Proton pump inhibitors – do we know them well and are they really that safe? – part 1

Czech version

Authors: Bultas J.
Authors‘ workplace: Ústav farmakologie, 3. LF UK Praha
Published in: Gastroent Hepatol 2020; 74(5): 431-441
Category:

Overview

Proton pump inhibitors (PPIs) are one of the most commonly used drug groups. More than 10% of patients being chronically treated in the adult population. Often patients with a high risk of vascular or renal impairment. In addition to the unquestionable effect in the treatment and in the prophylaxis of gastroduodenal diseases, PPIs have been promoted in combination with antithrombotic therapy in order to reduce bleeding in the gastrointestinal tract. In both of these indications, this is a chronic treatment, often for several years. Drug regulatory agencies (EMAs or FDA) warn against chronic PPIs use, warning of a number of serious side effects. However, chronic administration of PPIs is a common practice. It is therefore time to evaluate the benefit and risk of this important drug group. First of all, it should be noted that PPIs operate not only at the level of the classical gastric proton pump (H⁺/K⁺ ATPase), but also block the activity of the sister vacuolar proton pump (V-H⁺-ATPase) in a number of other organs or organelles, namely lysosomes of all somatic cells. Similarly, PPIs block the activity of a number of transporters and metabolic enzymes. Action at this level is likely to surprise the gastroenterologist. There is no doubt about the benefits of PPIs in the indication of treatment and prevention of ulcerative or reflux disease. However, what are the evidence to reduce the risk of gastriontestinal bleeding in antithrombotic treatment? In this area we have data at the level of observational studies, the decrease in the risk of bleeding by about a third is significant. However, with a relatively low incidence of bleeding in the gastrointestinal tract, the absolute decrease in risk is small, hovering at 0.3%. The observed number need to treat is around 250, i.e. for every 250 PPIs treated, we will prevent one bleeding (usually not critical). On the other hand, there are increasingly work that finds a higher incidence of cardiovascular events, renal failure, bronchial asthma and nervous disabilities in chronic PPIs treatment. In a population at high cardiovascular risk, i.e. in a typical population where we add antithrombotic treatment to PPIs, the risk is significant. The number need to harm value is around 50. Thus, in the chronic use of PPIs, the risk outweighs the benefit.

Keywords:

proton pump inhibitors – H2 receptor blockers – adverse events – atherothrombotic diseases – renal failure – overview

Sources

1. Spugnini EP, Citro G, Fais S. Proton pump inhibitors as anti vacuolar-ATPases drugs. J Exp Clin Cancer Res 2010; 29 (1): 44. doi: 10.1186/1756-9966-29-44.

2. Beyenbach KW, Wieczorek H, The V-type H⁺ ATPase: molecular structure and function, physiological roles and regulation. J Exp Biol 2006; 209 (Pt 4): 577–589. doi: 10.1242/jeb.02 014.

3. Whitton B, Okamoto H, Packham G et al. Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistence in cancer. Cancer Med 2018; 7 (8): 3800–3811. doi: 10.1002/cam4.1594.

4. Ariel H, Cooke JP. Cardiovascular risk of proton pump inhibitors. Methodist Debakey Cardiovasc J 2019; 15 (3): 214–219. doi: 10.14797/mdcj-15-3-214.

5. Duan X, Yang S, Zhang L et al. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics 2018; 8 (19): 5379–5399. doi: 10.7150/thno.28391.

6. Huijgen NA, de Ridder MAJ, Verhamme KM et al. Are proton-pump inhibitors harmful for the semen quality of men in couples who are planning pregnancy? Fertil Steril 2016; 106 (7): 1666–1672. doi: 10.1016/j.fertnstert. 2016.09.010.

7. Wright SH. Molecular and cellular physiology of organic cation transporter 2. Am J Physiol Renal Physiol 2019; 317 (6): F1669–F1679. doi: 10.1152/ajprenal.00422.2019.

8. Tommasi S, Elliot DJ, Hulin JA et al. Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance. Sci Rep 2017; 7 (1): 2871. doi: 10.1038/s41598-017-03069-1.

9. Kruszelnicka O, Swierszcz J, Bednarek J et al. Asymmetric dimethylarginine versus proton pump inhibitors usage in patients with stable coronary artery disease: a cross-sectional study. Int J Mol Sci 2016; 17 (4): 454. doi: 10.3390/ijms1704 0454.

10. Shin JM, Kim N, Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 2013; 19 (1): 25–35. doi: 10.5056/jnm.2013.19.1.25.

11. Hussaarts GAM, Marijn Veerman GD, Jansman FGA et al. Clinically relevant drug interactions with multikinase inhibitors: a review. Ther Adv Med Oncol 2019; 11: 1758835918818347. doi: 10.1177/1758835918818347.

12. Makunts T, Cohen IV, Awdishu L et al. Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis. Sci Rep 2019; 9 (1): 2282. doi: 10.1038/s41598-019-39335-7.

13. Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 2014; 37 (4): 201–211. doi: 10.1007/s40264-014-0144-0.

14. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver 2017; 11 (1): 27–37. doi: 10.5009/ gnl15502.

15. Zvyaga T, Chang SY, Chen C et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos 2012; 40 (9): 1698–1711. doi: 10.1124/dmd.112.045575.

16. Li L, Geraghty OC, Mehta Z et al. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017; 390 (10093): 490–499. doi: 10.1016/S0140-6736 (17) 30770-5.

17. Kuwayama T, Osanai H, Ajioka M et al. Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation. J Arrhythm 2017; 33 (6): 619–623. doi: 10.1016/j.joa.2017.07. 013.

18. Stangier J, Stähle H, Rathgen K et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47 (1): 47–59. doi: 10.2165/00003088-200 847010-00005.

19. Bolek T, Samoš M, Stančiaková L et al. The impact of proton pump inhibition on dabigatran levels in patients with atrial fibrillation. Am J Ther 2019; 26 (3): e308Apr 25. doi: 10.1097/MJT.0000000000000599.

20. Pradaxa 75 mg, SUMMARY OF PRODUCT CHARACTERISTICS [online]. Available from: https: //www.ema.europa.eu/documents/ product-information/pradaxa-epar-product-information_cs.pdf.

21. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139–1151.

22. Bultas J. Kyselina acetylsalicylová – stále neotřesitelné postavení i v roce 2018? Remedia 2018; 28: 127–136.

23. Bultas J, Karetová D. Enterosolventní forma kyseliny acetylsalicylové – ano, či ne? Remedia 2017; 27: 145–151.

24. Charlot M, Grove EL, Hansen PR et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ 2011; 342: d2690. doi: 10.1136/bmj.d2690.

25. Demcsak A, Lantos T, Balint ER et al. PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel – a systematic review and meta-analysis. Front Physiol 2018; 9: 1550. doi: 10.3389/fphys.2018.01550.

26. Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363 (20): 1909–1917. doi: 10.1056/NEJMoa1007964.

27. Moayyedi P, Eikelboom JW, Bosch J et al. Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology 2019; 157 (2): 403–412. doi: 10.1053/j.gastro.2019.04.041.

28. Melloni C, Washam JB, Jones WS et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: a systematic review. Circ Cardiovasc Qual Outcomes 2015; 8 (1): 47–55. doi: 10.1161/CIRCOUTCOMES.114.001177.

29. Khan SU, Lone AN, Asad ZU et al. Meta-analysis of efficacy and safety of proton pump inhibitors with dual antiplatelet therapy for coronary artery disease. Cardiovasc Revasc Med 2019; 20 (12): 1125–1133. doi: 10.1016/j.carrev.2019.02.002.