Meta-Analysis of the Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death

by Ivan Tkachenko

Medrxiv, an Internet site distributing complete but unpublished manuscripts in the areas of medicine, clinical research, and related health sciences, published a meta-analysis of the randomized controlled trials of early ambulatory hydroxychloroquine in the prevention of COVID-19 infection, hospitalization, and death.

This article is a preprint and has not been certified by peer review. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

AUTHOR INFORMATION

  1. Joseph A. Ladapo (jladapo@mednet.ucla.edu),
  2. John E. McKinnon (jmckinn3@hfhs.org),
  3. Peter A. McCullough (peteramccullough@gmail.com) and
  4. Harvey Risch (harvey.risch@yale.edu)

Abstract

Objective--To determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19). Design--Systematic review and meta-analysis of randomized clinical trials. Data sources--Search of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses. Study selection--Randomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19. Methods--Two investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I2 parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05. Results--Five randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal. Conclusion--Hydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare. Systematic review registration--This review was not registered.

Competing Interest Statement

Dr. Risch acknowledges past advisory consulting work with two of the more than 50 manufacturers of hydroxychloroquine, azithromycin and doxycycline. This past work was not related to any of these medications and was completed more than two years ago. He has no ongoing, planned or projected relationships with any of these companies, nor any other potential conflicts-of-interest to disclose. None of the other authors have any potential conflicts of interest to disclose.

Funding Statement

No funding received.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB/oversight body approval is not required per se. The study comprised an analysis of existing study data, in which each of the original studies had already obtained institutional review board approvals.

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes