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

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

doi:10.1186/s12916-021-02180-5

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

BMC Med. 2021 Dec 3;19(1):316. doi: 10.1186/s12916-021-02180-5.

Authors

Man Yang^#^{1

2

3}, Qiangsheng He^#^{4

5}, Fang Gao⁶, Krish Nirantharakumar⁷, Tonny Veenith⁶, Xiwen Qin^{8

9}, Amy T Page⁸, Martin C S Wong¹⁰, Junjie Huang¹⁰, Zi Chong Kuo², Bin Xia^{4

5}, Changhua Zhang^{2

5}, Yulong He^{2

4}, Wenbo Meng^{11

12}, Jinqiu Yuan^{13

14

15}, Yihang Pan¹⁶

Affiliations

¹ The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, China.
² Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
³ Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
⁴ Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
⁵ Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
⁶ Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
⁷ Institute of Applied Health Research, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK.
⁸ Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Science, Monash University, Melbourne, Australia.
⁹ School of Population and Global Health, Faculty of Medicine, Density and Health Sciences, University of Western Australia, Perth, Australia.
¹⁰ Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong.
¹¹ The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, China. mengwb@lzu.edu.cn.
¹² Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China. mengwb@lzu.edu.cn.
¹³ Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. yuanjq5@mail.sysu.edu.cn.
¹⁴ Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. yuanjq5@mail.sysu.edu.cn.
¹⁵ Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. yuanjq5@mail.sysu.edu.cn.
¹⁶ Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. panyih@mail.sysu.edu.cn.

^# Contributed equally.

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.

Keywords: Proton pump inhibitor, Stroke, Cohort, Meta-analysis, Randomized control trial.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Humans
Proton Pump Inhibitors* / adverse effects
Randomized Controlled Trials as Topic
Risk Factors
Stroke* / chemically induced
Stroke* / epidemiology

Substances

Proton Pump Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding