title: Risk of Cardiovascular Disease Associated with a Restless Legs Syndrome Diagnosis in a Retrospective Cohort Study from Kaiser Permanente Northern California.
abstract: BACKGROUND
  Recent cross-sectional studies suggest that restless legs syndrome (RLS) may be associated with an increased prevalence of cardiovascular disease (CVD) comorbidity or risk factors. We evaluated whether primary or secondary RLS was associated with an increased risk of incident cardiovascular disease in a retrospective cohort study within Kaiser Permanente Northern California (KPNC).
  
  
  METHODS
  We identified members of KPNC with primary RLS and secondary RLS between 1999 and 2008 by an algorithm that incorporated longitudinal clinical records related to the diagnosis and treatment of RLS and comorbidities. We then matched each RLS case with up to 50 individuals with no clinical records of RLS by age, sex, race/ethnicity, zip code, and membership duration. For the analyses we excluded any individual with coronary artery disease (CAD: angina, acute myocardial infarction, coronary revascularization procedure, CAD death), CVD (CAD plus stroke), and hypertension at baseline. New cardiovascular events were determined from clinical records. Follow-up ended at an outcome event, disenrollment from KPNC, or death, whichever occurred earliest. There were over 473,358 person-y of follow-up in this cohort analysis with a mean follow-up time of 3.91 y and range from 6 mo to 12 y. Survival analysis techniques, including survival curves and proportional hazard regression models, were used to assess the association between RLS status and CVD.
  
  
  RESULTS
  There were 7,621 primary RLS and 4,507 secondary RLS cases identified and included in the study. In general, primary RLS cases were younger and had less comorbidity than secondary RLS cases. During the follow-up period, CVD was diagnosed in 478 primary RLS cohort members, CAD was diagnosed in 310, and hypertension events were identified in 1,466. Diagnosis in secondary RLS cohort members was made during the follow-up period with 451, 338, and 598 CVD, CAD, and hypertension events, respectively. Subjects with primary RLS had a similar risk of incident CVD (hazard ratio (HR) = 0.95; 95% confidence interval (CI) = 0.86-1.04) and CAD (HR = 0.99; 95% CI = 0.89-1.13) to the comparison cohort, with a slight elevation in the risk of hypertension events (HR = 1.19; 95% CI = 1.12-1.25), after multivariable adjustment. Individuals classified as secondary RLS had a significant increased risk of CVD (HR = 1.33; 95% CI = 1.21-1.46), CAD (HR = 1.40; 95% CI = 1.25-1.56), and hypertension (HR = 1.28; 95% CI = 1.18-1.40).
  
  
  CONCLUSIONS
  Primary restless legs syndrome (RLS) was not associated with new-onset cardiovascular disease (CVD) or coronary artery disease (CAD) but was associated with a slight increased risk of hypertension. In contrast, secondary RLS was associated with an increased risk of CVD, CAD, and hypertension.
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Van Den Eeden
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA.
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Albers
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC and Stockley Park, UK.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Davidson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA.
authors.forename: Clete A
authors.initials: CA
authors.lastname: Kushida
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA.
authors.forename: Amethyst D
authors.initials: AD
authors.lastname: Leimpeter
authors.affiliation: Division of Epidemiology, Department of Health Research and Policy, Stanford University, Stanford, CA.
authors.forename: Lorene M
authors.initials: LM
authors.lastname: Nelson
authors.affiliation: Division of Epidemiology, Department of Health Research and Policy, Stanford University, Stanford, CA.
authors.forename: Rita
authors.initials: R
authors.lastname: Popat
authors.affiliation: The Parkinson's Institute, Sunnyvale, CA.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC and Stockley Park, UK.
authors.forename: Kristen
authors.initials: K
authors.lastname: Bibeau
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Quesenberry
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000175:diagnosis / Q000453:epidemiology; D002140:California / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000453:epidemiology; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000453:epidemiology; D015995:Prevalence; D016016:Proportional Hazards Models; D012148:Restless Legs Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000453:epidemiology; D013997:Time Factors; D055815:Young Adult
keywords: cardiovascular disease; cohort study; epidemiology; restless legs syndrome