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Last Words on Last Words?

Open ArchivePublished:July 27, 2018DOI:https://doi.org/10.1016/j.ejvs.2018.06.040
      In 2012, the Editors of the European Journal of Vascular and Endovascular Surgery commissioned a debate regarding the role of extracranial venous angioplasty in the treatment of chronic cerebrospinous venous insufficiency (CCSVI) associated multiple sclerosis (MS).
      • Ricco J.B.
      • Naylor A.R.
      Damned if you do and damned if you don't.
      At the time, many patients with MS demanded unfettered access to an (otherwise unproven) intervention, which they felt was being unfairly denied them. As far as they were concerned, the “liberation procedure” was a safe intervention and carried far fewer side effects than many of the medications they were being prescribed.

      Grady D. From M.S. patients; outcry for unproved treatment. Available at: www.nytimes.com/2010/06/29/health/29vein.html [Accessed 11 June 2018].

      In an editorial in Nature at around the same time, which introduced the scientific world to the concept of ‘Facebook equipoise’, Chafe proposed that it was no longer necessary to prove a “strong biological rationale” for venous angioplasty and that if the results of observational studies were to be delayed (or were unconvincing to patients), then it was totally reasonable to conduct randomised double blinded controlled trials (RCTs), without waiting for a valid hypothesis to be developed.
      • Chafe R.
      The rise of people power.
      Notwithstanding considerable scepticism at the time, two RCTs have now been completed (both including a “sham intervention arm”), but neither found evidence that venous angioplasty improved clinical outcomes in patients with MS.
      • Siddiqui A.H.
      • Zivadinov R.
      • Benedict R.H.
      • Karmon Y.
      • Yu J.
      • Hartney M.L.
      • et al.
      Prospective randomized trial of venous angioplasty in multiple sclerosis (PREMiSe).
      • Zamboni P.
      • Tesio L.
      • Galimberti S.
      • Massacesi L.
      • Salvi F.
      • D'Alesssandro R.
      • et al.
      Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial.
      In this issue of the Journal, however, Dr Zamboni proposes that there may still be a role for extracranial venous angioplasty in selected patients with MS,
      • Zamboni P.
      • Zivadinov R.
      Extracranial veins in multiple sclerosis: is there a role for vascular surgery?.
      based on a post-hoc (unplanned) analysis of data from the Brave Dreams RCT (Brain Venous Drainage Exploited Against Multiple Sclerosis), which suggested that patients who underwent a failed venous angioplasty were significantly more likely to develop new T2 lesions on magnetic resonance imaging (MRI) between 6 and 12 months post-operatively (hazard ratio 5.27, 95% confidence interval 1.5–18.69; p < .007).
      • Zamboni P.
      • Tesio L.
      • Galimberti S.
      • Massacesi L.
      • Salvi F.
      • D'Alesssandro R.
      • et al.
      Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial.
      Opposing Dr Zamboni, Dr Zivadinov argues that the two published RCTs have conclusively determined that there is no role for venous angioplasty in patients with MS and that there are other more effective treatments available to patients.
      • Zamboni P.
      • Zivadinov R.
      Extracranial veins in multiple sclerosis: is there a role for vascular surgery?.
      Dr Zivadinov was one of the investigators of the PREMiSe RCT, which only randomised 19 patients, and which found no evidence that venous angioplasty modified clinical or MRI based outcomes in patients with MS.
      • Siddiqui A.H.
      • Zivadinov R.
      • Benedict R.H.
      • Karmon Y.
      • Yu J.
      • Hartney M.L.
      • et al.
      Prospective randomized trial of venous angioplasty in multiple sclerosis (PREMiSe).
      One of the key issues in this debate is whether an unplanned post-hoc analysis from a small RCT can be used to develop a new and valid hypothesis. As has befallen many RCTs in the past, the Brave Dreams RCT failed to recruit its intended cohort (115 of 400 planned patients with relapsing remitting MS and only 15 of 200 planned patients with secondary progressive MS) and was, therefore, considerably underpowered. Moreover, only 54% of patients randomised to venous angioplasty underwent a successful intervention in terms of restoring extracranial venous flow.
      • Zamboni P.
      • Tesio L.
      • Galimberti S.
      • Massacesi L.
      • Salvi F.
      • D'Alesssandro R.
      • et al.
      Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial.
      In the 2012 EJVES debate, Dr Zivadinov was a supporter of Dr Zamboni and requested that he be allowed to develop his research programme into CCSVI and MS,
      • Zivadinov R.
      • Salvi F.
      • Weinstock-Guttman B.
      Regarding CCSVI and MS: a never-ending story or a new chapter?.
      amidst a growing furore over uncontrolled numbers of vulnerable patients with MS undergoing the “liberation procedure” in private institutions around the world. That toxic environment has now subsided and there has been less pressure applied to vascular surgeons and interventionists to offer this service by lobbyists. Accordingly, given the negative RCT results in Brave Dreams and PREMiSe, has the debate over whether extracranial venous angioplasty has any remaining role in the treatment of CCSVI associated MS been resolved, or is there still a need to identify a smaller subgroup of patients with MS who might benefit from intervention? Our debaters will offer their “last words on last words”.

      References

        • Ricco J.B.
        • Naylor A.R.
        Damned if you do and damned if you don't.
        Eur J Vasc Endovasc Surg. 2012; 43: 114-115
      1. Grady D. From M.S. patients; outcry for unproved treatment. Available at: www.nytimes.com/2010/06/29/health/29vein.html [Accessed 11 June 2018].

        • Chafe R.
        The rise of people power.
        Nature. 2011; 472: 410-411
        • Siddiqui A.H.
        • Zivadinov R.
        • Benedict R.H.
        • Karmon Y.
        • Yu J.
        • Hartney M.L.
        • et al.
        Prospective randomized trial of venous angioplasty in multiple sclerosis (PREMiSe).
        Neurology. 2014; 83: 441-449
        • Zamboni P.
        • Tesio L.
        • Galimberti S.
        • Massacesi L.
        • Salvi F.
        • D'Alesssandro R.
        • et al.
        Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial.
        JAMA Neurol. 2018; 75: 35-43
        • Zamboni P.
        • Zivadinov R.
        Extracranial veins in multiple sclerosis: is there a role for vascular surgery?.
        Eur J Vasc Endovasc Surg. 2018; 56: 618-621
        • Zivadinov R.
        • Salvi F.
        • Weinstock-Guttman B.
        Regarding CCSVI and MS: a never-ending story or a new chapter?.
        Eur J Vasc Endovasc Surg. 2012; 43: 129-130

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