The largest ever review of cardiovascular safety of hydroxychloroquine in patients with arthritic disorders has flagged a potential raised risk of cardiovascular death with long term use in patients with RA.

The disease-modifying drug has been routinely used for many years in the treatment of RA and SLE, and rheumatologists are familiar with risks highlighted in product information such as retinopathy.

However, recent consideration of the drug as a potential treatment for COVID-19 has led to trials that have reported a short-term elevation in risk of cardiovascular death.  The adverse findings prompted a consortium of researchers to review safety data for routine use of hydroxychloroquine in RA patients.

An international team of researchers used cohort studies of new users of hydroxychloroquine from Germany, Japan, the Netherlands, Spain, the UK and the US to identify serious adverse events, both within 30 days of starting the drug and long term. The review included 956,374 users of hydroxychloroquine, 310,350 users of sulfasalazine, 323,122 users of hydroxychloroquine plus azithromycin, and 351,956 users of hydroxychloroquine plus amoxicillin.

Because the studies were not randomised, the researchers used ‘propensity scores’ to try to adjust for bias between the groups. Their study published in Lancet Rheumatology found:

• No short-term (30-day) excess risk for users of hydroxychloroquine compared to other RA treatments (sulfasalazine);
• A 65% increased risk of cardiovascular death for long-term users of hydroxychloroquine compared to sulfasalazine;
• More than two-fold increased risk of 30-day cardiovascular death for users of hydroxychloroquine combined with azithromycin.

The study investigators said the doubling in cardiovascular mortality seen with short term hydroxychloroquine use with a macrolide was presumably due to the synergistic effects on QT length and subsequent induction of lethal arrhythmia. The finding reinforced the advice to avoid to avoid co-prescribing, they said.

They concluded that the over result from almost a million patients, “builds our confidence in the evidence around the safety profile of hydroxychloroquine.”

“In line with consensus expert guidance, our findings suggest that a cautious assessment of cardiovascular risk is needed before initiating high-dose hydroxychloroquine or hydroxychloroquine plus azithromycin combination therapy, and in long-term monitoring of patients with rheumatoid arthritis, especially those with cardiovascular risk factors,” they advised.

Current patient advice information for hydroxychloroquine provided by the Australian Rheumatology Association make no recommendations on use in cardiovascular risk factors.

The product information for hydroxychloroquine in Australia warns that it may prolongs the QTc interval and should not be used concurrently with drugs that also have this property such as  antiarrhythmics, tricyclic antidepressants, and some antibiotics such as macrolides. It also advises that hydroxychloroquine should be used with caution in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval. However there is no advice on a possible increase in cardiovascular risk or use in patients with cardiovascular risk factors.

Dr Rachel Knevel, clinical fellow and assistant professor at the Department of Rheumatology, Leiden University Medical Centre, Netherlands, who co-authored an editorial  in Lancet Rheumatology, told the limbic there should be no rush to change practice.

“I do not think [prescribing practice] should change at this moment. I think the kind of research that the authors performed is very interesting because it does inform us about a possible problem, but I would argue that there is really much more additional research needed before we can give a definite answer that will inform us about practice,” she told the limbic.

“As the authors discuss, there is still the risk of bias between the patient that received hydroxychloroquine versus the one that receives sulfasalazine. We tend to use hydroxychloroquine more in elderly patients. We haven’t really noticed it [the excess cardiovascular risk] and we are prescribing these medicines very often. The current study doesn’t really balance the benefits versus the risks,” she said.