A new study shows that the initially lauded combination of drugs against COVID-19 - Hydroxychloroquine and Chloroquine combined with azithromycin, could lead to abnormal and life-threatening heart rhythms. In patients hospitalized with the novel coronavirus infection or SARS CoV-2, this combination can lead to prolonged QT interval as can be detected on ECG. The study titled, “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),” was published in the latest issue of the journal JAMA Cardiology.
What was this study about?
The study led by Dr. Howard S. Gold from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston was essentially observational. First author of the study was Nicholas J. Mercuro. The authors of the study write that this combination of drugs was initially touted as the treatment for persons who had been diagnosed with COVID-19 associated pneumonia. The main objective of the study was 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.” They measured the correct QT interval for the participants of the study.
QT Interval in ECG signaling 3d illustration. Image Credit: sciencepics / Shutterstock
What was done?
This observational cohort study was conducted at a tertiary care center in Boston, Massachusetts. The participants were patients who had been detected at least once with the viral infection. One of their nasopharyngeal swabs at least had tested positive on polymerase chain reaction test (PCR test) for the SARS CoV-2. These participants had all been clinically diagnosed to have pneumonia and had received at least 1 day of hydroxychloroquine between 1st March 2020 and 7th April 2020.
Electrocardiogram (ECG) records of the patients were measured. On the ECG, several waves are noted – P, Q, R, S, and T. Intervals between the waves are measured. Two significant waves measured include PR interval and QT interval. Other potential adverse effects of the drug or its combination were also recorded.
What was found?
For this study, a total of 90 participants receiving hydroxychloroquine were included. Of these, 53 had received azithromycin in combination. Among the participants, 48.9 percent (44 in number) were females, and the average body mass index was 31.5 for all the participants. Among the patients, 53.3 percent had high blood pressure (48 patients), and 28.9 percent had diabetes mellitus (26 patients). These two conditions were most commonly found among the patients.
Results revealed that at the start of the study, the median baseline QTc was 455 (430-474) milliseconds. Median QTc for those on hydroxychloroquine is 473 milliseconds (ranging between 454 milliseconds to 487 milliseconds). Among those on hydroxychloroquine and azithromycin, the median QTc was 442 milliseconds (ranging between 427 milliseconds to 461 milliseconds). The prolongation after administration of the drug combination was found to be statistically significant.
The researchers wrote, “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.”
Serious heart rhythm arrhythmia was noted in some patients. Among the participants, seven (19 percent) who had received hydroxychloroquine alone had a prolonged QTc interval of 500 milliseconds or more. Three of the patients had a difference of 60 milliseconds from baseline. Among those that received azithromycin in addition, 21 percent (11 of the 53 who had received the combination) had a QTc interval of over 500 milliseconds. The change was 60 milliseconds or more among 13 percent (7 out of 53 participants).
The researchers also noted that those patients who were administered loop diuretics such as furosemide had a higher risk of prolongation of QTc interval compared to those who did not receive such drugs. The odds ratio found the researchers, of developing prolonged QTc among those receiving these combinations was 3.38. The risk was raised for those who had a baseline QTc interval of 450 milliseconds or more (odds ratio of 7.11).
One of the participants developed a severe heart rhythm abnormality called torsades de pointes. Ten of the patients had to stop the hydroxychloroquine due to the side effects of the drug, including nausea and low blood sugar.
Conclusions and importance of the study
The researchers concluded that participants diagnosed with COVID-19 pneumonia who were administered hydroxychloroquine were at a higher risk of QTc prolongation. This risk was heightened with the addition of azithromycin. They also wrote that their one case of torsades de pointes was the first reported such case with this combination of drugs. They called for more detailed studies to assess the risks and benefits of using these drugs among patients diagnosed with COVID-19. They recommended that all patients need “routine electrocardiograms, and electrolyte monitoring” during therapy.
The authors wrote, “Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.”
In an accompanying editorial titled “Hydroxychloroquine, Coronavirus Disease 2019, and QT Prolongation,” by Robert O. Bonow, Adrian F. Hernandez, and Mintu Turakhia spoke about the complexities in decision making while treating COVID-19 patients.
They emphasize the fact that there is an absence of proven treatment strategies for this infection. They wrote, “Lacking robust trial evidence, clinicians are forced to consider all options based on preclinical and small observational studies, often in heart-wrenching settings of patients who are deteriorating in the throes of severe pneumonia…”
The authors wrote that hydroxychloroquine is capable of prolonging the QT interval due to the “blockade of inward cellular potassium current.” Azithromycin also carries a similar risk. They call these findings “welcome and important.” They add, however, that in the intensive care setting, it is easy to monitor the ECG of the patients, and if proven beneficial, the drugs could be used.
The authors said that there are two trials that are ongoing – “Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID) trial (NCT04332991)12 and the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial (ISRCTN50189673)”. These would provide a detailed safety profile of the drugs.
They concluded, “Until then, treatment decisions for this disease will remain based on clinical judgment and, ideally, in the context of enrolling patients into clinical trials to provide definitive answers.”