HCQ-Arrhythmia Link Bolstered by Global Adverse Event Data

Hydroxychloroquine (HCQ) and azithromycin both carry elevated risk of potentially fatal arrhythmias, the World Health Organization (WHO)’s global pharmacovigilance database affirmed amid negative study results.

In the analysis of the WHO’s VigiBase, prolonged-QT interval or ventricular tachycardia including torsades-de-pointes (LQT/TdP) or both was reported significantly more often with those drugs than for other drugs. The IC₀₂₅, the lower end of the 95% credibility interval for disproportionate Bayesian reporting with 0 as the threshold for significance, was 1.67 for azithromycin and 1.04 for HCQ.

HCQ also was associated with atrioventricular and bundle branch block conduction disorders (IC₀₂₅ 1.04) and heart failure (IC₀₂₅ 0.06).

While the results don’t indicate the absolute risk or incidence of arrhythmias with these drugs given the unknown denominator, they do support the warnings on the FDA product labels about this risk, wrote Joe-Elie Salem, MD, PhD, of Sorbonne Université in Paris, and colleagues in Circulation.

The findings follow an FDA drug safety communication in April highlighting the known risks of arrhythmia with hydroxychloroquine.

On Friday, a 96,000-patient study in the Lancet provided the strongest evidence yet for increased mortality among COVID-19 patients who received HCQ or chloroquine, with nearly double the adjusted risk compared with controls, along with a higher risk of ventricular arrhythmia during hospitalization (6.1% for hydroxychloroquine and 4.3% for chloroquine vs 0.3% for controls).

In response, the WHO announced Monday that it had halted enrollment in the hydroxychloroquine arm of its global clinical trial.

Cardiovascular adverse drug reactions “are important to bear in mind in the setting of COVID-19 with patients presenting additional risk factors of LQT/TdP due to inflammation with elevated interleukin-6, hypokalemia, numerous interacting drugs, bradycardia and higher hydroxychloroquine dosages,” Salem’s group wrote.

Dose of hydroxychloroquine appeared to matter, with significantly higher doses reported in cases who developed heart failure than seen in reports of long QTc or ventricular tachycardia cases.

In the retrospective analysis of the WHO pharmacovigilance database that collects data from over 130 countries, there were 76,822 adverse drug reaction cases reported associated with hydroxychloroquine alone, 89,692 with azithromycin alone, and 607 with the combination of both out of a total of more than 21 million reports since 1967.

Of the 83 cases of ventricular tachycardia with HCQ in the database, 8.4% were fatal; for azithromycin, 20.2% of the 257 such cases resulted in death. No deaths were reported for long QTc without ventricular tachycardia, although the mortality rate was 5.4% of the 223 such cases with the combination of HCQ and azithromycin.

In the 203 cases where hydroxychloroquine users developed heart failure, 20.7% died.

Azithromycin’s arrhythmias had much faster onset than seen with HCQ (3 vs 51 days, P<0.01). With hydroxychloroquine, arrhythmias were reported with a shorter time to onset than heart failure (51 vs 348 days, P=0.027), which “may reflect chronic use in lupus or rheumatoid arthritis,” the researchers noted.