Xing Wu
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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
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.
