Supplementary Table 1.
Study Characteristics
| Study, Year, Country | Study Design | No. of Patients | Dose of Famotidine or PPI | Exposure to PPI or Famotidine | Patients on Supplemental Oxygen | No. of Intubated Patients | No. of Deaths | No. of Patients Receiving Steroids or Remdesivir | No. of Patients With Severe Disease | Methods for Controlling Confounders | Confounders Adjusted | Indicators of Disease Severity | Immortal Time Bias |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cheung et al, 2020, Hong Kong | Retrospective, cohort | 952 | NA | Exposure to PPI or famotidine on day of admission | NA | NA | NA | NA | 51 | Multivariable logistic regression model | Age, sex, comorbidities (DM, HTN, ischemic heart disease, stroke, and atrial fibrillation), other medications | Presence of (1) critical complication (respiratory failure, septic shock, and/or multiple-organ | Unclear risk of immortal time bias. Exposure to PPI or famotidine was defined as on day of admission. It is not reported when the outcome assessment was started. |
| (ACEIs, ARBs, aspirin, statins, and prednisolone), and laboratory parameters | dysfunction), (2) ventilatory support (invasive or noninvasive), (3) ICU admission, and/or (4) death | ||||||||||||
| (leukocyte, platelet, C-reactive protein, urea, creatinine, sodium, potassium, bilirubin, alkaline phosphatase, alanine aminotransferase, albumin, globulin, and lactate dehydrogenase | |||||||||||||
| Freedberg et al, 2020, USA | Retrospective, cohort | 1620 | Total median dose of famotidine: 136 mg (range, 63–233), over median 5.8 days. 28% of all famotidine doses were intravenous; 47% were 20 mg, 35% were 40 mg, and 17% | Exposure to famotidine within 24 h of admission | 1217 | 142 | 238 | NA | 340 | Cox proportional hazard model and PS matching | DM, HTN, coronary artery disease, heart failure, end-stage renal disease, CKD, chronic pulmonary disorders, obesity (classified based on BMI), and age (classified as <50 y, 50–65 y, and | Composite of death or endotracheal intubation | Immortal time bias not present. Exposure to famotidine was defined as within 24 h of admission and outcome assessment started from day 2. |
| were 10 mg. | >65 y). To assess severity of COVID-19, the first recorded form of supplemental oxygen after triage was captured and classified as room air, nasal cannula oxygen, or non-rebreather/similar. | ||||||||||||
| Yeramaneni et al, 2020, USA | Retrospective, cohort | 7158 | Median cumulative dose of 160 mg (range, 80– | Exposure to famotidine within 24 h of admission | 2922 | 220 | 687 | Remdisivir: 32 | 687 | Coarsened exact matching and multivariable logistic regression model | Age, sex, race, ethnicity, BMI, coronary artery | Mortality | Immortal time bias not present. Exposure to famotidine within 24 h of admission and deaths or intubations within 48 h of admission were excluded. |
| 300) over median of 6 days | Steroids: 1177 | disease, DM, renal disease, COPD, congestive heart failure, HTN, World Health Organization severity index, smoking status, in hospital medications such as azithromycin, ACEIs, ARBs, antivirals, remdisivir, tocilizumab, steroids, and PPI use. | |||||||||||
| Mather et al, 2020, USA | Retrospective, cohort | 878 | 83% received famotidine orally and 17% received it intravenously. Dose of oral famotidine was 20 mg/d in 95.2% of cases and 40 mg/d in 4.8% of cases. Dose of intravenous famotidine was | Exposure to famotidine within ±7 days of COVID-19 screening and/or hospital admission | NA | NA | 191 | Remdisivir: 27 | 430 | Multivariable logistic regression model and PS matching | Age, sex, race, smoking status, BMI, HTN, DM, obesity (BMI 30 kg/m2), coronary artery disease, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, CKD, prior history of malignancy, use of hydroxychloroquine, azithromycin, | Mortality, requirement for mechanical ventilation, composite of death, or requirement for mechanical ventilation | High risk of immortal time bias. Exposure to famotidine was defined as within ±7 days of COVID-19 screening and/or hospital admission and assessment of outcome was started after hospitalization. |
| 20 mg. Median total famotidine dose was 80 mg | Steroids: 377 | remdesivir, and corticosteroids | |||||||||||
| (range, 40–160) over a median of 4 days (range, 2–8). | |||||||||||||
| Luxenburger et al, 2020, Germany | Retrospective, cohort | 152 | PPI: 20 mg daily (4.8%), 40 mg daily (87%), 80 mg daily (8%) | Patients already on PPI as outpatient | NA | NA | 17 | NA | 45 | NA | NA | ARDS, mortality | Could not be assessed because adequate information was not available regarding when the outcome assessment was started. |
| Lee et al, 2019, Korea | Retrospective, cohort | 4785 | NA | Current or past use of PPI as outpatient | NA | NA | NA | Steroids: 224 | 81 | PS matching | Age; sex; region of residence (urban or rural); history of DM, cardiovascular disease, cerebrovascular disease, COPD, HTN, or CKD; Charlson comorbidity index (0, 1, or ≥2); and current use of systemic steroid, metformin, or aspirin. | Composite endpoint 1 (requirement for oxygen therapy, ICU admission, invasive ventilation, or death). | Low risk of immortal time bias |
| Composite endpoint 2 (severe clinical outcomes of COVID-19, ICU admission, invasive ventilation, or death) | |||||||||||||
| Ramachandran et al, 2020, USA | Retrospective, cohort | 295 | NA | PPI exposure before admission | NA | NA | 56 | NA | 129 | Multivariable logistic regression | NA | Mortality, ARDS | Low risk of immortal time bias. PPI exposure was defined as PPI use before admission and outcome assessment started after hospitalization |
| Zhou et al, 2020, Hong Kong | Retrospective, cohort | 4445 | Median cumulative PPI dose: 1080 mg (range, 600–2430) | Exposure to famotidine and PPI as inpatient and outpatient | NA | NA | NA | Steroids: 632 | 212 | PS matching | Age, cardiovascular disease, renal disease, stroke, Kaletra, diuretics for heart failure, other antihypertensives, | Need for ICU admission or intubation, or death | High risk of immortal time bias. Both inpatient and outpatient exposure to famotidine was considered and outcome assessment started after admission. Only exposure to famotidine after ICU admission was not considered. |
| Median cumulative famotidine dose: 1040 mg (range, 480–2440) | Remdesivir: NA | PPI/famotidine, neutrophils, lymphocytes, platelets, urea, | |||||||||||
| creatinine, albumin and glucose | |||||||||||||
| Argenziano et al, 2020 | Retrospective, case series | 1000 | NA | NA | NA | 233 | 211 | Steroids: 178 | 233 | NA | NA | ICU admission | Could not be assessed |
| Remdesivir: 18 |
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; ARDS, acute respiratory distress syndrome; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; HTN, hypertension; ICU, intensive care unit; NA, not available; PS, propensity score.