Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized Patients With Coronavirus Disease 2019 From a Large Healthcare System.

Previous reports have found that in-hospital famotidine use in coronavirus disease 2019 (COVID-19) patients was associated with reduced risk of death or intubation. , In 1 of these studies the authors proposed that famotidine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease, 3-chymotrypsin-like protease, that is essential for breakdown of the immature SARS-CoV-2 protein particles that contribute to the inflammatory response seen in some COVID-19–infected individuals, which in turn can lead to acute respiratory distress syndrome, multiorgan dysfunction, physiologic deterioration, and death.

In a global pandemic with a lack of US Food and Drug Administration–approved targeted therapeutic agents, identification and repurposing of well-established drugs with a proven track record of safety, affordability, and widespread availability are necessary. The purpose of this study was to evaluate the reported protective effect of famotidine on mortality in hospitalized COVID-19 patients.

Methods

Refer to Supplementary Methods for complete details. In brief, admitted adults to affiliated hospitals who tested positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction between February 11, 2020 and May 8, 2020 were included. Exclusion criteria were 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 nonrandomized assignment of treatment, a coarsened exact matching (CEM) technique was used for famotidine users and nonusers on age (by 10-year intervals), sex, race, ethnicity, body mass index, comorbidities, and in-hospital hydroxychloroquine (HCQ) use. A multivariable logistic regression model within the CEM cohort and adjusted for baseline World Health Organization (WHO) severity and use of other medications was performed to evaluate the association between famotidine use and 30-day mortality.

Results

A total of 8915 patients were assessed for eligibility. Of these, 1441 patients (16.2%) 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 patients (15.7%) were exposed and 6031 patients (84.3%) were unexposed. After CEM of the 1156 patients, 410 patients (35.5%) were exposed and 746 patients (64.5%) were unexposed (Supplementary Figure 1).

Prematch and Postmatch Characteristics

Overall, 15.7% of patients (n = 1127) received famotidine and 84.3% (n = 6031) did not. Mean age was 57.9 ± 19.3 years, 50.9% were women, 44.6% white, and 25.2% black. Famotidine was used for a median of 6.0 days and at a median cumulative dose of 160 mg (interquartile range, 80-300). Famotidine users were on average 6 years older (P < .0001), with higher admission WHO severity (P < .0001), higher proportions of comorbid conditions (all P < .001), and more likely to receive HCQ, azithromycin, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, antibiotics, antivirals, remdesivir, tocilizumab, and steroids (all P < .001). Home use of famotidine was documented in 2.5% of famotidine users (n = 181) versus 2.4% of non-famotidine users (n = 170) (P < .0001).

The postmatch cohort had 1156 patients (famotidine 35.5% [n = 410] vs non-famotidine 64.5% [n = 746]). The prematch imbalance of 35% in baseline characteristics dropped to 0% after CEM (Supplementary Table 1).

Supplementary Table 1

Pre-Match and Post-Match Baseline Characteristics of the Study Cohort

Baseline characteristics	Pre-Match			Post-Match
	Famotidine N = 1127	Non-Famotidine N = 6031	P value	Famotidine N = 410	Non-Famotidine N = 746	P value
Demographics
Age in yrs (Mean, SD)∗	63.2 (17.71)	56.9 (19.42)	<0.0001	62.2 (16.86)	62.1 (16.76)	0.97
Male∗, n (%)	556 (49.4)	2959 (49.1)	0.0675	193 (47.1)	351.2 (47.1)	1.0
Race∗, n (%)			0.0091			1.0
White	549 (48.7)	2642 (43.8)		233 (56.8)	423.9 (56.8)
Black	306 (27.2)	1499 (24.9)		123 (30.0)	223.8 (30.0)
Asian	44 (3.9)	221 (3.7)		5 (1.2)	9.1 (1.2)
Other	196 (17.4)	1,267 (21)		49 (11.9)	89.2 (11.9)
Hispanic∗, n (%)	318 (28.2)	1608 (26.7)	0.0297	87 (21.2)	158.3 (21.2)	1.0
BMI∗, n (%)			<0.0001			1.0
Normal	264 (23.4)	888 (14.7)		85 (20.7)	154.7 (20.7)
Overweight	274 (24.3)	1008 (16.7)		118 (28.8)	214.7 (28.8)
Obese	397 (35.2)	1483 (24.6)		207 (50.5)	376.6 (50.5)
Smoking Status, n (%)			<0.0001			0.18
Current Smoker	48 (4.3)	195 (3.2)		16 (4.1)	31.3 (4.4)
Former Smoker	177 (15.7)	673 (11.2)		73 (18.5)	106.2 (15.0)
Never Smoker	652 (57.9)	2567 (42.6)		245 (62.2)	486.7 (68.8)
Comorbidities, n (%)
CAD∗	72 (6.4)	239 (4)	<0.0001	7 (1.7)	12.7 (1.7)	1.0
DM∗	471 (41.8)	1639 (27.2)	<0.0001	156 (38.1)	283.8 (38.1)	1.0
Renal Disease∗	259 (23)	848 (14.1)	<0.0001	69 (16.8)	125.6 (16.8)	1.0
COPD∗	321 (28.5)	1257 (20.8)	<0.0001	92 (22.4)	167.4 (22.4)	1.0
CHF∗	211 (18.7)	747 (12.4)	<0.0001	36 (8.8)	65.5 (8.8)	1.0
Hypertension∗	729 (64.7)	2809 (46.6)	<0.0001	281 (68.5)	511.3 (68.5)	1.0
In-Hospital Medication Use, n (%)
Hydroxychloroquine∗	654 (58.0)	1,875 (31.2)	<0.0001	256 (62.4)	465.8 (62.4)	1.0
ACE Inhibitors	141 (12.5)	485 (8.0)	<0.0001	50 (12.2)	104.9 (14.1)	0.37
ARBs	103 (9.1)	385 (6.4)	0.0008	38 (9.3)	86.4 (11.6)	0.22
Antibiotics	1,023 (90.8)	3747 (62.1)	<0.0001	375 (91.5)	618.3 (82.9)	<0.0001
Azithromycin	870 (77.2)	3133 (52)	<0.0001	325 (79.3)	563.2 (75.5)	0.15
Antivirals	116 (10.3)	207 (3.4)	<0.0001	56 (13.7)	48.9 (6.6)	<0.0001
Remdesivir	11 (1)	21 (0.4)	0.0037	4 (1)	3.7 (0.5)	0.34
Tocilizumab	63 (5.6)	101 (1.7)	<0.0001	21 (5.1)	19.1 (2.6)	0.02
Steroids	414 (36.7)	763 (12.7)	<0.0001	154 (37.6)	135.7 (18.2)	<0.0001
PPIs	129 (11.5)	940 (15.6)	0.0003	46 (11.2)	153.5 (20.6)	<0.0001
At-Home Medication Use, n (%)
Famotidine Use	181 (16.1)	170 (2.8)	<0.0001	71 (17.3)	24.4 (3.3)	<0.0001
PPI use	275 (24.4)	1327 (22.0)	0.0762	100 (24.4)	201.4 (27.0)	0.33
Other Hospitalization Characteristics, n (%)
WHO Severity Index			<0.0001			<0.0001
Level 2	355 (31.5)	1596 (26.5)		122 (30.3)	273.8 (37.9)
Level 3	541 (48.0)	2069 (34.3)		214 (53.1)	396.9 (55.0)
Level 4	106 (9.4)	206 (3.4)		45 (11.2)	48.7 (6.8)
Level 5	71 (6.3)	28 (0.5)		22 (5.5)	1.8 (0.3)
Intubated during hospitalization	96 (8.5)	124 (2.1)	<0.0001	28 (6.8)	21.4 (2.9)	0.0014
Received mechanical ventilation during hospitalization	196 (17.4)	187 (3.1)	<0.0001	63 (15.4)	27.7 (3.7)	<0.0001
Mortality Outcomes, n (%)
30-Day Mortality	205 (18.2)	482 (8)	<0.0001	62 (15.1)	72.9 (9.8)	0.007

NOTE. Cell counts may not add up to 100% due to missing values. CAD, Coronary artery disease; DM, Diabetes mellitus; COPD, Chronic Obstructive Pulmonary Disease; CHF, Congestive 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

Covariates used in the Coarsened Matching Algorithm

Thirty-day Mortality

Overall, 687 patients (9.6%) in the prematch cohort and 133 patients (11.5%) in the postmatch cohort died within 30 days of admission. Prematch 30-day mortality was 18.2% of famotidine users versus 8.0% of non-famotidine users (P < .0001). Postmatch 30-day mortality was 15.1% of famotidine users versus 9.5% of non-famotidine users (P = .007).

The multivariable logistic regression within the matched cohort showed no association between in-hospital famotidine use and 30-day mortality (adjusted odds ratio, 1.59; 95% confidence interval, 0.94–2.71) after adjustment 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 in-hospital 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 (adjusted odds ratio, 1.77; 95% confidence interval, 1.03–3.03).

Table 1

Multivariable Logistic Regression Association Between In-hospital Famotidine Use and 30-day Mortality

Variables	Adjusted Odds Ratio (95% Confidence Interval)
In-hospital famotidine use
World Health Organization Severity Index
Level 2	Reference
Level 3	1.55 (0.83–2.87)
Level 4	2.75 (1.18–6.45)
Level 5	37.66 (7.45–190.14)
Smoking status
Never smoker	Reference
Former smoker	2.05 (1.18–3.56)
Current smoker	2.06 (0.80–5.32)
In-hospital medications
Azithromycin use	0.93 (0.49–1.78)
Angiotensin-converting enzyme inhibitor use	0.69 (0.31–1.55)
Angiotensin-receptor blocker use	0.97 (0.46–2.04)
Antiviral use	1.48 (0.71–3.10)
Remdesivir use	1.24 (0.11–14.19)
Tocilizumab use	2.73 (1.17–6.41)
Steroid use	2.29 (1.34–3.90)
Proton pump inhibitor use	1.49 (0.76–2.95)
At-home medications
Famotidine use	0.49 (0.16–1.52)
Proton pump inhibitor use	1.49 (0.80–2.79)

World Health Organization Severity Index: level 2, not requiring supplemental oxygen; level 3, requiring low-flow supplemental oxygen; level 4, noninvasive ventilation or high-flow oxygen; level 5, invasive mechanical ventilation or extracorporeal membrane oxygenation. Age, sex, race, ethnicity, body mass index, and comorbidities (coronary artery disease, diabetes mellitus, renal disease, chronic obstructive pulmonary disease, congestive heart failure, and hypertension) were the covariates used in the CEM algorithm.

Discussion

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 in the hospital had a 77% higher risk of 30-day mortality. This significant finding was independent of known adverse outcomes and potential confounders in COVID-19 including age, body mass index, smoking status, comorbid conditions, WHO severity, HCQ use, and other medications.

Freedberg et al reported that famotidine provided a 2-fold reduction in risk of death or intubation for COVID-19 inpatients. Median duration of days and cumulative dose of administration was 5.8 days and 136 mg, respectively, similar to our study. Mather et al reported a similar 2-fold reduction in risk of death or intubation in patients receiving famotidine within ±7 days from COVID-19 screening or hospitalization. These 2 single-center studies had a small cohort of famotidine users (n = 84) compared with our cohort of 476 users. Further, it is unclear whether these 2 studies adjusted for other in-hospital medications. Although Freedberg et al adjusted for traditional confounders including HCQ use, it is unclear whether baseline severity and other in-hospital medications were adjusted. Mather et al adjusted for baseline severity based on NEWS score but did not report on controlling for medications. Given the reports on protective effects of remdesivir and steroids in COVID-19 patients, it is essential to adjust for the effects of medications for valid conclusions.

Limitations of our study include an inability to establish causality and possibility of unmeasured confounding because of the observational design. We did not analyze serum biomarkers or viral load for assessment of anti-inflammatory or antiviral properties. Finally, over 95% of our cohort received low to medium doses, excluding the possibility of evaluating famotidine’s effectiveness on mortality at high doses. Despite these limitations, our study captures real-world data from large, multicenter, heterogeneous healthcare institutions allowing generalizability of findings. Matching our comparison groups on 12 covariates reduced an imbalance in baseline characteristics to 0% and adjusted for multiple confounders (n = 12) with association between COVID-19 and mortality.

In summary, our study findings do not support the evidence of in-hospital famotidine use on reduced risk of mortality in COVID-19 patients. Investigation of off-label use of low cost, better tolerated, and widely available drugs in COVID-19 patients is warranted. Until safety and efficacy of these drugs are established by randomized controlled trials, results from these observational studies should be interpreted with caution.