SIR panel sets CCSVI research agenda

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SIR panel sets CCSVI research agenda

Postby PCakes » Tue Jun 07, 2011 7:54 am

Original post credit to CCSVI at UBC MS Clinic
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SIR panel sets CCSVI research agenda
'Interventional News' Monday, 06 Jun 2011 18:17
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Ziv Haskal, Michael Dake and Gary Siskin
A multidisciplinary panel has published its discussions of research priorities evaluating chronic cerebrospinal venous insufficiency (CCSVI) interventions and says “not yet” to a large-scale multicentre trial. At the SIR meeting in Chicago, USA, several key questions surrounding the unproven syndrome of CCSVI were also highlighted

The panel has agreed that there is currently not enough information on the specific parameters required to run a large-scale, pivotal multicentre trial. However, these types of trials are the “mandatory goal” for the study of CCSVI, it states.

JVIR has recently published the proceedings as a special communication titled “The Development of a Research Agenda for Evaluation of Interventional Therapies for Chronic Cerebrospinal Venous Insufficiency: Proceedings from a Multidisciplinary Research Consensus Panel. The panel comprises Gary P Siskin (New York, USA), Ziv Haskal and Walter Royal III (both from Baltimore, USA), Gordon McLennan (Cleveland, USA), Michael Dake (Palo Alto, USA), Mark Haacke (Detroit, USA), Sandy McDonald (Barrie, Canada) Suresh Vedantham (St Louis, USA), Salvatore Sclafani (Brooklyn, USA), R Torrance Andrews (Seattle, USA), David Hubbard and Heidi Sauder (San Diego, USA).

The panel further recommends that prospective safety and efficacy trials should be conducted in well-defined and potentially smaller controlled populations under institutional review board approval. It advocates that it is critical to support and continue the basic science work which seeks to clarify the relationship between venous stenoses and hypertension and the subsequent contribution of CCSVI to patients with multiple sclerosis.

Treatment for the unproven syndrome of CCSVI is controversial, with some interventional radiologists believing that this could be a new and rewarding area to contribute their services in. Others feel strongly that while rigorous scientific data are lacking, any treatment for this putative theory must be limited to the setting of a randomised trial.

The JVIR special communiqué also states that “there was near-universal agreement that randomised trials would be required to confirm the role of venous interventions in multiple sclerosis.” However, the proceedings say “It was equally clear from the discussion that several factors could be better understood before large-scale randomised trials are initiated. Among these are […] confirmatory prevalence and diagnosis data, but also the need to define the appropriate study population, the need to optimise the interventional techniques for diagnosis and treatment, and to agree on appropriate endpoints for primary and secondary endpoint analysis.” The panel has encouraged the performance of investigator-initiated single-centre and multicentre studies so that safety and outcome data can be reported. They write that “a foundation of knowledge in these areas can be gathered. This knowledge will help provide the information necessary to appropriately power a prospective randomised trial.”

There are also interventionalists who are already calling for randomised controlled trials. Lindsay Machan, Vancouver, Canada, told delegates at the Charing Cross Symposium in London in April,“To answer the question if the CCSVI syndrome is real, I still have absolutely no idea, but what I do know is that a sham controlled trial is urgently needed.” He also said, “There is no consensus on the criteria for diagnosis of venous stenosis in the upper body, we do not know what we are treating and we do not have a documented durable method to treat jugular venous stenosis.”

The JVIR communication also notes that there are likely to be practitioners who will offer endovascular therapy to patients with multiple sclerosis before definitive peer-reviewed data backing this practice is available. The panellists write: “It was the general hope of the committee that this work would lead to additional peer-reviewed studies generating data that clarify the role in multiple sclerosis of treating venous disease with angioplasty and possibly stent placement and the potential adverse events associated with these interventions.”

Some interventionalists might question the panel’s recommendation by asking whether further non-randomised studies would really satisfy the conditions set, and how treating more patients would facilitate issues such as agreeing on primary and secondary endpoints. The explanations of the panel could also be viewed as procrastination.

A CIRSE commentary published on 7 December 2010 in CVIR, by authors Jim A Reekers (Amsterdam, The Netherlands), Michael J Lee (Dublin, Ireland), Anna Maria Belli (London, UK), and Frederik Barkhof, (The Netherlands) takes the view that while there has been widespread promotion of balloon dilatation to treat CCSVI, and alleviate multiple sclerosis symptoms, “This theory does not fit into the existing bulk of scientific data concerning the pathophysiology of multiple sclerosis.”

Reekers et al question whether the anecdotes of successful outcomes which are widely being disseminated on the Internet could be the result of a placebo effect. They write: “In itself, there is nothing with the placebo effect as long as we recognise that this is at play. […] Furthermore, multiple sclerosis can affect emotional and labile responses and is characterised by spontaneous relapses and remissions. This makes the gathering of scientific evidence to support CCSVI theory difficult in anything other than a randomised controlled trial.”

At the Society of Interventional Radiology’s meeting Dake said, “Personally, I want to know if a patient with multiple sclerosis has CCSVI, and if the narrowing is successfully treated, is it possible to objectively demonstrate physiological improvement in relevant parameters and an associated relief of symptoms.”

Dake set out some of the unknowns and uncertainty surrounding CCSVI diagnosis. He asked: Is CCSVI something we are born with, develop, or both? What percentage of multiple sclerosis patients and healthy controls has CCSVI? Is CCSVI a consequence of multiple sclerosis or part of the disease pathogenesis? How do we reliably diagnose CCSVI and know if it is physiologically relevant? How does CCSVI fit into the current immune concept of multiple sclerosis pathogenesis or does it not? How can we engage neurologists in meaningful collaboration to study a concept they truly regard as total lunacy?

With regard to the treatment and endpoint assessment, Dake outlined yet another series of questions: Are any lesions outside the valves important? Is angioplasty the best possible treatment? What about oversized balloons, cutting balloon and when are stents warranted, if at all? What per cent of lesions respond to angioplasty, how do you judge? How do we know intraprocedurally if CCSVI is adequately treated? Is it necessary to treat all lesions? What are the risks and complications of the procedure? Do individuals ever get worse after treatment? Is post-treatment with angioplasty or a stent? What is the ideal regimen for adjunctive medications to prevent thrombus formation?

Questions also remain with regard to the potential benefits of endovascular treatment and follow-up. “How do we know if there is any real benefit from treating CCSVI, i.e. that it is not a placebo? What percentage of patients notice improvement; in what percentage of patients do these symptoms return? Do cerebral perfusion, tissue oxygenation and venous flow measurements improve post-treatment? What evaluations should be monitored on follow-up? If symptoms return, what is the typical timeframe for this? What should interventionalists do when they return and why do they return? Is there any evidence that the trajectory of disease progression is slowed post-therapy?,” Dake asked.He referred to the scepticism the CCSVI theory has met with from several neurologists, and illustrated it with an editorial published in the American Journal of Neuroradiology (AJNR2011;32: 424–427) which said: “CCSVI is a sonographic construct that is poorly reproducible and questionable in terms of known pathophysiologic factors established in multiple sclerosis. The neuroimaging findings reviewed here do not support the CCSVI theory in multiple sclerosis [...]. As a consequence, endovascular treatment of presumed vascular abnormalities in multiple sclerosis should be discouraged violently.”

Dake told delegates, “The current state of CCSVI discussions in the medical literature is centred in two silos: its frequency/diagnosis/association with multiple sclerosis and the results of endovascular treatment. The former is highly contentious, confusing and still quite hypothetical, with positions often being argued by those with a pre-existing agenda/bias. In either case, new metrics are needed to specifically address the effects of treatments on new targets—studies that allow an acceleration of the current cycle time to determine if the desired effect of therapy is achieved,” he said.

Siskin, who presented some results from the latest literature on CCSVI, said that it was important to differentiate between “what we know and what we do not know in order to help effective communication with potential patients, to make sure that discussions with neurology are balanced and to be certain that research is directed towards answering the unanswered questions.”

At the SIR session, Haskal cautioned against close mindedness on both ends of the spectrum both from the “opposers” of the theory and the “converted.” He noted that reproducibility of results was vital.

Haskal stated that there was a broad need and opportunity for methodical disassembly of the problem into research elements. “Ultrasound protocols need to be validated and others created that can be accomplished and validated locally. Magnetic resonance screening protocols need to be defined at the highest level and set for local reproducibility; reporting standards must be defined for uniformity; and we need to define appropriate endpoints for studies,” he said.

With regard to therapeutic gray areas, Haskal questioned: “Are the endpoints being used currently in studies suitable/correct? Are the diagnostic tools not restrictive or too fine? Is the technology adequate? Is investigator bias introduced early regarding mechanism? Can early trials truly mimic existing standards, at this point? We need to identify objective measures: MRI lesions, exams, cytokines, immune mediators,” he said.

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Postby PCakes » Tue Jun 07, 2011 8:01 am

another from 'Interventional News'...

CCSVI remains controversial: SIR debate shows divergent views among interventionalists
Monday, 06 Jun 2011 18:14

An SIR session titled “The Sterile Gloves Are Off” featured a heated debate on the proposition “The level of evidence linking chronic cerebrospinal venous insuffiency (CCSVI) and multiple sclerosis is inadequate and the clinical benefits of endovascular treatment are suspect”.

Jim Reekers argued for the motion and Gary Siskin against.

Reekers, professor of Interventional Radiology, University of Amsterdam Medical School, AMC, The Netherlands, began by stating that he had a commitment to “honesty, good evidence-based science and unbiased, non-commercialised medicine.” He used the historical example of Perkin’s tractors to set out his case. Reekers drew a parallel between what happened in the 18th century, when Elisha Perkins, a physician from the USA began to use metal rods to cure inflammation, rheumatism and pain in the head and the face. Perkins applied the pointed ends of the rod on the aching body part and passed them over the part for about 20 minutes. He claimed they could “draw off the noxious electrical fluid which lay at the root of suffering”.

Reekers told delegates that the Connecticut Medical Society condemned the tractors as “delusive quackery” and expelled Perkins from membership, yet he still managed to garner support from surgeons in Copenhagen and Denmark. Perkins talked about 5,000 cured cases,which were certified by professors, physicians and clergymen, noted Reekers, while criticism from other physicians was met with charges of elitism and professional arrogance. He said that in 1800 John Haygarth published a randomised, blinded study where patients derived the same effect from wooden rods.

“Have we learned anything in the last 200 years?,” asked Reekers. “Again criticism from physicians regarding the CCSVI hypothesis are met with charges of elitism and professional arrogance. We also hear the terms ‘pharmaceutical lobby’ and ‘being afraid to lose patients’ being bandied about.”

Referring to the widespread patient testimony about CCSVI, Reekers cautioned: “Remember even with Perkin’s tractors, patients felt better. This is placebo effect,” he said.

He called for a prospective randomised controlled trial, performed by unbiased physicians with one sham arm (with percutaneous transluminal angioplasty for the subclavian vein) which would have independent blinded follow-up in order to settle the issue.

On the issue of deferring a randomised controlled trial, Reekers told Interventional News: “Offering a non-proven treatment, without any objective parameters of success, which is mainly physician- and patient-driven carries a huge risk of damaging the reputation of interventional radiology as being a serious clinical specialty. With any future negative trial outcome, patients will have a strong case to go to court for deceit, and claim damages. Finally, all new introduced techniques in interventional radiology, like uterine fibroid embolization, had objective parameters of technical success which supported their introduction. The so-called abnormality, CCSVI, is completely unproven and is only a chimera.”

Siskin, who argued against the motion, said “as long as a reasonable percentage of patients are telling us that they are “feeling better” and are “satisfied” with their outcome after this procedure, we are going to continue offering it to our patients. It is our responsibility as physicians to do that.”

However, he acknowledged that there has not been enough research on CCSVI and that ongoing research would be critical to the understanding of CCSVI and the role of angioplasty in treating patients with multiple sclerosis.

“It is an important responsibility for us to make sure that appropriate research is performed so that we can grow our understanding of CCSVI as an entity and to determine its influence on multiple sclerosis-related symptoms. It is important that we improve our understanding of the basic science behind CCSVI, validate previously reported data and perform a prospective randomised trial,” he said.

He also argued that “I do not remember any of the pioneers of many of our other procedures waiting until all the questions were answered before performing procedures such as subintimal angioplasty, chemoembolization, radioembolization and uterine fibroid embolization on patients.” He told delegates that his group was currently enrolling into a prospective randomised, blinded trial to evaluate angioplasty as a treatment for CCSVI in multiple sclerosis patients. “I am aware of several other trials getting underway,” he noted.

Gary Siskin told Interventional News: “Interventional radiology has achieved its success as a specialty by constantly looking for new solutions to old problems, and this newly described entity is just another example of that. Many prominent members of our specialty have found preliminary success with treating this condition, which has provided the basis and impetus for further research. The difficulty in finding objective parameters of success and the possibility of discovering that angioplasty is not bringing about the success that patients are looking for should not stop our specialty from performing well designed clinical trials to answer this question. Patients suffering with multiple sclerosis deserve this.”

Before the debate, 80% of the audience voted in favour of the proposition “The level of evidence linking chronic cerebrospinal venous insuffiency (CCSVI) and multiple sclerosis is inadequate and the clinical benefits of endovascular treatment are suspect” and 20% against. After the debate, 74% of the audience voted that they were for the proposition and 26% voted that they were against.
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Postby Cece » Tue Jun 07, 2011 9:46 am

Furthermore, multiple sclerosis can affect emotional and labile responses and is characterised by spontaneous relapses and remissions.

I've wondered, do other people with MS fatigue have relapses and remissions of the fatigue? I've had other things come and go (numbness, eye "special effects," foot drop) but the fatigue was constant. No relapses or remissions, when it came to fatigue.
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Postby Cece » Tue Jun 07, 2011 9:50 am

Dake set out some of the unknowns and uncertainty surrounding CCSVI diagnosis. He asked: Is CCSVI something we are born with, develop, or both? What percentage of multiple sclerosis patients and healthy controls has CCSVI? Is CCSVI a consequence of multiple sclerosis or part of the disease pathogenesis? How do we reliably diagnose CCSVI and know if it is physiologically relevant? How does CCSVI fit into the current immune concept of multiple sclerosis pathogenesis or does it not? How can we engage neurologists in meaningful collaboration to study a concept they truly regard as total lunacy?

With regard to the treatment and endpoint assessment, Dake outlined yet another series of questions: Are any lesions outside the valves important? Is angioplasty the best possible treatment? What about oversized balloons, cutting balloon and when are stents warranted, if at all? What per cent of lesions respond to angioplasty, how do you judge? How do we know intraprocedurally if CCSVI is adequately treated? Is it necessary to treat all lesions? What are the risks and complications of the procedure? Do individuals ever get worse after treatment? Is post-treatment with angioplasty or a stent? What is the ideal regimen for adjunctive medications to prevent thrombus formation?

Questions also remain with regard to the potential benefits of endovascular treatment and follow-up. “How do we know if there is any real benefit from treating CCSVI, i.e. that it is not a placebo? What percentage of patients notice improvement; in what percentage of patients do these symptoms return? Do cerebral perfusion, tissue oxygenation and venous flow measurements improve post-treatment? What evaluations should be monitored on follow-up? If symptoms return, what is the typical timeframe for this? What should interventionalists do when they return and why do they return? Is there any evidence that the trajectory of disease progression is slowed post-therapy?,” Dake asked.

So many important questions!
Our IRs have their work/careers cut out for them. ASAP....
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Postby Cece » Tue Jun 07, 2011 10:04 am

Dake told delegates, “The current state of CCSVI discussions in the medical literature is centred in two silos: its frequency/diagnosis/association with multiple sclerosis and the results of endovascular treatment. The former is highly contentious, confusing and still quite hypothetical, with positions often being argued by those with a pre-existing agenda/bias. In either case, new metrics are needed to specifically address the effects of treatments on new targets—studies that allow an acceleration of the current cycle time to determine if the desired effect of therapy is achieved,” he said.

Did he have ideas for what metrics could be used? 'An acceleration of the current cycle time' - does that mean getting studies done faster by using shorter time periods? A typical time period from an MS study is two years.
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Postby Lyon » Tue Jun 07, 2011 10:04 am

..
Last edited by Lyon on Wed Jun 22, 2011 4:49 pm, edited 1 time in total.
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Postby AMcG » Tue Jun 07, 2011 10:42 am

Cece wrote:
Furthermore, multiple sclerosis can affect emotional and labile responses and is characterised by spontaneous relapses and remissions.

I've wondered, do other people with MS fatigue have relapses and remissions of the fatigue? I've had other things come and go (numbness, eye "special effects," foot drop) but the fatigue was constant. No relapses or remissions, when it came to fatigue.


I couldn't agree more Cece. MS fatigue is not something that could possibly go away due to placebo effects. It was there all the time for me too and is completely gone now. This is obvious when you are on the inside but to non MS patients placebo sounds plausible. So unfortunately we (liberati) are left in the position where we are sure it is not placebo but our experience is subjective not objective so we have no way of proving it.

But I am pleased in general with the outcome of this session. Although the participants started off with a very negative view they did move significantly towards CCSVI by the end. I am far happier with open debate like this than the closed sessions of the CIHR. The more honest debate the better.
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Postby cheerleader » Tue Jun 07, 2011 12:08 pm

Cece wrote:
Dake told delegates, “The current state of CCSVI discussions in the medical literature is centred in two silos: its frequency/diagnosis/association with multiple sclerosis and the results of endovascular treatment. The former is highly contentious, confusing and still quite hypothetical, with positions often being argued by those with a pre-existing agenda/bias. In either case, new metrics are needed to specifically address the effects of treatments on new targets—studies that allow an acceleration of the current cycle time to determine if the desired effect of therapy is achieved,” he said.

Did he have ideas for what metrics could be used? 'An acceleration of the current cycle time' - does that mean getting studies done faster by using shorter time periods? A typical time period from an MS study is two years.


Yes, Dr. Dake has a different metric than two years...because he doesn't want to wait two years to treat those in the "sham" side of the procedure. He would like his trial to be blinded and at 3 months past angio, unblinded. This is because he has already seen how specific results of symptom relief occurred in the original group he treated two years ago. He would then want to offer angioplasty to those with venous malformations who were on the sham side. There is a very specific reason why he feels this way...he believes these malformations should be treated in a timely fashion, if the patient so desires.
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