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      Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: a systematic review and meta-analysis

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          Abstract

          Background and aims

          Chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used in patients with rheumatic diseases, but their effects on the cardiovascular system remain unclear. We aimed to assess whether CQ/HCQ could reduce the risk of cardiovascular disease (CVD).

          Materials and methods

          We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and the ClinicalTrials.gov for studies investigating the association between CQ/HCQ and the risk of CVD from inception to 20 December 2017. We carried out the quality assessment using the Newcastle-Ottawa Quality Assessment Scale (NOS). Random-effects model was used to pool the risk estimates relative ratio (RR), hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) for the outcomes.

          Results

          A total of 19 studies (7 case-control studies, 12 cohort studies, and no clinical trials) involving 19,679 participants were included in the meta-analysis. Pooled results for HRs or RRs showed that CQ/HCQ was associated with a significantly reduced risk of CVD (pooled RR 0.72, 95% CI 0.56–0.94, p=0.013). Results based on ORs showed a similar tendency towards a reduced risk of CVD with CQ/HCQ (pooled OR 0.41, 95% CI 0.25–0.69, p=0.001).

          Conclusion

          Our results suggested that CQ/HCQ was associated with a reduced risk of CVD in patients with rheumatic diseases. Randomized trials are needed to confirm the potential of CQ/HCQ in cardiovascular prevention in patients with and without rheumatic diseases.

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          Most cited references 49

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          Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus.

          Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular disease and lupus-related factors have not been examined in a case-control study. In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment. The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies. Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy. Copyright 2003 Massachusetts Medical Society
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            Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.

            Antimalarial drugs (AMs), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in patients with lupus with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. The aim of the present work was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in systemic lupus erythematosus (SLE). A systematic review of the English literature between 1982 and 2007 was conducted using the MEDLINE and EMBASE databases. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence. A total of 95 articles were included in the systematic review. High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss. Toxicity related to AMs is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, high levels of evidence were found that AMs, particularly HCQ, decrease lupus activity without harming the baby. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting patients with lupus against cancer. Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.
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              Cardiotoxicity of antimalarial drugs.

              There are consistent differences in cardiovascular state between acute illness in malaria and recovery that prolong the electrocardiographic QT interval and have been misinterpreted as resulting from antimalarial cardiotoxicity. Of the different classes of antimalarial drugs, only the quinolines, and structurally related antimalarial drugs, have clinically significant cardiovascular effects. Drugs in this class can exacerbate malaria-associated orthostatic hypotension and several have been shown to delay ventricular depolarisation slightly (class 1c effect), resulting in widening of the QRS complex, but only quinidine and halofantrine have clinically significant effects on ventricular repolarisation (class 3 effect). Both drugs cause potentially dangerous QT prolongation, and halofantrine has been associated with sudden death. The parenteral quinoline formulations (chloroquine, quinine, and quinidine) are predictably hypotensive when injected rapidly, and cardiovascular collapse can occur with self-poisoning. Transiently hypotensive plasma concentrations of chloroquine can occur when doses of 5 mg base/kg or more are given by intramuscular or subcutaneous injection. At currently recommended doses, other antimalarial drugs do not have clinically significant cardiac effects. More information on amodiaquine, primaquine, and the newer structurally related compounds is needed.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                11 June 2018
                : 12
                : 1685-1695
                Affiliations
                [1 ]Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
                [2 ]Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
                [3 ]Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu 610052, China
                [4 ]Jockey Club School of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
                [5 ]Department of Clinical Epidemiology and Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan
                [6 ]Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China
                [7 ]Division of Molecular & Clinical Medicine, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK
                Author notes
                Correspondence: Sheyu Li, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu 610041, Sichuan, China, Tel +86 131 9487 4843, Fax +86 28 8542 2982, Email lisheyu@ 123456gmail.com
                [*]

                These two authors contributed equally to this work

                Article
                dddt-12-1685
                10.2147/DDDT.S166893
                6001837
                © 2018 Liu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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