Pauline Anderson

June 10, 2013

ORLANDO, Florida — Doctors should encourage their patients with multiple sclerosis (MS) who are curious about chronic cerebrospinal venous insufficiency (CCVSI) to "hold off" getting the related procedure until results are in from what some view as a potentially definitive trial on the merits of this intervention, according to Alexander Rae-Grant, MD, neurologist and chair, Neurological Education, Cleveland Clinic, Ohio.

The multicenter trial, led by Anthony Traboulsee, MD, assistant professor, neurology, and medical director, University of British Columbia Hospital MS Clinic, Vancouver, Canada, will compare venous angioplasty with a sham procedure in patients with MS. The theory behind CCSVI is that blocked veins in the head and neck result in excessive iron in the brain and may contribute to the disease process in MS.

"Until you subject this to a well-designed, randomized trial in which it's compared to a sham procedure, and you're sure that you've excluded the possibility that there isn't a therapeutic effect because of small sample size, you really don't know" if it works or not, said Dr. Rae-Grant told Medscape Medical News here during an interview.

He spoke during a symposium on Controversial Unconventional Therapies at the 5th Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

Prove Once and for All?

The Canadian trial should "prove the point once and for all" in terms of the effect of treatment, said Dr. Rae-Grant. "One way or the other, the Canadian trial will be the ultimate answer in terms of therapeutics, not in terms of whether there are vascular abnormalities, but in terms of whether this therapeutic intervention is something we should be looking to."

So far, said Dr. Rae-Grant, there have really been only 2 treatment trials: the initial positive trial in 2009, led by Paolo Zamboni, MD, that launched the controversy surrounding the validity of the procedure, and a subsequent negative but "fairly small" trial.

The Prospective Randomized Endovascular Therapy in MS (PREMiSe) enrolled 10 patients in a phase 1 safety trial and 20 patients with active relapsing MS in a phase 2 trial, which randomly assigned patients to treatment or placebo. According to the results released earlier this year at the American Academy of Neurology 65th Annual Meeting, the study looked at whether the procedure was safe or associated with adverse events at 24 hours and 1 month. The primary endpoint was venous outflow restoration at month 1, as well as MRI disease activity and relapse rate.

There were no safety issues at either time point, noted the study's co-principal investigator, Robert Zivadinov, MD, PhD, professor, neurology, University of Buffalo, New York, but for venous outflow restoration, this endpoint was met only in phase 1. In phase 2, venous outflow did not improve with the actual or with the sham procedure.

"The main outcome of the study was very surprising to us," Dr. Zivadinov told Medscape Medical News at that time. Of the 9 patients who underwent venoplasty, 5 had increased disease activity after intervention, with a total of 19 new gadolinium-enhancing lesions and 17 new T2 lesions, vs 3 total new lesions in the sham procedure group. There were 4 relapses in treated patients vs 1 in the sham group. Treatment groups did not differ for quality of life, with all patients reporting improvements.

"So there was a clear-cut increase of disease activity in treated people," he said. "In people with active relapsing MS, I don't think this treatment is appropriate and could lead to potential harm." The researchers will be following these patients for more long-term results.

At the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), results of the COSMO trial, a case-control observational study carried out by Italian researchers, showed the incidence of CCSVI was low and did not differ between groups of patients with MS, those with other neurologic diseases, or healthy controls. Another observational study, also by Italian researchers, looking at the safety of venoplasty to correct CCSVI suggested that the procedure was not without risk, with serious adverse events occurring in about 3% of patients who elected to be treated.

At that time, Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, concluded that given their findings and those in the venoplasty study, further interventional studies were not needed. "I think that because there is no rationale for a trial exploring the efficacy of liberation therapy, I personally think it's absolutely inappropriate that the government finances any type of investigation or research."

However, Dr. Zivadinov said the low incidence of CCVSI as seen in COSMO did not agree with their own experience using a larger variety of imaging modalities, including invasive techniques. The fact that they saw an increase in disease activity argues that venoplasty for CCSVI is having an effect in the brain, even though it was a negative effect.

"I strongly believe we should have further research on CCSVI as a concept, maybe switching from the MS population to more normal populations — aging and healthy people who have this problem, and understand what it means," he said. "It's not unique to MS, and for sure, the endovascular treatment is not an option that should be done on a clinical basis."

Baby With the Bathwater?

Still addressing delegates during the joint CMSC/ACTRIMS meeting, Dr. Rae-Grant emphasized the importance of not dismissing the possibility that CCSVI really does work.

… we don't have the data yet to dismiss it. Dr. Alexander Rae-Grant

"What if we're missing something? What if there is a vascular piece to this? What if there's a subset in which this means something? What if we're throwing the baby out with the bathwater?" And what if, down the road, it becomes clear that "we missed it," he said.

Neurologists should not be dismissive of a therapy that a good proportion of their patients are interested in and may even want to try, he added. "We can't throw it out; we don't have the data yet to dismiss it."

It's also important to "avoid concerns that there is a conspiracy" of industry and scientists to sabotaging the research, said Dr. Rae-Grant.

Instead, it's important to take "a considered reasonable approach" and find "a place in between," said Dr. Rae-Grant.

After a flurry of interest in what came to be called by some "liberation therapy," anecdotal evidence suggests that the demand for information on this intervention has leveled off in the last 3 years, possibly because of increasing questions surrounding its efficacy, said Dr. Rae-Grant.

The $6 million Canadian trial, a collaborative effort between the Canadian Institutes of Health Research, the MS Society of Canada, and the relevant provinces, will enroll 100 patients with MS at 4 centers (Vancouver, Winnipeg, Montreal, and Quebec City). The patients will be randomly assigned to undergo venoplasty or a sham treatment. Each group will cross over to the other treatment after a year.

Recruitment has not yet begun at her center, said Ruth Ann Marrie, MD, PhD, University of Manitoba, Winnipeg, although she and her colleagues are gathering information on what factors are linked to the decision to have the venoplasty procedure.

Disease Progression Linked to Procedure

At the meeting, she presented results from a survey showing that, contrary to what many expected, patients with MS who have comorbid conditions are less likely to have the procedure.

The study, carried out by the Alberta Multiple Sclerosis Initiative (TAMSI), included 683 participants (77.7% female; 64.2% with relapsing-remitting MS; mean age, 47.9 years). Of these, 20.2% reported having had CCSVI treatment.

Of the sample, 34.1% reported no comorbid conditions, while 28.7% reported 1, 19.5% reported 2, 9.5% reported 3, and 8.2% reported 4 or more. The most commonly reported comorbid conditions were depression (27.7%), hyperlipidemia (15.8%), hypertension (15.7%), and migraine (15.1%).

Individuals with any comorbidity were less likely (odds ratio, 0.68; 95% confidence interval, 0.46 - 0.99) to report undergoing venous angioplasty than those with no comorbidity, and the likelihood of having the procedure decreased with increasing number of comorbid conditions. The type of comorbidity did not seem to matter in the decision to have the operation.

A progressive disease course, greater disability, older age, and male sex were associated with greater frequency of venous angioplasty (all P < .05). Adjusting for these factors did not change the association between venous angioplasty and any comorbidity or number of comorbid conditions.

The researchers now plan to try to find out where patients with MS go to get the procedure, how much they spend on it, and whether they feel it was beneficial, said Dr. Marrie.

In the past year Dr. Rae-Grant has given talks for Biogen and Teva Neurosciences.

5th Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Controversial Unconventional Therapies. Presented May 30, 2013. Abstract #DX45. Presented May 30, 2013.


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