Clinical Evidence for improved outcomes in 22,560 COVID-19 patients taking antihistamines, H2 blockers and aspirin.

Key Messages

This retrospective study examined over 250,000 COVID-19 patients, 22,560 of whom were taking H1 antihistamines and H2 blockers. The analysis focused on 1,379 severely ill patients.

The patient outcomes were analyzed for treatment with H1 antihistamines (loratadine, cetirizine), the H2 blocker famotidine, aspirin, and a combination of famotidine and aspirin.

For patients who required respiratory support, the fatality risk in those taking famotidine was significantly reduced.

Patients taking famotidine also had lower levels of worrisome serum markers and for severe cases, a significantly lower chance of death. The combination of famotidine and aspirin reduced the relative risk of death by 32.5%.

The authors propose that famotidine may help COVID-19 patients because of the drug’s ability to reduce the strong inflammatory responses that are a complicating problem in severe cases - the so called “cytokine storms” which activate pro-fibrotic pathways eventually causing lung damage.

The role for famotidine in COVID-19 may be due to indirect mechanisms which are unrelated to the drug’s role in treating gastric ulcers.

MedRxiv

Publication Date: April 5, 2021
Peer Reviewed: No
Publication Type: Original | Clinical Retrospective
DOI: https://www.doi.org/10.1101/2021.03.29.21253914

Clinical Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

Cameron Mura, Saskia Preissner, Susanne Nahles, Max Heiland, Philip E. Bourne, Robert Preissner

Abstract

COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs. A family of acid-reducing drugs, known as histamine H2 receptor antagonists (H2RA), competitively bind the H2R and block its stimulation by histamine; examples of such drugs are famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac). A dense web of functionalities between histamine and H2RAs, on the one hand, and downstream cellular pathways, on the other hand, links disparate physiological pathways in gastrointestinal contexts (e.g., acid reduction) to the dysregulated inflammatory cas-cades (cytokine storm) underlying the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, though not for lack of effort: over 10 studies have examined the potential therapeutic value of famotidine in COVID-19, but have found conflicting results (pro-famotidine, anti-famotidine, and neutral). Given the contradictory reports, we have undertaken the new analysis reported herein. Notably, studies published thus far rest upon substantially smaller datasets than drawn upon in the present work. We analyzed a cohort of 22,560 COVID-19 patients taking H1/H2 receptor antagonists, focusing on 1,379 severe cases requiring respiratory support. We analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, aspirin, and a famotidine & aspirin combination. For cases that reached the point of respiratory support, we found a significantly reduced fatality risk for famotidine treatment. We did not detect a benefit from dual-histamine receptor blockade (concurrently targeting H1 and H2 receptors). Notably, famotidine combined with aspirin did exhibit a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%–an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. We found lower levels of serum markers for severe disease (e.g., C-reactive protein) in famotidine users, consistent with prior findings by others and with a role for famotidine in attenuating cytokine release. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of popular drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.