key: cord-1007671-zvttpnyh
authors: Yeramaneni, Samrat; Doshi, Pratik; Sands, Kenneth; Cooper, Mandelin; Kurbegov, Dax; Fromell, Gregg
title: Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized COVID-19 Patients from a Large Healthcare System
date: 2020-10-12
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.10.011
sha: 96f8ec7767b4e3cb41851ecdc305422ff70708da
doc_id: 1007671
cord_uid: zvttpnyh

nan

Previous reports have found that in-hospital famotidine use in COVID-19 patients was associated with reduced risk of death or intubation 1, 2 . In one of these studies, authors propose that famotidine inhibits the SARS-CoV-2 protease, 3-chymotrypsin-like protease (3CL pro ), that is essential for breakdown of the immature SARS-CoV-2 protein particles which contribute to the inflammatory response seen in some COVID-19 infected individuals 1 , which in turn can lead to acute respiratory distress syndrome, multi-organ dysfunction, physiological deterioration, and death. 3 In a global pandemic with a lack of Food and Drug Administration approved targeted therapeutic agents; identification and re-purposing of well-established drugs with a proven track record of safety, affordability, and wide-spread availability is necessary. 4 The purpose of this study was to evaluate the reported protective effect of famotidine on mortality in hospitalized COVID-19 patients.

Refer to Supplementary Material for complete methods. In brief, admitted adults to affiliated hospitals who tested positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction between 02/11/2020 and 05/08/2020 were included. Exclusion criteria was death or intubation within 48 hours of admission or if famotidine was received >24 hours after admission. The primary outcome was 30-day all-cause mortality. Primary exposure was in-hospital famotidine use, regardless of dose and route, within 24 hours of admission. To mitigate bias from non-randomized assignment of treatment, a Coarsened Exact Matching (CEM) 5 technique was used for famotidine users and non-users on age (by 10-year intervals), sex, race, ethnicity, BMI, comorbidities and in-hospital HCQ use. A multivariable logistic regression model within the CEM cohort and adjusted for baseline WHO severity and use of other medications was performed to evaluate the association between famotidine use and 30-day mortality.

A total of 8915 patients were assessed for eligibility. Of these, 1441 (16.2%) patients were excluded; because of death (1.4%), intubation (5.0%), or famotidine >24 hours after admission (9.8%).

Of the 7474 eligible patients, 316 patients were excluded; for missing discharge disposition status (0.9%), or >30-day mortality (3.4%), resulting in a final sample of 7158 patients. Of the 7158 patients included in the analysis, 1127 (15.7%) patients were exposed and 6031 (84.3%) patients were unexposed. After CEM, of the 1156 patients, 410 (35.5%) patients were exposed and 746 (64.5%) patients were unexposed (Supplementary Figure 1) .

Overall, 15.7% (n=1127) of patients received famotidine and 84.3% (n=6031) did not. Table 1) .

Overall, 687 (9.6%) patients in the pre-match cohort and 133 (11.5%) patients in the post-match cohort died within 30-days of admission. Pre-match 30-day mortality, was 18.2% famotidine users vs.

8.0% non-famotidine users (p<0.0001). Post-match 30-day mortality, was 15.1% famotidine users vs. 9.5% non-famotidine users (p=0.007).

The multivariable logistic regression within the matched cohort, showed no association between in-hospital famotidine use and 30-day mortality (aOR 1.59, 95% CI 0.94-2.71) after adjustment J o u r n a l P r e -p r o o f for WHO severity, smoking status, and listed medications. The lack of association remained after controlling for smoking status (Table 1) . Secondary analysis, accounting for interaction between inhospital and at-home famotidine use showed that patients not using famotidine at-home, but receiving famotidine in the hospital were at higher risk of 30-day mortality (aOR 1.77, 95% CI 1.03-3.03).

In this multicenter retrospective study among hospitalized COVID-19 patients, famotidine use within 24 hours of admission did not confer additional risk or benefit to 30-day mortality. In fact, in those not receiving famotidine at-home, but receiving famotidine inpatient had 77% higher risk of 30day mortality. This significant finding was independent of known adverse outcomes and potential confounders in COVID-19 including age, BMI, smoking status, comorbid conditions, WHO severity, HCQ use, and other medications. 

This study was a retrospective analysis of a consecutive series of patients admitted to HCA Healthcare hospitals between 02/11/2020 and 05/08/2020. During this time period, HCA Healthcare operated 185 locally-managed hospitals ranging in size from 26 to 1,000 beds across 21 states. Facility types included community hospitals, acute care facilities, academic health centers, and large tertiaryreferral hospitals. Data for this study was obtained from HCA healthcare's electronic clinical data warehouse. Patients, 18 years or older, who tested positive or presumptive positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction (RT-PCR) were eligible for the study. Because our hypothesis was aimed at evaluating mild and moderate COVID-19 patients, we excluded patients that were intubated or died within 48 hours of admission.

The primary outcome was all-cause mortality in the hospital within 30 days of admission.

The primary exposure was in-hospital use of famotidine. Patients who received famotidine, either orally or intravenously, within 24 hours of admission were considered exposed to famotidine.

Patients who did not receive famotidine at any time during their hospitalization were considered nonexposed. Patients who received famotidine more than 24 hours after admission were excluded from the analysis. For patients who received famotidine during their hospitalization, total cumulative dose, total number of doses, and total days of exposure during the hospital stay were calculated.

Patient demographic characteristics included age, sex, race, ethnicity, BMI at admission (normal; overweight; obese), and smoking status (never smoker; former smoker; current smoker). Patient 

Demographic, clinical, treatment, and outcome characteristics of the patients by famotidine use status are presented as means (SD) or frequencies. Differences in these characteristics between the two groups were assessed using t-test or chi-square test, as appropriate. To mitigate the bias resulting from non-randomized assignment of treatment, a Coarsened Exact Matching (CEM) technique was used to match patients in the comparison group. A 1:n matching, with one famotidine user being matched to many non-famotidine users, on patient age (by 10-year age intervals), sex, race, ethnicity, BMI, all six comorbidities and in-hospital HCQ use was conducted. The matching process assigned weights to all patients in the comparison group, and all further statistical analyses were conducted accounting for these weights.

A multivariable logistic regression model within the matched cohort and adjusted for baseline WHO severity and use of other medications was used to assess the association between famotidine use and 30-day mortality. Additional models were constructed adjusting for the covariates listed above and sequential controlling for smoking status and an interaction effect between in-hospital and at-home famotidine use. Adjusted odds ratio (ORs) and 95% confidence interval (95% CI) for the variables were reported. All statistical analyses were performed using SAS 9.4 (SAS Inc., Cary, NC).

J o u r n a l P r e -p r o o f 

The American journal of gastroenterology 2020

*Covariates used in the Coarsened Matching Algorithm CAD -Coronary artery disease; DM -Diabetes mellitus; COPD -Chronic Obstructive Pulmonary Disease

Heart Failure WHO Severity Index: level 2 -not requiring supplemental oxygen; level 3 -requiring low-flow supplemental oxygen; level 4 -non-invasive ventilation or high-flow oxygen; level 5 -invasive mechanical ventilation or ECMO