|Year : 2021 | Volume
| Issue : 1 | Page : 78-82
Hydroxychloroquine and azithromycin use in COVID-19 era and cardiovascular concerns: Current perspective
Aditya Kapoor, Ankit Kumar Sahu
Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||25-Aug-2020|
|Date of Decision||08-Feb-2021|
|Date of Acceptance||12-Mar-2021|
|Date of Web Publication||24-Apr-2021|
Ankit Kumar Sahu
Department of Cardiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
In the present era of coronavirus disease 2019 (COVID-19) pandemic, lack of an established and effective targeted therapy sans a vaccine is proving to be a major hurdle in containing the contagion. Hydroxychloroquine (HCQ), a widely used antimalarial and anti-inflammatory drug, has been proposed for coronavirus infection management by various drug regulatory authorities for emergency use including Indian Council of Medical Research. However, clinical safety concerns primarily regarding cardiovascular issues have been raised against HCQ usage, especially in relatively higher dosage in conjunction with azithromycin (AZM) coprescription. HCQ and to some extent, AZM have proven to be effective against COVID-19. Barring a small at-risk population for cardiovascular adverse effects, their clinical use in the treatment and prevention of COVID-19 was deemed to be beneficial and even recommended by various national and international representative societies including the World Health Organization, especially in high-risk individuals such as health-care workers and exposed contacts of coronavirus positive patients under due medical supervision. Multiple studies evaluating the anticoronaviral efficacy for prevention as well as for treatment prospect were conducted, but none could convincingly demonstrate a beneficial effect of HCQ with or without AZM on alleviating symptoms, shortening hospitalization, improving survival, or preventing disease transmission.
Keywords: Azithromycin, cardiotoxicity, coronavirus, hydroxychloroquine, QT prolongation
|How to cite this article:|
Kapoor A, Sahu AK. Hydroxychloroquine and azithromycin use in COVID-19 era and cardiovascular concerns: Current perspective. J Pract Cardiovasc Sci 2021;7:78-82
|How to cite this URL:|
Kapoor A, Sahu AK. Hydroxychloroquine and azithromycin use in COVID-19 era and cardiovascular concerns: Current perspective. J Pract Cardiovasc Sci [serial online] 2021 [cited 2021 Jun 22];7:78-82. Available from: https://www.j-pcs.org/text.asp?2021/7/1/78/314480
| Introduction|| |
Various unproven experimental treatment modalities are in foray for evaluating their role in the management of novel coronavirus (nCoV 2019). Hydroxychloroquine (HCQ) and/or azithromycin (AZM) have been proclaimed as potential options for the prevention and treatment of coronavirus disease 2019 (COVID-19) infection. This is a brief attempt at summarizing the current scenario regarding the contemporary utility and application of HCQ with or without AZM in the treatment and prophylaxis against nCoV disease.
| Hydroxychloroquine|| |
HCQ is a 4-aminoquinoline widely employed in the treatment of a large spectrum of autoimmune, inflammatory, and dermatological disorders such as systemic lupus erythematosus, scleroderma, and rheumatoid arthritis, as disease-modifying antirheumatic drug. Chemically, HCQ is a hydroxylated derivative of chloroquine which in turn is an established antimalarial that has been in vogue for a long time, with similar pharmacodynamic properties.
| Mechanism of Action|| |
Antimalarial drugs affect multiple phases regulating the influx and postreplication processing of viruses belonging to coronavirus family, which alters the lysosomal pH and resulting in dysglycosylation of angiotensin-converting enzyme 2 receptors that are extremely crucial for viral ingress., In addition, it has various pleiotropic effects such as counter-inflammatory and immunomodulatory actions which blunts the detrimental effect of cytokines storm emanating from COVID-19 infection-related inflammatory cascade.,
| Potential Cardiovascular Adverse Effects of Hydroxychloroquine/Azithromycin|| |
Overall, adverse drug effects related to HCQ affecting the cardiovascular system, i.e., cardiomyopathy, QT prolongation, and ventricular arrhythmias are uncommon. Elementary electrophysiological studies suggest that both drugs predispose for and can precipitate pro-arrhythmia through mechanisms apart from blockage of IKr channels involved in the usual cases of torsade de pointes., Critically ill patients often have underlying comorbidities including hypokalemia, hypomagnesemia, fever, and inflammatory state that can amplify the risk of serious arrhythmias. Coprescription of QT-prolonging medications such as macrolides, quinolones, HIV protease inhibitors, first-generation antihistamines (fexofenadine), azole antifungals, and certain antiarrhythmic drugs (William-Vaughan class I/III drugs) tends to enhance the likelihood of drug-associated torsades de pointes (TdP) many-fold. Despite the paucity of concrete pharmacodynamic proof of IKr inhibition by AZM, epidemiological studies have approximated >47 arrhythmogenic CV deaths per 1 million AZM doses. However, certain recent data propounds that this estimation might have been overinflated., In vivo observational studies, however, have shown no synergistic arrhythmogenic effects on adding AZM to chloroquine.
QT prolongation caused by certain drugs has conventionally been considered as a proxy indicator for enhanced likelihood of TdP despite the association between QT prolongation and the threat of TdP being nonlinear and complex, as some QTc prolonging drugs have not been associated with increased arrhythmogenic death., Multiple predictive analytic tools include Mayo clinic pro-QTc score, Risk of QT-prolongation and Torsade de Pointes in Patients Treated With Acute Medication in a University Hospital (RISQ-PATH) score, and Tisdale et al. Risk scores have been developed to identify the patients at risk for QT prolongation. Tisdale et al. developed morbidity predicting, externally validated, and widely used model [Figure 1] for forecasting drug-induced QT prolongation among critically ill hospitalized patients having sensitivity, specificity, positive predictive value, and negative predictive value of 67%–74%, 77%–88%, 55%–79%, and 76%–88%, respectively. A score of ≤6 suggests low risk, 7–10 suggests medium risk, and ≥11 predicts high risk of drug-induced QT prolongation.
|Figure 1: Scoring system for predicting the risk for drug-associated QTc prolongation. aIf a patient is receiving two or more QTc interval-prolonging drugs, he or she is assigned a total score of 6: 3 points for receiving one QTc interval-prolonging drug and 3 points for receiving two or more QTc interval-prolonging drugs (Adapted from Tisdale et al.).|
Click here to view
| Monitoring Protocol for Clinical Usage of Hydroxychloroquine/Azithromycin in COVID-19|| |
Electrocardiographic screening for QTc should be assimilated into an individualized risk-benefit approach for treatment basis. In-hospital COVID-19 patients are anticipated to have higher arrhythmic potential due to the pathophysiological residue of their underlying illness and accompanying comorbidities. The objective of QTc screening in this scenario is to pinpoint those who are candidates for anticoronaviral therapy and also are at increased risk for TdP so that precautionary measures may be executed. [Figure 2] and [Figure 3] show the proposed algorithm for management protocol regarding HCQ therapy in COVID inpatients and outpatients, respectively.
|Figure 2: Flowchart showing monitoring protocol for clinical HCQ/AZM use in COVID-19 inpatients. HCQ: Hydroxychloroquine, AZM: Azithromycin, COVID-19: Coronavirus disease 2019.|
Click here to view
|Figure 3: Flowchart showing monitoring protocol for clinical HCQ/AZM use in COVID-19 outpatients. HCQ: Hydroxychloroquine, AZM: Azithromycin, COVID-19: Coronavirus disease 2019.|
Click here to view
| Appropriate Protocol Modifications in Resource-Limited Setting|| |
- Effort should be to maximizing telephone assessment to identify patients with markers of arrhythmogenic risk (namely, syncope, dehydration, initiation of new drugs with possible TdP potential, and recent alteration in symptom status)
- It is preferable to delay electrocardiogram-based screening so that patients remain in isolation/quarantine facility if no high-risk arrhythmogenic factors counter-in (namely, history of long QT syndrome, concurrent administration of QTc enhancing medications, underlying cardiac disorder, previously documented incidences of QTc prolongation, history of dyselectrolytemia, and renal dysfunction)
- For high-risk patients not suitable for inpatient telemetry, mobile cardiac outpatient telemetry should be considered. During the context of this evaluation, any syncopal event should be scrutinized further considering the default likelihood of polymorphic VT in this scenario
- Mobile outpatient telemetry in the form of direct-to-patient mobile devices (e.g., KardiaMobile©, AliveCor® Inc., Mountain View, CA, USA; Apple Watch©, Apple Inc., Cupertino, CA, USA) or digital cardiac outpatient telemetry devices (e.g., iRhythm©, iRhythm technologies Inc., San Francisco, CA, USA; BioTel©, BioTelemetry Inc., Malvern, PA, USA; and Preventice©, Preventice solutions Inc., Houston, TX, USA) may be used.
| Clinical Evidence for Role of Hydroxychloroquine and Azithromycin in the Management of COVID-19|| |
Ex vivo and basic clinical experimentation have indicated that HCQ with or without AZM could have a potential role in the treatment for COVID-19., A small placebo-controlled, nonrandomized, open-label French study involving 42 COVID-19 patients showed that HCQ with or without AZM promoted viral clearance by lowering the duration of viral shedding. However, recently a randomized CloroCovid-19 trial on 81 corona-positive patients demonstrated a whopping 2.6 times increase in mortality within 2 weeks of treatment with higher doses (600 mg bid) of chloroquine diphosphate for which the study has to be terminated prematurely. About 15.1% of patients in the trial had QTc >500 msec, which can be accounted by the fact that many of these patients were already on QT-prolonging drugs such as AZM and oseltamivir. The United States Food and Drug Administration had also issued alert against the use of HCQ or chloroquine for COVID-19 patients outside the purview of a hospital setting or a clinical trial and that too with close clinical monitoring of patients treated with these therapies, citing cardiac side effects.
To address some of these issues and to get a clarity about HCQ role in COVID-19 management, multiple randomized trials were initiated in the first half of 2020. Most notable among them were the ORCHID trial (ClinicalTrials.gov Identifier NCT04332991), a multicenter placebo-controlled randomized placebo-controlled clinical trial of 510 COVID-19 patients along with studies by RECOVERY collaborative group and Coalition COVID-19 Brazil-I investigators. The ORCHID trial was prematurely terminated at the recruitment of only 479 patients for lack of demonstration of any tangible benefit in terms of multiple clinical parameters either in low-dose (200 mg bid) or high-dose (400 mg bid) HCQ arm over placebo. Similarly, no mortality benefit was perceived in a randomized trial involving 4716 hospitalized COVID patients with HCQ. On the contrary in the HCQ arm, those not on mechanical ventilatory support at baseline were a higher risk of death as compared to “usual care” arm patients. Furthermore, HCQ with or without AZM did not alter the clinical status of hospitalized COVID-19 patients with mild-to-moderate disease. On the other front too, HCQ failed to deliver as preexposure, or postexposure prophylaxis and was not found effective to prevent the occurrence of COVID infection in high-risk susceptible individuals.
| Conclusion|| |
HCQ and AZM have proven in vitro efficacy against nCoV infection. Limited observational data showed their promising role in lowering viral load, preventing complications, improving recovery rates, and preventing infection in the susceptible population. However, routine monitoring and caution must be exerted regarding their use in vulnerable population at risk of developing adverse drug effect, especially affecting the cardiovascular system. Recently, in a number of systematic large randomized clinical studies, HCQ with or without AZM failed to document the clinical efficacy in reducing mortality or need for oxygenation support and safety in hospitalized COVID patients. However, their role in promoting recovery of asymptomatic, nonhospitalized patients is unknown and needs to be studied on a wider scale before any recommendation for commencing their use in such patient population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc 2020;95:1213-21.
Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020;55:105932.
Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006;6:67-9.
Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: What to expect for COVID-19? Int J Antimicrob Agents 2020;55:105938.
Zhang M, Xie M, Li S, Gao Y, Xue S, Huang H, et al
. Electrophysiologic studies on the risks and potential mechanism underlying the proarrhythmic nature of azithromycin. Cardiovasc Toxicol 2017;17:434-40.
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;12:2186-94.
Kauthale RR, Dadarkar SS, Husain R, Karande VV, Gatne MM. Assessment of temperature-induced hERG channel blockade variation by drugs. J Appl Toxicol 2015;35:799-805.
Aromolaran AS, Srivastava U, Alí A, Chahine M, Lazaro D, El-Sherif N, et al
. Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation. PLoS One 2018;13:e0208321.
Malaria Policy Advisory Committee. The Cardiotoxicity of Antimalarials: WHO Evidence Review Group Meeting, October 13-14, 2016, Varembé Conference Centre. Geneva, Switzerland: World Health Organization; 2017.
Ray W, Murray K, Hall K, Arbogast P, Stein M. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-90.
Fossa A, Wisialowski T, Duncan J, Deng S, Dunne M. Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig. Am J Trop Med Hyg 2007;77:929-38.
Rock EP, Finkle J, Fingert HJ, Booth BP, Garnett CE, Grant S, et al
. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 2009;157:827-36.
Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994;121:529-35.
Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman MJ. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc 2013;88:315-25.
Vandael E, Vandenberk B, Vandenberghe J, Spriet I, Willems R, Foulon V. Development of a risk score for QTc-prolongation: The RISQ-PATH study. Int J Clin Pharm 2017;39:424-32.
Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al
. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013;6:479-87.
Tomaselli Muensterman E, Tisdale JE. Predictive analytics for identification of patients at risk for QT interval prolongation: A systematic review. Pharmacotherapy 2018;38:813-21.
Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 (Coronavirus Disease 2019) treatment. JACC 2020;75:2623-4.
Kapoor A, Pandurangi U, Arora V, Gupta A, Jaswal A, Nabar A, et al
. Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society. Indian Pacing Electrophysiol J 2020;20:117-20.
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al
. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
. Cell Discov 2020;6:16.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al
. In vitro
antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020;71:732-9.
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;56:105949.
Borba MG, Val FF, Sampaio VS, Alexandre MA, 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:e208857.
Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al
. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: A randomized clinical trial. JAMA 2020;324:2165-76.
RECOVERY Collaborative Group; Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al
. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020;383:2030-40.
Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al
. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med 2020;383:2041-52.
Abella BS, Jolkovsky EL, Biney BT, Uspal JE, Hyman MC, Frank I, et al
. Efficacy and safety of hydroxychloroquine vs. placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: A randomized clinical trial. JAMA Intern Med 2021;181:195-202.
Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, et al
. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: A randomized trial. Clin Infect Dis 2020:ciaa1571. [doi: 10.1093/cid/ciaa1571].
Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al
. A Randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med 2020;383:517-25.
[Figure 1], [Figure 2], [Figure 3]