Does hydroxychloroquine reduce mortality in patients with COVID-19? A meta-analysis with sequential analysis of trials – Chen – 2021 – International Journal of Clinical Practice

The COVID-19 epidemic has caused an unprecedented global health and financial crisis. As of August 2020, more than 20 million people worldwide had been infected; however, specific treatments remain under study. Hydroxychloroquine, a classic chloroquine-derived drug for rheumatologic diseases, has shown activity against the novel coronavirus in vitro and has been approved in some national regulatory bodies to treat patients with COVID-19.1, 2 However, some studies have reported no effect on the rate of intubation or mortality.3 We therefore performed a meta-analysis to assess the effects of hydroxychloroquine on overall mortality in patients with COVID-19. In addition, we used trial sequence analysis (TSA) to check whether the results of the meta-analysis were conclusive.

Full literature searches using PubMed, Google Scholar, MedRxiv, and preprints literature were undertaken for studies published up to February 2021, using the keywords “COVID-19”, “hydroxychloroquine” and “Mortality” with related MeSH terms. Two reviewers (PHC and HJJ) independently reviewed titles and abstracts and extracted data. Any discrepancies were resolved by group discussion. A DerSimonian-Laird random-effects model was used to estimate the odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity between studies was detected by I2 > 50% and Cochran Q-test P <.1. subgroup analyzes were performed on study designs treatment regimens and severities of covid-19 to detect clinical statistical heterogeneity. all using the software packages r foundation for computing vienna austria double-sided function>?? = 5% and 1 – ?? = 80% power. We assumed a relative risk reduction by calculating from the average of the event proportions for the intervention and control arms. Random-effect TSA was performed using TSA software (version 0.9.5.10 Beta; Copenhagen Trial Unit, Copenhagen, Denmark).

A total of 26 studies (n = 30,167, Table 1) were selected for the meta-analysis. The use of hydroxychloroquine with or without azithromycin did not reduce mortality rates compared to standard care (random-effects OR: 1.01; 95% CI: 0.81-1.25; I2 = 82%; Cochran P-value <.01 the asd revealed a proportion of intervention events control and diversity cumulative>Z– the curve did not cross the conventional limit, and the required information size of 14,064 was reached, demonstrating no difference in overall mortality in patients who received hydroxychloroquine with or without azithromycin compared to care standard (OR adjusted for ASD: 1.01; 95% CI, 0.79-1.28; I2 = 77%; Cochran QP-value

TABLE 1.
Studies included on the use of hydroxychloroquine regarding mortality
First author Newspaper Type Patient characteristics Processing
Randomized control trial

Chen et al

IDPM: 32391667

J Zhejiang Univ (Med Sci) Randomized control trial Hospitalized patients (exclude severe symptoms) HCQ 400 mg / day for 5 days

Skipper et al

PMID: 32673060

Annals of Internal Medicine Randomized control trial Outpatient adults with early-onset COVID-19 HCQ (800 mg once, followed by 60 mg over 6-8 hours, then 600 mg daily for an additional 4 days)

Cavalcanti et al

PMID: 32 706 953

NEJM Randomized control trial Mild to moderate hospitalized patients HCQ 800 mg / day for 7 days with / without AZI

RECOVERY Collaboration Group

PMID: 33031652

N English J Med Randomized control trial Hospitalized patients HCQ 1600 mg on day 1, followed by 800 mg / d for 9 d

Abd-Elsalam et al

PMID: 32828135

The American Journal of Tropical Medicine and Hygiene Randomized control trial Hospitalized patients HCQ 800 mg on day 1, followed by 400 mg / d for 15 d

Mitjà et al

PMID: 32674126

Clinical infectious diseases Randomized control trial Non-hospitalized adults with mild COVID-19 HCQ 800 mg on day 1, followed by 400 mg / d for 6 d

Tang et al

PMID: 32409561

BMJ Randomized control trial Mild to moderate hospitalized patients HCQ 1200 mg / d for 3 d, followed by 800 mg / d for 2-3 weeks

WHO Solidarity Trials Consortium

PMID: 33264556

N English J Med Randomized control trial Hospitalized patients HCQ 2400 mg on day 1, followed by 400 mg / d for 9 days
Non-randomized clinical trial

Gautret et al

PMID: 32205204

Int J Antimicrobial agents Non-randomized clinical trial Mild symptoms in hospital patients HCQ 600 mg / day for 10 days with AZI

Rosenberg et al

IDPM: 32392282

JAMA Cohort / observation Hospitalized patients HCQ with / without AZI

Mahevas et al

PMID: 32554525

BMJ Cohort / observation Mild to moderate hospitalized patients HCQ 600 mg / day

Geleris et al

PMID: 32379955

N English J Med Cohort / observation Patients hospitalized with moderate to severe respiratory disease HCQ 1200 mg on day 1, followed by 400 mg / d for an additional 4 days with / without AZI

Yu et al

IDPM: 32418114

Sci. China Life Sci. Cohort / observation Critically ill patients with COVID-19 HCQ 400 mg / day for 7-10 days

Lagier et al

PMID: 32593867

Travel Med Infect Dis Cohort / observation Hospitalized patients HCQ 600 mg / day for 10 days with AZI

Magagnoli et al

PMC7274588

Med (NY). Cohort / observation Hospitalized patients HCQ with / without AZI

Paccoud et al

PMID: 32556143

Clin Infect Dis. Cohort / observation Mild to severe hospitalized patients HCQ 600 mg / day for 10 days

Arshad et al

PMID: 32623082

International Journal of Infectious Diseases Cohort / observation Hospitalized patients HCQ with / without AZI

Huang et al

PMC7313782

National scientific journal Cohort / observation Non-critical hospitalized patients QC 300-600 mg / d for a maximum of 10 days

Grimaldi et al

PMID: 33025225

Annals of Intensive Care Cohort / observation Moderately to severe hospitalized patients HCQ 400-800 mg / d for 5-10 d
Joshua Barbosa (preprint) Unpublished Cohort / observation Moderate to severe symptoms in hospital patients HCQ 800 mg on day 1, followed by 200-400 mg / d for an additional 4 days
RB Esper (preprint) Unpublished Cohort / observation Outpatients HCQ 800 mg on day 1, followed by 400 mg / d for an additional 6 days with AZI

Ip et al

PMID: 32790733

PLoS One. Cohort / observation Hospitalized patients HCQ 800 mg on day 1, followed by 400-600 mg / d for an additional 4 days with / without AZI
FJM de Novales (preprint) Preprints (www.preprints.org) Cohort / observation Hospitalized patients HCQ 800 mg on day 1, followed by 400 mg / day

Mallat et al

PMID: 33350752

Medicine (Baltimore) Cohort / observation Hospitalized patients HCQ 800 mg on day 1, followed by 400 mg / d for 10 d

Shailendra Singh

(preprint)

MedRxiv Cohort / observation Hospitalized patients HCQ with / without AZI
Emilie Sbidian (prepublication) MedRxiv Cohort / observation Hospitalized patients HCQ with / without AZI
  • Abbreviations: AZI, azithromycin; HCQ, hydroxychloroquine.

Sequential analysis of trials in the meta-analysis of overall mortality. In this figure, the TSA has shown that the Z-the curve crossed the required information size but did not cross the conventional limit, suggesting that treatment with hydroxychloroquine is no different from conventional treatment in terms of reducing overall mortality. The result is conclusive and robust based on the TSA. X axis, size of accumulated information; Y axis, cumulative Z-Goal; blue line, cumulative Z-value; solid red lines, trial sequential monitoring limits and futility limits (statistical significance level in ASD); dark red horizontal line, conventional limits (significance level in conventional meta-analysis); and vertical solid red line, size of information required. TSA, trial sequence analysis

As the COVID-19 pandemic has reached critical new levels, there is an urgent need for effective treatments for the disease. A previous meta-analysis evaluating the effects of hydroxychloroquine in the treatment of COVID-19 was characterized by insufficient and often conflicting evidence.4 However, with many studies emerging since its publication, the previous meta-analysis, which included limited studies, does not reflect the current understanding of the literature. Thus, we performed an updated meta-analysis that showed no evidence of a benefit for hydroxychloroquine in reducing mortality.4

Even if the meta-analysis alone concluded that the intervention had no effect, it might still have insufficient statistical power to investigate the true effects.5 The TSA is a realistic and reliable tool to test whether the meta-analysis is powerful enough or reports erroneous results due to systematic bias or random errors. The benefits of ASD include re-estimating the sample size needed or stopping other trials when the benefits of the intervention do not exist.6 We performed an ASD in the present meta-analysis and demonstrated that it might be futile to conduct future trials. Regarding opportunity costs, further hydroxychloroquine trials aimed at reducing mortality should not be a top priority in the war against the COVID-19 pandemic.

In conclusion, our meta-analysis with TSA suggests that the use of hydroxychloroquine in patients with COVID-19 has no benefit in reducing overall mortality.

ACKNOWLEDGEMENT

The authors thank Enago (www.enago.tw) for supporting the review in English.

    DISCLOSURE

    The authors have declared no conflict of interest.

    CONTRIBUTIONS FROM AUTHORS

    PHC and CHL were involved in the conceptualization; PHC and HJJ in methodology and writing — preparation of the original draft; SSP in formal analysis; HJJ and LJOY under investigation; and LJOY and CHL in writing — review and editing.

    About Mark A. Tomlin

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