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Meta-Analysis
. 2021 Nov 4;10(1):294.
doi: 10.1186/s13643-021-01835-x.

Systematic review and meta-analysis of the safety of chloroquine and hydroxychloroquine from randomized controlled trials on malarial and non-malarial conditions

Mayra Souza Botelho  1 , Fernanda Bolfi  1 , Renata Giacomini Occhiuto Ferreira Leite  1 , Mauro Salles Ferreira Leite  1 , Luisa Rocco Banzato  1 , Luiza Teixeira Soares  1 , Thaina Oliveira Felicio Olivatti  1 , Amanda Sampaio Mangolim  1 , Flávia Ramos Kazan Oliveira  1 , Luciana Patrícia Fernandes Abbade  2 , Joelcio Francisco Abbade  3 , Ricardo Augusto Monteiro de Barros Almeida  2 , Julia Simões Corrêa Galendi  4 , Lehana Thabane  5   6   7 , Vania Dos Santos Nunes-Nogueira  8
Affiliations
Meta-Analysis

Systematic review and meta-analysis of the safety of chloroquine and hydroxychloroquine from randomized controlled trials on malarial and non-malarial conditions

Mayra Souza Botelho et al. Syst Rev. .

Abstract

Background: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained.

Objectives: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs).

Methods: The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used a random-effects model to pool results across studies and Peto's one-step odds ratio (OR) for event rates below 1%. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence.

Results: One hundred and six RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95% confidence interval [CI]: 0.76-1.26, 33 trials, 15,942 participants, moderate certainty of evidence). However, there was a moderate certainty of evidence that CQ/HCQ increases the incidence of cardiac complications (RR: 1.62, 95% CI: 1.10-2.38, 16 trials, 9908 participants). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1.63, 95% CI: - 0.4-6.57, 5 trials, 344 participants, very low certainty of evidence).

Conclusions: CQ and HCQ probably do not increase SAEs, with low frequency of these adverse events on malarial and non-malarial conditions. However, they may increase cardiac complications especially in patients with COVID-19. No clear effect of their use on the incidence of retinopathy was observed.

Systematic review registration: PROSPERO CRD42020177818.

Keywords: Adverse effects; COVID-19; Chloroquine; Hydroxychloroquine; Safety; Systematic review.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Flow diagram of selected studies
Fig. 2
Fig. 2
Risk of bias according to RoB 2 for serious adverse events (SAE)
Fig. 3
Fig. 3
Meta-analysis for frequency of serious adverse events. Subgroup analysis according to the type of intervention. CQ, chloroquine; HCQ, hydroxychloroquine. Peto’s method was adopted and studies with both-armed zero-event were excluded from the analysis. Significance test(s) of OR = 1, overall, z = 0.16, p = 0.872
Fig. 4
Fig. 4
Meta-analysis for frequency of retinopathy. CQ, chloroquine; HCQ, hydroxychloroquine. Peto’s method was adopted and studies with both-armed zero-event were excluded from the analysis. Significance test(s) of OR = 1, z = 0.69, p = 0.492
Fig. 5
Fig. 5
Meta-analysis for frequency of cardiac complications. Studies with both-armed zero-event were excluded from the analysis. Significance test(s) of RR = 1, z = 2.60, p = 0.009
See this image and copyright information in PMC

References

    1. Plantone D, Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin Drug Investig. 2018;38(8):653–671. - PubMed
    1. Shukla AM, Wagle Shukla A. Expanding horizons for clinical applications of chloroquine, hydroxychloroquine, and related structural analogues. Drugs Context. 2019;8. - PMC - PubMed
    1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antivir Res. 2020;177:104762. - PMC - PubMed
    1. Helal GK, Gad MA, Abd-Ellah MF, Eid MS. Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients. J Med Virol. 2016;88(12):2170–2178. - PMC - PubMed
    1. Chauhan A, Tikoo A. The enigma of the clandestine association between chloroquine and HIV-1 infection. HIV Med. 2015;16(10):585–590. - PubMed

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