The trade-off dilemma in pharmacotherapy of COVID-19: systematic review, meta-analysis, and implications

ABSTRACT

Introduction

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and has contributed to over 650,000 deaths. This review synthesizes the literature on COVID-19 pharmacotherapy to inform practice and policymaking.

Areas covered

The authors systematically review the published literature on COVID-19 therapeutics, grouping candidate treatments into repurposed, adjunct, and experimental agents. They conducted meta-analysis where appropriate and provide recommendations based on compilation from real-time/interim therapeutic guidelines. They then advise on how to navigate and advance the evidence in the current context of uncertainty and urgency and provide expert opinion on suggested framework.

Expert opinion

Current evidence does not support a clear role for pharmacotherapy in COVID-19. While promising signals have been found through limited number of RCTs, these must be interpreted with caution. Without proper protection from bias and confounding we risk exposing patients to treatments where the potential for benefit is at best unclear, yet the potential for harm from adverse effects is high leading to a trade-off dilemma in decision making. Advancing the evidence requires a coordinated effort to design and conduct robust trials and to systematically synthesize and critically evaluate findings. Therapies should be reserved for use in clinical trials, emergency or compassionate access until we gain more confidence in the balance of benefit and harm.

KEYWORDS:

• COVID-19
• pharmacotherapy
• expert opinion
• efficacy
• pandemic
• evidence-based

Article highlights

• Numerous pharmacotherapies, novel, and repurposed, are being explored to prevent and treat COVID-19 as well as manage associated complications.

• Numerous studies are ongoing to explore the potential of these therapies, yet few robustly protect from bias and confounding.

• The current evidence does not clearly support the use of any pharmacotherapeutic regimen.

• At the time of revision of this manuscript findings from dexamethasone trial provides preliminary trend toward reducing mortality in severe COVID-19. Further studies are required for conclusive recommendation

• At the time of revision of this manuscript hydroxychloroquine papers were retracted from two major medicine journals raising concern over opacity of primary data.

• In context to current and rapidly changing therapeutics this paper provides revised recommendations on hydroxychloroquine (with/without azithromycin), new recommendations on the use of remdesivir and new recommendations on famotidine (based on findings from collated living clinical guidelines).

• Coordinated efforts to design and conduct rigorous randomized controlled clinical trials and synthesize the emerging evidence are necessary to generate evidence that practitioners, patients, and policy makers can have high confidence in.

This box summarizes key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript has not been funded.