Hydroxychloroquine use lessens AFib risk in lupus patients


A new study has found that the use of hydroxychloroquine in patients with systemic lupus erythematosus (SLE) greatly decreased their risk of incident atrial fibrillation (AFib).

“Given the relative safety and low cost of hydroxychloroquine, and its favorable antithrombotic and cardiovascular risk benefit, a broader investigation in other cohorts or randomized studies to confirm its antifibrillatory effect would be warranted,” wrote first author Alisha Gupta, MD, a rheumatology fellow at Emory University, Atlanta, and colleagues. The study was published in Arthritis Care & Research.

To investigate a possible link between hydroxychloroquine (HCQ) and new-onset AFib, the researchers launched a retrospective cohort study of adult patients with SLE. Patients with a previous history of AFib were excluded. The 1,647 participants were categorized into two groups: HCQ users (n = 917) and nonusers (n = 730). The mean age in the HCQ group was 51.8 years, compared with 55.9 years in the nonuser group, and the cohort overall was 92% female and 84% White.

Patients in the nonuser group were more likely to smoke, compared with the HCQ group (45% vs. 40%). They were also more likely to have hypertension (35% vs. 27%), diabetes (12% vs. 7.4%), coronary artery disease (8.4% vs. 4%), and heart failure (4.9% vs. 2.9%).

In total, 23 AFib events occurred during the study period, 3 in HCQ users and 20 in nonusers. The three AFib events in the HCQ group were all paroxysmal; in the nonuser group, 14 were paroxysmal, 1 was persistent, 1 was permanent, and 4 were unspecified.

In addition, four ventricular arrhythmias occurred during the study, three in HCQ users and one in a nonuser. The three events in the HCQ group included two ventricular tachycardias and one torsades de pointes, none of which were fatal.

We’re talking here about a generic medicine that’s cheap and has several other benefits in addition to being a cornerstone therapy in lupus, so in a way this is just the icing on the cake.
After simple logistic regression analysis, HCQ users had an 88% decreased risk of AFib (odds ratio, 0.117; 95% confidence interval, 0.034-0.39; P = .0005). Additional adjusted analyses that factored in demographics, comorbidities, and medications reiterated HCQ’s protective effect against AFib. There also was no association between HCQ use and ventricular arrhythmias (OR, 2.39; 95% CI, 0.25-23; P = .45).

The authors acknowledged their study’s limitations, including a lack of SLE disease activity data that restricted their ability to evaluate HCQ’s antifibrillatory effect as tied to better disease control. There were also additional data noted as incomplete, including the duration and cumulative exposure to HCQ and prescription claims data on the use of glucocorticoids and immunosuppressive medications, which could’ve had an impact on cardiovascular risk.

“AFib is the most common arrhythmia in the general population, with multifold increased risk in lupus patients, specifically,” study coauthor Tarun S. Sharma, MD, of the division of rheumatology at the Allegheny Health Network in Pittsburgh, said in an interview. “It just made sense to study HCQ in this regard given that there’s no clinical studies done yet, given its antithrombotic tendencies, its cardiovascular benefits, given its molecular structural similarities to its parent molecules with antiarrhythmic properties to begin with.

“We’re talking here about a generic medicine that’s cheap and has several other benefits in addition to being a cornerstone therapy in lupus,” he added, “so in a way this is just the icing on the cake.”

Dr. Tarun S. Sharma

The importance of recognizing HCQ as an antiarrhythmic agent

Though the COVID-19 pandemic has raised awareness of HCQ’s cardiac effect, this study by Gupta et al. raises its own awareness of HCQ’s value in lupus patients with high AFib risk, wrote Julianna Desmarais, MD, of the division of arthritis and rheumatic diseases at the Oregon Health & Science University, Portland, and Mark S. Link, MD, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas, in an accompanying editorial.

Since the pandemic began, reports have emerged of HCQ’s potential prolonging of the QTc interval. However, Dr. Desmarais and Dr. Link instead emphasized the context and comorbidities that often accompanied those findings and could’ve contributed to an increased risk of cardiac arrhythmias. They also noted that because of HCQ’s genesis as a derivative of quinidine – one of the “earliest developed antiarrhythmic drugs, efficacious for both atrial and ventricular arrhythmias” – its effect on AFib are not surprising.

Dr. Mark S. Link
That said, regarding overall cardiac risks associated with HCQ use, they reinforced that this drug has been “used for years in patients with SLE and rheumatoid arthritis with clear benefits in mitigating disease activity and progression” and that any risks need to be weighed against these positives.

As for next steps, “we just need more data,” said Dr. Link in an interview. “We need bigger and bigger cohorts of lupus and RA patients that are treated with HCQ, ideally, in a prospective fashion. You would follow them, you would measure the QTs, look for incident AFib.

“No one thinks it’s going to be taken off the market,” he added. “It’s not that bad. You really have to put it in the class of drugs, of which there are probably a hundred approved by the FDA, that slightly prolong the QT. The real danger is when you start adding several of those drugs together, or if the person has congenital long-QT syndrome.”

Additional studies reinforce HCQ’s overall cardiac safety

At the 2020 annual meeting of the American College of Rheumatology, two studies also investigated the cardiac effects of HCQ in lupus patients.

The first study – led by Mayce Haj-Ali, MD, a fellow in New York University’s division of rheumatology – showed that lupus patients on HCQ did not have any significant differences with their QTc levels, even if they also had chronic kidney disease. The second study – led by Elizabeth Park, MD, a rheumatology fellow at Columbia University, New York – found that HCQ use does not affect QTc length or prolongation in patients with lupus or rheumatoid arthritis.

Image credit: Southern Illinois University / Science Source

Overall, their findings did not surprise Dr. Sharma, who said he did not expect to see unexpected results among a traditional lupus cohort.

“These studies confirm that there are no deleterious effects in terms of QTc with HCQ, which we didn’t anticipate in the non-COVID population, in our rheumatic disease population,” he said.

“COVID is a very different animal,” he added. “It’s a different sort of condition which potentially affects the cardiac tissue; there are some effects of the virus itself. These studies put some of those fears to rest in non-COVID patients and confirmed our practice.”

The Park et al. study, in particular, references COVID-19 and HCQ’s initial involvement as a potential treatment for the virus. But beyond those timely ties to the ongoing pandemic, Dr. Link recognized something notable in their results that rheumatologists and cardiologists should consider regarding specific patient responses.

“There was no overall difference in QTc length between those given HCQ and those who were not, but 11 people had prolonged QTc greater than 500 milliseconds and 9 of those were on HCQ. That’s where we start to get nervous,” he said. “If you look at the aggregate, it didn’t increase the QTc length. But we’re looking at susceptible patients, genetically susceptible or on other drugs. That’s the worry.

“I think it’s a safe drug,” he added, “but it’s not without some potential danger.”

The authors of these studies and the editorial disclosed no relevant conflicts of interest.