Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study.

See Covering the Cover synopsis on page 803.

Coronavirus Disease 2019 (COVID-19) caused 2 million cases and more than 150,000 deaths worldwide as of mid-April 2020. Clinical trials are under way to assess the efficacy of a variety of antiviral drugs; however, many of these drugs have toxicities and thus far no drug has been proven to improve outcomes in patients with COVID-19.

Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid production. In vitro, famotidine inhibits human immunodeficiency virus replication. Recently, Wu et al. used computational methods to predict structures of proteins encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome and identified famotidine as one of the drugs most likely to inhibit the 3-chymotrypsin-like protease (3CLpro), which processes proteins essential for viral replication. We hypothesized that famotidine would be associated with improved clinical outcomes among hospitalized patients with COVID-19. To explore this, we performed a retrospective cohort study at a single academic center located at the epicenter of the COVID-19 pandemic in the United States.

Methods

Complete methods are available in the Supplementary Materials. In brief, adults were eligible for the study if they were admitted to our institution from February 25, 2020, to April 13, 2020, and tested positive for SARS-CoV-2 within no more than 72 hours following admission. Patients were excluded if they died or were intubated within 48 hours following hospital admission. The primary exposure was use of famotidine (any dose, form of administration, or duration), classified as present if famotidine was received within 24 hours of hospital admission and otherwise as absent. The primary outcome was a composite of death or endotracheal intubation from hospital day 2 to day 30 (intubation-free survival). This follow-up period avoided immortal time bias because the exposure was classified based on the 24-hour period after hospitalization and the at-risk period began on hospital day 2. Cox proportional hazards modeling was performed on the full cohort, and a matched subset was examined with propensity scoring matching to balance baseline characteristics based on use of famotidine.

Results

Population and Use of Famotidine

A total of 1620 patients met criteria for analysis, including 84 patients (5.1%) who received famotidine within 24 hours of hospital admission. Home use of famotidine was documented on admission medication reconciliation in 15% of those who used famotidine while hospitalized compared with 1% of those who did not (P < .01). Twenty-eight percent of all famotidine doses were intravenous; 47% were 20 mg, 35% were 40 mg, and 17% were 10 mg. Famotidine users received a median 5.8 days of drug for a total median dose of 136 mg (63–233 mg). There were minimal differences comparing patients who used famotidine with those who did not, and balance between the groups was further improved after propensity score matching (Supplementary Table 1).

Supplemental Table 1

Patient Characteristics at the Time of Hospital Admission for COVID-19, Stratified by Use of Famotidine

Characteristics	Complete cohort			After propensity score matching
	Famotidine (n = 84), n (%)	No famotidine (n = 1536), n (%)	P value	Famotidine (n = 84), n (%)	No famotidine (n = 420), n (%)	P value
Age (y)			.39			.51
<50	13 (15)	320 (21)		13 (15)	57 (14)
50–65	31 (37)	483 (31)		31 (37)	184 (44)
>65	40 (48)	733 (48)		40 (48)	179 (43)
Female sex	39 (46)	864 (56)	.63	39 (46)	208 (50)	.60
Race/ethnicity			.20			.90
Hispanic	25 (30)	601 (39)		25 (30)	127 (30)
White, non-hispanic	19 (23)	336 (22)		19 (23)	82 (20)
Black, non-hispanic	18 (21)	322 (21)		18 (21)	102 (24)
Other	22 (26)	277 (18)		22 (26)	109 (26)
BMI, kg/m2			.17			.97
<25.0	15 (18)	295 (19)		15 (18)	66 (16)
25.0–29.9 (overweight)	30 (36)	388 (25)		30 (36)	157 (37)
≥30 (obese)	22 (26)	434 (28)		22 (26)	110 (26)
Not recorded	17 (20)	419 (27)		17 (20)	87 (21)
Comorbidities
Diabetes	24 (29)	311 (20)	.07	24 (29)	106 (25)	.52
Hypertension	29 (35)	428 (28)	.19	29 (35)	124 (30)	.36
CAD	9 (11)	109 (7)	.21	9 (11)	37 (9)	.58
Heart failure	7 (8)	85 (6)	.28	7 (8)	26 (6)	.47
ESRD or CKD	11 (13)	130 (8)	.14	11 (13)	47 (11)	.62
Chronic pulmonary disorders	2 (2)	120 (8)	.07	2 (2)	6 (11)	.52
Initial oxygen requirement			.39			.85
Room air	25 (30)	378 (25)		25 (30)	116 (28)
Nasal canula	38 (45)	678 (44)		38 (45)	187 (44)
Non-rebreather or similar	21 (25)	480 (31)		21 (25)	117 (28)

BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; ESRD, end-stage renal disease.

Death or Intubation

A total of 142 (8.8%) patients were intubated and 238 (15%) died; 340 (21%) patients met the composite study outcome. In crude analysis, use of famotidine was significantly associated with reduced risk for the composite outcome of death or intubation (Figure 1 A, log-rank P < .01). This association was driven primarily by the relationship between famotidine and death (Figure 1 B, log-rank P < .01) and when those who died before intubation were excluded, there was no association between use of famotidine and intubation (log-rank P = .40). After adjusting for baseline patient characteristics, use of famotidine remained independently associated with risk for death or intubation (Supplementary Table 2, adjusted hazard ratio 0.42, 95% confidence interval [CI] 0.21–0.85) and this remained unchanged after propensity score matching to further balance the covariables (hazard ratio 0.43, 95% CI 0.21–0.88).

Figure 1

Kaplan-Meier plot showing (A) intubation-free survival and (B) survival through a maximum of 30 days after hospital admission, stratified by use of famotidine. Patients were included in the study if they survived without intubation for 2 days following hospital admission. Use of famotidine was classified as present if it was received within the first 24 hours following hospital admission (any dose, form of administration, or duration) and otherwise as absent. The at-risk time began on hospital day 2 (indicated with a dashed red line) and patients were followed until hospital day 30. This study design avoided potential for immortal time bias because the exposure was classified before the start of the at-risk period.

Supplemental Table 2

Final Cox Proportional Hazards Model of risk factors for death or Intubation Among Patients With COVID-19

Characteristics	Death or intubation/n at risk (%)	Hazard ratio (95% CI)
		Full model	Final model
Famotidine
No	332/1536 (22)	Reference	Reference
Yes	8/84 (10)	0.43 (0.21–0.86)	0.42 (0.21–0.85)
Age (y)
<50	19/333 (5.7)	Reference	Reference
50–65	75/514 (15)	2.94 (1.77–4.89)	3.03 (1.83–5.03)
>65	246/773 (32)	7.51 (4.66–12.1)	7.68 (4.79–12.3)
Sex
Male	197/909 (22)	Reference	—
Female	143/711 (20)	1.11 (0.89–1.38)
Race/ethnicity
Hispanic	129/626 (21)	Reference	—
White, non-Hispanic	84/355 (24)	0.99 (0.75–1.31)
Black, non-Hispanic	59/340 (17)	0.82 (0.60–1.13)
Other	68/299 (23)	1.14 (0.85–1.53)
Body mass index, kg/m2
<25.0	86/310 (28)	Reference	—
25.0–29.9 (overweight)	92/418 (22)	0.88 (0.65–1.18)
≥30 (obese)	89/456 (20)	0.97 (0.72–1.31)
Not recorded	73/436 (17)	0.67 (0.49–0.92)
Comorbidities
Diabetes	72/335 (21)	1.02 (0.75–1.37)	—
Hypertension	94/457 (21)	0.72 (0.54–0.97)	0.74 (0.58–0.94)
CAD	24/118 (20)	0.77 (0.49–1.21)	—
Heart failure	24/92 (26)	1.06 (0.67–1.67)	—
ESRD or CKD	33/141 (23)	1.16 (0.77–1.75)	—
Chronic pulmonary disorders	29/122 (24)	1.29 (0.87–1.93)	—
Initial oxygen requirement
Room air	52/403 (13)	Reference	—
Nasal canula	155/716 (22)	1.60 (1.17–2.19)	1.63 (1.19–2.24)
Non-rebreather	133/501 (27)	2.48 (1.79–3.44)	2.39 (1.73–3.29)

CAD, coronary artery disease; CKD, chronic kidney disease; ESRD, end-stage renal disease.

Additional Analyses

Use of proton pump inhibitors (PPIs) was analyzed because PPIs are also gastric acid suppression medications with similar indications as famotidine. There was a no protective effect associated with use of PPIs (adjusted hazard ratio 1.34, 95% CI 1.06–1.69). Next, 784 patients without COVID-19 who were hospitalized during the same study period were analyzed; among these patients, famotidine was not associated with reduced risk for death or intubation (24 deaths or intubations, log-rank P = .70). The maximum plasma ferritin value during the hospitalization was assessed to address the hypothesis that, by blocking viral replication, famotidine reduces cytokine storm during COVID-19. Median ferritin was 708 ng/mL (interquartile range 370–1152) among users of famotidine vs 846 ng/mL (interquartile range 406–1552) among nonusers (rank-sum P = .03).

Conclusions

This retrospective study found that, in patients hospitalized with COVID-19, famotidine use was associated with a reduced risk of clinical deterioration leading to intubation or death. The study was premised on the assumption that use of famotidine represented a continuation of home use, but documentation of why famotidine was given was poor. The results were specific for famotidine (no protective association was seen for PPIs) and also specific for COVID-19 (no protective association in patients without COVID-19). A lower peak ferritin value was observed among users of famotidine, supporting the hypothesis that use of famotidine may decrease cytokine release in the setting of SARS-CoV-2 infection. A randomized controlled trial is currently under way to determine whether famotidine can improve clinical outcomes in hospitalized patients with COVID-19 (NCT04370262).

Famotidine has not previously been studied in patients for antiviral effects, and there are limited relevant prior data. An untargeted computer modeling analysis identified famotidine as one of the highest-ranked matches for drugs predicted to bind 3CLpro, a SARS-CoV-2 protease that generates nonstructure proteins critical to viral replication. In the 1990s, histamine-2 receptor antagonists including famotidine were shown to inhibit human immunodeficiency virus replication without affecting lymphocyte viability in vitro. , ,

There are limitations to the study. It was observational, and we cannot exclude the possibility of unmeasured confounders or hidden bias that account for the association between famotidine use and improved outcomes. No samples were gathered, and mechanism cannot be directly assessed. Finally, this was a single-center study, which may limit generalizability of the findings.

In sum, in patients hospitalized with COVID-19 and not initially intubated, famotidine use was associated with a 2-fold reduction in clinical deterioration leading to intubation or death. These findings are observational and should not be interpreted to mean that famotidine has a protective effect against COVID-19. Randomized controlled trials are under way.