Famotidine for COVID-19: real-time analysis of all 23 studies

Famotidine for COVID-19: real-time meta analysis of 22 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, hospitalization, and recovery. 11 studies from 11 independent teams in 5 different countries show statistically significant improvements in isolation (7 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 14% [2‑24%] improvement. Results are better for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

• In exclusion sensitivity analysis, statistical significance is lost after excluding only one of 22 studies in pooled analysis.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. None of the famotidine studies show zero events in the treatment arm.

Multiple treatments are typically used in combination, and other treatments are significantly more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 5/20/2022, preprint, 1 author.

Screening Large Population Health Databases for Potential COVID-19 Therapeutics: A Pharmacopeia-Wide Association Study (PWAS) of Commonly Prescribed Medications

MacFadden et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac156

Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing no significant differences in cases with chronic use of famotidine.

risk of case, 7.0% lower, OR 0.93, p = 0.16, RR approximated with OR.

MacFadden et al., 3/29/2022, retrospective, Canada, North America, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020.

Efficacy of Various Treatment Modalities on Patient-related Outcome in Hospitalized COVID-19 Patients – A Retrospective Study

Siraj et al., Indian Journal of Clinical Practice, 32:9

Retrospective 1,000 COVID+ hospitalized patients in India, showing lower mortality with famotidine and remdesivir in multivariable logistic regression.

risk of death, 36.2% lower, RR 0.64, p = 0.002, treatment 183 of 711 (25.7%), control 122 of 289 (42.2%), NNT 6.1, adjusted, OR converted to RR, multivariable.

Siraj et al., 2/28/2022, retrospective, India, South Asia, peer-reviewed, median age 56.0, 13 authors, study period March 2020 - December 2020.

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

Efficacy of Oral Famotidine in Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2

Pahwani et al., Cureus, doi:10.7759/cureus.22404

RCT with 89 famotidine and 89 control patients in Pakistan, showing faster recovery but no significant difference in mortality. 40mg oral famotidine daily.

risk of death, 11.1% lower, RR 0.89, p = 1.00, treatment 8 of 89 (9.0%), control 9 of 89 (10.1%), NNT 89.

risk of mechanical ventilation, 12.5% lower, RR 0.88, p = 0.73, treatment 21 of 89 (23.6%), control 24 of 89 (27.0%), NNT 30.

risk of ICU admission, 10.0% lower, RR 0.90, p = 0.86, treatment 18 of 89 (20.2%), control 20 of 89 (22.5%), NNT 44.

hospitalization time, 16.5% lower, relative time 0.83, p < 0.001, treatment mean 8.6 (±1.6) n=89, control mean 10.3 (±2.2) n=89.

recovery time, 9.6% lower, relative time 0.90, p = 0.001, treatment mean 8.5 (±1.7) n=89, control mean 9.4 (±1.9) n=89.

Pahwani et al., 2/20/2022, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, mean age 52.0, 8 authors, study period December 2020 - September 2021.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial

Brennan et al., Gut, doi:10.1136/gutjnl-2022-326952

Small RCT with 27 famotidine and 28 placebo patients, showing improved recovery with treatment. Recovery was faster with treatment for 14 of 16 symptoms. There was no mortality or hospitalization. NCT04724720.

risk of no recovery, 48.1% lower, RR 0.52, p = 0.23, treatment 5 of 27 (18.5%), control 10 of 28 (35.7%), NNT 5.8, day 28, ITT.

risk of no recovery, 43.2% lower, RR 0.57, p = 0.34, treatment 4 of 19 (21.1%), control 10 of 27 (37.0%), NNT 6.3, day 28, PP.

estimated time to 50% resolution, 28.1% lower, relative time 0.72, p < 0.01, treatment 27, control 28.

Brennan et al., 2/10/2022, Double Blind Randomized Controlled Trial, USA, North America, peer-reviewed, 31 authors, study period January 2021 - April 2021, average treatment delay 4.0 days, trial NCT04724720.

Comparative risk of incidence and clinical outcomes of COVID-19 among proton pump inhibitor and histamine-2 receptor antagonist short-term users: a nationwide retrospective cohort study

Park et al., BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00549-7

Retrospective 62,117 histamine-2 receptor antagonist users in South Korea, showing lower risk of COVID-19 with histamine-2 receptor antagonist use (famotidine, ranitidine, nizatidine, lafutidine, and cimetidine), without statistical significance (RR 0.48 [0.17–1.37] with 1:4 PSM).

Park et al., 1/17/2022, retrospective, South Korea, Asia, peer-reviewed, 7 authors, study period 1 January, 2020 - 15 May, 2020.

Association of the patterns of use of medications with mortality of COVID-19 infection: a hospital-based observational study

Wallace et al., BMJ Open, doi:10.1136/bmjopen-2021-050051

Retrospective 9,532 hospitalized COVID+ veterans in the USA, showing no significant difference in mortality with famotidine use. The study provides results for use before, after, and before+after. Before+after should more accurately represent prophylaxis up to COVID-19 infection (and continued use). Before included use up to 2 years before, and after included use up to 60 days later.

risk of death, 11.0% higher, RR 1.11, p = 0.33, treatment 98 of 423 (23.2%), control 1,436 of 7,521 (19.1%), adjusted, OR converted to RR, multivariable.

Wallace et al., 12/31/2021, retrospective, database analysis, USA, North America, peer-reviewed, 6 authors.

Famotidine versus Pantoprazole Use and Clinical Outcomes in Patients Hospitalized With COVID-19: A Retrospective Study

Wagner et al., American Journal of Gastroenterology, doi:10.14309/01.ajg.0000779364.64867.ec

Retrospective 2,184 hospitalized patients in the USA, 638 treated with famotidine, showing lower mortality with treatment.

risk of death, 70.0% lower, OR 0.30, p < 0.001, treatment 638, control 819, adjusted, multivariable, RR approximated with OR.

Wagner et al., 10/31/2021, retrospective, USA, North America, peer-reviewed, 5 authors, study period March 2020 - March 2021.

A Retrospective Review: Famotidine Use Is Not Associated With Improved Outcomes in Hospitalized Patients With COVID-19

Stolow et al., American Journal of Gastroenterology, doi:10.14309/01.ajg.0000778736.01714.cd

Retrospective 489 COVID+ hospitalized patients in the USA, showing higher mortality with famotidine treatment.

risk of death, 518.9% higher, OR 6.19, p < 0.001, treatment 137, control 352, RR approximated with OR.

risk of ICU admission, 2389.6% higher, OR 24.90, p < 0.001, treatment 137, control 352, RR approximated with OR.

Stolow et al., 10/31/2021, retrospective, USA, North America, peer-reviewed, 9 authors.

Smoking Status and Factors associated with COVID-19 In-Hospital Mortality among US Veterans

Razjouyan et al., Nicotine & Tobacco Research, doi:10.1093/ntr/ntab223

Retrospective 10,074 veterens in the USA, showing lower mortality with existing famotidine use.

risk of death, 27.0% lower, OR 0.73, p = 0.006, treatment 93, control 9,981, adjusted, RR approximated with OR.

Razjouyan et al., 10/25/2021, retrospective, USA, North America, peer-reviewed, 7 authors.

The association between famotidine and in‐hospital mortality of patients with COVID‐19

Kuno et al., Journal of Medical Virology, doi:10.1002/jmv.27375

PSM retrospective 9,565 COVID-19 hospitalized patients in the USA, 1,593 receiving famotidine, showing no significant difference in mortality.

risk of death, no change, OR 1.00, p = 0.97, treatment 1,593, control 7,972, RR approximated with OR.

Kuno et al., 10/11/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 4 authors, study period 1 March, 2020 - 30 March, 2021.

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients

Fung et al., PLoS ONE, doi:10.1371/journal.pone.0266922 (preprint 10/1/2021)

Retrospective database analysis of 374,229 patients in the USA, showing higher cases, lower hospitalizations, and no change in mortality with famotidine use.

risk of death, no change, HR 1.00, p = 1.00, vs. never used.

risk of hospitalization, 6.0% lower, HR 0.94, p < 0.001, vs. never used.

risk of case, 12.0% higher, HR 1.12, p < 0.001, vs. never used.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Fung et al., 10/1/2021, retrospective, population-based cohort, USA, North America, peer-reviewed, 6 authors.

Famotidine in COVID-19 treatment

Taşdemir et al., Konuralp Tıp Dergisi, doi:10.18521/ktd.935888

Retrospective 179 hospitalized patients in Turkey, 85 treated with famotidine and 94 treated with pantoprazole, showing faster recovery with famotidine in unadjusted results.

risk of death, 44.7% lower, RR 0.55, p = 0.29, treatment 5 of 85 (5.9%), control 10 of 94 (10.6%), NNT 21.

risk of ICU admission, 36.8% lower, RR 0.63, p = 0.36, treatment 8 of 85 (9.4%), control 14 of 94 (14.9%), NNT 18.

hospitalization time, 18.1% lower, relative time 0.82, p = 0.003, treatment 85, control 94.

recovery time, 20.0% lower, relative time 0.80, p = 0.04, treatment 85, control 94, duration of fever.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Taşdemir et al., 7/12/2021, retrospective, Turkey, Europe, peer-reviewed, 7 authors, this trial compares with another treatment - results may be better when compared to placebo.

Epidemiology, outcomes, and utilization of intensive care unit resources for critically ill COVID-19 patients in Libya: A prospective multi-center cohort study

Elhadi et al., PLOS ONE, doi:10.1371/journal.pone.0251085

Prospective study of 465 COVID-19 ICU patients in Libya showing no significant differences with treatment.

risk of death, 7.1% lower, RR 0.93, p = 0.57, treatment 34 of 60 (56.7%), control 247 of 405 (61.0%), NNT 23.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Elhadi et al., 4/30/2021, prospective, Libya, Africa, peer-reviewed, 21 authors, study period 29 May, 2020 - 30 December, 2020.

Association Between Famotidine Use and COVID-19 Severity in Hong Kong: A Territory-wide Study

Cheung et al., Gastroenterology, doi:10.1053/j.gastro.2020.05.098

Retrospective 952 COVID-19 patients in Hong Kong, showing no significant difference in severe disease with famotidine use.

risk of severe case, 34.0% higher, OR 1.34, p = 0.72, treatment 23, control 929, adjusted, multivariable, RR approximated with OR.

Cheung et al., 4/30/2021, retrospective, China, Asia, peer-reviewed, 3 authors.

The Efficacy of Famotidine in improvement of outcomes in Hospitalized COVID-19 Patients: A phase III randomised clinical trial

Samimagham et al., Research Square, doi:10.21203/rs.3.rs-462937/v1 (Preprint)

Very small RCT with 20 patients in Iran, showing shorter hospitalization time with famotidine treatment. There was no mortality or ICU admission. Famotidine 160mg four times a day. IRCT20200509047364N2.

hospitalization time, 33.3% lower, relative time 0.67, p = 0.04, treatment 10, control 10.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 5 of 10 (50.0%), control 5 of 10 (50.0%), >50% CT lung involvment.

risk of no recovery, 50.0% lower, RR 0.50, p = 0.37, treatment 3 of 10 (30.0%), control 6 of 10 (60.0%), NNT 3.3, no improvement in cough.

Samimagham et al., 4/27/2021, Single Blind Randomized Controlled Trial, placebo-controlled, Iran, Middle East, preprint, 6 authors.

Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients

Mura et al., Signal Transduction and Targeted Therapy, doi:10.1038/s41392-021-00689-y (preprint 3/31/2021)

PSM retrospective TriNetX database analysis of 1,379 severe COVID-19 patients requiring respiratory support, showing lower mortality with aspirin (not reaching statistical significance) and famotidine, and improved results from the combination of both.

risk of death, 20.9% lower, RR 0.79, p = 0.02, treatment 563, control 563, OR converted to RR, famotidine only, control prevalence approximated with treatment prevalence, propensity score matching.

risk of death, 37.3% lower, RR 0.63, p = 0.001, treatment 305, control 305, OR converted to RR, famotidine and aspirin, control prevalence approximated with treatment prevalence, propensity score matching.

Mura et al., 3/31/2021, retrospective, database analysis, multiple countries, multiple regions, peer-reviewed, 6 authors.

The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication

Loffredo et al., Scientific Reports, doi:10.1038/s41598-021-84782-w (In Vitro)

In Vitro study showing that famotidine does not bind or inhibit 3CL^pro and PLpro, and no direct antiviral activity was observed with concentrations up to 200µM in Vero E6 and A549 cells.

Loffredo et al., 3/8/2021, peer-reviewed, 12 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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

Yeramaneni et al., Gastroenterology, doi:10.1053/j.gastro.2020.10.011

Retrospective 7,158 hospitalized COVID-19 patients in the USA, showing higher risk or mortality with in-hospital famotidine use and lower risk with pre-existing use, without statistical significance in both cases.

risk of death, 51.0% lower, OR 0.49, p = 0.22, treatment 351, control 6,807, adjusted, home use, multivariable, RR approximated with OR.

risk of death, 59.0% higher, OR 1.59, p = 0.09, treatment 410, control 746, adjusted, hospital use, multivariable, RR approximated with OR, late treatment result.

Yeramaneni et al., 2/28/2021, retrospective, USA, North America, peer-reviewed, 6 authors, study period 11 February, 2020 - 8 May, 2020.

Role of Famotidine and Other Acid Reflux Medications for SARS-CoV-2: A Pilot Study

Balouch et al., Journal of Voice, doi:10.1016/j.jvoice.2021.01.007

Survey of 307 patients in the USA, showing no significant difference in COVID-19 cases with famotidine use.

risk of symptomatic case, 22.0% lower, RR 0.78, p = 0.49, treatment 18 of 80 (22.5%), control 49 of 227 (21.6%), adjusted, OR converted to RR, multivariable.

recovery time, 36.9% lower, relative time 0.63, p = 0.32, treatment 80, control 227.

Balouch et al., 1/20/2021, retrospective, USA, North America, peer-reviewed, 5 authors.

Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study

Zhou et al., Gut, doi:10.1136/gutjnl-2020-323668

Retrospective 4,445 COVID+ patients in China, showing higher risk of combined death/intubation/ICU with famotidine treatment.

risk of severe case, 81.0% higher, HR 1.81, p < 0.001, treatment 72 of 519 (13.9%), control 198 of 2,595 (7.6%), death/intubation/ICU, propensity score matching, Cox proportional hazards.

Zhou et al., 12/4/2020, retrospective, propensity score matching, China, Asia, peer-reviewed, 7 authors, study period 1 January, 2020 - 22 August, 2020.

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

Shoaibi et al., American Journal of Gastroenterology, doi:10.14309/ajg.0000000000001153 (preprint 9/24/2020)

Retrospective 1,816 famotidine users and 26,820 non-users hospitalized for COVID-19 in the USA, showing no significant differences with treatment.

risk of death, 3.0% higher, RR 1.03, p = 0.67, treatment 1,816, control 26,820.

risk of death/ICU, 3.0% higher, RR 1.03, p = 0.62, treatment 1,816, control 26,820.

Shoaibi et al., 9/24/2020, retrospective, database analysis, USA, North America, peer-reviewed, 5 authors.

Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19

Mather et al., American Journal of Gastroenterology, doi:10.14309/ajg.0000000000000832

PSM retrospective 878 hospitalized patients in the USA, 83 with existing famotidine use, showing significantly lower mortality with treatment.

risk of death, 61.4% lower, HR 0.39, p = 0.004, treatment 83, control 689, propensity score matching, Cox proportional hazards.

risk of death/intubation, 50.5% lower, HR 0.49, p = 0.003, treatment 83, control 689, propensity score matching, Cox proportional hazards.

Mather et al., 8/26/2020, retrospective, USA, North America, peer-reviewed, 3 authors.

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

Freedberg et al., Gastroenterology, doi:10.1053/j.gastro.2020.05.053

PSM retrospective 1,620 hospitalized patients in the USA, 84 with existing famotidine use, showing lower risk of combined death/intubation with treatment.

risk of death/intubation, 57.0% lower, RR 0.43, p = 0.02, treatment 8 of 84 (9.5%), control 332 of 1,536 (21.6%), NNT 8.3, propensity score matching.

Freedberg et al., 5/21/2020, retrospective, propensity score matching, USA, North America, peer-reviewed, 15 authors.

Antiandrogens	(meta)	Lactoferrin	(meta)
Aspirin	(meta)	Melatonin	(meta)
Bamlaniv../e..	(meta)	Metformin	(meta)
Bebtelovimab	(meta)	Molnupiravir	(meta)
Bromhexine	(meta)	N-acetylcys..	(meta)
Budesonide	(meta)	Nigella Sativa	(meta)
Cannabidiol	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption