key: cord-010585-hasoaa0k
authors: Szekely, Yishay; Lichter, Yael; Shrkihe, Bander Abu; Bruck, Hila; Oster, Howard S.; Viskin, Sami
title: Chloroquine-induced torsade de pointes in a COVID-19 patient
date: 2020-05-05
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.04.046
sha: 
doc_id: 10585
cord_uid: hasoaa0k

nan

The case for chloroquine and hydroxychloroquine, as treatment for the COVID-19 pandemic, has been voiced not only in medical journals 1 , but also in the popular press. 2 Not only is the efficacy of these antimalarial and anti-inflammatory compounds as antiviral drugs uncertain, but there is also ongoing debate as to their safety. 3 In particular, the magnitude of the proarrhythmic potential of these drugs, specifically related to their QT-prolongation effects, is questioned: On the one hand, the fact chloroquine and hydroxychloroquine block the I Kr potassium-channel at the myocyte level, therefore causing QT-prolongation, is well documented. 4 that we report a case of drug-induced torsade de pointes (TdP) due to chloroquine therapy for COVID-19.

An 84-year-old woman with COVID-19 was admitted to a designated ward. Her medical history includes metastatic breast cancer and a remote history of pulmonary embolism. She also has treated arterial hypertension and evidence of left ventricular hypertrophy but is otherwise free of heart disease. Her medications include bisoprolol, letrozole (an aromatase inhibitor prescribed for breast cancer), memantine (an N-Methyl-D-Aspartate receptor antagonist used to treat Alzheimer's disease) and apixaban. On admission, she was in no obvious distress but her chest X-ray revealed typical bilateral opacities. Her ECG ( Figure 1A) showed sinus rhythm 63/min, PR interval of 320 msec and narrow QRS with small Q waves in the inferior leads. Her QT and QTc were 450 and 462 msec, respectively. Her laboratory results were significant for positive SARS-CoV-2 PCR from throat and nasal swab, lymphopenia, C-reactive protein (CRP) of 14 mg/L, Troponin I of 22 ng/L (range 0-50), brain natriuretic peptide (BNP) of 105 pg/mL, creatinine of 0.81 mg/dL, potassium of 4.51 mmol/L and magnesium of 1.84 mg/dL, along with normal venous blood gases. Her COVID-19 modified early warning score (COVID-19 MEWS) was 3. The next day, her ambient O 2 saturation declined to 93%, and her COVID-19 MEWS was updated to 5. According to our institutional COVID-19 therapeutic approach, oral therapy with chloroquine diphosphate (Remedica Ltd, Cyprus) 500 mg twice daily was initiated. After 5 days of treatment, there was no significant clinical change. A follow-up ECG showed sinus rhythm of 47 beats/min with an extremely prolonged QT-interval (QT=720 msec and QTc=627 msec) ( Figure 1B) .

Chloroquine was discontinued and other known or suspected QT-prolonging medications, as well as non-essential medications were withheld, including memantine and letrozole.

Bisoprolol was also stopped due to bradycardia. She was placed under continuous electrocardiographic monitor and was given additional oral potassium supplements. Her blood potassium level was 4.17 mmol/L. Six hours later, multiple episodes of typical pausedependent TdP were noted (Figure 2) . The patient remained asymptomatic and alert. She was treated with intravenous magnesium (2 gr of magnesium sulfate injected over 10 minutes), potassium (3 gr diluted in 1L 0.9% normal saline administered over 5 hours) and lidocaine (100 mg in slow bolus followed by a 2mg/min infusion). Also, to prevent the pauses precipitating TdP, isoproterenol (1 mg/50 cc glucose 5%) was administered intravenously at an infusion-rate titrated to raise her heart rate to 80-90/min. This led to immediate resolution of all ventricular arrhythmias. Repeated blood potassium level was 4.43 mmol/L and magnesium was 2.55 mg/dL. The isoproterenol infusion was discontinued after 18 hours. The patient remained free of arrhythmias with no apparent clinical change. Subsequent electrocardiograms showed gradual normalization of her QT interval ( Figure 1C) . She was discharged two weeks later.

We present the first case of TdP in a COVID-19 patient treated with chloroquine. As in many institutions worldwide, our patient was admitted to a designated COVID-19 ward and chloroquine therapy was initiated. After 5 days on this therapy, she developed major QT prolongation and recurrent TdP. As most cases of drug-induced TdP, our patient is female and elderly. 9

The fact that our patient was receiving memantine, a drug rated as a medication with "possible risk for TdP" likely contributed to the proarrhythmic effects of chloroquine.

However, such use of "contributory drugs" in drug induced long QT syndrome (LQTS) is the rule rather than the exception. 9 Furthermore, her QTc at the time of hospitalization was only borderline high despite long-term therapy with this drug. Yet, in increased from 462 to a QTc of 627 msec after chloroquine was initiated, clearly pointing to chloroquine as the culprit drug of her TdP. Letrozole, an aromatase inhibitor, is a breast cancer therapy that is actually considered safer, from the QT point of view, than selective estrogen receptor modulators. 10 Both drugs, as well as chloroquine, were discontinued when the QT prolongation was noted.

Despite this measure, and despite oral potassium supplementation, the patient developed multiple episodes of TdP 6 hours later.

Recommendations to help coping with the dilemmas surrounding the use of QT-prolonging medications during the COVID-19 pandemic have recently been published. [11] [12] [13] [14] Based on our patient's baseline QT interval (QTc of 462 msec), it was permissible to treat her with chloroquine according to each of these four documents. [11] [12] [13] [14] However, all 4 documents emphasize the importance of discontinuing all QT-prolonging drugs at the onset of chloroquine treatment rather than when excessive QT prolongation is first recognized (as done in our case). Furthermore, all 4 documents emphasize the need for repeated QTassessment at shorter time intervals (rather than after 5 days, as done here). Our patient developed an arrhythmic storm of recurrent TdP 6 hours after discontinuation of chloroquine despite potassium supplementation, probably reflecting the relatively long half-life of chloroquine. 15 A huge number of patients are being treated with chloroquine during the COVID-19 pandemic. Excessive QT prolongation, defined as prolongation to a QTc >500 msec, has already been reported for 11%-25% of COVID-19 patients treated with hydroxychloroquine/azithromycin. 7 Many of these patients are elderly and have comorbidities that increase the risk of drug-induced LQTS. Given its questionable efficacy in the treatment of COVID-19 and its risk of QT-prolongation, chloroquine treatment must be considered thoroughly, and reviewed on a regular basis. Clinicians should monitor COVID-19 patients when treating them with chloroquine or other QT-prolonging drugs, with special attention to females, patients with structural heart disease, baseline QT interval on ECG, concomitant use of other QT-prolonging medications, potassium or magnesium abnormalities and bradycardia. 

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The New York Times: Trump's Aggressive Advocacy of Malaria Drug for Treating Coronavirus Divides Medical Community

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 6