HomeJournalsCardiovascular Considerations for the Internist and Hospitalist in the COVID-19 Era
Cardiovascular Considerations for the Internist and Hospitalist in the COVID-19 Era
Drug-induced QT interval prolongation and torsades de pointes
Chloroquine, hydroxychloroquine with or without azithromycin and other antiviral medications are purported to benefit COVID-19 patients. These medications are relatively weak inhibitors of cardiac potassium channels (mainly Ikr) responsible for repolarization; when used alone in healthy patients result in only minor QT-prolongation. Chloroquine has been used for malaria prophylaxis worldwide and drug-induced torsades de pointes and life-threatening ventricular tachyarrhythmias are rare in these patients, even with prolonged use.,
The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review.
In contrast, anticipated duration of exposure to these medications for COVID-19 is relatively short, 5-10 days.
However, when two or more QT-interval prolonging drugs are used together, or used in older critically ill patients with multiple risk factors for arrhythmias related to QT-prolongation (see below), prolongation of repolarization may be sufficient to result in life-threatening proarrhythmia, polymorphic ventricular tachycardia/torsades de pointes.
Considerations for drug interactions on QTc in exploratory COVID-19 (Coronavirus Disease 2019) treatment.
Although only a small proportion of patients with QT-prolongation develop torsades, it is most likely to occur when the QTc is ≥500 msec. The half-life of hydroxychloroquine is 40-60 days
Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.
, raising the possibility that drug-induced QTc prolongation could remain for a substantially longer period than actual drug administration, and if a QT-prolonging drug were added, risk of torsades may increase. QT-prolongation may not be the only cause of ventricular arrhythmias in COVID-19 patients receiving hydroxychloroquine or other antivirals; viral myocarditis, and/or other organ damage altering drug metabolism may increase arrhythmia susceptibility.
Preliminary data indicate that most COVID-19 patients showed minor increases in QTc duration on combination hydroxychloroquine and azithromycin, yet 12% had QTc prolongation >60 milliseconds from baseline and 11% developed QTc intervals >500 milliseconds. Another study found QTc prolongation >500 msec in 19% of patients given higher doses of chloroquine.
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.
Most of these patients were also receiving oseltamivir, which also may prolong the QTc. ICU patients with COVID-19 pneumonia may be particularly prone to excessive QT-prolongation, especially when hydroxychloroquine is combined with azithromycin.
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.
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).
Prior to COVID-19, a risk score for predicting QT-prolongation in ICU patients was developed.
Development and validation of a risk score to predict QT interval prolongation in hospitalized patients.
Risk factors receiving: 1-point included age ≥68 years, female sex and loop diuretic; 2-points serum potassium ≤3.5, admission QTc ≥450 msec, acute myocardial infarction; 3-points one QTc-prolonging drug, two or more QTc-prolonging drugs, sepsis, and heart failure. The maximum risk score was 21. Patients at low risk for QT prolongation/torsades de pointes were defined as those with a score ≤6 points, moderate risk 7-10 points, and high risk ≥11 points. Importantly, loop diuretic, low potassium, concomitant QT-prolonging drugs are modifiable. This scoring system was incorporated into an algorithm by others
Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19.
(Figure 4). A baseline QTc is obtained using 12-lead ECG. If the QRS is wide (bundle branch block or ventricular pacing), a correction can be estimated by the following formula:
Figure 4UF Health algorithm for initiation of QTc prolonging drugs* in COVID-19 pathway. Modified from Giudicessi et al.31
Development and validation of a risk score to predict QT interval prolongation in hospitalized patients.
, patients are categorized as low, intermediate, or high risk and any modifiable risk factors for QT-prolongation should be addressed. Serum potassium should be maintained >4 meq/l and magnesium >2 meq/l. If the patient is receiving concomitant drugs that prolong the QT-interval, including dofetilide or sotalol, consider discontinuing them, if possible. A list of offending drugs is at www.qtdrugs.org. If the patient is low or intermediate risk for QT-prolongation and reversible factors have been addressed, QT-prolonging COVID-19 drugs can be initiated. The high-risk category is not an absolute contraindication to hydroxychloroquine with or without azithromycin, but potential benefit versus risk must be addressed with the patient.
The intensity of QTc follow-up for patients receiving these drugs depends on the patient’s risk category. Due to proarrhythmia and difficulty with QT-interval follow-up, FDA recommends chloroquine, hydroxychloroquine, or azithromycin use in COVID-19 patients be limited to clinical trials or for certain hospitalized patients. Even in the inpatient setting, COVID-19 patients present unique challenges obtaining serial ECGs due to isolation issues. If the patient is low risk, it may be reasonable to forego serial ECG monitoring, or obtain QTc measurements on day 2 and 4 of therapy if feasible. For patients at intermediate risk, telemetry should be maintained and QTc measurement on day 2 and 4 of therapy. For high-risk patients, QTc measurements should be obtained 2-4 hours after the first dose and daily thereafter if feasible, and the patient should be monitored via telemetry.
Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19.
Single-lead telemetry or smart-phone tracings are not sufficiently accurate for QTc monitoring, but many telemetry systems have the ability to obtain multiple simultaneous leads, and the longest QT-interval measured from those leads is a reasonable estimate of the QTc. The FDA has approved smart-phone applications providing simultaneous 6-lead ECGs for QTc monitoring. The smart-phone can either be a placed in a sterile bag and the recording apparatus sanitized after every use, or the patient can use their own smart-phone.
