Comparative risk of incidence and clinical outcomes of COVID-19 among proton pump inhibitor and histamine-2 receptor antagonist short-term users: a nationwide retrospective cohort study
Jimyung Park, Seng Chan You, Jaehyeong Cho, Chan Hyuk Park, Woon Geon Shin, Rae Woong Park, Seung In Seo
BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00549-7
Background: This study aimed to evaluate incidence risk and adverse clinical outcomes in COVID-19 disease among short-term users of acid-suppressants in South Korea. Methods: This retrospective cohort study, conducted using a nationwide claims database for South Korea, used data from patients with COVID-19 tested between January 1 and May 15, 2020. Patients aged over 18 years and prescribed proton pump inhibitors (PPI) or histamine-2 receptor antagonist (H 2 RA) for more than 7 days were identified. Primary outcome was COVID-19 while secondary outcomes were all-cause mortality, hospitalization with respiratory disease, or intensive respiratory intervention. Large-scale propensity scores were used to match patients, while the Cox proportional hazard model was utilized to evaluate any association between exposure and outcome(s). The risk estimates were calibrated by using 123 negative control outcomes. Results: We identified 26,166 PPI users and 62,117 H 2 RA users. After propensity score matching, compared to H 2 RA use, PPI use was not significantly associated with lower risk of COVID-19 (calibrated hazard ratio [HR], 0.81 [95% confidence interval (CI), 0.30-2.19]); moreover, PPI use was not associated with adverse clinical outcomes in COVID-19, namely, hospitalization with respiratory disease (calibrated HR, 0.88 [95% CI, 0.72-1.08]), intensive respiratory interventions (calibrated HR, 0.92 [95% CI,), except for all-cause mortality (calibrated HR, 0.54 [95% CI, 0.31-0.95]).
Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s40360-022-00549-7.
Additional file 1. Authors' contributions JP, SCY, JC, RWP, SIS, CHP, WGS contributed study concept and design. JP contributed statistical analysis of the study. JP, SCY, JC, SIS, and RWP contributed analysis and interpretation of data, drafting of the manuscript. RWP, SIS, WGS contributed obtaining funding. RWP and SIS contributed supervision of the study. JP and SCY contributed equally to this work. RWP and SIS contributed equally to this work. All author(s) read and approved the final manuscript.
Declarations Ethics and approval and consent to participate The Institutional review board of the Kangdong Sacred Heart Hospital has approved study and informed consent waiver. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication Not applicable.
Competing interests The authors declare that they have no competing interests.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Austin, An introduction to propensity score methods for reducing the effects of confounding in observational studies, Multivar Behav Res,
doi:10.1080/00273171.2011.568786
Barkun, Bardou, Pham, Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis, Am J Gastroenterol,
doi:10.1038/ajg.2011.474
Charpiat, Bleyzac, Tod, Proton pump inhibitors are risk factors for viral infections: even for COVID-19?, Clin Drug Investig,
doi:10.1007/s40261-020-00963-x
Eom, Jeon, Lim, Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis, CMAJ,
doi:10.1503/cmaj.092129
Gulmez, Holm, Frederiksen, Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based casecontrol study, Arch Intern Med,
doi:10.1001/archinte.167.9.950
Ho, Teng, Yang, Yeh, Wang et al., Association of Proton Pump Inhibitors Usage with risk of pneumonia in dementia patients, J Am Geriatr Soc,
doi:10.1111/jgs.14813
Laheij, Sturkenboom, Hassing, Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs, Jama,
doi:10.1001/jama.292.16.1955
Lee, Ha, Yeniova, Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching, Gut,
doi:10.1136/gutjnl-2020-322248
Lipsitch, Tchetgen, Cohen, Negative controls: a tool for detecting confounding and bias in observational studies, Epidemiology,
doi:10.1097/EDE.0b013e3181d61eeb
Luxenburger, Sturm, Biever, Rieg, Duerschmied et al., Treatment with proton pump inhibitors increases the risk of secondary infections and ARDS in hospitalized patients with COVID-19: coincidence or underestimated risk factor?, J Intern Med,
doi:10.1111/joim.13121
Maclaren, Reynolds, Allen, Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit, JAMA Intern Med,
doi:10.1001/jamainternmed.2013.14673
Malfertheiner, Kandulski, Venerito, Proton-pump inhibitors: understanding the complications and risks, Nat Rev Gastroenterol Hepatol,
doi:10.1038/nrgastro.2017.117
Othman, Crooks, Card, Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population based study, BMJ,
doi:10.1136/bmj.i5813
Rho, Cho, Son, COVID-19 international collaborative research by the health insurance review and assessment service using its nationwide real-world data: database, outcomes, and implications, J Prev Med Public Health,
doi:10.3961/jpmph.20.616
Savarino, Tosetti, Benedetto, Compare, Nardone, Appropriateness in prescribing PPIs: a position paper of the Italian Society of Gastroenterology (SIGE) -study section "digestive diseases in primary care, Dig Liver Dis,
doi:10.1016/j.dld.2018.07.004
Schuemie, Ryan, Dumouchel, Interpreting observational studies: why empirical calibration is needed to correct p-values, Stat Med,
doi:10.1002/sim.5925
Suchard, Simpson, Zorych, Massive parallelization of serial inference algorithms for a complex generalized linear model, ACM Trans Model Comput Simul,
doi:10.1145/2414416.2414791
Taştemur, Ataseven, Is it possible to use Proton Pump Inhibitors in COVID-19 treatment and prophylaxis?, Med Hypotheses,
doi:10.1016/j.mehy.2020.110018
Tian, Schuemie, Suchard, Evaluating large-scale propensity score performance through real-world and synthetic data experiments, Int J Epidemiol,
doi:10.1093/ije/dyy120
Voss, Boyce, Ryan, Accuracy of an automated knowledge base for identifying drug adverse reactions, J Biomed Inform,
doi:10.1016/j.jbi.2016.12.005
Zhang, Li, Wu, Analysis of the Effect of Proton-Pump Inhibitors on the Course of COVID-19, J Inflamm Res,
doi:10.2147/jir.s292303