Study Reassures on HCQ Heart Risks in Rheumatoid Arthritis Save

Among U.S. veterans receiving hydroxychloroquine (HCQ) as long-term therapy for rheumatoid arthritis, development of long QT syndrome was rare and not markedly more common compared with similar patients treated with other agents, researchers said.

Among 4,462 rheumatoid arthritis patients in the VA healthcare system who started HCQ, new-onset long QT syndrome was found in 38 during 19 years of follow-up, while 21 such cases were seen in 4,462 matched patients receiving other anti-rheumatic drugs, reported Ali Ahmed, MD, MPH, of the VA Medical Center in Washington, D.C., and colleagues.

The excess worked out to an increased risk of 73% associated with HCQ, the researchers noted in Arthritis Care & Research, almost all occurring between years 2 and 10 of treatment.

But this heightened risk should not be a major concern, Ahmed's group contended, at least for the population studied.

The "absolute risk was very low, and the absolute risk difference was even lower," they wrote, noting that annual incidence dropped during the last years of follow-up.

Numbers of incident long QT syndrome cases were too small to analyze year by year. Over years 1 to 2 after treatment initiation, there were five in the non-HCQ patient group and seven with HCQ. Through year 5, the cumulative totals reached six among controls and 17 in the HCQ group. By year 10, these grew to 13 and 29, respectively. But in the final 9 years of follow-up, the number of new cases was nearly identical in the two groups, at eight and nine, respectively.

Moreover, the researchers observed, "there was no associated higher risk of arrhythmia-related hospitalizations or death." Numerically, all-cause mortality over the 19 years of follow-up was 36.0% in the HCQ group versus 37.8% with other treatments, and hospitalizations for arrhythmia stood at 3.89% with HCQ and 3.66% among the controls.

"These findings provide new evidence for the long-term safety of hydroxychloroquine in patients with RA [rheumatoid arthritis]. Future studies need to examine the safety of hydroxychloroquine in women with RA," Ahmed and colleagues wrote.

That last statement highlights the study's chief limitation: its focus on people in the VA healthcare system, who are predominantly male. Only 14% of the patients included were women, versus around 70% of rheumatoid arthritis patients in the general population. The authors also pointed out that the findings can't be assumed to apply to people with systemic lupus erythematosus, a condition for which HCQ is more commonly prescribed.

On the other hand, the study came with some major strengths. Because the VA system is so massive, the researchers were able to find nearly 4,500 patients undergoing long-term treatment with HCQ, which is among the lesser-used therapies in rheumatoid arthritis. (Adverse ocular effects are fairly common with chronic HCQ -- up to 20% incidence with 20 years of treatment, according to one recent review -- so it is generally reserved for patients who cannot tolerate methotrexate or other standard agents.)

And for all the VA's faults, its records are extraordinarily comprehensive and consistent, having gone electronic long before most other large systems. That allowed the researchers to match the HCQ and other-treatment patient groups on a whopping 87 baseline characteristics -- which in turn made it nearly impossible that the results were affected by unmeasured confounders. (If there is one, it "would need to be a near-perfect predictor of long QT syndrome, not be strongly correlated with any of the 87 balanced baseline characteristics, and be able to increase the odds of its association with hydroxychloroquine initiation by 7.13%," Ahmed and colleagues wrote.)

"To the best of our knowledge, this is the first long-term comparative safety study of hydroxychloroquine that provides new evidence regarding its cardiovascular safety, specifically in regards to the risk of long QT syndrome," the group concluded.

Source Reference: Quiñones M, et al "Hydroxychloroquine and risk of long QT syndrome in rheumatoid arthritis: a veterans cohort study with 19-year follow-up" Arthritis Care Res 2022; DOI: 10.1002/acr.25005.