Prospective randomized trial of venous angioplasty in MS (PREMiSe)

Abstract

Objective: We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072).

Methods: Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life.

Results: No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected.

Conclusion: Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity.

Classification of evidence: This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty. This study also includes a Class IV phase 1 study of safety in 10 patients receiving the angioplasty procedure.

Figure 1. Graphic representation of venous outflow dilation outcomes

Changes in venous hemodynamic insufficiency severity score (VHISS) at 1, 3, and 6 months, compared to baseline, in phases 1 and 2 plotted by using mixed-effect model analysis. p Values in the plot are based on comparison between phase 2 groups. Time effect p values within groups are phase 1 (p < 0.0001), phase 2 treated arm (p = 0.02), and phase 2 sham arm (p = 0.04), respectively.

Figure 2. Graphic representation of MRI lesion activity

Changes in accumulation of mean new contrast-enhancing (CE) lesions (A), mean new T2 lesions (B), and mean T1 lesions (C), between 0–1, 1–3, and 3–6 months in phases 1 and 2, by using mixed-effect model analysis. Some means for new T2 and T1 lesions have standard error = 0 since only values of 0 are presented. p Values in the plot are based on comparison between the phase 2 groups. Time effect p values within these groups are for mean new CE lesions: phase 1 (p = 0.198), phase 2 treated arm (p = 0.593), and phase 2 sham arm (p = 0.766), respectively; for mean new T2 lesions: phase 1 (p = 0.617), phase 2 treated arm (p = 0.254), and phase 2 sham arm (p = 0.991), respectively; and for mean new T1 lesions: phase 2 treated arm (p = 0.057) and phase 2 sham arm (p = 0.776), respectively.