key: cord-1031600-rlxrn3ap
authors: Chorin, Ehud; Wadhwani, Lalit; Magnani, Silvia; Dai, Matthew; Shulman, Eric; Nadeau-Routhier, Charles; Knotts, Robert; Bar-Cohen, Roi; Kogan, Edward; Barbhaiya, Chirag; Aizer, Anthony; Holmes, Douglas; Bernstein, Scott; Spinelli, Michael; Park, David S.; Stefano, Carugo; Chinitz, Larry A.; Jankelson, Lior
title: QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin
date: 2020-05-12
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.05.014
sha: 5e28216d206bdf411652342f178ac046c76313e4
doc_id: 1031600
cord_uid: rlxrn3ap

BACKGROUND: There is no known effective therapy for patients with COVID-19. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP). OBJECTIVE: to assess the change in QTc interval and arrhythmic events in patients with COVID-19 treated with HY/AZ METHODS: This is a retrospective study of 251 patients from two centers, diagnosed with COVID-19 and treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality. RESULTS: QTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia (VT) suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting extreme QTc prolongation was normal. CONCLUSION: The combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.

The evidence supporting effective drug therapy for COVID-19 is limited. In vitro studies have suggested that Hydroxychloroquine alone and in combination with Azithromycin could be a viable therapy 1, 2 . A small, controversial study enrolling 26 treated patients and 16 non-randomized controls showed that HY/AZ shortened the viral shedding of SARS-CoV-2 3 . Based on this, clinicians in many countries have begun using these medications, and multiple randomized trials are ongoing 4 .

However, HY and AZ have each been independently shown to increase the risk for QT interval prolongation, drug-induced torsade de pointes (TdP), and sudden cardiac death (SCD) [5] [6] [7] [8] . We recently reported QT prolongation in a preliminary series of 84 patients with COVID-19 treated with HY/AZ 9 . Here we report a study from two centers evaluating the effects of HY/AZ on the QT interval and the arrhythmic risk in patients with COVID-19.

This is a retrospective study including 251 consecutive adult patients hospitalized at NYU Langone Health (211 patients) and at San Paolo University Hospital (40 patients) with COVID-19 disease, treated with the combination of HY/AZ. Patients with a baseline ECG and at least one ECG performed after medication administration were included. Of 325 patient screened, we excluded 40 (12.3%) patients without baseline ECG and 34 (10.4%) patients without follow up ECG.

Of the 211 patients from the NYU site, 84 were reported in our recent publication 9 .

Hydroxychloroquine was given orally at 400 mg BID for one day (loading dose) followed by 200 mg BID for 4 days. Azithromycin was given orally at a dose of 500 mg daily for 5 days. For QTc measurement, five cardiologists trained and experienced in QT measurement performed all electrocardiographic measurements.

The QT interval was measured using the "Tangent" method 10 

We included 251 patients in our cohort with a maximal follow up of 8 days and mean ECG follow up time of 5.2 ± 2 days ( Table 1 ). The median age was 64±13 years and Specifically, QTc>500 msec was seen in 28 of 222 (13%) patients with QRS<120.

JTc>410 was seen in 4 of 29 (14%) patients with QRS >120, and ΔQTc>60 was seen in 51 of 251 (20%) patients with any QRS. These numbers include 25 patients who had more than one of these endpoints. Thirty five (60%) of the 58 patients who met the composite endpoint were not on any other QTc prolonging medication. In this high risk group, QTc increased from a baseline of 431 ± 32 to 513 ± 38 ms and JTc increased from 335±28 to 417± ms (p<0.01 for both). In 8 patients, extreme QTc prolongation triggered discontinuation of therapy prematurely, including the patient who developed TdP where therapy was halted on day 4. In 29 (11.5%) patients, baseline QRS was more than 120 ms. The baseline JTc and the maximal ∆JTc were similar between patients with and without QRS>120 ( Table 2) . On multivariate analysis, baseline QTc and co-administration of Amiodarone were significant predictors of QTc > 500 ms, while baseline Creatinine and co-administration of Amiodarone were predictors of ∆QTc > 60 ms (Tables 3 and 4 ). The predictors of extreme JTc prolongation > 410 ms included baseline JTc and Creatinine (Supplementary Table 1 ). Patients with extreme QTc prolongation had lower body weight, greater frequency of kidney disease, and greater Amiodarone exposure (Supplementary Table 2 ).

Drug-induced QT prolongation is an important substrate for TdP, a potentially lethal polymorphic VT. In our study of 251 patients with COVID-19, we found high incidence of QTc prolongation, with at least one documented polymorphic VT (suspected TdP) for a rate of 0.4%. To put the incidence of TdP in perspective, the risk of TdP induction by Sotalol is estimated at 0.1% 16 

Treatment of COVID-19 with HY/AZ prolongs the QTc to an extreme degree in a significant proportion of patients, increasing the risk for TdP. Risk/benefit considerations should be carefully and individually evaluated and preventive measures should be applied when using this regimen.

Our study has several limitations. This is an observational, retrospective study. We did not include patients treated with each medication separately and each patient served as a self-control. Patients without baseline or follow up ECG were excluded from analysis, which can represent a bias. This is partially mitigated by the consecutive inclusion of patients meeting study criteria. The population in our study was primarily Caucasian, thus applicability to other populations warrants further study. Relatively short follow-up time after HY/AZ regimen completion was available.

We did not assess serum drug concentrations. Tables: Table 1 

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

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)

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Chloroquine and hydroxychloroquine in covid-19

Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia

Suspected hydroxychloroquine-associated QTinterval prolongation in a patient with systemic lupus erythematosus

Azithromycin-induced torsade de pointes

Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin

The measurement of the QT interval

Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome

Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome

Journal of the American College of Cardiology

Prevention of Torsade de Pointes in Hospital Settings A Scientific Statement From the American Heart Association and the American College of Cardiology Foundation

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19)

Meta-analysis of the risk of torsades de pointes in patients treated with intravenous racemic sotalol

An algorithm for continuous real-time QT interval monitoring

Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Genetic Susceptibility for COVID-19-Associated Sudden Cardiac Death in African Americans

Risk factors and predictors of Torsade de Pointes ventricular tachycardia in patients with left ventricular Systolic dysfunction receiving Dofetilide

Torsades de pointes induced by antibiotics

Torsade de Pointes due to noncardiac drugs -Most patients have easily identifiable risk factors

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study

Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded

Chloroquine-induced torsade de pointes in a COVID-19 patient

Azithromycin Causes a Novel Proarrhythmic Syndrome

SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes. Heart Rhythm

Guidance for Cardiac Electrophysiology During the Coronavirus (COVID-19) Pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology

Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients

ENHANCED ECG MONITORING OF COVID-19 PATIENTS

The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19)

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