Inappropriate use of proton pump inhibitors increases cardiovascular events in patients with coronary artery disease

Juan Riofrío Forero; Edison Haro Freile; Esteban Maggi Arteaga; Juan García Cordova; Gloria Loor Romero; Paula Vásconez Molina; Marilyn Leon Cadena

doi:10.18203/2320-6012.ijrms20252440

Authors

Juan Riofrío Forero UDLA University, Quito, Ecuador
Edison Haro Freile USFQ University, Quito, Ecuador
Esteban Maggi Arteaga UDLA University, Quito, Ecuador
Juan García Cordova UDLA University, Quito, Ecuador
Gloria Loor Romero PUCE University, Quito, Ecuador
Paula Vásconez Molina UIDE University, Quito, Ecuador
Marilyn Leon Cadena ESPOCH University, Quito, Ecuador

DOI:

https://doi.org/10.18203/2320-6012.ijrms20252440

Keywords:

Antiplatelet agents, Cardiovascular events, Lower gastrointestinal bleeding, Proton pump inhibitors, Vascular endothelial function

Abstract

Various antiplatelet drugs are currently a cornerstone of treatment for various coronary artery diseases. They help control disease progression, but they can also increase the risk of gastrointestinal bleeding. Various clinical practice guidelines recommend the use of proton pump inhibitors (PPIs) to reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. However, in people at low risk of gastrointestinal bleeding, the harms associated with routine PPI use may far outweigh the benefits. PPIs increase the risk of gastrointestinal bleeding, inhibit the effect of antiplatelet agents, impair vascular endothelial function and induce hypomagnesemia, iron deficiency and vitamin D and K deficiencies. Furthermore, PPIs can increase cardiovascular events. This review elucidates the mechanisms by which PPIs increase cardiovascular events, reminding physicians of the importance of prescribing them rationally.

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References

Passacquale G, Sharma P, Perera D, Ferro A. Antiplatelet therapy in cardiovascular disease: current status and future directions. Brit J Clin Pharmacol. 2022;88(6):2686–99. DOI: https://doi.org/10.1111/bcp.15221

Levine GN, Bates ER, Bittl JA. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2016;68(10):1082–115. DOI: https://doi.org/10.1016/j.jacc.2016.03.513

Chen WC, Lin KH, Huang YT. The risk of lower gastrointestinal bleeding in low-dose aspirin users. Aliment Pharmacol Ther. 2017;45 (12):1542–50. DOI: https://doi.org/10.1111/apt.14079

Guo CG, Zhang F, Wu JT. Divergent trends of hospitalizations for upper and lower gastrointestinal bleeding based on population prescriptions of aspirin, proton pump inhibitors and Helicobacter pylori eradication therapy: trends of upper and lower gastrointestinal bleeding. United European Gastroenterol J. 2021;9(5):543–51. DOI: https://doi.org/10.1002/ueg2.12067

Shi W, Ni L, Yang J. The clinical impact of proton pump inhibitors when co-administered with dual antiplatelet therapy in patients having acute myocardial infarction with low risk of gastrointestinal bleeding: insights from the china acute myocardial infarction registry. Front Cardiovasc Med. 2021;8:685072. DOI: https://doi.org/10.3389/fcvm.2021.685072

Maret-Ouda J, Santoni G, Xie S, Rosengren A, Lagergren J. Proton pump inhibitor and clopidogrel use after percutaneous coronary intervention and risk of major cardiovascular events. Cardiovasc Drugs Ther. 2021;36:1121–8. DOI: https://doi.org/10.1007/s10557-021-07219-6

Ono M, Onuma Y, Kawashima H. Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention: insights from the GLOBAL LEADERS trial. Catheter Cardiovasc Interv. 2022;100(1):72–82. DOI: https://doi.org/10.1002/ccd.30217

Yang HG, Kim DK. Concomitant Use of Antiplatelet Agents and Proton-Pump Inhibitors Increases the Risk of Adverse Cardiovascular Events: A Nationwide Population-Based Cohort Study Using Balanced Operational Definitions. J Cardiovasc Dev Dis. 2023;10(6):78. DOI: https://doi.org/10.3390/jcdd10060264

Padhi BK, Khatib MN, Zahiruddin QS, Rustagi S, Sharma RK, Sah R, et al. Adverse cardiovascular outcomes associated with proton pump inhibitor use after percutaneous coronary intervention: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2024;24(1):76. DOI: https://doi.org/10.1186/s12872-024-04029-0

Smith CA, Ebrahimpour A, Novikova L, Farina D, Bailey AO, Russell WK, et al. Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors. Biochim Biophys Acta-Gen Subj. 2022;1866(8):130149. DOI: https://doi.org/10.1016/j.bbagen.2022.130149

Duarte GJ, Lopez J, Sosa F, Molina G, Shaban M, Mark J, et al. Proton pump inhibitors and cardiovascular risk: a critical review. Future Cardiol. 2024;20(14):779–94. DOI: https://doi.org/10.1080/14796678.2024.2412910

Manolis AA, Manolis TA, Melita H, Katsiki N, Manolis AS. Proton pump inhibitors and cardiovascular adverse effects: Real or surreal worries. Eur J Intern Med. 2020;7:15–26. DOI: https://doi.org/10.1016/j.ejim.2019.11.017

Dalal J, Desai S, Pebbilli KK. Cardiac Safety of Proton Pump Inhibitors when Used with Antiplatelet Agents. 2024;5(4):344–9. DOI: https://doi.org/10.1177/26324636241287665

Bruno G, Zaccari P, Rocco G, Scalese G, Panetta C, Porowska B, et al. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol. 2019;14;25(22):2706–19. DOI: https://doi.org/10.3748/wjg.v25.i22.2706

Kiecka A, Szczepanik M. Proton pump inhibitor-induced gut dysbiosis and immunomodulation: current knowledge and potential restoration by probiotics. Pharmacol Rep. 2023;75(4):791–804. DOI: https://doi.org/10.1007/s43440-023-00489-x

Weitsman S, Celly S, Leite G, Mathur R, Sedighi R, Barlow GM, et al. Effects of Proton Pump Inhibitors on the Small Bowel and Stool Microbiomes. Dig Dis Sci. 2022;67(1):224–32. DOI: https://doi.org/10.1007/s10620-021-06857-y

Wallace JL, Syer S, Denou E, De Palma G, Vong L, McKnight W, et al. Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis. Gastroenterology. 2011;141(4):1314-22. DOI: https://doi.org/10.1053/j.gastro.2011.06.075

Gwee KA, Goh V, Lima G, Setia S. Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits. J Pain Res. 2018;11:361–74. DOI: https://doi.org/10.2147/JPR.S156938

Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15(3):679. DOI: https://doi.org/10.1186/ar4175

Wang X, Tang Q, Hou H, Zhang W, Li M, Chen D, et al. Gut Microbiota in NSAID Enteropathy: New Insights From Inside. Front Cell Infect Microbiol. 2021;6;11:679396. DOI: https://doi.org/10.3389/fcimb.2021.679396

Wu W, Liu J, Yu H, Jiang Z. Antiplatelet therapy with or without PPIs for the secondary prevention of cardiovascular diseases in patients at high risk of upper gastrointestinal bleeding: A systematic review and meta-analysis. Exp Ther Med. 2020;19(6):3595. DOI: https://doi.org/10.3892/etm.2020.8657

Jung YS, Park JH, Park CH. Impact of proton pump inhibitors on the risk of small bowel or colorectal bleeding: A systematic review and meta‐analysis. United European Gastroenterol J. 2023;11(9):861. DOI: https://doi.org/10.1002/ueg2.12448

Khan MY, Siddiqui WJ, Alvarez C, Aggarwal S, Hasni SF, Ahmad A, et al. Reduction in postpercutaneous coronary intervention angina in addition to gastrointestinal events in patients on combined proton pump inhibitors and dual antiplatelet therapy: A systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018;30(8):847–53. DOI: https://doi.org/10.1097/MEG.0000000000001125

Barkun AN, Almadi M, Kuipers EJ, Laine L, Sung J, Tse F, et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the international consensus group. Ann Intern Med. 2019;171(11):805. DOI: https://doi.org/10.7326/M19-1795

Triantafyllou K, Gkolfakis P, Gralnek IM, Oakland K, Manes G, Radaelli F, et al. Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2021;53(8):850–68. DOI: https://doi.org/10.1055/a-1496-8969

Sengupta N, Feuerstein JD, Jairath V, Shergill AK, Strate LL, Wong RJ, et al. Management of Patients With Acute Lower Gastrointestinal Bleeding: An Updated ACG Guideline. American J Gastroenterol. 2023;118(2):208–31. DOI: https://doi.org/10.14309/ajg.0000000000002130

Oakland K, Desborough MJ, Murphy MF, Schachter M, Jairath V. Rebleeding and mortality after lower gastrointestinal bleeding in patients taking antiplatelets or anticoagulants. Clin Gastroenterol Hepatol. 2019;17(7):1276-1284. DOI: https://doi.org/10.1016/j.cgh.2017.12.032

Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Therapeutic Advan Drug Safety. 2013;4(3):76. DOI: https://doi.org/10.1177/2042098613482484

Lisanne MM. Mechanisms of proton pump inhibitor‐induced hypomagnesemia. Acta Physiologica. 2022;5(4):987

Losurdo G. Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study. J Clin Med. 2023;12(8):98. DOI: https://doi.org/10.3390/jcm12082910

Vinke P. The Use of Proton Pump Inhibitors May Increase Symptoms of Muscle Function Loss in Patients with Chronic Illnesses. International J Mol Sci. 2020;21(1):98. DOI: https://doi.org/10.3390/ijms21010323

Wen Hu 1 YL2XY. Inappropriate use of proton pump inhibitors increases cardiovascular events in patients with coronary heart disease. Int J Gen Med. 2022;15:86. DOI: https://doi.org/10.2147/IJGM.S392767