In a brief report, a team of pharmacists and clinicians at Beth Israel Deaconess Medical Center (BIDMC), part of Beth Israel Lahey Health, found evidence suggesting that patients who received hydroxychloroquine for COVID-19 were at increased risk of electrical changes to the heart and cardiac arrhythmias. The combination of hydroxychloroquine with azithromycin was linked to even greater changes compared to hydroxychloroquine alone.
"While hydroxychloroquine and azithromycin are generally well-tolerated medications, increased usage in the context of COVID-19 will likely increase the frequency of adverse drug events (ADEs)," said co-first author Dr Nicholas J Mercuro, a pharmacy specialist in infectious diseases at BIDMC. "This is especially concerning given that that patients with underlying cardiac co-morbidities appear to be disproportionately affected by COVID-19 and that the virus itself may damage the heart."
Hydroxychloroquine and azithromycin each can cause an electrical disturbance in the heart known as a QTc prolongation, indicated by a longer space between specific peaks on an electrocardiogram. QTc prolongation denotes that the heart muscle is taking milliseconds longer than normal to recharge between beats. The delay can cause cardiac arrhythmias, which in turn increases the likelihood of cardiac arrest, stroke or death.
In this single-centre, retrospective, observational study, Mercuro and colleagues evaluated 90 adults with COVID-19 who were hospitalised at BIDMC between 1 March and 7 April, 2020, and received at least one day of hydroxychloroquine. More than half of these patients also had high blood pressure, and more than 30% had diabetes.
Seven patients (19%) who received hydroxychloroquine alone developed prolonged QTc of 500 milliseconds or more, and three patients had a change in QTc of 60 milliseconds or more. Of the 53 patients who also received azithromycin, 21% had prolonged QTc of 500 milliseconds or more, and 13% experienced a change in QTc of 60 milliseconds or more.
"In our study, patients who were hospitalized and receiving hydroxychloroquine for COVID-19 frequently experienced QTc prolongation and adverse drug events," said co-first author Dr Christina F Yen, of BIDMC's department of medicine. "One participant taking the drug combination experienced a potentially lethal tachycardia called torsades de pointes, which to our knowledge has yet to be reported elsewhere in the peer-reviewed COVID-19 literature."
In 2003, preliminary data suggested hydroxychloroquine may be effective against SARS-CoV-1, a fatal but hard-to-transmit respiratory virus related to the coronavirus that causes COVID-19. More recently, a small study of patients with COVID-19 appeared to benefit from the anti-malarial drug. Subsequent research, however, has failed to confirm either finding. In light of their data, Gold and colleagues urge caution and careful consideration before administering hydroxychloroquine as treatment for COVID-19.
"If considering the use of hydroxychloroquine, particularly combined with azithromycin, clinicians should carefully weigh the risks and benefits, and closely monitor QTc – particularly considering patients' co-morbidities and concomitant medication use," said senior author Dr Howard S Gold, an infectious disease specialist at BIDMC and an assistant professor of medicine at Harvard Medical School. "Based on our current knowledge, hydroxychloroquine for the treatment of COVID-19 should probably be limited to clinical trials."
Abstract
Importance: Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)–associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias.
Objective: To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin.
Design, Setting, and Participants: This was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020.
Main Outcomes and Measures: Change in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events.
Results: Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [−15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI, 1.75-28.87]). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes.
Conclusions and Relevance: In this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.
Authors
Nicholas J Mercuro, Christina F Yen, David J Shim, Timothy R Maher, Christopher M McCoy, Peter J Zimetbaum, Howard S Gold
[link url="https://www.bidmc.org/about-bidmc/news/2020/05/hydroxychloroquine-for-treatment-of-covid-19-linked-to-increased-risk-of-cardiac-arrhythmias"]Beth Israel Deaconess Medical Centre material[/link]
[link url="https://jamanetwork.com/journals/jamacardiology/fullarticle/2765631"]JAMA Cardiology abstract[/link]