QT Intervals in Patients With COVID-19 Treated With Hydroxychloroquine With or Without Azithromycin
abstract
This abstract is available on the publisher's site.
Access this abstract nowThe novel coronavirus disease 2019 (COVID-19) outbreak is an ongoing situation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Studies in patients with mild to moderate COVID-19 symptoms have suggested benefits of hydroxychloroquine alone or in combination with azithromycin against SARS-CoV-2 and raised hope for treating the disease. As a result, these treatments are increasingly used off-label for patients with COVID-19, including for those in intensive care units (ICUs). However, both medications are known to induce QT prolongation via a human Ether-à-go-go–related gene potassium channel blockade, which can promote life-threatening ventricular arrhythmias. Safety data for these treatments are largely lacking for patients with COVID-19. This is even more relevant for critically ill patients who are particularly exposed to electrolyte imbalance and/or drugs leading to an increased risk of QT prolongation.Therefore, we aimed to examine the safety of hydroxychloroquine with or without azithromycin regarding QT interval in ICU patients with COVID-19.
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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
JAMA Cardiol 2020 May 01;[EPub Ahead of Print], F Bessière, H Roccia, A Delinière, R Charrière, P Chevalier, L Argaud, M CourFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Hydroxychloroquine (HCQ), chloroquine (CQ), and azithromycin (AZT) are drugs known to prolong ventricular repolarization (QT interval) and occasionally provoke torsades de pointes (TdP), primarily by blocking a K channel. When used together, their action can be amplified, as it also can be by clinical settings of electrolyte abnormalities, myocardial diseases characterized by prolonged ventricular repolarization, female sex, and other situations. Thus, it should come as no surprise that several studies testing these drugs to combat COVID-19 have found that patients exhibit QT prolongation. What did come as a surprise was when US political leadership blithely said, referring to those drugs, “What have you got to lose? Take it.” Only your life!
In fact, sudden death is exactly what happened in a recent trial of 81 patients in Manaus, Brazil. Coronavirus–infected patients were randomized to receive CQ 600 mg twice daily for 10 days, or a total dose 12 g, or 450 mg for 5 days, twice daily only on the first day, or a total dose 2.7 g (ClinicalTrials.gov, number NCT04323527). In addition, all patients received ceftriaxone and AZT. The high-dose arm presented more QTc >500 ms (25%) and a trend toward higher lethality (17%) than the lower-dose arm. The New York Times reported that, by the sixth day of treatment, 11 patients had died, leading to an immediate end to the high-dose segment of the trial. The investigators found that, in 14 patients with paired samples, respiratory secretion at day 4 was negative in only 1 patient.
Now we have three additional studies assessing the same endpoint of QTc prolongation. The first by Saleh et al included 201 patients, of whom 10 patients received CQ, 191 received HCQ, combined with AZT in 119.1 They found that the maximum QTc (Bazett) was 470 ms in the combination group versus 453 ms in the monotherapy group, and no patient had an episode of TdP.
In contrast, Mercuro et al treated 90 patients with HCQ, of whom 53 received concomitant AZT.2 The latter had a greater median increase in QTc interval compared with those receiving HCQ alone (23 vs 5.5 ms). Of the patients receiving HCQ alone, 7 developed QTc of ≥500 ms. Of those receiving concomitant AZT, 11 of 53 had prolonged QTc of ≥500 ms. One patient developed TdP.
Bessiere et al treated 18 patients with HCQ and AZT and 22 patients with HCQ alone.3 Prolonged QTc was observed in 14 patients, 10 with a change in QTc >60 ms and 7 with QTc ≥500 ms. Among patients treated with HCQ and AZT, 6 of 18 developed an increase in QTc of ≥500 ms versus 1 of 22 of those treated with HCQ. Overall, 17 patients had their drugs stopped because of QTc increase and no patient developed TdP.
What are the takeaways from these studies?
CQ and HCQ, particularly when combined with AZT, increase the QTc in virtually all patients.
QTc prolongation is used as a surrogate of risk for TdP, but the relationship is imperfect. Risk generally increases when the QTc exceeds 500 ms.
The amount of QTc increase varies with drug dose, drug combination, sex, underlying heart disease in addition to COVID-19, use of other drugs, such as diuretics, and comorbidities, such as electrolyte imbalance and renal or liver disease.
Patients receiving CQ, HCQ, and AZT for COVID-19 should probably do so as part of a clinical trial, receive the drugs for relatively short intervals, and be monitored closely so the drugs can be discontinued if the QTc prolongs dangerously to avoid the risk of TdP…and sudden death.
Despite these findings, the reality is that several hundred million courses of CQ have been used worldwide to treat malaria, lupus, and rheumatoid arthritis without reports of sudden death under WHO surveillance (Simpson et al. Cardiology. 2020; 49:38). However, the absence of close surveillance and active reporting may challenge the validity of no sudden deaths.
As with all drugs, physicians should evaluate risk–benefit closely. Evidence supporting the benefit of these drugs in coronavirus patients is meager.
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