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

Published:April 05, 2021DOI:


      • 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.



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


      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.


      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.


      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.


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        • Kitchen L.W.
        • Vaughn D.W.
        • Skillman D.R.
        Reviews of anti-infective agents: role of US military research programs in the development of US food and drug administration–approved antimalarial drugs.
        Clin Infect Dis. 2006; 43: 67-71
        • Loeb F.
        Activity of a new antimalarial agent, chloroquine (SN 7618).
        J Am Med Assoc. 1946; 130: 1069
        • Hoekenga M.T.
        Treatment of malaria with oral or intravenous Plaquenil.
        Am J Trop Med Hyg. 1953; 2: 805-807
        • Wallace D.
        The history of antimalarials.
        Lupus. 1996; 5: 2-3
        • Khraishi M.
        • Singh G.
        The role of anti-malarials in rheumatoid arthritis – the American experience.
        Lupus. 1996; 5: 41-44
        • Kingsbury S.R.
        • Tharmanathan P.
        • Adamson J.
        • Arden N.K.
        • Birrell F.
        • Cockayne S.
        • et al.
        Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial.
        Trials. 2013; 14 (64-64)
        • Kravvariti E.
        • Koutsogianni A.
        • Samoli E.
        • Sfikakis P.P.
        • Tektonidou M.G.
        The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary antiphospholipid syndrome: a pilot open label randomized prospective study.
        Autoimmun Rev. 2020; 19 (102491–102491)
        • Maksymowych W.
        • Russell A.S.
        Antimalarials in rheumatology: efficacy and safety.
        Semin Arthritis Rheum. 1987; 16: 206-221
        • Chatre C.
        • Roubille F.
        • Vernhet H.
        • Jorgensen C.
        • Pers Y.-M.
        Cardiac Complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature.
        Drug Saf. 2018; 41: 919-931
        • Wang M.
        • Cao R.
        • Zhang L.
        • Yang X.
        • Liu J.
        • Xu M.
        • et al.
        Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
        Cell Res. 2020; 30: 269-271
        • Zhong H.
        • Wang Y.
        • Zhang Z.-L.
        • Liu Y.-X.
        • Le K.-J.
        • Cui M.
        • et al.
        Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: a systematic review and meta-analysis.
        Pharmacol Res. 2020; 157104872
        • Huang M.
        • Tang T.
        • Pang P.
        • Li M.
        • Ma R.
        • Lu J.
        • et al.
        Treating COVID-19 with Chloroquine.
        J Mol Cell Biol. 2020; 12: 322-325
        • Gautret P.
        • Lagier J.-C.
        • Parola P.
        • Hoang V.T.
        • Meddeb L.
        • Mailhe M.
        • et al.
        Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
        Int J Antimicrob Agents. 2020; 56105949
        • Moher D.
        • Shamseer L.
        • Clarke M.
        • Ghersi D.
        • Liberati A.
        • et al.
        • PRISMA-P Group
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Sterne J.A.C.
        • Savović J.
        • Page M.J.
        • Elbers R.G.
        • Blencowe N.S.
        • Boutron I.
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; : l4898
        • Balduzzi S.
        • Rücker G.
        • Schwarzer G.
        How to perform a meta-analysis with R: a practical tutorial.
        Evid Based Ment Health. 2019; 22: 153-160
        • Guevara J.P.
        • Berlin J.A.
        • Wolf F.M.
        Meta-analytic methods for pooling rates when follow-up duration varies: a case study.
        BMC Med Res Methodol. 2004; 4: 1-7
      1. Higgins JPT G.S. (editors). Cochrane handbook for systematic reviews of interventions 2011.

        • Friedrich J.O.
        • Adhikari N.K.
        • Beyene J.
        Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data.
        BMC Med Res Methodol. 2007; 7: 5
        • Higgins J.P.T.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Egger M.
        • Smith G.D.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • The RECOVERY Collaborative Group
        Effect of hydroxychloroquine in hospitalized patients with Covid-19.
        N Engl J Med. 2020; 383: 2030-2040
        • Cavalcanti A.B.
        • Zampieri F.G.
        • Rosa R.G.
        • Azevedo L.C.P.
        • Veiga V.C.
        • Avezum A.
        • et al.
        Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.
        N Engl J Med. 2020; (NEJMoa2019014)
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Viechtbauer W.
        • Cheung M.W.-L.
        Outlier and influence diagnostics for meta-analysis.
        Res Synth Methods. 2010; 1: 112-125
        • Mao R.
        • Qiu Y.
        • He J.-S.
        • Tan J.-Y.
        • Li X.-H.
        • Liang J.
        • et al.
        Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis.
        Lancet Gastroenterol Hepatol. 2020; 5: 667-678
        • Shee J.C.
        Lupus erythematosus treated with chloroquine.
        Lancet. 1953; 262: 201-202
        • Harvey G.
        • Cochrane T.
        The treatment of lupus erythematosus with chloroquine sulphate1.
        J Invest Dermatol. 1954; 22: 89-91
        • Zirwas M.J.
        Dramatic response to chloroquine and mirtazapine for recalcitrant atopic dermatitis.
        Dermatitis. 2006; 17: 208-209
        • Chen D.
        • Li X.
        • Song Q.
        • Hu C.
        • Su F.
        • Dai J.
        • et al.
        Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019.
        JAMA Netw Open. 2020; 3 (e2011122)
        • Shi S.
        • Qin M.
        • Shen B.
        • Cai Y.
        • Liu T.
        • Yang F.
        • et al.
        Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
        JAMA Cardiol. 2020; 5: 802
        • Burrell Z.L.
        • Martinez A.C.
        Chloroquine and hydroxychloroquine in the treatment of cardiac arrhythmias.
        N Engl J Med. 1958; 258: 798-800
        • Alkmim Teixeira R.
        • Borba E.F.
        • Pedrosa A.
        • Nishioka S.
        • Viana V.S.T.
        • Ramires J.A.
        • et al.
        Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus.
        Europace. 2014; 16: 887-892
        • Huang H.-.Y.
        • Andrews E.
        • Jones J.
        • Skovron M.L.
        • Tilson H.
        Pitfalls in meta-analyses on adverse events reported from clinical trials: PITFALLS IN META-ANALYSES ON ADVERSE EVENTS.
        Pharmacoepidemiol Drug Saf. 2011; 20: 1014-1020
        • Thuan P.D.
        • Ca N.T.N.
        • Van Toi P.
        • Nhien N.T.T.
        • Thanh N.V.
        • Anh N.D.
        • et al.
        A Randomized comparison of chloroquine versus dihydroartemisinin–piperaquine for the treatment of Plasmodium vivax infection in Vietnam.
        Am J Trop Med Hyg. 2016; 94: 879-885
        • Popovici J.
        • Vantaux A.
        • Primault L.
        • Samreth R.
        • Piv E.P.
        • Bin S.
        • et al.
        Therapeutic and transmission-blocking efficacy of dihydroartemisinin/piperaquine and chloroquine against Plasmodium vivax Malaria, Cambodia.
        Emerg Infect Dis. 2018; 24: 1516-1519
        • Heimans L.
        • Akdemir G.
        • Boer K.V.C.W.
        • Goekoop-Ruiterman Y.P.
        • Molenaar E.T.
        • van Groenendael J.H.L.M.
        • et al.
        Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study).
        Arthritis Res Ther. 2016; 18: 23
        • de Jong P.H.
        • Hazes J.M.
        • Han H.K.
        • Huisman M.
        • van Zeben D.
        • van der Lubbe P.A.
        • et al.
        Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial.
        Ann Rheum Dis. 2014; 73: 1331-1339
        • O'Dell J.R.
        • Mikuls T.R.
        • Taylor T.H.
        • Ahluwalia V.
        • Brophy M.
        • Warren S.R.
        • et al.
        Therapies for active rheumatoid arthritis after methotrexate failure.
        N Engl J Med. 2013; 369: 307-318
        • Moreland L.W.
        • O'Dell J.R.
        • Paulus H.E.
        • Curtis J.R.
        • Bathon J.M.
        • et al.
        A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of early aggressive rheumatoid arthritis trial.
        Arthritis Rheum. 2012; 64: 2824-2835
        • van Vollenhoven R.F.
        • Geborek P.
        • Forslind K.
        • Albertsson K.
        • Ernestam S.
        • Petersson I.F.
        • et al.
        Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.
        Lancet. 2012; 379: 1712-1720