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Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study
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  1. Jiandong Zhou1,
  2. Xiansong Wang2,
  3. Sharen Lee3,
  4. William Ka Kei Wu2,
  5. Bernard Man Yung Cheung4,
  6. Qingpeng Zhang1,
  7. Gary Tse5
  1. 1School of Data Science, City University of Hong Kong, Kowloon, Hong Kong
  2. 2Department of Anaesthesia and Intensive Care, Li Ka Shing Institute of Health Sciences, Hong Kong, China
  3. 3Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, China
  4. 4Department of Medicine, The University of Hong Kong, Hong Kong, China
  5. 5Tianjin Institute of Cardiology, Tianjin Medical University, Tianjin, China
  1. Correspondence to Professor Gary Tse, Tianjin Institute of Cardiology, Tianjin Medical University, Tianjin 300070, China; garytse86{at}gmail.com; Professor Qingpeng Zhang, School of Data Science, City University of Hong Kong, Hong Kong, China; qingpeng.zhang{at}cityu.edu.hk

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We read the recent articles published in Gut on the relationship between proton pump inhibitor (PPI) use and outcomes in COVID-19 with great interest.1 2 In the meta-analysis, the authors found that current or regular PPI users were more likely to have severe outcomes of COVID-19 than non-users, but no significant association was observed for previous PPI use.2 The reason may be reduced secretion of gastric acid that can neutralise the SARS-CoV-2. By contrast, the use of famotidine, another medication for gastric ulcers or gastro-oesophageal reflux disease, was associated with better clinical outcomes in some studies,3 4 but not others.5 6

Given these conflicting findings, we conducted this territory-wide study to investigate whether PPI or famotidine use was associated with a higher risk of severe disease using propensity score matching. The detailed methodology of the present analyses is shown in the online supplemental appendix. A total of 4445 patients (median age 44.8 years old, 95% CI: (28.9 to 60.8)); 50% male) were diagnosed with the COVID-19 infection between 1 January 2020 and 22 August 2020 in Hong Kong public hospitals or their associated ambulatory/outpatient facilities. On follow-up until 8 September 2020, a total of 212 patients (4.8%) met the primary outcome of need for intensive care unit (ICU) admission or intubation, or death (online supplemental figure 1). The median duration between hospitalisation admission and ICU admission, intubation or death were 35 (95% CI: 24.5 to 50.5), 33 (95% CI: 21.0 to 140.0) and 15 days (95% CI: 7.5 to 24.5), respectively. The baseline clinical characteristics of patients with or without PPI/famotidine use during the inpatient stay are shown in online supplemental table 4. Those for the cohort stratified by PPI or famotidine use before and after propensity score matching for baseline demographics, medical comorbidities and medication history are shown in online supplemental tables 5 and 6, respectively.

Supplemental material

The percentage of COVID-19 patients meeting the primary outcome was significantly higher in PPI users than in non-users, both before (n=151/524, 28.8% vs n=61/3921, 1.6%; p<0.0001) and after 1:5 propensity score matching for age, sex, medical comorbidities and medication history (n=151/524, 28.8% vs n=173/2620, 6.6%; p<0.0001). Similarly, famotidine users also showed a higher percentage compared with non-users before (n=72/519, 13.9% vs n=140/3926, 3.6%; p<0.0001) and after matching (n=72/519, 13.9% vs n=198/2595, 7.6%; p<0.0001). Kaplan-Meier curves stratified by PPI or famotidine use are shown in figures 1 and 2. Based on the matched cohorts, univariable Cox regression showed that the use of PPI (HR: 6.32, 95% CI: (5.02 to 7.95); p<0.0001) or famotidine (HR: 1.98, 95% CI: (1.47 to 2.66); p<0.0001) was associated with a higher risk of the primary outcome (online supplemental table 7). On multivariable Cox regression adjusting for age, cardiovascular disease, renal disease, stroke, Kaletra, diuretics for heart failure, other anti-hypertensives, PPI/famotidine, neutrophils, lymphocytes, platelets, urea, creatinine, albumin and glucose, the associations remained significant for both PPI (HR: 2.73, 95% CI: (2.05 to 3.64), p<0.0001) and famotidine (HR: 1.81, 95% CI: (1.28 to 2.58), p<0.0001). The Cox analyses were repeated on separate cohorts generated by 1:1 propensity score matching, demonstrating similarly increased risks with PPI (HR: 11.76, 95% CI: (7.77 to 17.79); p<0.0001) or famotidine (HR: 1.81, 95% CI: (1.35 to 2.43); p<0.0001) use. Similarly, on multivariate Cox regression, the associations remained significant for both PPI (HR: 2.65, 95% CI: (1.75 to 4.00), p<0.0001) and famotidine (HR: 1.84, 95% CI: (1.16 to 2.92), p<0.0001).

Figure 1

Kaplan-Meier curve stratified by proton pump inhibitor (PPI) use before and after propensity score matching.

Figure 2

Kaplan-Meier curve stratified by famotidine use before and after propensity score matching.

Our data indicate that the use of PPIs or famotidine is associated with a higher risk of severe COVID-19 disease after propensity score matching in a Chinese cohort. Our findings should be validated in future studies.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

  • Supplementary Data

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Footnotes

  • JZ and XW are joint first authors.

  • QZ and GT are joint senior authors.

  • Twitter @sharen212, @QPCN, @garytse1

  • Correction notice This article has been corrected since it published Online First. The funding statement has been added.

  • Contributors JZ and XW: data analysis, data interpretation, statistical analysis, manuscript drafting and critical revision of manuscript. SL, WKKW and BC: project planning, data acquisition, data interpretation and critical revision of manuscript. QZ and GT: study conception, study supervision, project planning, data interpretation, statistical analysis, manuscript drafting and critical revision of manuscript.

  • Funding This study was supported by the National Natural Science Foundation of China (NSFC) Grant Nos. 72042018, 71972164 and 71672163, in part by the Health and Medical Research Fund Grant (HMRF), the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region No. 16171991 and in part by The Theme‐Based Research Scheme of the Research Grants Council of Hong Kong Grant No. T32‐102/14N.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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