the above-mentioned drugs, risk factors of arrhythmia should be taken into account pri- or to treatment administration (Table 2) and, if possible, eradicated. Electrolyte imbalance ought to be corrected, other drugs causing QT prolongation should be discontinued. Lists of QT prolonging drugs is available at www.qt- drugs.org and www.crediblemeds.org. Through- out the treatment of high-risk patients, mon- itoring of the QTc interval and arrhythmia is necessary (management algorithm is present- ed in Figure 1).
In order to calculate the QTc interval, the Ba- zett formula is most commonly used. In case of problems when measuring QT (measuring the end of the T wave), a tangent to descending portion of the T wave should be drawn. The re- sult should be an average of at least 3 heart evolutions (Figure 3). The upper limit of a QTc interval for men is 450 ms and for women, 460 ms. QTc between 460 ms and 500 ms re- quires attention.
Introduction The purpose of this document is neither to evaluate the efficiency of treatment with antiviral and antimalarial drugs in patients with coronavirus disease 2019 (COVID-19), nor to influence the decision on the kind of treat- ment. The aim of the paper is to draw the at- tention to the possibility of reducing the risk of sudden cardiac death involving the use of these drugs as well as to ensure the utmost safety for patients requiring such treatment.
Some drugs used in the treatment of COV- ID-19 (chloroquine, hydroxychloroquine, lopi- navir / ritonavir, and azithromycin) may pro- long QT / corrected QT (QTc) and cause serious arrhythmias such as torsade de pointes (TdP), an atypical ventricular tachycardia. The induc- tion of such arrhytmias may lead to the loss of consciousness and possibly the cause of sud- den cardiac death. Azithromycin can addition- ally cause polymorphic tachycardia and atrio- ventricular conduction disturbances (Table 1).
In order to minimize the risk associated with
Correspondence to:
Prof. elżbieta K. biernacka, MD, PhD, Department of Congenital Heart Diseases, The Cardinal Stefan Wyszyński National institute of Cardiology, ul. alpejska 42, 04-628 Warszawa, Poland, phone: +48 22 343 44 00, email: k.biernacka@ikard.pl Received: May 10, 2020.
Accepted: May 11, 2020.
Published online: May 11, 2020.
Kardiol Pol. 2020; 78 (5): 493-497 doi:10.33963/KP.15354 Copyright by the Polish Cardiac Society, Warsaw 2020 Key words antimalarial drugs, azithromycin, coronavirus disease 2019, prolonged QT syndrome, QT interval
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R
Safety of antiviral and anti -inflammatory drugs prolonging QT interval in patients with coronavirus disease 2019: an opinion
of the Heart Rhythm Section of the Polish Cardiac Society
Writing Committee: Elżbieta K. Biernacka1, Dariusz A. Kosior2,3, Agnieszka Zienciuk ‑Krajka4, Maria Miszczak ‑Knecht5, Maciej Kempa4, Andrzej Przybylski6,7
Reviewers (on behalf of the Polish Cardiac Society): Rafał Baranowski8, Piotr Kułakowski9 1 Department of Congenital Heart Diseases, The Cardinal Stefan Wyszyński National institute of Cardiology, Warsaw, Poland
2 Department of Cardiology and Hypertension with electrophysiological lab, Central research Hospital, the Ministry of the interior and administration, Warsaw, Poland 3 Mossakowski Medical research Centre Polish academy of Sciences, Warsaw, Poland
4 Department of Cardiology and electrotherapy, Medical university of gdańsk, gdańsk, Poland 5 Department of Cardiology, The Children’s Memorial Health institute, Warsaw, Poland 6 Medical College, university of rzeszów, rzeszów, Poland
7 Cardiology Department with the acute Coronary Syndromes Subdivision, Clinical Provincial Hospital No 2, rzeszów, Poland 8 1st Department of Heart arrhythmia, The Cardinal Stefan Wyszyński National institute of Cardiology, Warsaw, Poland 9 Department of Cardiology, Centre of Postgraduate Medical education, Warsaw, Poland
• Restricted availability of telemetry: patients undergoing treatment in which QTc values as- sessed after the treatment administration are acceptable can be monitored telemetrically, similarly to patients at low risk. Patients at a higher risk should be monitored. If the hos- pital telemetry is unavailable, mobile meth- ods of monitoring are acceptable. Every syn- cope should be treated as potentially caused by polymorphic ventricular tachycardia.
• Limiting contact: in patients staying in house care with a low risk of arrhythmia, baseline ECG can be omitted. QTc moni- toring should be performed according to the proposed outlines, additional, unnec- essary ECG registration should not be per- formed as it increases the infection risk of personnel and involves the use of addition- al protective equipment.
A simple method of evaluating QTc prolon- gation is checking whether the QT interval does not exceed half of the preceding R -R inter- val. In such case, QTc does not exceed 460 ms, which means that the patient has a low risk of TdP.
Monitoring of treatment safety in given clin- ical cases
• Restricted availability of personal protective equipment: it is advisable to perform electro- cardiography (ECG) within 2 to 4 hours af- ter drug administration. QTc measurements by means of telemetry or mobile devices, for example, Apple Watch, AliveCor, KardiaMo- bile, or others, are acceptable. Proper pro- tection of the phone and leads for ECG en- sures sterility and minimizes the risk of vi- rus transmission.
Table 2 Risk factors for a prolonged QT interval and serious arrhythmias (modified from Behr et al)2 Female sex
Age >68 y
Heart diseases Myocardial infarction Heart failure
Left ventricular hypertrophy
First hours after atrial fibrillation cardioversion to sinus rhythm
Prolonged QT syndrome and genetic factors predisposing to QT prolongation Bradycardia and atrioventricular disturbances
Sepsis
Increased bioavailability
of the drug Genetic versions of P450 cytochrome
Other drugs metabolized by cytochrome P450 used simultaneously Liver disease
Kidney disease Electrolytic disturbances Hypokalemia
Hypomagnesemia Hypocalcemia
Table 1 Drugs used in the treatment of coronavirus disease 2019 that have proarrhythmic effect (based on Giudicessi et al)1
Drug Risk of TdP/VF/CA Mechanism
Antimalarial drugs
Chloroquine Confirmed Blocking of potassium channel Kv11.1
Hydroxychloroquine Confirmed Blocking of potassium channel Kv11.1
Anitviral drugs
Lopinavir / ritonavir Possible Blocking of potassium channel Kv11.1, although its proarrhythmic effect was not proven
Supportive drugs
Azithromycin Confirmed QT prolongation in unknown mechanism (rarely TdP)
Polymorphic tachycardia in the mechanism of enhanced channel Nav1.5
Bradycardia, atrioventricular conduction disturbances Abbreviations: CA, cardiac arrest; TdP, torsade de pointes; VF, ventricular fibrillation
Figure 1 Management algorithm in hospitalized patients with coronavirus disease 2019 treated with QT / QTc prolonging drugs (based on Simpson et al,3 Mitra et al)4 Abbreviations: BBB, bundle branch block; Ca, calcium; COVID-19, coronavirus disease 2019; ECG, electrocardiography; K, potassium; Mg, magnesium; QTc, corrected QT
Discontinue other QT prolonging drugs Hospital care of a patient with COVID-19
Decision on the administration of chloroquine, hydroxylorquine, or azithromycin
• Perform ECG 2–3 hours after the second drug dose or on the following day
• If possible, use telemetry; monitor the symptoms (syncope, dizziness, etc)
• If QTc increased by >60 ms or >500 ms (for BBB or rhythm >120/min 530–550 ms), discontinue azithromycin, reduce the dose of hydroxylorquine; perform ECG daily
• If QTc prolongation persists, consider the risk of treatment continuation, consult a cardiologist Evaluate the risk of polymorphic arrhythmia; patients at higher risk
Treatment administered Mg <2 mmol/l
K <4 mmol/l Ca <2.2 mmol/l
In case of QTc >500–550ms, if arrhythmia does not occur and heart rate ≥80 bmp, lidocaine administration can be considered
(bearing in mind liver function). If heart rate <80 bpm, isoprenaline or temporary stimulation can be used. Initiate continuous
infusion of Mg. When QTc is shortened, treatment administration can be
reconsidered.4 Correct defi ciency
Evaluate kidney
and liver function Previously diagnosed long QT syndrome or QTc >500 ms, for rhythm >120/min 530–550 ms
Evaluate the necessity of treatment vs the risk of arrhythmia
Outpatient care for a patient with COVID-19
Decision on the administration of chloroquine, hydroxylorquine, or azithromycin
• In case of using the drug, perform ECG 2–3 hours after administration on the third day of treatment
• In case of QTc prolongation >30–60 ms or QTc >500 ms (for BBB or frequency
>120/min QTc >530–550 ms), terminate the treatment
• Monitor the symptoms; every syncope should be treated as potentially caused by ventricular tachycardia
Evaluate the risk of polymorphic arrhythmia; patients at a higher risk
Mg <2 mmol/l K <4 mmol/l Ca <2.2 mmol/l
Correct defi ciency Discontinue other QT prolonging drugs
Previously diagnosed long QT syndrome or QTc >480 ms, for rhythm >120/min 510–530 ms
Evaluate the necessity of treatment vs the risk of arrhythmia
Treatment administered
Evaluate kidney and liver function
Figure 2 Management algorithm in patients with coronavirus disease 2019 treated with QT / QTc prolonging drugs in the outpatient setting (based on Simpson et al,3 Mitra et al)4
Abbreviations: see Figure 1
of consciousness, or cardiac arrest requires imme- diate cardiopulmonary resuscitation, including de- fibrillation. In case of good tolerance of arrhyth- mia (single or multiple self -terminating tachycar- dia), every patient requires monitoring and treat- ment due to a substantial risk of sudden deteriora- tion. It is recommended to administer magnesium sulfate intravenously in a 2-g dose and to correct potassium and calcium deficiency (up to the up- per limit). In case of subsequent recurrence of TdP, temporary heart stimulation can be applied with a frequency of 70 to 80 per minute or intravenous infusion of izoproterenol in a dose of 1 to 5 µg per minute (Figure 4).5,6 In every case of TdP, urgent car- diology consultation is advised.
Supplementary material
The Polish version of the paper is available at www.mp.pl/kardiologiapolska.
article information
conflict of intereSt None declared.
open acceSS This is an Open access article distributed under the terms of the Creative Commons attribution -NonCommercial -NoDerivatives 4.0 in- ternational license (CC bY -NC -ND 4.0), allowing third parties to download ar- ticles and share them with others, provided the original work is properly cited, not changed in any way, distributed under the same license, and used for non- commercial purposes only. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.
How to cite biernacka eK, Kosior Da, Zienciuk -Krajka a, et al. Safety of antiviral and anti -inflammatory drugs prolonging QT interval in patients with
• Ensuring safe monitoring: all patients with the following symptoms should be monitored: syn- cope, dehydration, ion disturbances. Monitor- ing can be in a form of a phone call. Every syn- cope should be treated as potentially caused by polymorphic ventricular tachycardia.3 The procedure in case of torsade de pointes tachycardia Sustained tachycardia of the TdP type causing hemodynamic instability, loss
Torsade de pointes (TdP) Evaluate the patient’s condition
Single TdP episode
• Magnesium intravenously (1 amp. 10 ml MgSO4 20% for 3 min)
• Balance electrolyte / metabolic disturbances:
– Potassium, up to the upper norm limit (4.5–5 mmol/l)
– Total calcium, if concentration below 2.2 mmol/l
• Discontinue QT prolonging drugs
Recurrent TdP
(multiple, self-terminating episodes)
• Magnesium intravenously
(1 amp. 10 ml MgSO4 20% for 3 min), continuation 2–4 mg/min intravenously
• Balance electrolyte / metabolic disturbances:
– Potassium, up to the upper norm limit (4.5-5 mmol/l)
– Total calcium, if concentration below 2.2 mmol/l
• Discontinue QT prolonging drugs
• Heart rate acceleration (overdrive pacing by temporary wire >70–80/min) or intravenous isoprenaline (1–5 µg/min)
Hemodynamically unstable Start CPR Defi brillation
Magnesium intravenously (1 amp. 10 ml MgSO4 20% for 3 min) We do not recommend to use proarrhythmic drugs during CPRa
Monitor ECG further until concentrations of electrolytes are balanced and QT is normal → possibility of TdP recurrence!
Hemodynamically stable Attention: it is necessary to begin the treatment due to the high risk of deterioration
Figure 4 Procedure in case of torsade de pointes tachycardia.
a It does not apply to possible use of lidocaine at a later stage
Abbreviations: CPR, cardiopulmonary resuscitation; others, see Table 1 and Figure 1
Figure 3 A formula for corrected QT (online calculator: http://zwr.cmj.org.pl/biblioteka- wiedzy/qtc-skorygowany-odstep-qt-wzor-bazetta/)
Abbreviations: see Figure 1
QTc = QT/√RR QT
coronavirus disease 2019: an opinion of the Heart rhythm Section of the Polish Cardiac Society. Kardiol Pol. 2020; 78: 493-497. doi:10.33963/KP.15354
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