND PURPOSE cardiovascular ADRs. Odds CONCLUSIONS ratios were calculated by Celecoxib vs Ketorolac 11.53 comparing MI, HTN, and stroke Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely Overall, our results revealed that NSAIDs had a significantly higher risk of Celecoxib vs Diclofenac 22.36 ADRs of Celecoxib to other prescribed drugs worldwide. They are used by over thirty million people daily NSAID pain medications. cardiovascular adverse effects when compared to non-NSAID pain 1 Celecoxib vs Naproxen 28.726 medications. Out of these NSAID medications, Celecoxib exhibited the highest seeking their anti-inflammatory and pain relieving properties . They work by NSAIDs rates of MI, HTN, and CVA adverse effects. In addition, male Celecoxib users selectively inhibiting the cyclooxygenase (COX) enzymes, of which there are Celecoxib vs Ibuprofen 198.58 two isoforms. COX-1 plays a protective role and is present in many tissues, had a higher risk of all three of these adverse effects when compared to female maintaining platelet activity, kidney functions, and protection of stomach Celecoxib vs Meloxicam 10.28 users, the highest being myocardial infarction. The FDA has released and 3 mucosa . On the other hand, COX-2 is present at sites of inflammation. In 1 10 100 1000 changed the Celecoxib label slightly over the past few years after adding a recent years, NSAIDs have come into the light due to their serious, life- ROR BBW 2007, a black box warning was added to the label to warn consumers threatening adverse effects, particularly the negative cardiovascular effects. about the potential cardiovascular risks associated with Celecoxib use while Odds ratios of hypertension reports of Celecoxib stating that “all NSAIDs may have a similar risk.” However, in 2016, the black Randomized clinical trials were performed and found an increased risk of when compared to other NSAIDs stroke, MI, and HTN associated with particularly celecoxib use. This promoted box warning was slightly altered, reporting that “based on available data, it is the FDA to include a black box warning in 2007. To date, the relationship Celecoxib vs Acetaminophen 1.1352 unclear that the risk for CV thrombotic events is similar for all NSAIDs. Our between NSAID and non-NSAID use and its effects on heart attack, stroke, and study has demonstrated that the CV risk for all NSAID pain medications is not Celecoxib vs Ketorolac 1.436 hypertension remains largely unclear and warrants further research. The similar and that Celecoxib has a significantly higher risk when compared to the previous studies showed conflicting evidence, which warrants further studies of Celecoxib vs Diclofenac 1.8887 other more commonly prescribed NSAIDs. Finally, this study aimed to provide post marketing ADR reports. It was necessary to expand on the evidence and more clarity to the FDA drug label put forth on Celecoxib and its potentially life- Celecoxib vs Naproxen 2.2552 introduce clarity on potentially fatal ADRs of these commonly used medications. NSAIDs threatening adverse effects. It highlights the necessity of exercising caution In this study, we analyzed 120,707 FAERS database reports to analyze the Celecoxib vs Ibuprofen 2.69 while prescribing this medication and also urges consumers to use Celecoxib relationship between NSAID use and cardiovascular adverse effects, namely for the shortest duration possible, or perhaps even use other NSAIDs which Celecoxib vs Meloxicam 1.5442 hypertension (HTN), cerebrovascular accident (CVA), and myocardial infarction have been well studied and have fewer known adverse effects. (MI). 0 0.5 1 1.5 2 2.5 3 3.5 ROR REFERENCES Odds ratios of cerebrovascular accident reports METHODS 1. Wongrakpanich, S., Wongrakpanich, A., Melhado, K. & Rangaswami, J. A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging and Disease of Celecoxib when compared to other NSAIDs 9,143–150 (2018). 2. Gaikwad, N., Vaishnavi, P. R. & Dhaneria, S. Assessment of nonsteroidal anti-inflammatory drug use pattern using world health organization indicators: A cross-sectional study in a tertiary care teaching hospital of Chhattisgarh. Indian Journal of Pharmacology 49,445–450 (2017). In this study, 102,702 reports were selected. Patients 18 years of age and older 3. Bavry, A. & Park, K. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vascular Health and Risk Management 25-30 (2014). doi:10.2147/vhrm.s54159 Celecoxib vs Acetaminophen 60.7177 4. Varga Z, Sabzwari SRA, Vargova V. Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue. Cureus. August 2017. doi:10.7759/cureus.1144. taking the following NSAIDs, ibuprofen, meloxicam, celecoxib, diclofenac, ketorolac, 5. Fries, S. The Cardiovascular Pharmacology of COX-2 Inhibition. Hematology 2005,445–451 (2005). Celecoxib vs Ketorolac 27.69 6. Whelton, A., White, W. B., Bello, A. E., Puma, J. A. & Fort, J. G. 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The NSAID group contained 100,202 reports and the non-NSAID group Expert Opinion on Drug Safety Celecoxib vs Naproxen 12.59 reports from Australia, Canada and the USA. 18,153–161 (2019). contained 20,700 reports. CV and CVA adverse drug events frequencies were NSAIDs calculated: celecoxib n=20,614, meloxicam n=1753, ibuprofen n=27,037, naproxen Celecoxib vs Ibuprofen 214.727 n=34,644, diclofenac n=14,866, ketorolac n=1288, and acetaminophen n=20,700. ACKNOWLEDGEMENTS Frequencies of MI, HTN, and CVA were reported for NSAIDs and compared to non- Celecoxib vs Meloxicam 21.7685 This work was supported by a Skaggs Scholarship from the UC San Diego NSAID pain medications (Fig. 1). We also analyzed male and female reports of CV 1 10 100 1000 Skaggs School of Pharmacy and Pharmaceutical Sciences adverse events among Celecoxib users (Fig. 3). ROR