Hydroxychloroquine lessens risk of major cardiac events in lupus patients


Patients with lupus erythematosus who are taking hydroxychloroquine (HCQ) have less risk of MI, ischemic stroke, or cardiovascular-associated death, according to a new nationwide Danish study.

“Increasing evidence indicates that HCQ has a cardiovascular protective role, working in multiple ways with a positive effect on the lipid profile,” wrote Jeanette Halskou Haugaard, MD, of the department of dermatology, allergy, and venereology at the Herlev and Gentofte University Hospital in Copenhagen, and colleagues. The study was published in the Journal of the American Academy of Dermatology.

To determine an association between HCQ use and major adverse cardiovascular events (MACE), the researchers launched an observational cohort study of Danish patients who were diagnosed with cutaneous lupus erythematosus (CLE) or systemic LE (SLE) between the years of 1997 and 2017. Anyone with a history of MI or ischemic stroke was excluded. Of the 4,587 total patients with LE, 3,036 had SLE and 1,551 had CLE; only 51% (n = 2,343) were treated with HCQ at some point during the study.

MACE occurred in 59 HCQ users, compared with 396 nonusers, and more major adverse events occurred in patients with SLE (n = 303) than in patients with CLE (n = 152). Overall, an inverse association was found between HCQ use and risk of MACE (adjusted hazard ratio, 0.67; 95% confidence interval, 0.51-0.89). Patients with SLE (aHR, 0.65; 95% CI, 0.46-0.90) had a lower risk of MACE than patients with CLE (aHR, 0.71; 95% CI, 0.42-1.19).

Subsequent sensitivity analyses – which included changing the HCQ treatment period to 80 or 160 days and adjusting for the use of tumor necrosis factor inhibitors, mycophenolate, and rituximab – did not alter the outcomes in any notable way. Applying a case-time-control study design reinforced the cohort study trend, with a MACE odds ratio of 0.07 (95% CI, 0.02-0.31). After an algorithm-centric analysis that further identified patients with SLE, an even stronger inverse association was uncovered between HCQ use and cardiovascular-associated death (aHR, 0.10; 95% CI, 0.01-0.74).

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HCQ’s cardiovascular benefits: Not surprising but very important

“One might’ve predicted that HCQ might be protective for cardiovascular disease, but this a very well-conducted study that really brings that home,” Christie M. Bartels, MD, associate professor in the division of rheumatology at the University of Wisconsin–Madison, said in an interview. “It provides sound evidence to present to our patients and counsel them on the importance of taking HCQ if you have lupus.”

Lupus can be a hard disease to study, she added, because most datasets – especially those used in the United States – aren’t substantial enough to catch a suitable number of patients with the condition and because “some of the patients who have codes don’t actually have disease.” To counter that, the investigators used a previously validated algorithm with a positive predictive value of over 80%, an effort that she called “robust.”

Dr. Christie M. Bartels
The authors highlighted their study’s other strengths, including the use of large nationwide registers and a fittingly sizable dataset of patients, a long-term period of follow-up, and the consistency of the results that emerged from several sensitivity analyses. Dr. Bartels did underline one limitation, however, something the authors also acknowledged: an inability to control for disease activity. But that often goes hand in hand with an observational study, she said, especially with wide variability on the data collected from lupus patients.

“Some of the data limitations are probably the reasons why this kind of study has not been performed previously,” she said, “which makes the work done here even more important.”
As for next steps regarding research on HCQ’s potential benefits, she emphasized the large number of participants who weren’t taking the cornerstone lupus drug in the first place. “The study looked at people who were ever- versus never-users of HCQ, and they highlighted that only 51% of patients were getting HCQ,” she said. “The first gap to fill is that we need to do better in prescribing.

“There’s also good data to suggest that there is not great adherence in people who are actually prescribed HCQ,” she added. “There would be a great opportunity here to look at dose relationship; if people are highly adherent, does it reduce their risk of heart attack even further? If so, we could really use that data to reinforce adherence, which is sorely needed in the lupus field.”

Two of the authors reported receiving grants and personal fees from various pharmaceutical companies during the conduct of the study. The others reported no potential conflicts of interest.