Restless Legs Syndrome Linked to Higher CV Death in Women

December 27, 2017

Women with restless legs syndrome (RLS) appear to have a higher risk for cardiovascular death, according to a new analysis of data from the large-scale Nurses' Health Study.

"This is further evidence that RLS can have major clinical implications and needs to be taken seriously. It is not just a benign nuisance condition," lead author, Xiang Gao, MD, PhD, from Pennsylvania State University, State Park, told Medscape Medical News.

"There are things that can be done to treat RLS," he added. "For example, we know that adopting healthy lifestyle reduces symptoms. In addition, about half of RLS patients are iron deficient, and correcting this may help. So clinicians need to be on the lookout for RLS. They should measure ferritin levels in these patients, and those with low levels should be prescribed iron supplements, and all patients should receive counseling on lifestyle."

The study was published online in Neurology on December 15.

Dr Gao explained that this was the first time a study has looked at cause-specific deaths among women with RLS. "We published a paper in 2013 in a male cohort with RLS showing an increased risk of all-cause mortality, and now we are looking at the female population."

Noting that a previous study has suggested a link between RLS and increased risk for coronary heart disease in women, also from the Nurses' Health Study cohort, Dr Gao said the current study set out to answer two questions: Is all-cause mortality increased in women with RLS similar to the effect seen in men? And is there a specific link to increased cardiovascular death in women?

"From our results, we cannot say anything definite about all-cause mortality," he said. "The primary analysis showed a marginally significant association, and after excluding women with chronic common morbidities associated with RLS, this became significant. But I would say this is still inconclusive."

"But for cardiovascular death, our results were more informative," he added. "We did find a significant association between RLS and increased cardiovascular death, and this became stronger after excluding patients with other associated comorbidities."

Dr Gao explained that patients with RLS are more likely to have other conditions such as hypertension, obesity, cardiovascular disease, and sleep disorders. "Any mortality increase could be due to these. But after excluding patients with these conditions, the relationship between RLS and increased cardiovascular death was still strong," he noted. "This suggests that RLS itself is a real risk factor. However, we would like to see another prospective study in a different patient cohort to confirm our findings."

He said the mechanism is not known, but previous studies have suggested RLS increases dopaminergic and autonomic dysfunction, leading to increased sympathetic activation, which may play a role.

The current study included 57,417 women (mean age, 67 years) from the Nurses' Health Study without cancer, renal failure, or cardiovascular disease at baseline (2002). The researchers used the Cox proportional hazards model to calculate hazard ratios for all-cause and cardiovascular mortality based on RLS status, adjusting for age, presence of major chronic diseases, and other potential confounders.

There were 6448 deaths during 10 years of follow-up. Results did not show a significant association between presence of physician-diagnosed RLS and increased risk for total mortality (adjusted hazard ratio [HR], 1.15; 95% confidence interval {CI], 0.98 - 1.34).

However, women with RLS had a significantly higher risk for cardiovascular mortality (adjusted HR, 1.43; 95% CI, 1.02 - 2.00) relative to those without RLS after adjustment for potential confounders.

Longer duration of RLS diagnosis was significantly associated with a higher risk for cardiovascular mortality (P for trend = .04).

Excluding participants with common RLS comorbidities strengthened the association between RLS and total mortality (adjusted HR, 1.43; 95% CI, 1.03 - 1.97) and cardiovascular mortality (adjusted HR, 2.27; 95% CI, 1.21 - 4.28).

The researchers say the strengths of this study included a large sample size, long follow-up duration, a large number of outcome events (6448 deaths vs from <55 to 2765 deaths in previous studies), and availability of cause-specific mortality data and detailed information on potential confounders.

There was no significant association between RLS and mortality resulting from cancer and other causes.

This study was supported by grants from the National Institutes of Health. One coauthor is a consultant for Merck, Flex Pharma, and Otsuka; has provided expert testimony for Cantor Colburn; receives royalties from UpToDate; and has received research grants from Xenoport, UCB Pharma, NeuroMetrix, National Institute of Mental Health, and Luitpold Pharmaceuticals. Another coauthor receives an RLS research grant from and was a consultant to Xenoport/Arbor Pharmaceuticals, MundiPharma, and UCB Pharma. Dr Gao and the remaining authors have disclosed no relevant financial relationships.

Neurology. Published online December 15. Abstract

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