Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome

Abstract

Objective:This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)–associated nocturnal systolic blood pressure (SBP) elevations.Methods:Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1–3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI).Results:Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] −160.34 [−213.23 to −107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (−161.13 [−264.47 to −57.79]; p = 0.0028), PLM-associated elevations (−88.45 [−126.12 to −50.78]; p < 0.0001), and total DBP elevations (−93.81 [−168.45 to −19.16]; p = 0.0146), PLMI (−32.77 [−44.73 to −20.80]; p < 0.0001), and PLMSAI (−7.10 [−11.93 to −2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%).Conclusions:Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk.Classification of evidence:This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1–3 mg/24 h) reduced PLM-associated nocturnal SBP elevations.

Cardiovascular comorbidity in patients with restless legs syndrome: current perspectives

“…In the same line, multiple studies, but not all, have associated RLS/PLMS with sympathetic hyperactivity. 7,[30][31][32][33] Increased sympathetic activity can lead to alterations in heart rate and nocturnal hypertension/nondipping phenotype. Moreover, other studies have shown that nocturnal non-dipping by itself is associated with increased cardiac structural alterations, 120 more cardiovascular events, 121 and confers increased risk for the development of CVD.…”

“…Recently, well-designed studies have expanded the investigation in this topic by testing dopaminergic medications in PLMS. 7,62 The results are promising, showing evidence of improvement in autonomic alterations related to PLMS. Finally, some studies argued against an abnormality in RLS patients of the baseline (tonic) sympathovagal balance during the sleep free of PLMS, but an abnormal increase in autonomic phasic activation when the PLMS occur.…”

“…This study provided class I evidence for the reduction of PLM-associated nocturnal BP in patients with moderate to severe RLS. 7 A study of 20 RLS patients free of cardiovascular comorbidities and 20 matched controls found lower baroreflex gain (P=0.04), lower leg blood flow (P<0.001), and greater leg vascular resistance (P<0.0001) in RLS patients. As other indices of cardiovagal control (respiratory sinus arrhythmia and Valsalva ratio) did not vary by RLS status, the authors hypothesized that autonomic alterations in RLS are specific to baroreflex and vascular resistance, but not to cardiovascular autonomic control more generally.…”

“…[27][28][29] Multiple studies but not all have demonstrated increased sympathetic activity in RLS/ PLMS leading to higher nocturnal blood pressure (BP), nondipping BP at night, and/or increased 24-hour BP. 7,[30][31][32][33][34] This section reviews the association between hypertension and RLS/PLMS. Table S1 summarizes studies related to RLS and hypertension.…”

“…However, a recent placebo-controlled trial 7 treatment of PLMS with rotigotine patch in patients with moderate to severe RLS resulted in the improvement of nocturnal high BP in this population (see "Association between RLS/PLMS and autonomic nervous system alteration" section). Future pharmacologic studies for RLS/PLMS are needed to clarify whether such therapies decrease the risk of developing HTN, and thus CVD in the long term.…”