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

Abstract COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs, such as acid-reducing drugs that act as histamine H2 receptor antagonists (H2RA). These compounds, exemplified by famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac), bind the H2R and block the histamine-triggered stimulation of signal transduction cascades. Histamine and H2RAs, on the one hand, and downstream physiological pathways, on the other hand, form a dense web of disparate pathways and signaling networks; these networks are ultimately tied to the dysregulated inflammatory cascades (cytokine storm) that underlies the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, despite much recent effort: over 10 studies have examined the potential value of famotidine in COVID-19, but have found largely contradictory results. Given the conflicting reports, we have undertaken a new analysis reported herein, drawing upon a cohort of 22,560 COVID-19 patients. Using electronic health records, we statistically analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, the general-purpose anti-inflammatory aspirin, and a famotidine & aspirin combination. For severe cases (requiring respiratory support), we found a significantly reduced fatality risk for famotidine treatment. Notably, famotidine combined with aspirin exhibited 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. The large, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases internationally, 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 common over-the-counter drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.