Safety of treatment with chloroquine and hydroxychloroquine: A ten-year systematic review and meta-analysis

https://doi.org/10.1016/j.ejim.2021.03.028Get rights and content

Highlights

  • Our data reinforces the notion that chloroquine and hydroxychloroquine have a good safety profile.

  • Users of both antimalarial presented a higher risk of mild and self-limited adverse events.

  • A ten-year meta-analysis did not reveal a statistically significant higher risk of cardiovascular events in chloroquine and hydroxychloroquine users.

  • Ventricular arrhythmias and myocardial infarction were reported in hospitalized COVID-19 patients using higher than usual doses of chloroquine or hydroxychloroquine.

Abstract

Objective

To estimate the incidence rate ratio (IRR) of adverse events (AE) in chloroquine or hydroxychloroquine users.

Methods

We systematically reviewed randomized controlled trials (RCTs), using MEDLINE (2010-2020) and EMBASE (2010-2020) databases, reporting AE in chloroquine or hydroxychloroquine users during treatment for lupus, rheumatoid arthritis, malaria and COVID-19. The protocol for this systematic review is registered at the PROSPERO database (CRD42020197938). The quality of the included studies was assessed using the Cochrane risk-of-Bias tool and relevant data were extracted though a customized data collection form, independently, by two authors. The IRR of AE was estimated using a random-effect model meta-analysis and heterogeneity was evaluated by T2 and I2. Subgroup analysis was performed, and publication bias was assessed by funnel-plot.

Results

Forty-six RCTs met our eligibility criteria and were included in our analysis (23132 patients). There was not a single death attributed to chloroquine or hydroxychloroquine use in the included RCTs. The IRR of general AE during antimalarial use was 1.15 [CI 95% 1.01-1.31]. COVID-19 patients treated with either antimalarial presented an 83% and 165% higher risk of developing general and gastrointestinal AE, respectively, in comparison with controls. The use of antimalarial increased the risk of developing dermatological AE by 92% in malarial studies and reduced by 65% in lupus studies. We did not find a significatively higher risk of cardiovascular nor ophthalmological AE in antimalarial users.

Conclusions

Our data reinforces that chloroquine and hydroxychloroquine have a good safety profile though caution is advised when using higher than usual doses in hospitalized COVID-19 patients.

Introduction

Previously known as SN7618, chloroquine has been used since the early 1940s for the treatment of malaria [1]. In 1946 Loeb F. et al., in a statement approved by the board for coordination of malarial studies, highlighted the efficacy and safety profile of the drug – “with minor side effects as mild and transient headache, visual disturbances, pruritus, and gastrointestinal complaints”. The authors also noted that none of the adverse symptoms was serious and all of them were readily reversible [2]. In 1953, Hoenkenga M.T. et al. reported encouraging results for the treatment of malaria with 7-chloro-4-[4-(N-ethyl-N-β-hydroxyethylamino)-1-methylbutylamino], later known as hydroxychloroquine. Besides its efficacy, the authors did not find any side effects during its first clinical study [3].

Since its discovery, other diseases besides malaria – like lupus [4], rheumatoid arthritis (RA) [5], hand osteoarthritis [6], and antiphospholipid syndrome [7], – have been successfully treated with chloroquine and hydroxychloroquine. In general, both drugs have been considered safe for nearly 60 years, even for long term use. Gastrointestinal complaints are the most frequent side effects, although retinopathy has been the most feared one. Dermatological, neurological, musculoskeletal, and cardiovascular side effects are also reported, though less frequently [8].

In 2018, Chatre C. et al. systematically reviewed the cardiac toxicity attributed to chloroquine and hydroxychloroquine and concluded that both drugs were safe and well-tolerated, but cardiotoxicity could be a rare, severe, and overlooked complication of such therapy [9].

In 2020, the world spread of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) – the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), has demanded innovative treatment options to halt the disease progression and the already high, death toll. Wang M. et al. suggested, in February of that same year, that chloroquine was highly effective in the control of SARS-Cov-2 infection in vitro [10]. With the potential use of chloroquine and hydroxychloroquine for the treatment of COVID-19, the debate on its safety have reemerged, and studies with conflicting results have been published [11], [12], [13].

Considering that both drugs have been in the market for a long time, the extensive body of evidence supporting them, and the recent doubts on its safety, we decided to conduct a systematic review to assess the safety of hydroxychloroquine and chloroquine for the treatment of lupus, RA, malaria, and COVID-19.

Section snippets

Objectives

We systematically reviewed randomized controlled trials (RCTs) reporting adverse events (AE) in users of chloroquine or hydroxychloroquine - for the treatment of lupus, RA, malaria and COVID-19 - in comparison to non-users, to estimate the incidence rate ratio (IRR) of developing AE, in general and categorized by system.

Methods

This systematic review with meta-analysis was conceived according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) [14], its checklist is provided as a supplementary file and its protocol is available online at the PROSPERO database (identifier CRD42020197938).

Study selection

Our research generated 938 records for evaluation. After excluding duplicates, a total of 925 titles and abstracts were screened. As we did not find any information about AE in 787 studies, they were considered irrelevant and excluded from our analysis. We retrieved 138 articles for full-text appreciation. 42 studies met our eligibility criteria and were included in our systematic review and meta-analysis.

As we found only 2 RCTs evaluating the use of hydroxychloroquine in patients with lupus,

Publication bias

The visual inspection of the funnel plot suggested some asymmetry, later confirmed in a weighted linear regression of the treatment effect on its standard error (P-value = 0.003229) (fig.S30).

Considering the asymmetry observed in our funnel plot, we performed Duval S. and Tweedie R.'s “Trim and fill” procedure [24] to estimate potentially missing studies and adjust the overall effect estimate. This analysis revealed an IRR of 1.41(CI 95% 1.25 - 1.59) suggesting that we may have underestimated

Sensitivity analysis

We performed a sensitivity analysis to assess the robustness of our results. Firstly, we repeated our main analysis excluding outliers as described by Viechtbauer and Cheung [25]. This procedure significantly reduced the heterogeneity of our analysis (I2 from 89% to 35%) (fig.S31) and the pooled IRR still suggested a statistically significant higher risk of developing any AE in hydroxychloroquine and chloroquine users (IRR 1.11 [CI 95% 1.04 – 1.18]).

We conducted the same analysis for

Discussion

We found a higher IRR of total AE in hydroxychloroquine or chloroquine users. This risk was 83% higher in patients infected with COVID-19 in comparison with non-users.

A higher IRR of gastrointestinal AE was observed in patients treated with either antimalarials, after exclusion of outliers (IRR 1.14 [CI 95% 1.01 – 1.29]). This risk was significantly higher in COVID-19 patients (IRR 2.65[CI 95% 1.60– 4.39]). Gastrointestinal complaints are the most reported AE in hydroxychloroquine and

Conclusions

We found that chloroquine and hydroxychloroquine have in general a good safety profile, as most of their side effects were mild and not fatal. COVID-19 patients seem to have a higher risk of general and gastrointestinal AE during their use. These AE may be related to an interaction between virus, host and polypharmacy, not the antimalarial use itself. Although our analysis did not suggest a significantly higher IRR of cardiovascular AE in antimalarial users when compared to non-users,

Declarations: funding

M.B.S. has received a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The government funding agency had no role in study design, manuscript elaboration, authors decisions, or manuscript approval for publication.

Availability of data and materials

The authors declare that this systematic review is an original work and all the data will be available from the corresponding author on request.

Ethics approval and consent to participate

As all the data used in this systematic review is available for public access, there is no need of ethics committee approval.

Consent

Not applicable.

Author's contribution

FLBE conceptualized, drafted and is the guarantor of this manuscript. FLBE and SG developed the selection criteria, the risk of bias assessment strategy and data extraction criteria. MBS and SG reviewed the manuscript. All authors read, provided feedback and approved this systematic review.

Declaration of Competing Interest

The authors declare that they have no competing interest.

Acknowledgments

The authors would like to thank Evidence Partners for providing us free access to their systematic review software – Distiller SR – through COVID-19 initiative.

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