Abstract
BackgroundDespite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained.ObjectivesThe objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs).MethodsThe 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.ResultsOne 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).ConclusionsCQ 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 registrationPROSPERO CRD42020177818
Highlights
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
For studies in which such losses were higher than 5%, we considered a low risk of bias in this domain if the rates were balanced between groups, the causes were justified, and not related with any Serious adverse events (SAE)
For outcomes where assessors were aware of the intervention received by study participants, we considered that the assessment of the retinopathy and cardiac complications could have been influenced by the knowledge of the intervention received, but not for SAE
Summary
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. The effectiveness of these drugs has been studied in relation to a variety of acute infectious diseases, including Zika, influenza A H5N1, Ebola, dengue, and chikungunya, as well as chronic viral infections, including hepatitis C and human immunodeficiency virus [3,4,5]. The most common adverse events (AEs) of these medications are related to gastrointestinal intolerance, such as vomiting, nausea, diarrhea, and abdominal discomfort [6]. Cutaneous manifestations, such as itching, skin rash, photosensitivity, and hyperpigmentation [7] can occur. Less frequent adverse effects, such as myopathy, neuromyopathy, and cardiotoxicity can be more severe and irreversible [1]
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