Effects of Chloroquine and Hydroxychloroquine on the Cardiovascular System - Limitations for Use in the Treatment of COVID-19

Stephani Correia Brazão Lis Jappour Autran Rosane de Oliveira Lopes Christianne Brêtas Vieira Scaramello Fernanda Carla Ferreira de Brito Nadia Alice Vieira Motta About the authors

Abstract

Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial drugs, with anti-inflammatory properties that justify their use in the treatment of systemic lupus erythematosus and rheumatic diseases. A pandemic caused by the new coronavirus led the entire world’s scientific community to look for drugs already available on the market, capable of exercising beneficial actions in the fight against the disease. Preliminary studies in patients, as well as in vitro studies, suggested possible therapeutic effects associated with the use of HCQ and CQ in the treatment of COVID-19. Despite controversies over the effects of these drugs in combating the “cytokine storm” associated with COVID and the dismal of results in different clinical trials in Brazil, their use has been encouraged and several ongoing investigative studies are underway. In addition to the possible beneficial effects on the prognosis of patients with SARS-CoV-2, such drugs include varied effects on the cardiovascular system, ranging from positive developments related to their vasodilator properties to potential negative effects, such as cardiotoxicity. This work presents the main effects exerted by these drugs on the cardiovascular system, in order to contribute to a scientific discussion about the repurposing of these drugs in the context of COVID-19.

Cardiovascular System; Chloroquine/toxicity; Hydroxychloroquine/toxicity; Betacoronavirus; COVID-19; Azithromycin/ therapeutic use

Introduction

COVID-19, a disease caused by the coronavirus (SARS-CoV-2), was discovered in Wuhan, China, and spread rapidly throughout the world (World Health Organization - WHO). 11. World Health Organization. Coronavirus disease (COVID-19) pandemic. [acesso em 01 de junho de 2020]. Disponível em: https://www.who.int/emergencies/diseases/novel-coronavirus-2019 .
https://www.who.int/emergencies/diseases...
Recent reports have highlighted the possible benefits of chloroquine (CQ) and hydroxychloroquine (HCQ) use in COVID-19 treatment. 22. Touret F, Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020 May;177:104762. Chloroquine emerged in the 1940s and is clinically used in malaria treatment due to its effectiveness, low cost, safety, and easy manufacture. CQ was synthesized for the first time in 1934, and although its antimalarial properties have been identified, its development was blocked due to the high toxicity observed for this class of drugs. Subsequently, CQ was resynthesized, presenting less toxicity and reported to be superior to sontoquine and quinacrine in malaria treatment. 33. Slater AFG. Chloroquine: mechanism of drug action and resistance in plasmodium falciparum. Pharmacol Ther. 1993;57(2-3):203-35. HCQ, clinically introduced in 1955, is an analogue of CQ, also used on malaria treatment, sharing the same mechanism of action. Its clinical indications include skin diseases, sarcoidosis, extra-intestinal amebiasis, chronic Q fever, rheumatoid, and autoimmune diseases. 44. Costedoat-Chalumeau N, Leroux G, Amoura Z, Piette JC. Hydroxychloroquine dans le traitement du lupus : le renouveau. Rev Med Interne. 2008;29(9):735-7. , 55. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review. Ann Rheum Dis. 2010;69(1):20-8.

Its antimalarial actions are associated with lysosomal activity and autophagy signaling pathways. 66. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-66. CQ and HQ bind preferentially to phospholipids, accumulating in lysosomes which promote changes in pH and direct inhibition of lysosomal enzymes. These effects lead to the impairment of intracellular degradation processes, along with the accumulation of pathological metabolic products (especially phospholipids and glycogen). Histologically, these seem to be vacuolar granule cell mutations and ultrastructural as lamellar membrane inclusion bodies and as "curvilinear bodies" in the cytoplasm. 77. Gérard JM, Stoupel N, Collier A, Flament-Durand J. Morphologic study of a neuromyopathy caused by prolonged chloroquine treatment. Eur Neurol. 1973;9(6):363-79.

HCQ has some benefits, such as a reduced incidence of kidney injury and a lower risk of developing serious comorbidities, including venous thromboembolism and pregnancy complications. 88. Alarcón GS, McGwin G, Bertoli AM, Fessler BJ, Calvo-Alén J, Bastian HM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: Data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66(9):1168-72.

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Investment in the development of malaria treatments has led to a decrease in cases, reducing morbidity and mortality of the disease. WHO estimates that between 2000 and 2010, the incidence of malaria was reduced, and this is due to vector control, improvements in the health system, effective treatments, an increase in notifications, and cases of surveillance. 1313. Cotter C, Sturrock HJW, Hsiang MS, Liu J, Phillips AA, Hwang J, et al. The changing epidemiology of malaria elimination: New strategies for new challenges. Lancet. 2013;382(9895):900-11. In addition to their antimalarial effects, CQ and HCQ have immunomodulatory actions that are recommended for the treatment of autoimmune diseases. Moreover, it has recently been shown to be effective in reducing cardiovascular risk factors, including hyperlipidemia and hyperglycemia. 1414. Wasko MCM, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, et al. Risk of diabetes in patients with rheumatoid arthritis taking hydroxychloroquine. JAMA. 2007;298(20):2368-9. , 1515. Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006;4(5):377-89.

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CQ and HCQ are administered orally, with bioavailability between 70-80%, a long half-life time (30-60 days) and a large volume of distribution (116-285 L/kg). 2828. Tett S, Cutler D, Day R, Brown K. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol. 1989;27(6):771-9. Like all aminoquinolines, metabolites are eliminated through the kidney and liver, thus their excretion decreases in patients with renal or hepatic dysfunction, placing them at high risk for developing toxic effects. 2525. Ding HJ, Denniston AK, Rao VK, Gordon C. Hydroxychloroquine-related retinal toxicity. Rheumatology (Oxford). 2016;55(6):957-67. Even after treatment is discontinued, they remain detectable in the urine for years. 2929. Rubin M, Zvaifler N, Bernstein H MA, Mansour A. Chloroquine toxicity.In: Brodie BB, Gillette JR. Drug and enzymes: Proceedings of the Second International Pharmacological Meeting. Oxford: Pergamon Press;1965. v.4. p:467-87

In general, CQ and HCQ can be considered safe drugs, and side effects are usually mild and transient. However, the therapeutic index is narrow and CQ intoxication has been associated with cardiovascular disorders which can be fatal. 3030. Frisk-Holmberg M, Bergqvist Y, Englund U. Chloroquine intoxication. Br J Clin Pharmacol. 1983;15(4):502-3. Therefore, the use of CQ and HCQ should be restricted and self-medication poses potential risk to patients.

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Effects of CQ and HCQ on the Cardiovascular System

The effects of CQ and HCQ on the cardiovascular system are diverse. In the literature, positive effects are reported in patients who used HCQ for SLE treatment, such as a reduction in the incidence of acute myocardial infarction, coronary artery disease, and peripheral arterial disease. These effects are associated with a potential antiplatelet, antithrombotic, and antihypertensive activity of HCQ. 5353. Sharma TS, Wasko MCM, Tang X, Vedamurthy D, Yan X, Cote J, et al. Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc. 2016;5(1):e002867. In addition, reports indicate that HCQ has a potential to reduce the diabetes development, low-density lipoprotein (LDL) levels, as well as atherosclerosis progression which can contribute to the decrease in cardiovascular events. 5454. Sun L, Liu M, Li R, Zhao Q, Liu J, Yang Y, et al. Hydroxychloroquine, a promising choice for coronary artery disease? Med Hypotheses. 2016 Aug;93:5-7.

However, despite its anti-inflammatory effects and potential antithrombotic action, the literature indicates cardiotoxicity cases with the use of CQ and HCQ. At the molecular level, CQ and HCQ are amphipathic cationic drugs with the capacity to bind to myocyte phospholipids and accumulate in lysosomes, thereby inhibiting their enzymatic activity. This process impairs intracellular degradation, allowing the accumulation of toxic metabolic products. 5555. Page RL, O’bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(6):e32-69. A study conducted by Chatre et al. 5656. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919-31. demonstrated that cardiac disorders associated with HCQ and CQ treatment lead to ventricular arrhythmias and irreversible damage, which can lead to death. Cardiac side effects are less reported than effects such as retinopathy, but in some cases, they can be severe and irreversible.

Among the main reported effects, conduction disorders and cardiomyopathy, usually with hypertrophy and congestive heart failure, are highlighted. As the clinical characteristics of cardiotoxicity are nonspecific, the identification and monitoring of potentially affected patients is extremely important. Diagnostic confirmation requires histological examination of myocardium associated with electron microscopy. Reports in the literature indicate cases of hypertrophic cardiomyopathy, 5757. Lenfant T, Dion J, Maisonobe T, Costedoat-Chalumeau N. A rare cause of impaired general condition: muscular and cardiac toxicity of antimalarials. Rev Med Interne. 2020;41(5):335-8.

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Some previous risk factors can increase the incidence of cardiomyopathy, The most important of which are: age, sex, time of use, high doses, pre-existence of heart disease, and renal failure. 6969. Dogar MU, Shah NN, Ishtiaq S, Shah PN, Shah P, Mathew S, et al. Hydroxychloroquine-induced restrictive cardiomyopathy: a case report. Postgrad Med J. 2018;94(1109):185-6. The HCQ use is associated with diffuse ventricular myocardial thickening, the main secondary myocardial alteration being related to its use. 1818. Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy-a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434-42. , 7070. Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care. 2013;2(1):77-83. In addition, patients with severe heart failure, a worsening of exercise capacity, dyspnea, and angina can also be observed. 6868. Yogasundaram H, Hung W, Paterson ID, Sergi C, Oudit GY. Chloroquine-induced cardiomyopathy: a reversible cause of heart failure. ESC Hear Fail. 2018;5(3):372-5.

In the literature, it is described that the CQ and HCQ use can present long-term effects, even after the diagnosis and immediate suspension of treatment, with clinical and histological characteristics for years. 1818. Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy-a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434-42. , 6161. Naqvi TZ, Luthringer D, Marchevsky A, Saouf R, Gul K, Buchbinder NA. Chloroquine-induced cardiomyopathy-echocardiographic features. J Am Soc Echocardiogr. 2005;18(4):383-7. Thus, cardiomyopathy is a relevant adverse effect associated with CQ and HCQ treatment. Early diagnosis and periodic cardiological follow-up of the patients are essential for preventing cardiotoxicity and, consequently, the evolution of heart failure.

In addition to morphofunctional changes in cardiomyocytes, conduction disorders have also been reported. Conduction disorders are reported more frequently after chronic treatment with HCQ and CQ, as seen in patients on long-term treatment for SLE, in which cumulative doses are high. However, it is important to note that patients affected by severe form of COVID-19 often have other comorbidities and/or use pro-arrhythmic drugs such as azithromycin, factors that increase the risk of conduction disorders. 7171. Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai M-C. QT prolongation, torsades de pointes and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review. Heart Rhythm. 2020;17(9):1472-9. HCQ and CQ block I Kr potassium channels in cardiomyocytes, which can result in conduction disorders such as: prolongation of the QT interval, atrioventricular blocks, enlargement of the QRS complex, depression of the ST segment, and inversion of the T wave, 7272. Capel RA, Herring N, Kalla M, Yavari A, Mirams GR, Douglas G, et al. Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential. Heart Rhythm. 2015;12(10):2186-94. , 7373. Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004;484(1):41-8. which can result in conduction disturbances, including QT prolongation, atrioventricular block, expansion of the complex QRS, depression of the ST segment, and T-wave inversion. 7474. Sanghvi LM, Mathurm BBS. Electrocardiogram after chloroquine and emetine. Circulation. 1965;32(2):281-9. Some reports of HCQ intoxication have been described in the literature, such as the occurrence of sudden ventricular tachycardia after the use of high doses of the drug. 7575. McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z. Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol. 2018;36(4):545-51. As well as quinidine, an antiarrhythmic drug with a chemically similar structure, 7676. Queyriaux B, Carlioz R, Perrier E, Micaelli P, Gressard A, Deroche J, et al. Les effets cardiovasculaires liés à l’utilisation de la chloroquine. Ann Cardiol Angeiol (Paris). 2001;50(5):285-92. CQ and HCQ have the potential to cause changes in the QT interval, a risk factor for the development of ventricular tachyarrhythmia. 7777. Rey LD, Berneck A, Gonçalves L, Silva MB, Skare TL, Silva JA. ECG QT Interval prolongation in rheumatic patients using antimalarial drugs. Rev Bras Reumatol. 2003;43(5):275-8.

78. Newton-Cheh C, Lin AE, Baggish AL, Wang H. Case records of the Massachusetts General Hospital. Case 11-2011: a 47-year-old man with systemic lupus erythematosus and heart failure. N Engl J Med. 2011;364(15):1450-60.

79. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol. 2006;44(2):173-5.
- 8080. Stas P, Faes D, Noyens P. Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine. Int J Cardiol. 2008;127(2):e80-2. Long QT syndrome is an electrophysiological disorder characterized by an increase in the QT interval and abnormalities in the T wave, whose clinical consequences can be dizziness, syncope, and sudden death. 8181. Shah SR, Park K, Alweis R. Long QT syndrome: a comprehensive review of the literature and current evidence. Curr Probl Cardiol. 2019;44(3):92-106.

In the literature, cases of syncope and torsade de pointes secondary to HCQ-induced cardiotoxicity have been described. 7979. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol. 2006;44(2):173-5. , 8282. O’Laughlin JP, Mehta PH, Wong BC. Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine. Case Rep Cardiol. 2016 Jul 12;2016:4626279. A study developed by van den Broek et al. 8383. Broek MPH, Möhlmann JE, Abeln BGS, Liebregts M, Dijk VF, Garde EMW. Chloroquine-induced QTc prolongation in COVID-19 patients. Neth Heart J. 2020;28(7):406-9. demonstrated that CQ treatment was able to generate significant prolongation of the corrected QT interval (QTc) in 23% of the patients with COVID-19 (n = 95). In a cohort study conducted with 201 patients undergoing treatment for COVID-19 with HCQ (95%) and CQ (5%), with or without azithromycin, a high incidence of QTc interval prolongation was observed when compared to the baseline; 8.9% of the patients had a QTc interval above 500ms, of whom 3.5% were indicated for suspension of therapy and 1% were submitted to lidocaine use in order to reverse the condition. 8484. Saleh M, Gabriels J, Chang D, Kim BS, Mansoor A, Mahmood E, et al. The Effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol. 2020;13(6).e008662. A case of torsade de pointes was also reported by Szekely et al. 8585. Szekely Y, Lichter Y, Shrkihe BA, Bruck H, Oster HS, Viskin S. Chloroquine-induced torsade de pointes in a patient with coronavirus disease 2019. Heart Rhythm. 2020;17(9):1452-5. in a patient hospitalized with COVID-19, whose QTc interval was excessively prolonged (627 ms; baseline of 462 ms) after the introduction of HCQ therapy. In COVID-19 patients treated with the HCQ and azithromycin association, torsade de pointes has been reported. 8686. Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, et al. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425-33. , 8787. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493-502. To avoid electrophysiological complications, cardiological follow-up during treatment with HCQ or CQ is recommended, with emphasis on electrocardiographic monitoring of the QTc interval.

The occurrence of syncope associated with CQ use may also originate in cases of atrioventricular block or bundle branch block. 8888. Guedira N, Hajjaj-Hassouni N, Srairi JE, El Hassani S, Fellat R, Benomar M. Third-degree atrioventricular block in a patient under chloroquine therapy. Rev Rhum Engl Ed. 1998;65(1):58-62. A retrospective study conducted with 103 patients undergoing treatment for SLE has shown that 18 cases of conduction disorder were identified; 5 cases presented third degree atrioventricular block, of which 4 were using CQ in the treatment protocol. 8989. Godeau P, Guillevin L, Fechner J, Bletry O, Herreman G. Les troubles de conduction au cours du lupus érythémateux. Fréquence et incidence dans une population de 112 patients. Ann Med Interne (Paris). 1981;132(4):234-40. In addition, cases of right and left bundle branch secondary to CQ use have also been reported (90,91). The treatment of third-degree atrioventricular block usually requires a pacemaker implant to reverse the condition. 7575. McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z. Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol. 2018;36(4):545-51. , 8888. Guedira N, Hajjaj-Hassouni N, Srairi JE, El Hassani S, Fellat R, Benomar M. Third-degree atrioventricular block in a patient under chloroquine therapy. Rev Rhum Engl Ed. 1998;65(1):58-62. McGhie et al. 7575. McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z. Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol. 2018;36(4):545-51. observed 453 patients treated with HCQ and CQ drugs, and found, through electrocardiographic exams, that conduction disorders are more prevalent than structural changes, with right branch block being the most common among electrophysiological disorders, followed by bradycardia and first-degree atrioventricular block.

Pulmonary hypertension (PH) is a hemodynamic condition caused by an increase in mean pulmonary arterial pressure, caused by pulmonary dysfunctions or cardiovascular changes. 9292. Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin. 2018;14(3):255-69. In a model of PH induced in rats, CQ exerted a pulmonary vasodilator effect. The authors suggest that this effect may be related to direct or indirect blockage of voltage-operated calcium channels, store-operated calcium channels, and receptor-operated calcium channels on pulmonary artery smooth muscle cells. The potential therapeutic of CQ in PH is probably associated with the combination of its vasodilator, antiproliferative, and autophagy inhibitory effects. 9393. Wu K, Zhang Q, Wu X, Lu W, Tang H, Liang Z, et al. Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. Br J Pharmacol. 2017;174(22):4155-72.

CQ and HCQ were able to prevent right ventricular hypertrophy and vascular remodeling, as well as improve contractility and cardiac output parameters in PH experimental model. In this model, it was observed that CQ and HCQ treatment inhibited monocrotaline-induced autophagy, preventing the p62 expression, a key protein in autophagy modulation. 9494. Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ Res. 2013;112(8):1159-70. In addition, CQ has a therapeutic potential in the management of hereditary pulmonary hypertension, since it has the capacity to increase the expression of type II bone morphogenetic protein receptor (BMPR -II) on the cell surface. 9595. Dunmore BJ, Drake KM, Upton PD, Toshner MR, Aldred MA, Morrell NW. The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Hum Mol Genet. 2013;22(18):3667-79. On the other hand, despite the vasodilatory effects, the cardiotoxicity caused by CQ and HCQ may predispose PH development due to pulmonary circulation overload, as a result of congestion triggered by flow disorders through the left atrium and ventricle. 9696. Opitz CF, Hoeper MM, Gibbs JSR, Kaemmerer H, Pepke-Zaba J, Coghlan JG, et al. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol. 2016;68(4):368-78.

In a systematic review by Chatre et al., 5656. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919-31. 86 studies involving patients undergoing CQ or HCQ treatment were evaluated, in which 3.9% developed PH. In addition to this pathology, other important changes were observed, such as: conduction disorder (85%), ventricular hypertrophy (22%), hypokinesia (9.4%), and heart failure (26.8%). Therefore, it was possible to observe that PH, even if present, did not present such a significant prevalence in patients who used the drug. Table 1 shows a compilation of studies that describe electrophysiological and morphofunctional cardiovascular changes in patients after chronic treatment with CQ and HCQ.

Table 1
– Electrophysiological and morphofunctional cardiac alterations in patients after chronic treatment with chloroquine (CQ) and hydroxychloroquine (HCQ)

Drug Interactions of Clinical Importance Associated with CQ and HCQ Use

Patients with rheumatoid arthritis and SLE are treated chronically with CQ or HCQ. The continuous treatment exposes patients to the development of significant side effects, as well as contributes to an incidence of adverse reactions caused by drug interactions. CQ and HCQ interact with several drugs of clinical relevance, mainly through microsomal enzymes belonging to the cytochrome P450 family (CYP), culminating in the impairment of hepatorenal clearance caused by these therapies. 9797. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23(5):231-69. Drug interactions are of great clinical importance, and for this reason, they should receive particular attention. CQ and HCQ are substrates of CYP2D6, CYP3A4, CYP2C8, and CYP1A1, and may change the plasma levels of many drugs and vice versa. 9898. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-66.

CQ and HCQ interact with clinically important drugs, such as antibiotics, aspirin, paracetamol, cholestyramine, proton pump inhibitors, H2 receptor antagonists, imipramine, methotrexate, cyclosporine, caffeine, metoprolol, among others. Analgesics, often used as acetylsalicylic acid and paracetamol, need more attention. CQ both increases the maximum plasma concentrations of paracetamol 9999. Adjepon‐Yamoah K, Woolhouse N, Prescott LF. The effect of chloroquine on paracetamol disposition and kinetics. Br J Clin Pharmacol. 1986;21(3):322-4. and affects its clearance. 100100. Raina RK, Bano G, Amla V, Kapoor V, Gupta KL. The effect of aspirin, paracetamol and analgin on pharmacokinetics of chloroquine. Indian J Physiol Pharmacol. 1993;37(3):229-31. In vitro , HCQ inhibits the activity of plasmatic esterases responsible for aspirin degradation, thereby contributing to increase their circulating levels. 101101. Gupta JD, Gruca M, Ablett W. Effect of other drugs and chemicals on the degradation of aspirin in vitro: possible extrapolation to in vivo metabolism of aspirin. Eur J Drug Metab Pharmacokinet. 1978;4(2):103-8.

The use of CQ and HCQ associated with drugs used in the treatment of cardiovascular diseases requires adequate monitoring in order to minimize the possible cardiotoxic effects inherent to the combination therapy. CQ can increase the plasma digoxin concentration up to 4-fold and precipitates clinical manifestations, such as arrhythmia and cardiotoxicity. 102102. Leden I. Digoxin-hydroxychloroquine interaction ? Acta Med Scand. 1982;211(5):411-2. Additionally, metoprolol can present changes on its plasmatic concentration when used concomitantly with HCQ. This interaction occurs through competition for the same metabolizing enzyme of both drugs, CYP2D6, resulting in an increase of concentration and bioavailability of metoprolol. 103103. Somer M, Kallio J, Pesonen U, Pyykkö K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol. 2000;49(6):549-54.

Due to the pandemic caused by COVID-19, several clinical studies have been conducted in order to characterize a safe and effective therapy for the treatment of this disease. Some already published studies emphasize that HCQ associated with azithromycin presents potentialized effects, exerting promising actions in the COVID-19 treatment. 104104. Gautret P, Lagier JC, Parola P, Hoang VT, 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;56(1):105949. , 105105. Million M, Lagier JC, Gautret P, Colson P, Fournier PE, Amrane S, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. 2020 May-June;35:101738. In addition, a study by Fantini J et al. 106106. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal. Int J Antimicrob Agents. 2020;56(2):106020. , using a dynamic molecular simulation technique, demonstrated a synergistic antiviral effect of HCQ combined with azithromycin in the COVID-19 treatment. However, both treatments are able to promote prolongation of QT interval, which trigger refractory ventricular arrhythmia, even when used alone. 7979. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol. 2006;44(2):173-5. , 107107. Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, et al. Assessment of multi-ion channel block in a phase I randomized study design: results of the CiPA phase I ECG biomarker validation study. Clin Pharmacol Ther. 2019;105(4):943-53. Chorin et al. 8686. Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, et al. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425-33. reported cases of torsade de pointes in patients with COVID-19 who were treated with the HCQ and azithromycin association. In addition, they observed a prolongation of the QTc interval above 500 ms in 23% of the cases (n = 211). The French Pharmacovigilance Database reported that 14% of the adverse effects linked to the association of HCQ with azithromycin corresponded to blockage in the cardiac conduction system (n = 120). 8787. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493-502. Although CQ and HCQ show in vitro antiviral activity against COVID-19 in some studies, there is no robust evidence to demonstrate the clinical benefit of combined HCQ and azithromycin therapy in reducing the mortality of hospitalized patients with a severe form of COVID-19. Moreover, the deleterious effects on the cardiovascular system are notorious and should not be neglected. 6565. Cervara A, Espinosa G, Font J, Ingelmo M. Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis. 2001;60(3):301. , 108108. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384.

Other important drug interactions are associated with the widespread use of CQ and HCQ with immunosuppressive drugs in the treatment of rheumatoid arthritis and SLE, such as methotrexate and cyclosporine. CQ and HCQ impair the methotrexate absorption by pH variation, thereby reducing its oral bioavailability, which contributes to sub-therapeutic effects of methotrexate. 109109. Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996;5(Suppl 1):S11-5. , 110110. Bannwarth B, Péhourcq F, Schaeverbeke T, Dehais J. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996;30(3):194-210. CQ and HCQ may also increase cyclosporine plasma levels, enhancing the risk of nephrotoxicity. Thus, cyclosporine use should be monitored during combination therapy in order to avoid potentially toxic effects. 111111. Nampoory MR, Nessim J, Gupta RK, Johny KV. Drug interaction of chloroquine with ciclosporin. Nephron. 1992;62(1):108-9. , 112112. Borne BE, Landewé RB, Goei The HS, Rietveld JH, Zwinderman AH, Bruyn GA, et al. Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. J Rheumatol. 1998;25(8):1493-8. CQ is also able to reduce the bioavailability of some classes of antibiotics, such as penicillin and quinolones, limiting their therapeutic effects. 113113. Ali HM. Reduced ampicillin bioavailability following oral coadministration with chloroquine. J Antimicrob Chemother. 1985;15(6):781-4. , 114114. Ilo CE, Ezejiofor NA, Agbakoba N, Brown SA, Maduagwuna CA, Agbasi PU, et al. Effect of chloroquine on the urinary excretion of ciprofloxacin. Am J Ther. 2008;15(5):419-22.

On the other hand, drugs that raise gastric pH can reduce the CQ and HCQ bioavailability, such as proton pump inhibitors and H2 receptor antagonists, restricting their therapeutic effects. 115115. Namazi MR. The potential negative impact of proton pump inhibitors on the immunopharmacologic effects of chloroquine and hydroxychloroquine. Lupus. 2009;18(2):105-5. Since a range of drug interactions involving the long-term use of CQ and HCQ and these drugs have a low therapeutic index, it is extremely important to monitor patients who continuously use these drugs to ensure both clinical efficacy and safety.

Effects of Chloroquine and Hydroxychloroquine on other Systems

Retinopathy is an adverse effect widely described as a consequence of CQ and HCQ use. However, the mechanism involved in toxicity associated with retinopathy is not fully understood. 116116. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-94. Retinal toxicity can cause irreversible visual loss. The result of the analysis of 2,361 patients using HCQ revealed an overall prevalence of 7.5% of toxicity in patients treated for more than 5 years and 20% in those treated for more than 20 years. 117117. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453-60. The main identified risk factors were doses of HCQ above 5mg/kg or CQ above 2.3mg/kg, duration of use for more than 5 years, previous renal failure, use of tamoxifen, and macular disease. 116116. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-94. , 118118. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye (Lond). 2017;31(6):828-45.

Ponticelli and Moroni 119119. Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf. 2017;16(3):411-9. observed that 10% of patients treated with HCQ developed corneal deposits which were dose-dependent, transient and reversible. However, in most cases, the retinopathy was irreversible. It is important that patients treated with HCQ and CQ receive a warning of the risk of toxicity as well as a periodic evaluation. The most common visual symptoms include reading and sight difficulties, photophobia, and visual blur.

The multifocal electroretinography (mfERG) provides objective documentation of visual functions, and exerts an important role in screening and evaluation in order to manage the discontinuation of treatment. However, further studies are needed to define the relationship between the time of physiological evolution and structural abnormalities. In addition, the sensitivity and specificity of mfERG can be assessed when compared to automated visual fields, fundus autofluorescence imaging, and optical coherence tomography. 120120. Tsang AC, Ahmadi Pirshahid S, Virgili G, Gottlieb CC, Hamilton J, Coupland SG. Hydroxychloroquine and chloroquine retinopathy: a systematic review evaluating the multifocal electroretinogram as a screening test. Ophthalmology. 2015;122(6):1239-51.e4. A recent study showed that retinopathy progresses for 3 years even after HCQ treatment suspension. In this same study, they have observed more severe changes in patients who received doses above 11mg/kg/day. Thus, it is extremely important to periodically evaluate patients who use these drugs in order to diagnose the early stages of development of retinopathy and provide a detailed analysis of risk and progression of visual loss in these patients. 2525. Ding HJ, Denniston AK, Rao VK, Gordon C. Hydroxychloroquine-related retinal toxicity. Rheumatology (Oxford). 2016;55(6):957-67.

Undesirable dermatological events include such pathologies as psoriasis, alopecia, itching, skin pigmentation and mucous membranes, photosensitivity, and skin rashes. 121121. Soria A, Barbaud A, Assier H, Avenel-Audran M, Tétart F, Raison-Peyron N, et al. Cutaneous adverse drug reactions with antimalarials and allergological skin tests. Dermatology. 2015;231(4):353-9. Another adverse effect reported is myopathy, the main symptoms of which are muscle weakness, increased levels of muscle enzymes, electromyographic changes, and histological lesions. 122122. Le Quintrec JS, Le Quintrec JL. Drug-induced myopathies. Baillieres Clin Rheumatol. 1991;5(1):21-38.

Chloroquine and Hydroxychloroquine in the COVID-19 Treatment: Impact on the Cardiovascular System

Diseases that affect the cardiovascular system represent a risk factor for patients with COVID-19, as well as diabetes, pulmonary disorders, and obesity. Therefore, such individuals are more susceptible to developing the severe form of the disease. 123123. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

124. Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng J, et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J Infect. 2020;81(2):e16-25.
- 125125. Sanchis-Gomar F, Lavie CJ, Mehra MR, Henry BM, Lippi G. Obesity and outcomes in COVID-19: when an epidemic and pandemic collide. Mayo Clin Proc. 2020;95(7):1445-53. On its surface, SARS-CoV-2 expresses proteins that interact with its receptor, ECA2. 126126. Boopathi S, Poma AB, Kolandaivel P. Novel 2019 Coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. J Biomol Struct Dyn. 2020 Apr 30. [Epub ahead of print]. Tissues that widely express this receptor are more vulnerable to viral invasion, such as lungs, cardiovascular system, intestine, kidneys, central nervous system, and adipose tissue. 127127. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020;126(10):1456-74. , 128128. South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020;318(5):H1084-90.

Patients with COVID-19 have shown a higher incidence of acute heart failure, 123123. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. , 129129. Lei J, Li J, Li X, Qi X. CT imaging of the 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology. 2020;295(1):18. and critically ill patients are more susceptible to present cardiovascular damage. 123123. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. , 130130. Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020;109(5):531-8. , 131131. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846-8. Mehta et al. 132132. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. have observed that patients with COVID-19 have a cytokine production profile similar to secondary hemophagocytic lymphohistiocytosis (sHLH), which is associated with poor prognosis. This phenomenon has been described as "cytokine storm", characterized by an unregulated response of type 1 and type 2 auxiliary T cells. 123123. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. This “cytokine storm” is marked by exacerbated increase in interleukins (IL), such as IL-1, IL-6, and IL-7, granulocyte colony stimulating factor (G-CSF), protein 10 induced by γ-interferon (CXCL10/IP-10), monocyte chemotactic protein 1 (MCP-1), inflammatory macrophage protein 1-α (MIP-1α), and tumor necrosis factor-α (TNF-α). Mortality predictors from a recent retrospective, multicenter study of 150 confirmed cases of COVID-19 in Wuhan, China, included elevated ferritin (mean 1297.6 ng/mL in non-survivors vs. 614.0 ng/mL in survivors; p <0.001) and IL-6 (p <0.0001), suggesting that mortality may be associated with hyperinflammation promoted by the virus. 131131. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846-8.

Cardiac injury is related to direct damage caused by viral replication and cytokine storm. In addition, respiratory dysfunction and hypoxia generated by COVID-19 can also cause damage in cardiomyocytes. 123123. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. , 133133. Wong CK, Lam CWK, Wu AKL, Ip WK, Lee NLS, Chan IHS, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004;136(1):95-103. , 134134. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. Clerkin et al. 135135. Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. (COVID-19) and cardiovascular disease. Circulation. 2020;141(20):1648-55. reported that 7% of infected patients developed myocardial injury, diagnosed through echocardiographic examination or electrocardiogram, and presented elevated troponin I levels. Considering that the cardiovascular system is directly affected by SARS-CoV-2 infection, therapy with drugs that have a cardiotoxic potential becomes even more contraindicated.

Although the in vitro antiviral effects of CQ have been demonstrated by reducing the viral replication of SARS-CoV, 3434. Keyaerts E, Vijgen L, Maes P, Neyts J, Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323(1):264-8. , 136136. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.Virol J.2005;2:1-10. inhibiting HIV replication, 5050. Savarino A, Lucia MB, Rastrelli E, Rutella S, Golotta C, Morra E, et al. Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors. J Acquir Immune Defic Syndr. 2004;35(3):223-32. in addition to in vivo antiviral effects reported in an H1N1 animal model, 3737. Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013;23(2):300-2. clinical studies demonstrate controversial data regarding its effects on reducing viral loads in humans. Engchanil et al. 5151. Engchanil C, Kosalaraksa P, Lumbiganon P, Lulitanond V, Pongjunyakul P, Thuennadee R, et al. Therapeutic potential of chloroquine added to zidovudine plus didanosine for HIV-1 infected children. J Med Assoc Thai. 2006;89(8):1229-36. reported that CQ was not effective in improving clinical, immunological, and virological parameters in HIV-infected pediatric patients, and tended to cause an increase in undesirable gastrointestinal events. In a double-blind randomized study with 307 hospitalized adults with dengue fever, it was observed that CQ was not able to reduce viremia, 3939. Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, et al. A randomized controlled trial of chloroquine for the treatment of dengue in vietnamese adults. PLoS Negl Trop Dis. 2010;4(8):e785. and actually increased the incidence of adverse gastrointestinal effects. A study performed by Borges et al. 137137. Borges MC, Castro LA, Fonseca BAL. Chloroquine use improves dengue-related symptoms. Mem Inst Oswaldo Cruz. 2013;108(5):596-9. showed that CQ apparently reduced symptoms related to the disease, but was not able to decrease the time infection caused by dengue virus. CQ treatment in Chikungunya infection was evaluated in a double-blind, placebo-controlled study developed by Lamballerie et al., 4545. De Lamballerie X, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, et al. On chikungunya acute infection and chloroquine treatment. Vector-Borne Zoonotic Dis. 2008;8(6):837-9. which indicated that CQ did not reduce viral loads and in fact increased the incidence of arthralgia when compared to the placebo arm. The work performed by Gautret et al., 104104. Gautret P, Lagier JC, Parola P, Hoang VT, 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;56(1):105949. reported in March 2020, demonstrated that HCQ exerts beneficial effects in COVID-19 treatment. However, the study showed several limitations that were clarified by Toumi and Aballea, 138138.Toumi M, Aballea S. Commentary on “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial” by Gautret et al. J Mark Access Health Policy. 2020;8(1):1758390. such as a reduced number of enrolled patients, outcome measures, and a lack of homogeneity in both the control and treated groups. These questions compromise comparability between arms and lead to a deficiency in the control of the occurrence of type I statistical error and other inconsistencies in the protocol study.

Due to the widespread use of HCQ in hospitalized patients with COVID-19 without robust evidence to support its use, several clinical trials have been performed to confirm or refute its efficacy and safety in these patients. A randomized, controlled, multicenter clinical study conducted in China, evaluated 150 hospitalized patients with moderate and severe COVID-19. HCQ treatment did not promote additional beneficial effects in eliminating viral loads when compared to standard treatments, in addition to causing significant adverse events. 139139. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. An observational study by Geleris et al., 140140. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020;382(25):2411-8. evaluated 1,446 patients with COVID-19 and found that HCQ treatment neither reduced nor increased the risk of intubation or death in the evaluated patients. Another observational study evaluated the HCQ effectiveness in 181 patients admitted with COVID-19 pneumonia who needed oxygenotherapy. In this study, the use of HCQ was not indicated for these patients, since treatment did not reduce the length of hospital stay nor the mortality rate. In addition, 10% of patients treated with HCQ have presented significant electrocardiographic changes and discontinued treatment. 141141. Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m2328. Finally, a recent clinical study conducted with 1,438 hospitalized patients diagnosed with COVID-19, has shown that HCQ therapy is not associated with a reduction in mortality by COVID-19. 5252. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;6736(20):31180-6.

Given the unproven efficacy, it is possible to promote cardiotoxicity in isolated or combined therapy with other drugs commonly used in the treatment of COVID-19, in addition to the fact that patients infected with COVID-19 may have direct damage in their cardiovascular system. It is important to evaluate critically and ethically if the CQ and HCQ use is necessary as a therapeutic approach to SARS-CoV-2 infection, 142142. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. considering all the risks associated with their use ( figure 1 ).

Figure 1
– Associated risks with CQ and HCQ use in the treatment of patients with COVID-19.

Conclusion

Chloroquine and hydroxychloroquine represent drugs with a potential benefit in the treatment of several pathologies, presenting important anti-inflammatory and immunomodulatory actions, with their pharmacological effects evidenced in the chronic treatment of autoimmune diseases. However, their side effects should not be overlooked, especially ophthalmic and cardiovascular effects, which can lead to vision loss and cardiotoxicity. This article describes relevant negative impacts of these drugs on the cardiovascular system. The performance of several clinical trials with CQ and HCQ in COVID-19 patients leads to an ineffectiveness of these drugs. The absence of efficacy, in addition to potential deleterious effects on the cardiovascular system, suggest that this pharmacological approach should be used with caution, especially due to the large number of patients with COVID-19 who have pre-existing cardiovascular disorders.

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  • Study Association
    This study is not associated with any thesis or dissertation work.
  • Sources of Funding .There were no external funding sources for this study.

Publication Dates

  • Publication in this collection
    26 Feb 2021
  • Date of issue
    Mar-Apr 2021

History

  • Received
    05 June 2020
  • Reviewed
    10 Aug 2020
  • Accepted
    04 Sept 2020
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E-mail: sbc@cardiol.br