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Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching

Our take —

Preliminary results from this study suggest that recent and short-term proton pump inhibitor (PPI) use may be associated with more severe outcomes of COVID-19, however, causality may not be inferred as a number of biases could explain the observed association (i.e., residual confounding, selection bias, and reverse causation); concerns around reverse causation are more pronounced as the statistically significant effect of PPI use was only seen among short-term users (<30 days). PPI use was not associated with testing positive for SARS-CoV-2.

Study design

Case Series, Retrospective Cohort

Study population and setting

Data from the Korean national health insurance claims database were used to evaluate whether use of proton pump inhibitors (PPI) (a class of medication to reduce production of stomach acid) influence susceptibility to SARS-CoV-2 infection (primary outcome) or severe clinical complications of COVID-19 (admission to an intensive care unit, invasive mechanical intervention, or death). The study included 132,316 individuals who received COVID-19 testing between January 1 and May 15, 2020. Patients were excluded if they were <18 years, were prescribed H-2 blockers in the previous year, or had a record of NSAID use in the previous month. Given that participants were not randomized to PPI use, statistical techniques were employed that attempted to account for possible differences in factors between those who used PPIs and those who did not, specifically potential factors that might influence the propensity for using PPIs (i.e., propensity score matching). Four rounds of 1:1 propensity score matching were carried out using the greedy nearest-neighbor approach. Among all patients tested for COVID-19, current PPI users (PPI use within past 30 days) were matched to non-users (13,873 pairs), and past PPI users (PPI use 31-365 days before COVID-19 test) to non-users (6,153 pairs); to examine the risk of severe clinical outcomes, this was repeated only among individuals who tested positive (267 pairs for current PPI users vs. non-users, and 148 pairs for past PPI users vs. non-users). To see if duration of PPI use affected any association, the authors repeated the analysis dividing current PPI users into short-term users (<30 days of use) and long-term users (>30 days of use)

Summary of Main Findings

Of the 132,316 individuals who received SARS-CoV-2 testing (mean age 48 years, 51% male, 3.6% test positivity), 14,163 used PPIs in the prior 30 days (current use), 6242 used PPIs in the past, and 111,911 had no history of PPI use. In the final results, current or past PPI users did not experience a greater risk of testing positive for SARS-CoV-2 infection relative to non-users. However, adjusted matched analyses suggested that current PPI use, especially among those with short term use of PPIs (<30 days), was associated with increased likelihood of severe COVID-19 outcomes; there was not, however a statistically significant increase in severe Covid-19 outcomes among long-term PPI users (>30 days).

Study Strengths

The study uses data from a nationwide cohort of individuals tested for SARS-CoV-2 infection in Korea. The authors use sophisticated techniques (i.e., propensity score matching) with multivariable analyses to address some potential sources of confounding.

Limitations

This was an observational study and it is likely that differences between the PPI users and non-users remain even after efforts were taken to account for these potential confounding factors. A key concern is whether individuals who show mild COVID-19 symptoms, which can include gastrointestinal involvement, are prescribed PPIs prior to COVID-19 diagnosis; if so, there may be an issue of reverse causation, where COVID-19 causes prescription of PPIs, rather than PPIs causing severe clinical outcomes. Additionally, participants with missing data and individuals who were unmatched in propensity score matching were excluded from multivariable analysis, which may limit generalizability or introduce a bias if those who participated were different from those who did not participate regarding likelihood of being prescribed PPIs, susceptibility to SARS-CoV-2 infection, or likelihood of experiencing severe disease. Use of PPIs and other medications was determined by electronic health record of prescription and may not reflect actual usage of medications. Finally, relative to the number of variables adjusted for in the multivariable analyses, the number of severe outcomes was low; this may result in overfitting and the observation of spurious association when none actually exist.

Value added

This is one of the first large-scale studies to investigate the association between PPI use and susceptibility to SARS-CoV-2 infection and severe clinical outcomes of COVID-19 disease.

This review was posted on: 17 August 2020