Two studies add to concerns about hydroxychloroquine safety

Two studies published Friday raised new concerns about tachycardia risk from prolonged QT interval linked to hydroxychloroquine treatment in patients with Covid-19, with one study identifying increases in corrected QT (QTc) interval in more than 90% of patients who received the drug.

Late last week, news of negative findings from several other studies muted enthusiasm for the drug, which had been widely promoted by President Trump and conservative media outlets as a possible game-changer Covid-19 treatment.

Preliminary findings from a Brazilian study showed high doses of the drug (600 mg daily for 10 days) to be associated with higher death risk and a higher risk for QT prolongation.

And, findings from a study in U.S. veterans, made public prior to peer-review, showed that in patients with severe Covid-19, treatment with hydroxychloroquine did not appear to reduce the need for mechanical ventilation.

In one of the studies published online Friday in JAMA Cardiology involving 40 patients with severe Covid-19 (75% required mechanical ventilation), 93% of patients treated with hydroxychloroquine, with or without azithromycin, showed an increase in QTc after its administration and 36% experienced prolonged QTc within 2 to 5 days of treatment.

None of the hydroxychloroquine-treated patients in the study, conducted in Lyon, France, developed ventricular arrhythmias, including torsades de pointes, during observation.

Close monitoring of patients, which included continuous QTc interval recording, daily ECGs, and laboratory testing, led to the discontinuation of therapy in 17 of the 40 patients (42.5%), which “may have averted further complications, including drug-induced torsades de pointes,” wrote researcher Francis Bessiere, MD, PhD, of Lyon University, Lyon France, and colleagues.

The researchers noted that all patients in the study were receiving treatment in the ICU, which may limit the generalizability of the findings to Covid-19 patients with less severe illness.

They concluded, however, that “the finding that QTc intervals increased in more than 90% of patients raises concerns about the widespread use of hydroxychloroquine, with or without azithromycin, to treat Covid-19 in settings where patients cannot be adequately monitored.”

A study published in the same issue of JAMA Cardiology included 90 patients treated with hydroxychloroquine at an academic tertiary care center in Boston, including 53 who also received azithromycin.

In that study, 18 of the 90 patients (20%) treated with hydroxychloroquine, with or without azithromycin, developed QTc prolongation of 500 milliseconds or more, with the magnitude of increase greater in patients receiving the combination treatment.

Among patients treated with hydroxychloroquine and concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or greater and 7 of the 53 (13%) had a change in QTc of 60 milliseconds or more.

As a group, the patients were not as sick as the French cohort, with one-in-three (33%) receiving treatment in the ICU at treatment initiation.

“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 OR, 7.11, 95% CI, 1.75-28.87),” wrote researcher Nicholas Mercuro, PharmD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Ten patients in the Boston cohort were taken off hydroxychloroquine due to the potential for adverse events.

One case of torsades de pointes occurred in a patient treated with hydroxychloroquine and azithromycin 3 days after the combination therapy was discontinued due to a QTc interval of 499 milliseconds. This patient later developed other ventricular arrhythmias and was treated with lidocaine.

The researchers concluded that “there is a critical need for rigorous, large-scale studies and risk-benefit assessment prior to initiating Covid-19 therapeutics, with careful attention to medication interactions, cardiac manifestations, routine electrocardiograms and electrolyte monitoring.”

In an accompanying editorial, cardiologist Robert Bonow, MD, of Northwestern University Feinberg School of Medicine, Chicago, and colleagues, wrote that while QTc can largely be safely monitored within the ICU, findings from the studies conducted in Boston, France and Brazil “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected Covid-19.”

“Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” they wrote. “Whether signals of potential benefit outweigh signals of harm is unknown until well-controlled clinical trials are completed for the treatment or prevention of Covid-19 infections.”

They noted that two such studies — the Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID) trial (NCT04332991) and the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial (ISRCTN50189673) — are ongoing, with periodic safety reviews.

  1. 93% of patients treated with hydroxychloroquine, with or without azithromycin, showed an increase in QTc after its administration and 36% experienced prolonged QTc within 2 to 5 days of treatment in a study from Lyon, France.

  2. In the Boston study, 18 of the 90 patients (20%) treated with hydroxychloroquine, with or without azithromycin, developed QTc prolongation of 500 milliseconds or more.

Salynn Boyles, Contributing Writer, BreakingMED™

Researchers Nicholas Mercuro et al (Boston study) and Fracis Bessiere et al (Lyon study) reported no relevant conflicts of interest related to the reported research.

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