Famotidine for COVID-19: real-time meta analysis of 28 studies

An In Vitro study supports the efficacy of famotidine Loffredo.

Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.

Table 1 summarizes the results for all stages combined, with different exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.

To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.

The studies excluded are as below. Figure 17 shows a forest plot for random effects meta-analysis of all studies after exclusions.

Elhadi, unadjusted results with no group details.

Fung, not fully adjusting for the different baseline risk of systemic autoimmune patients.

Shamsi, unadjusted results with no group details.

Taşdemir, excessive unadjusted differences between groups.

Heterogeneity in COVID-19 studies arises from many factors including:

The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours McLean, Treanor. Baloxavir studies for influenza also show that treatment delay is critical — Ikematsu report an 86% reduction in cases for post-exposure prophylaxis, Hayden show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar report only 2.5 hours improvement for inpatient treatment.

Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 56 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.

Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in López-Medina).

Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.

There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics Faria, Karita, Nonaka, Zavascki. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective Peacock, Willett.

Effectiveness may depend strongly on the dosage and treatment regimen.

The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.

The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.

We present both pooled analyses and specific outcome analyses. Notably, pooled analysis often results in earlier detection of efficacy as shown in Figure 19. For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, etc. An antiviral tested with a low-risk population may report zero mortality in both arms, however a reduction in severity and improved viral clearance may translate into lower mortality among a high-risk population, and including these results in pooled analysis allows faster detection of efficacy. Trials with high-risk patients may also be restricted due to ethical concerns for treatments that are known or expected to be effective.

Pooled analysis enables using more of the available information. While there is much more information available, for example dose-response relationships, the advantage of the method used here is simplicity and transparency. Note that pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral replication or early stage disease could show no efficacy in pooled analysis if most studies only examine viral clearance. While we present pooled results, we also present individual outcome analyses, which may be more informative for specific use cases.

Currently, 38 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 91% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 3.3 months. When restricting to RCTs only, 57% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 3.9 months.

The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. This may have a greater effect than pooling different outcomes such as mortality and hospitalization. For example a treatment may have 50% efficacy for mortality but only 40% for hospitalization when used within 48 hours. However efficacy could be 0% when used late.

All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.

Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results Boulware, Meeus, Meneguesso. For famotidine, there is currently not enough data to evaluate publication bias with high confidence.

One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.

Figure 20 shows a scatter plot of results for prospective and retrospective studies. 43% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 80% of prospective studies, consistent with a bias toward publishing negative results. The median effect size for retrospective studies is 21% improvement, compared to 16% for prospective studies, showing similar results.

Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 21 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.

Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. Famotidine for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 famotidine trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all famotidine trials represent the optimal conditions for efficacy.

Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses by specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.

Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.

Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.

Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials affiliated with special interests may use designs better suited to the preferred outcome.

In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.

Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone Alsaidi, Andreani, Biancatelli, De Forni, Gasmi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Thairu. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.

This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.

No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. Efficacy may vary significantly with different variants and within different populations. All treatments have potential side effects. Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized advice, and provide details of risks and benefits based on individual medical history and situations.

1 of the 28 studies compare against other treatments, which may reduce the effect seen.

Famotidine is an effective treatment for COVID-19. Statistically significant lower risk is seen for mortality, hospitalization, recovery, and viral clearance. 14 studies from 14 independent teams in 7 countries show statistically significant improvements. Meta analysis using the most serious outcome reported shows 16% [5‑26%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and peer-reviewed studies. Early treatment is more effective than late treatment.

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

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Brennan: 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.

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

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Chowdhury: RCT 208 ICU patients in Bangladesh, showing improved recovery with famotidine. Famotidine 40mg (<60kg) or 60mg every 8 hours.

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

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

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

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Kim: PSM retrospective in South Korea, showing lower risk of COVID-19 cases with H2RA (including famotidine) and PPA use, but no significant difference in severe outcomes (few events, results provided for the combined groups only).

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

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Kwon: PSM retrospective 6,556 COVID-19 patients in South Korea, showing higher risk of poor outcomes with famotidine vs. other H2-blocker use.

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Loucera: Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, aspirin, vitamin D, vitamin C, and budesonide.

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

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

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Mura: 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.

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

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

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Samimagham: 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.

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Shamsi: Retrospective 183 hospitalized pediatric COVID-19 patients in Iran, showing no significant difference in mortality with famotidine in unadjusted results.

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

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

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

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

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

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Wallace: 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.

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Yeramaneni: Retrospective 7,158 hospitalized COVID-19 patients in the USA, showing higher risk or mortality with in-hospital famotidine use, but lower risk when there was pre-existing at-home use, without statistical significance in both cases.

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Zangeneh: Retrospective 193 ICU patients in Iran, showing lower mortality with famotidine treatment.

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

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We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.org. Search terms were famotidine, filtered for papers containing the terms COVID-19 or SARS-CoV-2. Automated searches are performed every few hours with notification of new matches. All studies regarding the use of famotidine for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.

We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO₂ is more important than cough. When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to Zhang. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. Adjusted primary outcome results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 Sweeting. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.11.5) with scipy (1.11.1), pythonmeta (1.26), numpy (1.25.0), statsmodels (0.14.0), and plotly (5.15.0).

Forest plots are computed using PythonMeta Deng with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome.

We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.

We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective McLean, Treanor.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. For pooled analyses, the first (most serious) outcome is used, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.

Supplementary Data