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Hydroxychloroquine does not increase the risk of arrhythmia, a large study in has found.

The study was precipitated by controversy surrounding hydroxychloroquine and a perceived increased risk of arrhythmia. One study found an association while others found no risk or even a decrease in arrhythmic events among people taking hydroxychloroquine. Still, when use of the drug became more widespread during the COVID-19 pandemic, reports surfaced of increased incidence rates of cardiac events among hydroxychloroquine users.

Researchers for the population-based study identified 11,518 propensity score-matched rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) individuals in each group. After an eight-year follow-up, there were 1,610 and 1,646 incident arrhythmias in the hydroxychloroquine initiator and non-initiator groups, respectively.

Crude incidence rates of arrhythmia were 17.5 and 18.1 per 1,000 person-years, respectively. Adjusted cause-specific hazard ratio (cHR) for hydroxychloroquine initiators was 0.96 (95% CI 0.89-1.03) compared to non-initiators.

Adjusted cHRs for hydroxychloroquine initiators in subtypes of arrhythmia: atrial fibrillation, abnormal electrocardiogram, and other unspecified arrhythmias were 0.93 (95% CI 0.83-1.04), 0.98 (95% CI 0.87-1.11), and 0.95 (95% CI 0.84-1.07), respectively.

Study coauthor Antonio Aviña-Zubieta, MD, PhD, is a senior research scientist with Arthritis Research Canada and an associate professor in the Department of Medicine at the University of British Columbia. He discussed the study and its findings with the Reading Room. The exchange has been edited for length and clarity.

This study appeared designed to help clear up a lingering uncertainty. What was the specific focus of your investigation?

Aviña-Zubieta: This study was initiated when people began to use hydroxychloroquine at the beginning of the pandemic. There were reports of abnormalities in the rhythm of the heart. Some of the adverse events data showed that when hydroxychloroquine was initially proposed as therapy for COVID-19, some patients developed long QT syndrome, which can be fatal if undetected.

That prompted a fear of patients using this medication. This medication is well known as an effective therapy for the treatment of inflammatory arthritis -- in particular lupus and RA. But that fear created anxiety among patients and, of course, some clinicians. In fact, some cardiologists are recommending obtaining an electrocardiogram before the initiation of hydroxychloroquine.

There has been controversy around this topic. Leaders in the field have posed the question: Do patients who use hydroxychloroquine actually have a higher risk of developing arrhythmias?

We wanted to answer that question using a population-based sample.

How was the study designed?

Aviña-Zubieta: All patient data came from administrative databases in British Columbia, Canada. We identified cases of incident RA or SLE with no arrhythmic events, anti-arrhythmic medications, or hydroxychloroquine use prior to the disease index date. We used patient data spanning January 1996 to December 2014.

To our knowledge, this was the largest population-based study evaluating hydroxychloroquine use on arrhythmic events in RA and lupus. We used propensity score matching within each calendar year of hydroxychloroquine initiation, ensuring a better balance between the two initiation groups.

How would you characterize the study's findings?

Aviña-Zubieta: When we compared the overall frequency of the arrhythmias, we observed that 14% of people who were taking hydroxychloroquine developed any type of arrhythmia. And that same number emerged -- 14% -- for people who were not initiated on hydroxychloroquine.

After we adjusted for a number of confounders, we observed that the risk was again identical. There was no difference in risk of arrhythmia over time between the two groups.

We also analyzed different types of arrhythmias, including atrial fibrillation or any electrocardiogram that was classified as abnormal. We did not observe any differences in the risk among them.

Therefore, we concluded that the risk of arrhythmias over time for those people who initiate hydroxychloroquine is identical to people who have not initiated hydroxychloroquine.

What do you see as the study's take-home message to rheumatology practices and care teams?

Aviña-Zubieta: Patients with RA, lupus, or any other inflammatory arthritis can take hydroxychloroquine with confidence.

People should be reassured that they can get the benefits of this medication. It's an extraordinary medication that not only treats the inflammatory arthritis but also prevents complications without a higher risk of arrhythmia.

Clinical implications

• Hydroxychloroquine use did not increase the risk of arrhythmias.
• Topic had been controversial, with some cardiologists recommending ECGs before initiating hydroxychloroquine.
• The drug can be prescribed with confidence to patients with RA, SLE, or any other inflammatory arthritis.

Read the study here and expert commentary on the clinical implications here.