Insights from Pharmacovigilance and Pharmacodynamics on Cardiovascular Safety Signals of NSAIDs

Overview

Journal Front Pharmacol

Date 2024 Sep 19

PMID 39295938

Authors

Shuang Liang

Xianying Wang

Xiuqing Zhu

Affiliations

Soon will be listed here.

Abstract

Background And Aim: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat fever, pain, and inflammation. Concerns regarding their cardiovascular safety have been raised. However, the underlying mechanism behind these events remains unknown. We aim to investigate the cardiovascular safety signals and receptor mechanisms of NSAIDs, employing a comprehensive approach that integrates pharmacovigilance and pharmacodynamics.

Methods: This study utilized a pharmacovigilance-pharmacodynamic approach to evaluate the cardiovascular safety of NSAIDs and explore potential receptor mechanisms involved. Data were analyzed using the OpenVigil 2.1 web application, which grants access to the FDA Adverse Event Reporting System (FAERS) database, in conjunction with the BindingDB database, which provides target information on the pharmacodynamic properties of NSAIDs. Disproportionality analysis employing the Empirical Bayes Geometric Mean (EBGM) and Reporting Odds Ratio (ROR) methods was conducted to identify signals for reporting cardiovascular-related adverse drug events (ADEs) associated with 13 NSAIDs. This analysis encompassed three System Organ Classes (SOCs) associated with the cardiovascular system: blood and lymphatic system disorders, cardiac disorders, and vascular disorders. The primary targets were identified through the receptor-NSAID interaction network. Ordinary least squares (OLS) regression models explored the relationship between pharmacovigilance signals and receptor occupancy rate.

Results: A total of 201,231 reports of cardiovascular-related ADEs were identified among the 13 NSAIDs. Dizziness, anemia, and hypertension were the most frequently reported Preferred Terms (PTs). Overall, nimesulide and parecoxib exhibited the strongest signal strengths of ADEs at SOC levels related to the cardiovascular system. On the other hand, our data presented naproxen and diclofenac as drugs of comparatively low signal strength. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were identified as central targets. OLS regression analysis revealed that the normalized occupancy rate for either COX-1 or COX-2 was significantly inversely correlated with the log-transformed signal measures for blood and lymphatic system disorders and vascular disorders, and positively correlated with cardiac disorders and vascular disorders, respectively. This suggests that higher COX-2 receptor occupancy is associated with an increased cardiovascular risk from NSAIDs.

Conclusion: Cardiovascular safety of NSAIDs may depend on pharmacodynamic properties, specifically, the percentage of the occupied cyclooxygenase isoenzymes. More studies are needed to explore these relations and improve the prescription process.

References

Stiller C, Hjemdahl P . Lessons from 20 years with COX-2 inhibitors: Importance of dose-response considerations and fair play in comparative trials. J Intern Med. 2022; 292(4):557-574. DOI: 10.1111/joim.13505. View

Schjerning A, McGettigan P, Gislason G . Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol. 2020; 17(9):574-584. DOI: 10.1038/s41569-020-0366-z. View

Marsico F, Paolillo S, Filardi P . NSAIDs and cardiovascular risk. J Cardiovasc Med (Hagerstown). 2016; :e40-e43. DOI: 10.2459/JCM.0000000000000443. View

Hazell L, Shakir S . Under-reporting of adverse drug reactions : a systematic review. Drug Saf. 2006; 29(5):385-96. DOI: 10.2165/00002018-200629050-00003. View

Sakaeda T, Tamon A, Kadoyama K, Okuno Y . Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013; 10(7):796-803. PMC: 3689877. DOI: 10.7150/ijms.6048. View

Bonnesen K, Schmidt M . Recategorization of Non-Aspirin Nonsteroidal Anti-inflammatory Drugs According to Clinical Relevance: Abandoning the Traditional NSAID Terminology. Can J Cardiol. 2021; 37(11):1705-1707. DOI: 10.1016/j.cjca.2021.06.014. View

Kohli P, Steg P, Cannon C, Smith Jr S, Eagle K, Ohman E . NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease. Am J Med. 2013; 127(1):53-60.e1. DOI: 10.1016/j.amjmed.2013.08.017. View

Khan S, Andrews K, Chin-Dusting J . Cyclo-Oxygenase (COX) Inhibitors and Cardiovascular Risk: Are Non-Steroidal Anti-Inflammatory Drugs Really Anti-Inflammatory?. Int J Mol Sci. 2019; 20(17). PMC: 6747368. DOI: 10.3390/ijms20174262. View

Reynolds G, McGowan O . Mechanisms underlying metabolic disturbances associated with psychosis and antipsychotic drug treatment. J Psychopharmacol. 2017; 31(11):1430-1436. DOI: 10.1177/0269881117722987. View

10.

Montastruc F, Palmaro A, Bagheri H, Schmitt L, Montastruc J, Lapeyre-Mestre M . Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase. Eur Neuropsychopharmacol. 2015; 25(10):1556-65. DOI: 10.1016/j.euroneuro.2015.07.010. View

11.

Lindhardsen J, Gislason G, Jacobsen S, Ahlehoff O, Olsen A, Madsen O . Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2013; 73(8):1515-1521. DOI: 10.1136/annrheumdis-2012-203137. View

12.

Braun J, Baraliakos X, Westhoff T . Nonsteroidal anti-inflammatory drugs and cardiovascular risk - a matter of indication. Semin Arthritis Rheum. 2019; 50(2):285-288. DOI: 10.1016/j.semarthrit.2019.07.012. View

13.

Chen Y, Fan Q, Liu Y, Shi Y, Luo H . Cardiovascular toxicity induced by SSRIs: Analysis of spontaneous reports submitted to FAERS. Psychiatry Res. 2023; 326:115300. DOI: 10.1016/j.psychres.2023.115300. View

14.

Minhas D, Nidhaan A, Husni M . Recommendations for the Use of Nonsteroidal Anti-inflammatory Drugs and Cardiovascular Disease Risk: Decades Later, Any New Lessons Learned?. Rheum Dis Clin North Am. 2022; 49(1):179-191. DOI: 10.1016/j.rdc.2022.08.006. View

15.

Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E . Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017; 357:j1909. PMC: 5423546. DOI: 10.1136/bmj.j1909. View

16.

Bech-Drewes A, Bonnesen K, Hauge E, Schmidt M . Cardiovascular safety of using non-steroidal anti-inflammatory drugs for gout: a Danish nationwide case-crossover study. Rheumatol Int. 2024; 44(6):1061-1069. PMC: 11108875. DOI: 10.1007/s00296-024-05584-7. View

17.

Soslau G . Cardiovascular serotonergic system: Evolution, receptors, transporter, and function. J Exp Zool A Ecol Integr Physiol. 2021; 337(2):115-127. DOI: 10.1002/jez.2554. View

18.

Jiao X, Pu L, Lan S, Li H, Zeng L, Wang H . Adverse drug reaction signal detection methods in spontaneous reporting system: A systematic review. Pharmacoepidemiol Drug Saf. 2024; 33(3):e5768. DOI: 10.1002/pds.5768. View

19.

Cepaityte D, Siafis S, Egberts T, Leucht S, Kouvelas D, Papazisis G . Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study. Schizophr Bull. 2020; 47(3):672-681. PMC: 8084433. DOI: 10.1093/schbul/sbaa163. View

20.

Wu K, Na K, Chen D, Wang Y, Pan H, Wang X . Effects of non-steroidal anti-inflammatory drug-activated gene-1 on Ganoderma lucidum polysaccharides-induced apoptosis of human prostate cancer PC-3 cells. Int J Oncol. 2018; 53(6):2356-2368. PMC: 6203158. DOI: 10.3892/ijo.2018.4578. View