"Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers

Abstract

Introduction: COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences.

Methods: Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.

Results: In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication.

Discussion and conclusion: "Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.

Keywords: Arrhythmia; Azithromycin; COVID-19; Cardiac adverse effects; Hydroxychloroquine; Lopinavir; QTc prolongation.

Figure 1

Spontaneous notifications’ profile. A. Cumulative notifications of cardiac adverse drug reactions (ADRs). Cardiac ADRs accrued from March 27th, 2020, beginning of the survey, till they reached 120 on April 27th, 2020. Insert: ADRs by type. B. Cardiotoxicity profile.

Figure 2

Mechanisms of QT prolongation and TdP. Prolongation of the QT interval on the electrocardiogram results from the prolongation of the action potential duration (APD) of ventricular myocytes, brought in this case by hydroxychloroquine (HCQ), chloroquine (CQ), azithromycin (AZI) or lopinavir-ritonavir (LOPI), hence by their association. They all reduce outward potassium currents during phase 3 of the action potential. Such reduction of net outward current augments the APD, which translates in an increased QT interval on the ECG. It also facilitates the development of early afterdepolarizations (EADs) associated with calcium influx, because of the delay in repolarisation and a membrane still relatively electropositive. These EADs can lead to extrasystoles which may trigger complex ventricular reentries such as Torsades de Pointes. The prolonged QT reflects the underlying arrhythmogenic substrate resulting from an increased dispersion of the repolarization. The development of early afterdepolarizations and TdP usually occurs with drugs that block I_Kr, the rapid component of the potassium current I_K A factor of particular importance for the genesis of TdP is a particular predisposition of individual patients aggravated by the presence of risk factors (hypokalemia, hypomagnesemia, feminine gender, bradycardia, multiple drugs prolonging the QT…), which reduce the repolarization reserve .

Figure 3

ECG abnormalities associated with hydroxychloroquine (HCQ), azithromycin (AZI) or lopinavir-ritonavir (LOPI) in COVID-19. A. Prolonged QTc interval: (lead II) of a 70 y.o. man started on HCQ and AZI for COVID-19. Four days after introduction, the patient had a prolonged QTc (491 ms), which normalized 2 days after treatment discontinuation. B. Bigeminy in an 81 y.o. hypertensive man treated with LOPI 400/100 for COVID-19 in a setting of severe bradycardia. Sudden and “serious” conduction AV conduction and rhythm problems (bigeminy) occurring on the 5th day of treatment. Outcome was favorable after treatment withdrawal. C. Torsades de pointes occurring 7 hours after the second and last administration of 200 mg oral HCQ in a 43 y.o. man hospitalized for COVID-19 with a previously undiagnosed long QT syndrome (baseline Bazett-corrected QT measured at 500 ms). Bazett-corrected QT was 667 ms minutes before the arrhythmia, which required cardioversion. Outcome was favorable after treatment withdrawal.