It’s been about four years since the COVID-19 pandemic shut down the entire world. Researchers continue to study not only the long-term effects of the virus but also the therapies that have been employed to manage this devastating infectious disease. The Agency for Healthcare Research and Quality (AHRQ) spearheaded a rapid review of the literature to determine if COVID treatments that received emergency use authorization (EUA) by the Food and Drug Administration (FDA) are associated with serious adverse events (AHRQ, 2024).

Methodology (AHRQ, 2024)

The review included the following pharmaceutical interventions used for treatment or prevention of COVID-19:

• Convalescent plasma from recovered COVID-19 patients
• Antivirals such as remdesivir (Veklury), nirmatrelvir and ritonavir combination (Paxlovid), and molnupiravir (Lagevrio)
• Monoclonal antibodies including bamlanivimab and etesevimab combination, bebtelovimab, casirivimab and imdevimab combination (Regeneron), sotrovimab (Xevudy), tixagevimab and cilgavimab combination (Evusheld), and tocilizumab (Actemra)
• Interleukin-1 receptor antagonist anakinra (Kineret) 

A total of 54 studies were evaluated in the review, each required to have either a placebo, untreated, or usual care comparison group. Case reports, case series, or uncontrolled surveillance studies were excluded. At least one U.S. site or territory had to be involved in each study.
 
Serious injuries were defined as physical changes and serious functional abnormalities at the cellular or tissue level in any bodily function. Only injuries that warranted hospitalization (regardless of the need for hospitalization) or injuries that led to a significant loss of function or disability (regardless of the need for hospitalization) were considered serious injuries. In addition, Common Terminology Criteria for Adverse Events level 3 was used. Level 3 is defined as severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization; or disabling. Pulmonary embolism and deep vein thrombosis were grouped as thrombotic events; arterial or venous bleeding were combined as bleeding events; and all serious infections including sepsis were aggregated. Timing for adverse events were categorized as occurring within either 45 days of initial pharmaceutical administration or greater than 45 days from administration.
 
The system below, outlined in the Institute of Medicine 2012 report on Adverse Effects of Vaccines: Evidence and Causality, was utilized to evaluate the certainty of evidence (Stratton et al., 2011).

• High certainty: two or more studies with minimal limitations that are consistent in the direction of the effect that provide high confidence.
• Moderate certainty: one study with minimal limitations, or a collection of studies generally consistent in the direction of effect, that provide moderate confidence.
• Limited certainty: one study or a collection of studies without precision or consistency that provides limited, or low, confidence.
• Insufficient: no epidemiologic studies of sufficient quality.

Summary of Findings (AHRQ, 2024)

The AHRQ review yielded the following results.

• There is moderate certainty that convalescent plasma while hospitalized with COVID-19 may cause an increased risk of serious bleeding events and infection, including sepsis, within 30 days in patients with hematologic cancers.
• There is limited certainty that convalescent plasma may be associated with serious thrombotic events within 90 days among patients hospitalized for COVID-19.
• There is insufficient evidence to associate any adverse events with antivirals used for COVID-19 (remdesivir, nirmatrelvir and ritonavir combination, molnupiravir).
• There is insufficient evidence to associate any adverse events with SARS-CoV-2 spike protein receptor binding antibodies bamlanivimab/etesevimab, bebtelovimab, sotrovimab, casirivimab/imdevimab, and tixagevimab/cigavimab.
• There is limited certainty that the monoclonal antibody tocilizumab, an IL-6 inhibitor, may be associated with increased risk of neutropenia within four weeks in patients hospitalized with COVID-19. There is limited certainty that COVID-19 patients on extracorporeal membrane oxygenation (ECMO) for respiratory support or intravenous infusion of a vasopressor or inotrope for cardiovascular support in the intensive care unit are at increased risk of bleeding events within 90 days.
• No studies of Anakinra for COVID-19 met inclusion criteria.

Conclusion

This review identified few associations between EUA pharmaceutical interventions for COVID-19 and serious adverse events. However, the review had several limitations. One major constraint was the requirement that each study include at least one U.S. site. Results from studies from other regions without a U.S. site could reduce or augment the findings. Another limitation was the exclusion of uncontrolled studies which might provide areas for additional research. Lastly, while most studies included patients with chronic conditions, most didn’t stratify adverse event data by specific pre-existing conditions.
 
It is important to note that the AHRQ commissioned this rapid review employing abridged methods to evaluate data in a compressed timeframe. The review will be used by the Health Resources & Services Administration (HRSA) Countermeasures Injury Compensation Program (CICP) to determine benefits eligibility for injuries or deaths.
 
To read the complete study, click here.
 

References
 
Agency for Healthcare Research and Quality (2024). Adverse Events Associated with COVID-19 Pharmaceutical Treatments. Department of Health & Human Services. https://effectivehealthcare.ahrq.gov/products/COVID-19-pharmaceutical-treatments/rapid-research
 
Stratton, K., Ford, A., Rusch, E., Clayton, E. W., Committee to Review Adverse Effects of Vaccines, & Institute of Medicine (Eds.). (2011). Adverse Effects of Vaccines: Evidence and Causality. National Academies Press (US).
 

 

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