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BMC Medicine
Published in: BMC Medicine 1/2021

Open Access 01-12-2021 | Stroke | Research article

Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials

Authors: Man Yang, Qiangsheng He, Fang Gao, Krish Nirantharakumar, Tonny Veenith, Xiwen Qin, Amy T. Page, Martin C. S. Wong, Junjie Huang, Zi Chong Kuo, Bin Xia, Changhua Zhang, Yulong He, Wenbo Meng, Jinqiu Yuan, Yihang Pan

Published in: BMC Medicine | Issue 1/2021

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Abstract

Background

Although randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk.

Methods

This is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method).

Results

We documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively.

Conclusions

Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.
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Literature
1.
Targownik LE, Metge C, Roos L, Leung S. The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use. Am J Gastroenterol. 2007;102(5):942–50.PubMedCrossRef
2.
Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706–15.PubMedCrossRef
3.
Nehra AK, Alexander JA, Loftus CG, Nehra V. Proton Pump inhibitors: review of emerging concerns. Mayo Clin Proc. 2018;93(2):240–6.PubMedCrossRef
4.
Yuan J, Zhang C, Sparks JA, et al. Regular use of proton pump inhibitor and risk of rheumatoid arthritis in women: a prospective cohort study. Aliment Pharmacol Ther. 2020;52(3):449–58.PubMedPubMedCentralCrossRef
5.
Yuan J, He Q, Nguyen LH, et al. Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies. Gut. 2021;70(6):1070–7.PubMedCrossRef
6.
Heintjes EM, Bezemer ID, Prieto-Alhambra D, et al. Evaluating the effectiveness of an additional risk minimization measure to reduce the risk of prescribing mirabegron to patients with severe uncontrolled hypertension in four European countries. Clin Epidemiol. 2020;12.
7.
Indini A, Petrelli F, Tomasello G, et al. Impact of use of gastric-acid suppressants and oral anti-cancer agents on survival outcomes: a systematic review and meta-analysis. Cancers (Basel). 2020;12(4).
8.
Cheung KS, Chan EW, Wong AYS, et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018;67(1):28–35.PubMedCrossRef
9.
Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153(6):378–86.PubMedCrossRef
10.
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.PubMedPubMedCentralCrossRef
11.
Malhotra K, Katsanos AH, Bilal M, et al. Cerebrovascular outcomes with proton pump inhibitors and thienopyridines: a systematic review and meta-analysis. Stroke. 2018;49(2):312–8.PubMedCrossRef
12.
Sehested TSG, Gerds TA, Fosbol EL, et al. Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction. J Intern Med. 2018;283(3):268–81.PubMedCrossRef
13.
Wang YF, Chen YT, Luo JC, et al. Proton-pump inhibitor use and the risk of first-time ischemic stroke in the general population: a nationwide population-based study. Am J Gastroenterol. 2017;112(7):1084–93.PubMedCrossRef
14.
Nguyen LH, Lochhead P, Joshi AD et al: No significant association between proton pump inhibitor use and risk of stroke after adjustment for lifestyle factors and indication. Gastroenterology 2018, 154(5):1290-1297. e1291.
15.
Yi X, Zhou Q, Wang C, et al. Concomitant use of proton pump inhibitors and clopidogrel is not associated with adverse outcomes after ischemic stroke in Chinese population. J Stroke Cerebrovasc Dis. 2016;25(12):2859–67.PubMedCrossRef
16.
Leonard CE, Bilker WB, Brensinger CM, et al. Comparative risk of ischemic stroke among users of clopidogrel together with individual proton pump inhibitors. Stroke. 2015;46(3):722–31.PubMedPubMedCentralCrossRef
17.
Attwood SE, Ell C, Galmiche JP, et al. Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies. Aliment Pharmacol Ther. 2015;41(11):1162–74.PubMedCrossRef
18.
Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17.PubMedCrossRef
19.
Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682–691.e682.PubMedCrossRef
20.
21.
Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension. 2017;69(3):e2–9.PubMedCrossRef
22.
Bittner VA. The new 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019.
23.
Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779.PubMedPubMedCentralCrossRef
24.
UK Biobank. Available at: https://​www.​ukbiobank.​ac.​uk/​.​ Accessed at: 1 Jun. 2020.
25.
26.
27.
Dai C, Jiang M, Cao Q. Proton-Pump inhibitor use and the risk of ischaemic stroke. J Intern Med. 2018;283(3):330-330.CrossRef
28.
Prasad V, Jena AB. Prespecified falsification end points: can they validate true observational associations? JAMA. 2013;309(3):241–2.PubMedCrossRef
29.
30.
Xie Y, Bowe B, Yan Y, et al. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. Bmj. 2019;365:l1580.PubMedPubMedCentralCrossRef
31.
McGowan J, Sampson M, Salzwedel DM, et al. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol. 2016;75:40–6.PubMedCrossRef
32.
Higgins JP, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. 2nd ed. Chichester (UK): John Wiley & Sons; 2019.CrossRef
33.
Puhan MA, Schünemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. Bmj. 2014;349:g5630.PubMedCrossRef
34.
Scheiman JM, Devereaux PJ, Herlitz J, et al. Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON). Heart. 2011;97(10):797–802.PubMedCrossRef
35.
Stupnicki T, Dietrich K, González-Carro P, et al. Efficacy and Tolerability of Pantoprazole Compared with Misoprostol for the Prevention of NSAID-Related Gastrointestinal Lesions and Symptoms in Rheumatic Patients. Digestion. 2003;68(4):198–208.PubMedCrossRef
36.
Sugano K, Choi MG, Lin JT, et al. Multinational, double-blind, randomised, placebocontrolled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the lavender* study. Gut. 2014;63(7):1061–8.PubMedCrossRef
37.
Sugano K, Matsumoto Y, Itabashi T, et al. Lansoprazole for secondary prevention of gastric or duodenal ulcers associated with long-term low-dose aspirin therapy: results of a prospective, multicenter, double-blind, randomized, double-dummy, active-controlled trial. J Gastroenterol. 2011;46(6):724–35.PubMedPubMedCentralCrossRef
38.
Yeomans N, Lanas A, Labenz J, et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol. 2008;103(10):2465–73.PubMedCrossRef
39.
Hsu PI, Lai KH, Liu CP: Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology 2011, 140(3):791-798. e792.
40.
Malhotra K, Katsanos AH, Bilal M, et al. Is the use of proton pump inhibitors associated with increased risk of ischemic stroke: a systematic review and meta-analysis. Am J Gastroenterol. 2019;114(p):S250–1.
41.
Aihara H, Sato A, Takeyasu N, et al. Effect of individual proton pump inhibitors on cardiovascular events in patients treated with clopidogrel following coronary stenting: results from the Ibaraki Cardiac Assessment Study Registry. Catheter Cardiovasc Interv. 2012;80(4):556–63.PubMedCrossRef
42.
Sun S, Cui Z, Zhou M, et al. Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil. 2017;29(2):e12926.CrossRef
43.
Kwok CS, Jeevanantham V, Dawn B, Loke YK. No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: meta-analysis. Int J Cardiol. 2013;167(3):965–74.PubMedCrossRef
44.
45.
Ghebremariam YT, LePendu P, Lee JC, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128(8):845–53.PubMedCrossRef
46.
Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23_suppl_1):III-27–32.CrossRef
47.
Roquer J, Segura T, Serena J, Castillo J. Endothelial dysfunction, vascular disease and stroke: the ARTICO study. Cerebrovasc Dis. 2009;27(Suppl. 1):25–37.PubMedCrossRef
48.
Nishiyama Y, Ueda M, Katsura K-i, et al. Asymmetric dimethylarginine (ADMA) as a possible risk marker for ischemic stroke. J Neurol Sci. 2010;290(1-2):12–5.PubMedCrossRef
49.
Sibal L. C Agarwal S, D Home P, H Boger R: The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev. 2010;6(2):82–90.PubMedPubMedCentralCrossRef
50.
Montenegro MF, Lundberg JO. Letter by Montenegro and Lundberg regarding article,“Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine”. Circulation. 2014;129(13):e426-e426.CrossRef
51.
Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. Jama. 2013;310(22):2435–42.PubMedCrossRef
52.
Imperatore N, Tortora R, Testa A, et al. Proton pump inhibitors as risk factor for metabolic syndrome and hepatic steatosis in coeliac disease patients on gluten-free diet. J Gastroenterol. 2018;53(4):507–16.PubMedCrossRef
Metadata
Title
Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials
Authors
Man Yang
Qiangsheng He
Fang Gao
Krish Nirantharakumar
Tonny Veenith
Xiwen Qin
Amy T. Page
Martin C. S. Wong
Junjie Huang
Zi Chong Kuo
Bin Xia
Changhua Zhang
Yulong He
Wenbo Meng
Jinqiu Yuan
Yihang Pan
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-021-02180-5

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