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QT interval prolongation remained a safety concern with hydroxychloroquine (HCQ) for COVID-19 in reports from Boston and France, highlighting the need for careful monitoring.

Risk was particularly elevated when HCQ was administered with azithromycin in both studies, published online in JAMA Cardiology. Both agents have been known to be mechanistically capable of extending the QT interval.

"The risk for significant QT prolongation is significant and must be balanced with the potential benefit of therapy. Excessive QT prolongation is associated with a risk for sudden death. Blithely taking these drugs can potentially be more harmful than good," commented Anil Gehi, MD, of the University of North Carolina School of Medicine in Chapel Hill, in an email.

Findings from Boston

The first report, a , showed that 19% of hospitalized COVID-19 patients getting HCQ monotherapy developed QTc lasting 500 ms or more, and 3% had QTc prolonged by at least 60 ms after receiving the medication.

For those receiving concomitant azithromycin, the rates were 21% and 13%, respectively, according to a group led by Nicholas Mercuro, PharmD, and Christina Yen, MD, both of Beth Israel Deaconess Medical Center, Boston.

Magnitude change in QT interval was also greater with the combination compared with HCQ alone (median +23 ms vs +5.5 ms, P=0.03).

One out of every nine HCQ users had administration of the drug stopped early because of adverse events. One patient developed torsades de pointes.

"Although hydroxychloroquine and azithromycin administration was discontinued 3 days prior to the event, the patient also had severe acute respiratory distress syndrome, bradycardia, hypothermia, propofol co-administration, and a new cardiomyopathy, raising concerns that the risk of QTc prolongation likely persisted, given the prolonged terminal half-life of each agent," Mercuro and Yen's group noted.

At the time that the manuscript was drafted, the COVID-19 patients had been followed for approximately 9 days. Half the 90-person group remained hospitalized after 41 people were discharged and four died.

The cohort study included patients hospitalized at Beth Israel Deaconess Medical Center with pneumonia related to COVID-19. All got at least 1 day of HCQ from March 1 to April 7. Of the 90, 53 received concomitant azithromycin.

Mean age was 60.1 years, and the group was roughly split between men and women. Hypertension (53.3%) and diabetes (28.9%) were among the most common comorbid conditions in this cohort.

One-third of the group were critically ill at the time of COVID-19 testing, and 26% were on mechanical ventilation.

The HCQ-only arm entered the study with a longer baseline QTc (473 vs 442 ms with azithromycin, P<0.001), the investigators noted.

Two factors predicted prolonged QTc with HCQ use:

• Concomitant loop diuretic administration (adjusted OR 3.38, 95% CI 1.03-11.08)
• Baseline QTc of 450 ms or more (aOR 7.11, 95% CI 1.75-28.87)

"While hydroxychloroquine and azithromycin administration likely contributed to the observed ADEs [adverse drug events], we cannot exclude COVID-19-associated stress cardiomyopathy or myocarditis," study authors acknowledged.

"Without a control arm, we cannot conclude that hydroxychloroquine and azithromycin conferred increased cardiotoxic risk," although the difference between the combination and HCQ alone likely could be attributed to azithromycin, the group wrote.

The Experience at a French ICU

The vast majority of COVID-19 patients in a French ICU who received HCQ with or without azithromycin developed an increase in QTc, according to a .

Fully 93% of patients had QTc increase, and 36% developed QTc prolongation (with QTc reaching 500 ms or a change in QTc of at least 60 ms) after 2 to 5 days of antiviral treatment. A third of those on both HCQ and azithromycin developed a QTc interval of 500 ms or greater compared with 5% of those receiving only hydroxychloroquine (P=0.03).

Unlike the Boston report, however, no HCQ user experienced any ventricular arrhythmias in the ICU, Martin Cour, MD, PhD, of Hôpital Edouard Herriot in Lyon, France, and colleagues reported.

"In our cohort, close monitoring of patients (including continuous QTc interval monitoring, daily ECGs, and laboratory tests), which led to an interruption of these drugs for 17 patients (42.5%), may have averted further complications, including drug-induced torsades de pointes," Cour's group reported.

Included in this report were 40 consecutive patients with confirmed COVID-19 who were in the ICU at some point from March 15 to 29. HCQ was combined with azithromycin for 45%. Median age was 68 years. Four out of five were men.

In this cohort, 75% required invasive mechanical ventilation, and 63% received vasoactive drugs. Half of the patients also received other treatments favoring QT prolongation in the ICU (e.g., propofol, amiodarone, ciprofloxacin, and ondansetron).

The findings in the case series may have limited generalizability beyond the ICU, the French group acknowledged.

"However, 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," they wrote.

Clinical Implications

"[R]igorous investigation is needed to guide treatment decisions. At a minimum, these reports should prompt clinicians to define guardrails before instituting novel therapeutics for new diseases," commented Daniel Frisch, MD, of Jefferson University Hospitals in Philadelphia.

HCQ had been given to treat various diseases over several decades without such safety fears, noted Dhanunjaya Lakkireddy, MD, of the Kansas City Heart Rhythm Institute at HCA Midwest Health.

The difference now is that almost all these COVID-19 patients were "deathly sick," explaining at least in part the "significantly increased incidence of QT prolongation than what you would typically expect in a community outpatient center," he said in an interview.

In careful consideration of HCQ use, clinicians should make sure that the patient is not on other QT-prolonging drugs and think about the patient's comorbidity profile, according to Lakkireddy.

And if the antiviral is used, close monitoring has to happen after each dose and be extended even long after the drug has been stopped or completed given that its effects can last for days, Lakkireddy suggested.

Well-controlled clinical trials are now needed to determine whether the benefits of the antiviral medication in COVID-19 outweigh its risks, urged a trio led by Robert Bonow, MD, MS, Northwestern University Feinberg School of Medicine, Chicago, in an .

They cited the ORCHID and RECOVERY trials as two such studies to watch out for.

"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," Bonow's group said.

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