|Year : 2021 | Volume
| Issue : 2 | Page : 224-227
Cardiovascular safety of hydroxychloroquine: Brief appraisal of data
Anil Pareek1, Shashank Joshi2, Ashok K Das3, Ravi Tejraj Mehta4
1 Department of Medical Affairs & Clinical Research, Ipca Laboratories Ltd., Mumbai, Maharashtra, India
2 Department of Endocrinology, Lilavati Hospital, Mumbai, Maharashtra, India
3 Department of Endocrinology, Pondicherry Institute of Medical Sciences, Puducherry, India
4 Department of Medical Affairs, Ipca Laboratories Ltd., Mumbai, Maharashtra, India
|Date of Submission||16-Jul-2020|
|Date of Decision||12-Sep-2020|
|Date of Acceptance||17-Sep-2020|
|Date of Web Publication||31-Mar-2021|
Dr. Anil Pareek
Ipca laboratories Limited, Plot 142 A/B, Kandivali Industrial Estate, Mumbai 400067, Maharashtra.
Source of Support: None, Conflict of Interest: None
Hydroxychloroquine (HCQ), widely used in rheumatology since decades and in type 2 diabetes (T2D) since 2014, has garnered special attention in the current pandemic caused by SARS-CoV-2. HCQ appears to be effective in early COVID-19 and prophylaxis, and more studies are ongoing; its efficacy in severe disease is unclear. Few studies evaluating usage of HCQ in patients hospitalized with COVID-19 have raised concerns about the cardiovascular safety of HCQ, particularly QT-prolongation. It is important to understand the distinct clinical settings where HCQ is being used and appraise the data on cardiac effects of this commonly used drug. Although COVID-19 is an acute pro-arrhythmogenic state, HCQ is extensively used in patients with chronic inflammatory conditions such as rheumatoid arthritis, lupus, and T2D. In these indications, data from clinical studies, real-world experiences, and exhaustive pharmacovigilance database inspires confidence and suggests the cardiac side-effects of HCQ to be rare in frequency. The physicians and patients using HCQ in approved indications at recommended doses need to be reassured of its clinical importance and risk-benefit profile.
Keywords: Cardiac safety, COVID-19, hydroxychloroquine, QT-prolongation, SARS-CoV-2
|How to cite this article:|
Pareek A, Joshi S, Das AK, Mehta RT. Cardiovascular safety of hydroxychloroquine: Brief appraisal of data. J Diabetol 2021;12:224-7
Approximately 400,000 cases of COVID-19 (coronavirus disease-2019) have been detected in India as of June 20, 2020 with more than 400 deaths every day. Unfortunately, there is no specific treatment or vaccine discovered against SARS-CoV-2, the causative virus of COVID-19 till now. Repurposing the existing drugs with antiviral properties, with minimal further testing, is an efficient approach to drug discovery in the scenario of this pandemic. Several such candidate drugs, including remdesivir, lopinavir, ritonavir, anti-malarials, and favipiravir are being rigorously evaluated as potential therapies to treat COVID-19. Among all these candidates, hydroxychloroquine (HCQ) has received huge interest in India, not just because India produces 70% of the global supply, but also due to the fact that more than 24 randomized controlled trials kicked off globally with potential sample size of over 25,000 participants. Most of the trials published till now have evaluated HCQ in patients hospitalized with COVID-19, and with the preliminary results from the RECOVERY (randomized evaluation of COVid-19 thERapY) trial, it appears that there is no beneficial effect of HCQ in patients hospitalized with severe COVID-19. On the contrary, it has been shown that HCQ might be efficacious in the early stages in patients with mild COVID-19 with an effect in reducing the infectivity. Some of the retrospective observational studies evaluating HCQ in combination with azithromycin in hospitalized patients with COVID-19 have reported QT-prolongation, raising concerns on the cardiovascular effects of HCQ, particularly when used with azithromycin. This sudden focus on the cardiovascular safety of HCQ has also posed questions among physicians and anxiety among patients who have been using HCQ for other approved indications. It is thus, important to understand the differences in these two distinct clinical settings where HCQ is being used and appraise the data on cardiovascular safety of this commonly used drug.
In an initial report on clinical characteristics of patients from Wuhan, arrhythmias were reported in 17% of hospitalized and 44% of patients admitted to ICU with COVID-19. Several other such reports have now led to establishing COVID-19 as a pro-arrhythmogenic state, created by the confluence of various pathologic effects––hypoxia, hypotension, enhanced inflammatory status, electrolyte abnormalities, concomitant QT-prolonging medications, underlying cardiovascular disease and even direct viral myocardial damage. This might be the explanation between the discrepancy of QT-prolongation reported by studies evaluating HCQ in those with severe vs. mild patients with COVID-19. Most of the observational studies highlighting the cardiovascular concerns have evaluated HCQ use in critically ill hospitalized COVID-19 patients who were requiring intensive care or concomitantly taking QT-prolonging medications such as azithromycin and oseltamivir., However, in a real-world analysis from France, 1061 COVID-19 patients (95% had mild disease at baseline) were treated with HCQ + azithromycin for ≥3 days under strict ECG monitoring. Overall, 98.7% patients were virologically cured––only nine patients had a QTc prolongation >60ms from baseline (none exceeded 500ms) and no arrhythmic events or sudden deaths were observed. In the large RECOVERY study, 1542 patients with COVID-19 were administered very high doses of HCQ (2400 mg on Day 1 followed by 800 mg for the next 9 days). The HCQ arm was stopped due to lack of efficacy, and not due to safety concerns, suggesting that no increased adverse cardiac signal was found. The WHO SOLIDARITY trial too had restarted recruitment to HCQ arm after no adverse safety signals were found by the data safety monitoring board (eventually halted again on June 17, 2020 due to lack of efficacy).
An important point to be noted is that the risk of torsades de pointes (TdP) or sudden cardiac death due to arrhythmias is not a linear function of either the basal QT duration or the extent of prolongation of QT induced by a drug. Although drug-induced QT-prolongation is a surrogate indicator of drug-associated torsades de pointes (TdP), the understanding of relationship between QT prolongation and risk of TdP is unclear and complex. As elaborated in the scientific statement from the Indian Heart Rhythm Society, not all patients with drug-induced QT prolongation develop TdP. This side effect is rare, but co-prescription of other drugs such as azithromycin could amplify this risk. In concurrence with this, it has been seen that even in COVID-19, although HCQ may prolong QT interval, it does not appear to be associated with a substantial risk of sudden cardiac death and TdP. In a recent study by electrophysiologists from New York involving 201 hospitalized patients treated with HCQ (±azithromycin) for COVID-19, no instances of TdP or arrhythmogenic death were reported. Though these medications resulted in QT prolongation, clinicians seldom needed to discontinue therapy.
HCQ has been in clinical use around the world since more than 6 decades and was approved in India in 2001 for rheumatoid arthritis (RA). It is considered to be the safest amongst the disease-modifying antirheumatic drugs with an excellent risk-benefit ratio in other approved indications including lupus. It is the first anti-inflammatory agent approved for the management of type 2 diabetes (T2D) in India in 2014. The safety reporting of a well-established molecule such as HCQ should be database-driven rather than based on isolated observations. There is huge global experience with use of HCQ in approved indications such as RA and lupus. In a recent analysis from the University of Florida, >13 million reports over the last 50 years (from 1969 to Q3/2019) from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) were examined. FAERS is an extensive database and includes adverse drug events reported via mandatory reporting by pharmaceutical companies as well as voluntary reporting by consumers. Due to this, it has the ability to capture rare safety events such as TdP/QT prolongation. In this analysis, HCQ was not associated with a safety signal related to TdP/QT prolongation or death when used alone in these approved indications, whereas azithromycin with or without HCQ was associated with QT prolongation. This data is an excellent example of the utility of huge pharmacovigilance databases. Regulators must proactively analyze their safety databases for reports of cardiac adverse events, and in particular QT prolongation, TdP and arrhythmia with the use of HCQ at recommended doses in approved indications. Package insert is another source of drug information that contains data based on regulatory guidelines for the safe and effective use of a drug. In this regard, the frequency of adverse effects is discussed in a clinically useful manner by the Electronic Medicines Compendium (EMC) which is regulated by UK Medicines and Healthcare Products Regulatory Agency and the European Medicines Agency. EMC reports frequency rating of side effects as follows: very common ≥ 10%; common ≥ 1 and <10%; uncommon ≥ 0.1 and <1%; rare ≥ 0.01 and <0.1%; very rare <0.01%; not known (frequency cannot be estimated from available data). The cardiac adverse effects of HCQ including cardiomyopathy and conduction disorders feature in the ‘Not known’ category. In fact, being a quinidine derivative, it has been suggested that HCQ has anti-arrhythmic effects and potential to prevent the appearance of high-risk arrhythmias such as supraventricular and ventricular ectopies. These remain under-evaluated though recognized as early as in the 1950s including a study from India., Thus, the concerns that currently recommended doses of HCQ given alone are likely to provoke TdP are largely unfounded; and there is no evidence for significant risk of TdP with the doses of HCQ that have been used in malaria or rheumatological conditions.
In India, HCQ is being used as a third-step agent in the management of T2D since more than 5 years. In a preliminary analysis from a 52-week phase 4 study involving 600 patients receiving HCQ for T2D (234 with completed 52 weeks of study), no case of TdP or sudden cardiac death was reported. Similarly, several real-world studies have evaluated use of HCQ in the management of T2D including 24 weeks study (n = 1523), 48 weeks study (n = 250), 72-week study (n = 498); and none of the studies have reported higher CV risk or TdP/arrhythmic events/sudden cardiac death. Also, it is known that auto-immune rheumatic conditions such as RA and lupus are associated with elevated risks of insulin resistance and diabetes mellitus; prevalence of diabetes in patients with RA has been estimated be as high as 20%. It has also been shown that atherosclerotic CV disease in RA usually occurs a decade earlier than age- and sex-matched controls and patients with RA are twice more likely to develop myocardial infarction. It can thus be deduced that, since decades, HCQ is being used in this high-risk group, with co-morbid diabetes and ASCVD; and there has not been any reported signal of elevated CV risk in such patients.
ECG monitoring is not part of standard clinical practice while using HCQ as monotherapy in rheumatology or for T2D. In an analysis of ECGs in 85 patients with connective tissue diseases treated with HCQ for >1 year, the QTc interval was not different from normal values and no atrio-ventricular block was observed. Nevertheless, as HCQ can lead to QT-prolongation in predisposed individuals, a baseline ECG can be a simple, useful and inexpensive screening clinical tool to identify such high-risk individuals. Clinical characteristics known to predispose an individual to HCQ-induced QT-prolongation and arrhythmias include structural heart diseases especially ventricular hypertrophy or left ventricular dysfunction, history of ventricular arrhythmia or syncope, and co-administration of other QT-prolonging drugs.
To summarize, there is huge clinical experience with HCQ in approved conditions and has been shown to possess a good safety profile at recommended doses. In COVID-19, HCQ has been predominantly been evaluated in severe cases where several factors could aggravate its QT-prolonging effect or given relatively late after the beginning of symptoms in mild-moderate disease. Use of HCQ in early mild disease appears to have a better risk–benefit ratio and must be evaluated further. Also, COVID-19 being a pro-arrhythmogenic state, a baseline ECG before initiation of HCQ followed by monitoring of serum electrolytes, heart rate and monitoring of QTc interval may be prudent. On the contrary, in approved indications of rheumatology and diabetes, there is sufficient evidence that HCQ does not appear to cause cardiovascular harm. Rather, HCQ is associated with metabolic and cardiovascular benefits in rheumatic conditions.,, Majority of evidence for current regimens of HCQ is very reassuring and the arrhythmia risks have been inferred from QT prolongation rather than observed. Wide emphasis on the rare cardiac effects, which usually does not result in clinically detrimental outcomes, can induce fear in patients taking HCQ at recommended doses for approved indications. Thus, it is critical that clinicians and patients using HCQ for approved indications be reassured about its continued usage.
Financial support and sponsorship
Conflicts of interest
Dr. Anil Pareek and Dr. Ravi Tejraj Mehta are employees of Ipca Laboratories Ltd., Mumbai and are involved in clinical research on hydroxychloroquine. Dr. Shashank Joshi and Dr. Ashok Kumar Das declare no conflicts of interest in relation to this manuscript.
| References|| |
Davis JS, Ferreira D, Denholm JT, Tong SYC Clinical trials for the prevention and treatment of coronavirus disease 2019 (COVID-19): The current state of play. Med J 2020. Available from: https://www.mja.com.au/journal/2020/clinical-trials-prevention-and-treatment-coronavirus-disease-2019-covid-19-current. [Preprint, 27 April 2020].
Available from: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19. [Last accessed on 2020 June 20].
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;35:101738.
Fihn SD, Perencevich E, Bradley SM Caution needed on the use of chloroquine and hydroxychloroquine for coronavirus disease 2019. JAMA Netw Open 2020;3:e209035.
Wang D, Hu B, Hu C, et al
. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA2020;323:1061-9.
Bessière F, Roccia H, Delinière A, et al
. Assessment of QT Intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol Published online May 1, 2020. doi:10.1001/jamacardio.2020.1787.
Mercuro NJ, Yen CF, Shim DJ, et al
. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus 2019 (COVID-19) infection. JAMA Cardiol Published online May 1, 2020. doi:10.1001/jamacardio.2020.1834.
Available from: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19. [Last accessed on 2020 June 2].
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.
Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, et al
. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-cov-2 infection. Circ Arrhythm Electrophysiol 2020;13:e008662.
Benjamin O, Bansal P, Goyal A, et al
. Disease Modifying Anti-Rheumatic Drugs (DMARD) [Updated 2020 Feb 27]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020.
Available from: https://scrip.pharmaintelligence.informa.com/SC027393/Ipca-gets-first-approval-for-HCQ-in-diabetes. [Last accessed on 2020 June 20].
Sarayani A, Cicali B, Henriksen CH, Brown JD Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine. Res Social Adm Pharm 2020;S1551-7411(20)30391-0. [published online ahead of print, 2020 Apr 19].
Available from: https://www.medicines.org.uk/emc/product/1764/smpc. [Last accessed on 2020 Jun 15].
Teixeira RA, Borba EF, Pedrosa A, Nishioka S, Viana VS, Ramires JA, et al
. Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus. Europace 2014;16:887-92.
Arora RB, Sharma VN, Madan BR Antiarrhythmics. I. Chloroquine in auricular fibrillation. Indian J Med Res 1955;43:659-66.
Burrell ZL Jr, Martinez AC Chloroquine and hydroxychloroquine in the treatment of cardiac arrhythmias. N Engl J Med 1958;258:798-800.
White NJ, Watson JA, Hoglund RM, Chan XH, Cheah PY, Tarning J COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. Available from: https://www.tropmedres.ac/news/covid-19-prevention-and-treatment-a-critical-analysis-of-chloroquine-and-hydroxychloroquine-clinical-pharmacology. [Last accessed on 2020 Jul 1].
Pareek A, Mehta RT, Dharmadhikari S, Naidu KB Safety and efficacy of 52 weeks’ therapy with hydroxychloroquine (HCQ)—first anti-inflammatory drug approved in India for T2D. Diabetes 2019;68:1167-P.
Pareek A, Dharmadhikari S, Mehta RT, Naidu KB Postmarketing real-world effectiveness of hydroxychloroquine (HCQ) in treatment of patients with T2D. Diabetes 2020;69:1084-P.
Gupta A Real-world clinical effectiveness and tolerability of hydroxychloroquine 400 mg in uncontrolled type 2 diabetes subjects who are not willing to initiate insulin therapy (HYQ-real-world study). Curr Diabetes Rev 2019;15:510-9.
Baidya A, Pattanaik SR, Shankar A, Ahmed R, Dora N, Behera S efficacy and safety of hydroxychloroquine as an add-on therapy in indian patients with type 2 diabetes mellitus inadequately controlled with two oral drug combination and basal insulin: A 72 week observational trial. Int J Res Rev 2019;6:218-24.
Chen YM, Lin CH, Lan TH, Chen HH, Chang SN, Chen YH, et al
. Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dose-dependent manner: A population-based cohort study. Rheumatology (Oxford) 2015;54:1244-9.
Albrecht K, Luque Ramos A, Hoffmann F, Redeker I, Zink A High prevalence of diabetes in patients with rheumatoid arthritis: Results from a questionnaire survey linked to claims data. Rheumatology (Oxford) 2018;57:329-36.
Mavrogeni S, Dimitroulas T, Bucciarelli-Ducci C, Ardoin S, Sfikakis PP, Kolovou G, et al
. Rheumatoid arthritis: An autoimmune disease with female preponderance and cardiovascular risk equivalent to diabetes mellitus: Role of cardiovascular magnetic resonance. Inflamm Allergy Drug Targets 2014;13:81-93.
Pastick KA, Nicol MR, Smyth E, Zash R, Boulware DR, Rajasingham R, et al
. A systematic review of treatment and outcomes of pregnant women with COVID-19-A call for clinical trials. Open Forum Infect Dis 2020;7:ofaa350.
Costedoat-Chalumeau N, Hulot JS, Amoura Z, Leroux G, Lechat P, Funck-Brentano C, et al
. Heart conduction disorders related to antimalarials toxicity: An analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford) 2007;46:808-10.
Pareek A, Sharma TS, Mehta RT Hydroxychloroquine and QT prolongation: Reassuring data in approved indications. Rheumatol Adv Pract 2020:rkaa044. doi: 10.1093/rap/rkaa044.
Cavalcanti AB, Zampieri FG, Rosa RG, et al
. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med 2020:NEJMoa2019014. [published online ahead of print, 2020 Jul 23].
Udwadia ZF, Malu KN, Rana D, Joshi SR Hydroxychloroquine for COVID-19: What is our current state of knowledge? J Assoc Physicians India 2020;68:48-52.
Rempenault C, Combe B, Barnetche T, Gaujoux-Viala C, Lukas C, Morel J, et al
. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: A systematic review and meta-analysis. Ann Rheum Dis 2018;77:98-103.
Liu D, Li X, Zhang Y, et al
. Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: A systematic review and meta-analysis. Drug Des Develop Ther 2018;12: 1685‐95.
Pareek A, Purkait I, Mehta RT, Grover A Metabolic and cardiovascular benefits of hydroxychloroquine: Exploration in a wider population at high CV risk. Ann Rheum Dis 2018;77:e59.