Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 24 - Evidence - November 1, 2012
OTTAWA, Thursday, November 1, 2012
The Standing Senate Committee on Social Affairs, Science and Technology, to which was referred Bill S-204, An Act to establish a national strategy for chronic cerebrospinal venous insufficiency (CCSVI), met this day at 10:29 a.m. to give consideration to the bill.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie, a senator from Nova Scotia and chair of the committee. I will ask my colleagues to identify themselves, starting on my right.
Senator Seidman: Judith Seidman from Montreal, Quebec.
Senator Martin: Yonah Martin from British Columbia.
Senator Seth: Asha Seth, Toronto, Ontario.
Senator Unger: Betty Unger, Edmonton, Alberta.
Senator Enverga: Tobias Enverga from Ontario.
Senator Cordy: Jane Cordy from Nova Scotia.
Senator Merchant: Pana Merchant from Saskatchewan.
Senator Eggleton: Art Eggleton, a senator from Toronto and deputy chair of this committee.
The Chair: Thank you very much, honourable senators, and thanks so much to our distinguished witnesses today for being with us, two thirds at the moment, and we hope to be complete shortly.
Dr. Laupacis, I will turn to you first.
Dr. Andreas Laupacis, Executive Director, Li Ka Shing Knowledge Institute, St. Michael's Hospital, as an individual: Hello, committee members. In my opening remarks to you, I will summarize the results of a study conducted by a number of Canadian researchers who have reviewed the scientific evidence from around the world about CCSVI and MS. CCSVI, as I am sure you know, is an abbreviation for chronic cerebrospinal venous insufficiency.
Our group has been funded to do this study by the Canadian Institutes of Health Research.
There are 10 of us in the research group and we have a variety of expertise covering multiple sclerosis, vascular surgery, neurosurgery, neuroradiology, statistics, epidemiology and health systems research.
I am a physician who practises palliative care at St. Michael's Hospital in Toronto. I would love to be with you, but I am on the clinical service right now. That is why I could not come up to Ottawa today.
I am also a researcher, and one of my areas of expertise is reviewing the scientific literature to assess what is known about the benefits and harms of tests and treatments. I also have extensive experience with using such evidence to advise ministries of health in this country about which tests and treatments should be paid for by the publicly-funded health care system and which should not.
Our research group released our first report in June 2011 and we have since produced two updates, the most recent in June of this year. Our next update will be released next month, in December.
Let me briefly summarize the results of our findings to date. We focused our review of the scientific literature on what is known about three questions. First, is CCSVI as diagnosed by ultrasound found more often in people with MS than in people without MS? Second, what do we know about the benefits of treating CCSVI in someone with MS? Third, what do we know about the harms of treating CCSVI?
Regarding the first question, as I sure the committee is aware, and Dr. Zamboni will be joining us shortly, he described an entity called CCSVI, which is an abnormality of the anatomy in the blood flow of the veins draining the brain and spinal cord. His initial paper indicated that CCSVI could be diagnosed using ultrasound, a non-invasive technique with no side effects.
In that study, Dr. Zamboni reported that all patients with MS had CCSVI and that he could not find CCSVI in people who did not have MS. This is an exciting and astonishing finding, and it is astonishing because it is almost unheard of to have an abnormality that occurs in 100 per cent of people with a disease and 0 per cent of people without the disease.
After his study, a number of other people have done studies to look for CCSVI in people with and without MS to see if they could replicate Dr. Zamboni's findings.
In our study, we identified all the published studies that diagnosed the CCSVI with ultrasound and compared the frequency of CCSVI in people with MS and in healthy people.
We found 11 such studies. When the results of all those studies were combined, essentially when we averaged the results, we found that CCSVI was about eight times more likely to be found in people with MS than in healthy people.
However, there was a huge difference in the results among the studies, with some studies finding a much lower frequency of CCSVI than others. For example, one study found no CCSVI in any patients, whether they had MS or not, and some studies found no difference in the frequency of CCSVI between people with MS and healthy people.
In my experience, it is very unusual to find such a large difference in results among studies. Unfortunately, the reason for the large difference is not clear.
What might explain these differences? Ultrasounds are very dependent upon their technique. For example, the results can be affected by how much pressure is put on the neck with the ultrasound probe, the position in which the patient is scanned, how the patient is breathing, and the experience of the person doing the ultrasound. For ultrasound studies, it is also important that the people doing and interpreting the test are not aware of whether or not the person they are examining has MS because this might accidently influence their interpretation or reading of the results.
It may well be that the differences in ultrasound technique and in the interpretation of the test caused the marked differences in the results of the studies, but we just do not know.
The bottom line from that first third of our review of the literature is that the results of these studies are not conclusive — they neither prove that CCSVI is more common in people with MS than those without MS, nor do they prove that CCSVI is not associated with MS.
In my opinion, such a wide variability in the results of the published studies of ultrasound for CCSVI means that this test is not ready for use in regular clinical practice.
The second question we looked at, the treatment for CCSVI is a venoplasty, basically dilating the narrowing in the vein with a balloon. Many people have reported a dramatic improvement in symptoms, often improvement in fatigue and strength and a feeling of increased warmth in the extremities after venoplasty treatment. Others have reported minor or no improvement.
After venoplasty, the narrowing recurs in the months after treatment in a considerable number of patients, between 30 and 45 per cent. This is an important thing to keep in mind.
The only way to definitively establish whether CCSVI causes an improvement in the symptoms of MS, and if it does, to determine how big those improvements are and how long they last, is to conduct what is called a randomized trial, where there is essentially a flip of a coin, and half of the patients undergo venoplasty and the other half do not. In the case of the randomized trial Dr. Zamboni is involved with in Italy, my understanding is that they are using essentially a three-sided coin because two thirds of the patients will get venoplasty and one third will not. Unfortunately, no randomized trials of venoplasty for CCSVI have been reported and therefore we do not know with any degree of scientific certainty whether venoplasty is beneficial of not.
There are currently a number of randomized trials of venoplasty under way. I am aware of six such studies, some of which are just getting started now, so it will be some time before the results of those studies are available.
Finally, around the harms of treating CCSVI, doing a venoplasty involves inserting a catheter through a vein in the groin and passing it through the heart chambers and into the neck veins where a balloon is briefly inflated and then deflated. A number of studies have reported the side effects caused by venoplasty. Some people get a headache, which usually gets better in a few hours to days. The most common serious side effect of venoplasty, which occurs in around 1 to 2 per cent of patients, is an abnormal rhythm of the heart, which occurs because of irritation from the catheter passing through the heart. Although these abnormal heart rhythms usually get better, they can be very serious.
There have also been reports of major bleeding from the blood thinners the patients are prescribed around the time of the procedure, some of which have been fatal. There have been instances of clots in the neck, leaking of the veins where the balloon was blown up, and stroke. In some instances, stents have been inserted as part of the treatment and some have moved, sometimes into the heart, and this is why stents now tend not to be used when treating CCSVI.
To summarize the harms of venoplasty, the majority of patients suffer no significant side effects. However, rarely there may be very severe side effects, which can be fatal.
Given what we know about the benefits and harms of venoplasty for CCSVI in people with MS, do I believe that the public health care systems in Canada should pay for the diagnosis or treatment of CCSVI? I do not. I do not think there is sufficiently high-quality evidence to establish that the benefits of treatment outweigh the harms or even that we can reliably diagnosis CCSVI in routine practice, let alone research studies.
This has been an exceptionally brief summary of our review of the literature. All of our reports and publications are on a website, www.ccsvi.reviews.ca. I encourage you and your staff to visit it for more information. We also have a comments section on the website where you can leave comments or ask question.
Thank you for the opportunity to present.
The Chair: Thank you very much, Dr. Laupacis. I will remind my colleagues that you are on-call this morning and we understand there is a chance you might be called away.
I will now turn to Dr. Robert Zivadinov, Director, Buffalo Neuroimaging Analysis Center. He has made a special effort to be able to get here to join us this morning, which we very much appreciate.
Dr. Robert Zivadinov, Director, Buffalo Neuroimaging Analysis Center, as an individual: Thank you very much. As the chair said, I am the Director of the Buffalo Neuroimaging Analysis Center and a professor in the Department of Neurology at the University of Buffalo, Buffalo, New York.
Mr. Chair and members of the committee, I would say like to thank you for this opportunity to speak about the state of the research relating to Bill S-204 and to provide what I believe is an important perspective on the scientific and public debate on chronic cerebrospinal venous insufficiency.
While I recognize that multiple sclerosis has appropriately provided the impetus for this public health discussion, I would like to commend the authors of this bill for taking a broader approach; namely, for seeking to establish a national strategy for CCSVI itself.
I would like to also acknowledge the very significant contributions of my colleagues at the University of Buffalo, including Dr. Bianca Weinstock-Guttman, Dr. Adnan Siddiqui, Dr. Ralph Benedict, Dr. Murali Ramanathan and many others for their collaboration in completing more than 25 studies on this subject.
It may come as a small surprise to you that as a research scientist I am here today to urge continuing commitment to the specific kinds of studies that will help avert risk and accelerate potential rewards to public health relating to CCSVI, MS and other neurological disorders.
As you know, after it was hypothesized that CCSVI is unique to MS patients, interest spiked and treatments were sought by and provided to patients here in Canada and around the world. These patients' risks and rewards became palpable, but they have been supported with media-reported anecdotes about the science itself as well as patient outcomes. I think you already agree that managing public health through the media is not a prescription for success. Specifically, it is my belief that given the short- and long-term risks related to use of stenting and medium to high risk for re-stenosis after venoplasty, CCSVI intervention should be restricted to blinded, randomized and controlled clinical trials that will establish the safety and efficacy of these procedures.
While our research points against CCSVI having a primary causative role in MS, we have established that there is a higher prevalence of CCSVI in progressive MS patients. This suggests that CCSVI may contribute to or be a consequence of disease progression with important implications for treating its symptoms.
In the next few minutes, I would like to explain why I believe there is a critical need to pursue studies on CCSVI to achieve three important outcomes. First, we must agree on our definition of diagnostic success. We must define and validate the spectrum of cranial/extra-cranial venous anomalies and establish reliable, diagnostic gold standards. This will require multi-model studies and improved test operator training.
Second, we must agree on our definition of clinical success. There is a critical need to undertake controlled, randomized and blinded studies to first establish what clinical outcomes should be used in MS CCSVI clinical trials before we can assess endovascular treatment in terms of these outcomes.
Moreover, we must close the yawning gap in CCSVI prevalence estimates, as you heard from previous presentations, that range from 0 to 100 per cent, depending on the population, the methodology, the criteria and the imaging technique. Then, based on valid diagnostic and clinical measures, we must determine the efficacy of endovascular treatment itself.
These are three distinct steps.
Determining the efficacy of endovascular treatment will require placebo-controlled trials using more advanced imaging techniques with a larger number of patients. It is significant that, notwithstanding our initial focus on MS, the science invites us to also explore whether CCSVI is a syndrome characterized by symptoms such as headache, fatigue, sleep disturbances and autonomic dysfunctions that can be improved with endovascular treatment. Second, it must be determined what treatment outcome constitutes efficacy for such procedures.
Let me briefly address important challenges in arriving at valid diagnostic measures. Veins have a tendency to collapse and change their morphology and size in relation to multiple factors that can vary during testing. While radiologists generally know how to perform diagnostic imaging and intervention, there are no standardized guidelines for the detection of abnormalities indicative of CCSVI. In our view, there is a need for standardized extra-cranial and trans-cranial echo- colour Doppler training, which assesses morphologic and hemodynamic parameters and detection of venous and intra- cranial and extra-cranial abnormalities by using multi-model imaging approach studies.
Due to the complexities of the inter-cranial and cervical venous system, it is almost impossible during testing to take all of these key factors into account, regardless of which single imaging modality is used. Therefore, a multi-model imaging approach is necessary.
In my remaining time, I would like to focus on the key issues associated with clinical outcomes. Contrary to the earlier-mentioned hypothesis, studies show CCSVI is not exclusive to MS patients. However, more recent studies have questioned the very existence of CCSVI in MS patients. These dramatic disparities must be explained before any exploration of treatment is possible.
In my view, the explanation may lie in the assumption built into most of the research to date that the diagnosis of CCSVI is either positive or negative, yes or no, with no allowance for variability or gradations of severity of these abnormalities in the result.
Our recent blinded study sought to reconcile these disparate findings by examining CCSVI prevalence in the larger cohort of MS patients to date, in patients with other neurological diseases, as well as with healthy controls using multi- model imaging approaches. By using echo-colour Doppler standardized in expert hands, we found that CCSVI was present in 56 per cent of MS patients. It was present in 42 per cent of other neurological diseases. It appeared in 38 per cent of patients at first clinical attack — so-called clinically isolated syndrome, or CIS — and we also found CCSVI in 22 per cent of healthy controls.
MS patients with CCSVI showed significantly lower net cerebrospinal fluid flow and brain perfusion, findings that were highly associated with severity of CCSVI compared to healthy control in MS patients without CCSVI. Despite these data, more evidence is needed to establish the association of CCSVI and MS.
More recent results that I presented last October at the European Committee for Treatment and Research in Multiple Sclerosis in Lyon, France, showed that the prevalence of CCSVI in those with other neurological disorders is as high as 54 per cent. The fact that patients with other neurological diseases and healthy individuals also present with CCSVI in significant percentages underscores a legitimate question regarding whether endovascular treatment for CCSVI is necessary, whether it should be restricted only to MS patients, or whether other individuals with CCSVI should also be considered.
I know you will understand how hard it is for me to limit my comments to seven minutes and leave out the many details that support my conclusions, but let me summarize what I believe to be the next horizon for CCSVI science as it relates to MS and other neurological disorders.
It is essential to acknowledge that the health benefits of endovascular treatments for CCSVI cannot be assessed before we properly understand who is affected by CCSVI, whether the treatment is necessary and, finally, what is the optimal treatment outcome and type of procedure to be used for determining the efficacy of the treatment.
We believe that current evidence for association between CCSVI and MS justifies blinded, randomized, controlled phase I/II clinical trials to assess the benefits of endovascular intervention. This should be done according to established clinical MRI and quality-of-life treatment outcomes, employing safe and ethical approaches. If an initial benefit for endovascular therapy is established, then properly powered phase III trials should be conducted to determine whether this treatment can be made widely available.
Moreover, I believe it is time to expand the discussion of CCSVI treatment beyond MS to other neurological disorders. Until these steps are accomplished, I believe there is no role for endovascular treatment of CCSVI in MS patients or in patients with other neurological disorders outside of approved and carefully designed clinical trials.
Fortunately, we know what studies need to be undertaken, their implications for improving public health, and how they should be conducted. Only time and, of course, funding will advance the moment when these answers can materially improve the lives of patients with MS and those with other neurological disorders.
The Chair: Dr. Zamboni has not arrived. I should inform you that it is a holiday in Italy today — it is All Saints' Day. Dr. Zamboni has been driving some distance to get to the only conference centre that we could arrange for him to present at. Clearly, there has been some delay.
Would you agree that when he arrives, we will complete the answer to any question on the table and then move immediately to Dr. Zamboni?
Hon. Senators: Agreed.
The Chair: I thank our guests for their presentations. I will open the meeting to senators' questions until Dr. Zamboni arrives.
Senator Cordy: Bill S-204 speaks to developing a national strategy for multiple sclerosis for Canada. It also seeks to collect the data from those who have had the procedure outside Canada, so that we can collect information in Canada about Canadians. It also asks for follow-up care. I have heard from hundreds of people who are very concerned about returning from treatment outside the country and not being allowed to have follow-up care.
The bill also speaks to starting clinical trials. Fortunately, the government has announced clinical trials to begin November 1, which is today; so I guess this is the day to celebrate the start of clinical trials. Canada is starting clinical trials to gather made-in-Canada scientific information, which we want.
Dr. Laupacis you spoke in great detail about the rate of complications. Dr. Alain Beaudet appeared before the committee and talked about the clinical trials in Albany, New York, and about the discussions with those at the clinic. Dr. Gary Siskin, who works in that clinic, says that the rate of complications as a result of the venous angioplasty treatment is 1.6 per cent. That differs from the information you gave us today. Could you comment on Dr. Siskin's rate of 1.6 per cent?
Dr. Laupacis: Perhaps I did not make myself clear. The rate of serious complications that I quoted was actually between 1 per cent and 2 per cent. Dr. Siskin's group's results were very influential in informing that. I do not think we disagree. In terms of serious complications, the rate is very low.
Senator Cordy: Thank you for that clarification.
You spoke about deaths and strokes. Do you have any figures for those incidences?
Dr. Laupacis: No. Unfortunately, that is a real limitation of the studies that have been done. My sense is that many clinics that provide this procedure provide it to individuals who come from a long distance away, and they do not do a particularly good job of following all of those patients. The clinic in Costa Rica might do a large number of venoplasties in people around the world, but they do not know how those patients do when they leave the clinics. I suspect that the serious complications may be higher than reported because the studies do not routinely follow patients for a long time.
Senator Cordy: This bill is important so that we can collect data from Canadians who have had the procedure outside the country and have come back.
You spoke about your website, ccsvireviews.ca, which is funded by the CIHR. You respond to patients who inquire about the CCSVI treatment. Have you observed the CCSVI treatment procedure? What is your area of expertise in practice or in observation of the procedure?
Dr. Laupacis: I am a general internist and palliative care physician. The procedure is not provided in Canada, so I have not seen the procedure. I do have lots of experience in evaluating the scientific literature for a number of procedures outside of MS. On your comment about the benefits of a study that would follow patients when they come back from elsewhere after having the procedure, I agree with you completely. It will give us a much better estimate of the serious complication rate of that procedure. If someone returns from treatment away and three weeks later has a big hematoma in the neck, it is obvious that it was due to the procedure. On the other hand, and I would agree with Dr. Zivadinov, I do not think that kind of study is helpful in helping us to figure out whether the procedure works. In order to do that, especially to assess the important symptoms of patients, such as fatigue and warmth, you need a control group and a randomized trial.
Senator Cordy: I would agree with you that we need the trials, but it is important that we gain some information from those who have had the procedure outside the country, whether it has been effective.
Dr. Zivadinov, you said that if we can prove the hypothesis that CCSVI is the underlying cause of MS, then it will change the face of how we understand the disease. Could you explain that further?
Dr. Zivadinov: That was in the initial phase when we started a pilot study with Dr. Zamboni. There were 16 MS patients in that study, half from Buffalo and half from Italy, and a healthy control group. The prevalence in that study was 100 per cent in MS patients and 0 per cent in the healthy control group. Based on that, we started a large cohort study. Phase I was published and included 499 subjects, including MS patients, healthy control patients with other neurological diseases, and patients with first clinical attack.
We continued that study and, as we speak, we are arranging the next 500 subjects in the study. The studied now has over 1,000 subjects. The data from the first part of phase II have been presented at the European Committee for Treatment and Research in Multiple Sclerosis, ECTRIMS, as I mentioned. This was a study of 234 healthy control patients versus 78 patients with other neurological diseases.
We established that there is a significantly higher prevalence of CCSVI in patients with other neurological disorders. These neurological disorders have been divided into four groups: neuromuscular, neurovascular, neurodegenerative and neuro-autoimmune. In each group of these four big groups of particular neurological disorders there have been several different diseases. To give you an idea, for example, in our neuromuscular group, there was myasthenia gravis, polyneuropathy, et cetera, and we found a very similar prevalence of CCSVI.
I would say that our earlier data, as well as this new data that has not yet been published that was presented at ECTRIMS and that I am sharing with you, suggests that CCSVI is not the cause of MS but it is probably a consequence. For this panel, one of the fundamental things might be to understand why patients with neurological disorders who are more disabled, less mobile, are suffering from a higher prevalence of CCSVI. I would say that no one knows that reason, and maybe our group is the only one in the world that published two risk factor studies for CCSVI. For the record, one was published last November in Plos One journal, and the other one was published a couple of weeks ago in Neurological Research. Both studies have been done on approximately 250 healthy controls and evaluated a range of different factors that lead to the increased prevalence of CCSVI in healthy people. Both studies have been very similar in their conclusion that cardiovascular risk factors — heart disease, obesity and being overweight, and smoking — have been most important risk factors for CCSVI. That would tell you that people who probably move less because they are disabled have a tendency, as we already know in neurological disorders, to develop more of these cardiovascular risk factors, overweight, et cetera, and they probably consequently develop more CCSVI.
The tricky point starts once you develop stenosis of the veins. Since you are less mobile and more disabled, what does that mean for your underlying disease, if you have a neurological disease, or what does that mean for you as a person, a healthy individual, if you have a CCSVI?
Our recent studies are moving in two different directions. In healthy individuals, we try to understand hemodynamic and structural changes of the brain if you have or do not have a CCSVI. My personal opinion is that this is research that will continue for decades and might be an important answer as a risk factor to many neurodegenerative diseases that we know these days are really a very big burden to the public health system.
The second point is, what does that mean to the neurological disorders? We have data from a large study of about 300- plus MS patients, and we found that patients who have more progressive disease, which means they are more disabled, more in the secondary progressive or primary progressive phase, are suffering more from CCSVI.
With respect to your initial comment — and I am sorry for the long answer — we cannot say whether CCSVI was the contributing factor for the secondary progressive disease or was a consequence, and this is definitely something to be explored in longitudinal studies.
Senator Cordy: You spoke today about multi-modal imaging in order to determine whether there is CCSVI in the MS patient or non-MS patient. I heard a presentation that you gave a while ago, and you spoke during that presentation about the positive and negative studies and what you tended to find about those that were positive and those that were negative and who was publishing which studies. I wonder about those positive and negative studies. Did they in fact use multi-modal imaging, which is what you certainly were proposing today?
Dr. Zivadinov: Thank you for this question, which I think is central to this debate. As you know, the prevalence, as I mentioned, ranges between 100 and 0. It is truly amazing that nowadays, with all the advanced imaging techniques, that someone can say it is 100 and someone can say it is 0.
I think one of the key elements of the diagnosis of CCSVI is the fact that a patient or a subject has to fulfill two extra- or intra-cranial criteria. From my experience on thousands of examinations we did, those patients who have three or more than three criteria are really in a low 25 percentile. Most of the patients have two criteria or between one and two criteria.
Criterion number two of the Doppler is the one that is looking at the intra-cranial reflux, deep cerebral brain reflux. In most of the negative studies, they report that this criterion is zero, so basically what they are left with is one positive criterion and they say there is no CCSVI. I am telling you this in very simple terms. If you look at the published papers, those that report 3 per cent or 0 per cent or 5 per cent or 16 per cent of CCSI, and you look at how many patients or how many subjects have had one or more than one positive criteria, you will see that there is between 30 to 50 per cent in all studies that have been published up to today.
I definitely disagree with many of my colleagues who are saying there is no CCSVI. Yes, there is no CCSVI in your hands as a categorical diagnosis, yes or no, but as I mentioned in my statement, this is a problem. Let me give you an example.
When you have carotid stenosis and you have blocks, you are not going to show symptoms until you have 70 per cent of the stenosis. Only when you have 70 per cent of the stenosis will you begin to show a transient ischemic attack and stroke and similar things. This is very similar, I would say, in the veins. You have certain stenosis in percentages, and it is very much more difficult to determine that in veins. We need to understand at what hemodynamic points of the stenosis there are clinically associated symptoms that could worsen the underlying disease or contribute to susceptibility of the new disease.
I would say that Doppler in expert hands is probably a very good screening tool, as we proved and reproved through multi-modal imaging, but in other hands it may not be as good. In order to standardize the diagnosis, I do not think we will be able to use one imaging modality but will need to confirm what we are finding with two or three non- invasive imaging modalities. If you just do the simple MRV — magnetic resonance venography — of these veins, you will find that progressive MS patients have about 50 per cent of these veins stenosed, which definitely decreases to 25 per cent in those who are not as disabled, and we found that 15 per cent of the healthy controls have these problems on MRV.
An end-of-the-line type of diagnostic standard could be the use of what is really an extra step in science, and that is called intravascular ultrasound. We just presented at ECTRIMS the first intravascular ultrasound studies in patients with CCSVI. That means that we entered with the Doppler into the veins of MS patients and showed that there are more abnormalities than we see with the so-called gold standard catheter venography.
Many people here on the committee, and in general, have said that catheter venography is the gold standard. However, we are saying that if you do even more sensitive tests than catheter venography, such as intravascular ultrasound, you will see more.
My point is that because of the controversy that has been created and because of the tendency now to report CCSVI presence of zero, although 30 to 40 per cent of patients may be suffering with some grade of severity of their vein stenosis, I think we should assess these problems with more than one non-invasive imaging test.
Senator Eggleton: I am glad the clinical trials are getting under way here in Canada, because obviously there are some unanswered questions and doubts that need to be responded to. Hopefully those studies will help clarify a number of issues.
Dr. Laupacis, you said, in summary, that the majority of patients suffer no significant side effects from venoplasty. You said, however, that rarely there can be severe side effects, which can be fatal. During questioning by Senator Cordy, you mentioned that perhaps we are talking between 1 to 2 per cent.
The committee previously heard about some of the drugs that are prescribed for MS patients. We were also told about severe side effects with respect to those drugs, and some fatalities as well. How does this procedure compare to the drug problems that may occur, in terms of side effects, for a number of people?
Dr. Laupacis: My main comment would be that the difference between what we know about the drugs and what we know about venoplasty for CCSVI is that the drugs have been submitted to high-quality randomized trials, many times, with a couple thousand patients. There is no question that the drugs cause serious side effects. However, we know what the benefits of the drugs are, from randomized trials.
My summary of the evidence from the drugs is that none of them are a home run; none of them cure disease, but they do appear, in a subset of patients — particularly patients with relapsing-remitting disease — to provide some benefit and quality of life.
My response would be that if I knew about the side effects of the drugs and had no idea about the benefits of the drugs, I would also be saying the drugs should not be provided by the publicly funded health care system. I think where we are at now with the drugs is that we do know the benefits and risks, and patients can make their own minds up about whether they wish to take the drugs, given what we know about their benefits and side effects.
Senator Eggleton: Your closing comments seemed to indicate that you are rather negative about the possibility of this endovascular treatment for CCSVI. Are you still open-minded about this or have you decided that there will not be any great value to this particular procedure?
Dr. Laupacis: If you look at material I have written, I was calling for randomized trials about two to three years ago. I have been in the health care system for 25 to 30 years. I have seen things that we really hoped would work be just as good as we thought they would be, and I have seen things that we thought would work turn out to do more harm than their benefits.
I am a strong believer in the need for evidence before introducing treatment, both for patients and also, frankly, for our health care system, which is pretty strained. I would be delighted if the randomized trials showed a benefit of the treatment, and I have been at this long enough to know that often the results surprise us.
Senator Eggleton: Perhaps Dr. Zivadinov might have a further comment on that.
I would also like to know the following: We are talking about starting these trials here. Surely there have been trials in other parts of the world. Can you enlighten us in that regard?
Dr. Laupacis: Actually, there have not. As I said, there are six randomized trials under way in the world that I am aware of. Dr. Zamboni is involved in one of them, which is the largest trial, over 600 patients in Italy. This is just getting under way. There have been some trials under way in the U.S. for quite a while, and they have obviously not come to a conclusion. There are no randomized trials of treatment for CCSVI reported in the world today.
Dr. Zivadinov: Many of you may know that in Buffalo we did two trials. One was a trial with Professor Zamboni, which was published this year — this was not a randomized trial — in which we evaluated 15 patients, 7 as a delayed arm and 8 as an immediate arm. We saw some small benefits, but clearly it was not a randomized trial.
As a consequence of that, we embarked on a study called PREMiSe. This is a prospective, randomized, placebo- controlled trial for MS. Thirty patients have been enrolled in that study, ten patients in phase I, to test the safety and eligibility of the procedure; and then twenty patients have been randomized to the sham, which is the placebo or treatment arm. They have been followed for six months, with a vast range of assessments at one, three and six months. These data have been logged. They are under statistical analysis and will probably be known soon. I think this is the first placebo-controlled randomized trial that has been done.
I would like to bring to the attention of this committee a couple of important points regarding treatment outcomes. The studies that have been done up to today looked at self-reported quality measurements of the patients: "I feel better,'' "I do not feel better.'' When we talk about MS clinical trials — and I have been involved for more than 15 years in doing MS clinical trials and I am a recognized expert in doing MRI readings for the biggest phase III trials in the world — you need to have objective measures that will determine whether this treatment can decrease the number of relapses in MS and the number of new T2 lesions and Gad-enhancing lesions, and whether it can promote quality of life. That is what we collected in our study.
In my opinion, as I mentioned here, it is a little premature to organize the studies based on 600 or 700 patients or 1,000 patients when we do not know, in smaller placebo-controlled trials, 100 to 200 people, which are called phase I/II studies, whether there is clearly a positive sign to conduct larger randomized control trials.
Let us not forget that in any drug development, there are certain steps that you must follow. After there has been some positive sign — which I think there was, both from the patient self-reports and from open-label studies that have been done — you need to begin with phase I/II randomized controlled trials; and then, based on these results, power the studies to conduct.
Maybe through my words you did not grasp enough, but I was referring to the fact that there are treatment outcomes specific to MS — clinical MRI, quality of life — but what about treatment outcomes specific to CCSVI that might be a decrease of headaches, fatigue, and sleep disturbances? Should we create treatment outcomes to be used in these studies that will evaluate this? Let us say you do surgery on a patient with Parkinson's disease. Maybe he will improve in terms of fatigue, headaches and sleep disturbances. Therefore, I think we are really talking about two types of clinical outcomes here. One is related to MS and the other in general to CCSVI.
The Chair: Thank you.
I see Dr. Zamboni has just arrived so, as per agreement, we will turn to him. When he has completed his remarks, I will go to Senator Cordy first. She must limit her questions because I want to get to our longer list. Then I will return to the list as I have it and continue with the senators who have not asked questions.
Is that acceptable to you, colleagues?
Hon. Senators: Agreed.
The Chair: Dr. Zamboni, can you hear me?
Dr. Paolo Zamboni, Director, Vascular Diseases Center, University of Ferrara, Italy: Yes. Thank you. I am sorry.
The Chair: We know you have had a long journey just to try to get to a site today where you could join us. We thank you very much for an extraordinary effort on your behalf to be able to be with us.
As you know, we have two other witnesses with us who have presented and we have had some questioning. We agreed that once you arrived, we would turn to you to make your presentation. We have copies of the presentation that you provided. Therefore, I would now like to turn to you to present.
Dr. Zamboni: Thank you very much. I tried to focus some points. However, in my opinion, it is very important to encourage further studies on CCSVI pathology. One of the points is that there is someone who questions the existence of stenosis or significant stenosis in veins.
However, in my opinion, the benchmark in medicine is still histology and pathology, so we have now two different studies. The former was of gross anatomy done in Cleveland, Ohio, showing clearly that there is in people who die with MS a significant number of intraluminal obstacles found, macroscopically, in their jugular veins with respect to controls. The latter, based on histology, clearly shows us that there is a marker in the vein wall that is tied with type III collagen that is much more represented in people with CCSVI with respect to specimens coming from people without problem of CCSVI.
This is a very important point. Also, the last study clearly showed that there is no T lymphocyte infiltration in the jugular wall, so it cannot be an epiphenomenon of autoimmune reaction linked to MS.
However, this kind of venous malformation seems to be completely independent. The inflammatory markers are equally distributed in tissue coming from CCSVI and in tissue coming from controls.
Also, science is increasing evidence of genetic markers. There is a study showing clearly that on chromosome 6, very close to the HLA loci showing susceptibility to MS, there are a number of mutations and the number of mutations is linearly related to the chance of developing malformation in the veins. This is very interesting because also shows us that HLA genes are not linked exclusively to immunity but also to angiogenesis and to several other regulatory functions.
There is a study coming from Buffalo — a very large one — showing specific environmental factors linked to CCSVI. They found clearly the presence of heart disease, especially heart murmurs, stories of infection and irritable bowel syndrome linked to the presence of CCSVI.
Thus, there is a lot of accumulating evidence showing how CCSVI is something to be inserted in the current nosography in medicine.
Showing the epidemiology, one of the major problems is linked to Doppler sonography because our initial proposal to establish criteria based on quality Doppler sonography subsequently demonstrated some problems. There are a lot of confirmatory but also not confirmatory studies linked with the operator dependency and the training dependency of this kind of system.
I think that now the majority of people who are interested in CCSVI actually are more oriented in considering multi- modalities for diagnosis of CCSVI, including Doppler, MRV, and venography.
What I show also is something related, for example, to the recent COSMO study. It is a very large blinded study by using ultrasound and showing no CCSVI in MS and normal people with very different rates with respect to what is normally published.
The problem is that 90 per cent of CCSVI recording found at the peripheral centres were cancelled at the central level by three independent lectures. Therefore, this kind of study does not replicate our seminal study, because we found CCSVI by comparing colour Doppler and catheter venography. The latter gold standard technique was in agreement with Doppler sonography. It shows both a hemodynamic problem and morphological problem.
In this COSMO study, we have colour Doppler performed blinded at the peripheral level, not versus venography but versus central lectures. Ninety per cent of false positives indicated our methodology was not followed or probably our methodology is not reproducible, but this did not prove the absence of CCSVI. However, there are many other studies that show significant CCSVI prevalence in MS and good reproducibility of Doppler when proper attention to sonographer training was given.
We propose a more objective, non-invasive, cost-effective system for screening CCSVI. This system needs to ameliorate the evidence by using a multi-centre trial. This kind of system is a cervical plethysmography system capable to detect the venous outflow by changing posture. It is a very objective, simple method and really cost effective with a concordant rate with other methodologies of 84 per cent. The Italian Ministry of Health funded a further study to verify the potentiality and reproducibility of cervical plethysmography in CCSVI diagnosis versus MRV and colour Doppler in a multi-centric fashion.
Catheter venography is of course invasive and is probably not the gold standard, but it is the best we have now. A study by using catheter venography clearly shows a rate often greater than 90 per cent of CCSVI prevalence in MS. Studies were published from eight different countries. It is very impressive the number of abnormalities seen by catheter venography. It is probably a more objective although debatable system.
MRV is non-invasive but is unfortunately a low-sensitivity system. Now it seems to be more useful, not in imaging but in flow detection. It is very interesting because it is an objective measurement by two-dimensional magnetic resonance imaging and flow measurement. Flow measurement especially seems to be a very sensitive system to elucidate the presence of CCSVI. I think a good strategy could be to use screening like cervical plethysmography and, after that, to confirm CCSVI by using multi-modalities, MRV, colour Doppler and also catheter venography just in case. This could be the future agenda in CCSVI diagnosis. Cervical plethysmography is a very promising technique and also gives us the opportunity to measure something that can be corrected by surgery or endovascular procedure and can be monitored easily in the future.
The last step of a national strategy is to properly investigate the safety and the effectiveness of the CCSVI treatment. In my opinion, we have, of course, very little data in this field because we have simple observational or case controlled studies, very limited in number. Now we have four ongoing or concluded double blinded clinical trials. One is PREMiSe, and that probably would be mentioned by Dr. Zivadinov. Now we are recruiting patients in a very large double blinded controlled study in Italy, completely funded with public funds. This study has a strong methodology because we objectively investigate the physical performance and also the mental performance of people at baseline and along the follow-up.
There are also other studies with this kind of design and we think this is for sure the path to follow in order to accumulate evidence about the possibility to improve the life condition of MS sufferers by adding also a solution to the venous problem.
There is also increasing evidence that these kinds of procedures may change something in brain pathophysiology, especially in brain perfusion and in cerebrospinal fluid flow. These are important points, but I think that Dr. Zivadinov is probably the most competent investigator to refer to regarding this emerging evidence.
Thank you very much.
The Chair: Thank you very much, Dr. Zamboni.
As per our agreement, I will get Senator Cordy to ask a key question, and then I will move to our colleagues and come back to her at the end if she has more questions.
Senator Cordy: Dr. Zamboni, there has been a lot of resistance to your theory. Could you briefly tell us about that and who leads this resistance? Secondly, at our last meeting of this committee dealing with Bill S-204, we talked about the Comi study funded by the MS society of Italy. I know that you opted out of that study. You left that study, and I wondered if you could give us your reasons for not being part of that study.
Dr. Zamboni: Regarding the second question, I decided to abandon the committee because there was no agreement between the researchers about the training of the people chosen for investigating the MS and the other controls. I asked simply to train the people because the main investigators were also not very expert in this kind of colour Doppler investigation, but there was no possibility to change the design of Comi and of our national MS society. I was very disappointed about that and also very sorry, but there was no possibility to change the decision to be the main trainer of the investigators.
I was also present at the initial training sessions, and I was completely not in agreement with the concept and the system of interpretation of the colour Doppler findings. Therefore, there was no agreement between me and between the main sonographers of this kind of study about the interpretation of the findings, and this is very clearly depicted in a recent statement of a European neurosonology society where their interpretation of duplex findings in investigating CCSVI is completely different from what was proposed by me. For instance, my proposal was in agreement with the experts of seven different international vascular societies who participated in a consensus conference.
I think that this is a major controversial point because duplex probably is not the best system to investigate people with MS in order to collect reliable epidemiological data because it is operator and training dependent. This is, to answer the first question, probably the main point of the controversy, namely, that duplex is not a good system. There are variable and controversial results, and this obviously shadows the presence of CCSVI in MS or not.
The Chair: Thank you very much.
I will now turn to my list, and we will start with Senator Seidman to, be followed by Senator Merchant.
Senator Seidman: Thank you so much to all of you for appearing before us today. Your knowledge and experience is invaluable to us as we study this proposed legislation.
When Senator Cordy testified before this committee, she told us that about 75,000 Canadians live with multiple sclerosis and that each year an additional 1,000 are diagnosed. This is an extremely cruel disease that disproportionately affects Canadians, and we all want the same thing — the best scientific evidence upon which medical decisions can be based. This is what Canadians expect and what they deserve.
In Canada, we are about to begin the recruitment of patients to participate in a phase I/II controlled double blinded clinical trial to test the safety and efficacy of CCSVI. This clinical trial will involve 100 MS patients with the intention to carry out the trial in four different sites. Therefore, as we move forward with our own trials in Canada, there continue to be a number of voices of caution raised both internationally and here at home.
For example, the Multiple Sclerosis International Federation recently released this statement:
The risks and benefits of procedures to treat CCSVI have not been established by properly controlled clinical trials. Unless and until strong supportive evidence is produced, and until the risks of treatment are thoroughly assessed, any procedures to mechanically correct the purported problem outside of a clinical trial are not recommended.
I would appreciate your comments on this statement. More specifically, what role do clinical trials play in clarifying our understanding and in ultimately giving MS patients the answers they deserve? For all of us, and our listening audience, who may not fully understand the scientific credentials of clinical trials, might you explain why you both stress the critical importance of doing clinical trials? I am referring here to Dr. Zivadinov and Dr. Laupacis whom we both heard before Dr. Zamboni arrived. In fact, in your presentation, Dr. Zivadinov, you stated that CCSVI intervention should be restricted to blinded, randomized and controlled clinical trials that will establish the safety and efficacy of these procedures, and you went on and said that given the current state of knowledge, there is no role for endovascular treatment of CCSVI in MS patients outside of approved clinical trials.
In this very long-winded way, I am asking you to help everyone, all of us here and our listeners, understand the importance of clinical trials. What do clinical trials offer us? What is the methodology that clinical trials offer us that is different than anything else, and why can we expect the kind of results we are all hoping for?
The Chair: I will go to Dr. Zivadinov and then to Dr. Laupacis.
That question could be answered in a three-hour seminar. However, I would ask you both to constrain the extent of the answer but still try to convey the correct answer.
Dr. Zivadinov: In a blind treatment trial placebo control group, it is state-of-the-art how we determine the efficacy of any drug or procedure and whether it is good. In terms of MS, primary, secondary and tertiary end-points have been established in control randomized trials. Usually the primary end-points are delay of disability over two years. Second end-points are the number of relapses that occur over two years, or the number of new T2 Gadolineum-enhancing lesions. Another very important end-point in clinical trials in MS is development of brain atrophy. These four outcomes are a kind of essence of conducting clinical trials in MS.
As you probably know from what has been said today and in the past, in not one study on CCSVI evaluated until today, except maybe our study with Professor Zamboni, for which these end-points were not randomized and blinded, was quality of life assessed, which, I concur, is a very important point for MS patients. However, it is only a tertiary end-point in clinical trials. We must understand whether CCSVI is a treatment that will help disease modification or is it a symptomatology treatment for headache, fatigue, sleep disturbances, et cetera. Once we determine that, we need to understand whether the risk is worthy of the treatment to improve the headache, fatigue, sleep disturbances for quality of life, if it has no effect on disease modification. This is the essence of the problem.
Dr. Laupacis: I would address the question in two ways. The first one is: Why do a randomized trial? You very eloquently described the very dire situation in which many patients with multiple sclerosis find themselves and their families. There is, therefore, an understandable wish on the part of patients and the physicians that treatment them when they get a treatment to think and hope it will work. Therefore, there is a placebo effect, not only in the treatment of multiple sclerosis but also in almost any disorder. If a patient gets something that they think will work, a few of them, on average, feel that it does work. If you gave them a placebo, or in this case a sham venoplasty, you might show the same benefit.
The second thing with multiple sclerosis with the subset that has relapsing remitting disease is that some of the patients after a relapse will get better spontaneously. If they had a venoplasty around the time they were spontaneously getting better, they might think it was due to the venoplasty. Obviously, that is not an issue with people with progressive MS.
To summarize, in terms of knowing for sure whether any benefit that is reported is due to the treatment, you need to have a randomized trial. Some people see that as a way of slowing down access to the CCSVI treatment. However, if well done randomized trials show that venoplasty actually improves any of the outcomes that Dr. Zivadinov talked about, whether quality of life or MRI, then that would markedly increase the chance that people would say, as he just said, that patients should be able to weigh the risks and benefits and decide whether they want the treatment.
I do not think we should be Canadian-centric. If Dr. Zamboni and his colleagues in two years report their Italian study before ours in Canada is done, we should accept all high quality evidence from around the world. One great thing would be if the people who are doing the various trials would collect information on the same outcome measures so that the results of those trials can then be combined when they are done. My final comment is that almost never does one trial answer all questions that one wants to have answered. Being able to combine the results of the studies, once they are reported, would be incredibly helpful.
The Chair: Dr. Zamboni, do you have anything to add to the comments on this specific question?
Dr. Zamboni: Yes. The last point is very important because probably in the trials we needed to use comparable measures. For instance, Dr. Zivadinov mentioned T1 and T2 active lesions or the number and volume of new T2 lesions by MRI. This is clearly something that can be done in a trial. Also, we developed an interesting system to get a picture of a disease. It is based on five physical functions that can be measured objectively by instrument. This is a very important methodology that can be shared with other clinical trials. This is very important because it has to compare by meta-analytic system the different results in the different double blinded, randomized control trials.
Senator Merchant: Dr. Zivadinov, is there a difference in the results of studies depending on whether the study is done by a vascular specialist or by a neurologist?
Dr. Zivadinov: There is a difference. Most studies done by neurologists have been negative so far. Most studies done by the vascular surgeons have been positive so far. You can look at that in a different way: Where the studies have been published, most of the radiological vascular journals are reporting positive findings and most of the neurological journals are reporting negative findings. Why is that? I do not know, but I strongly believe that every scientist and researcher is truly reporting the findings that they collect and that there is no bias at any level.
Whether vascular surgeons, as Professor Zamboni previously mentioned, are more familiar with the vascular system may be one of the reasons. That is why they are finding more objective anomalies than those who probably did not look at that before, like the neurologists, especially with respect to the venous system. As you know, before we started this work, we felt that it was very important to contact Professor Zamboni. We went through numerous training sessions. In some media coverage, I was categorized as being Zamboni-biased. I thought it was important to learn what other people know, and then go forward and create a large study to apply all these techniques in a multi-modal way.
One more thing: If CCSVI is true, there is no way that it will not be confirmed because the amount of information coming from 15 different modalities is pointing to the same point. That is what you want if the condition is real. In our hands, outcomes that we are using are pointing to the existence of this condition. Now, whether it is severe or mild depends on the different subjects you are looking at, but it probably exists in many people.
Senator Merchant: Dr. Zamboni, Dr. Laupacis said something before you were here. He said that after venoplasty, the narrowing reoccurs in the months after the treatment in a considerable number of patients, between 30 and 45 per cent. This is an important limitation to the procedure.
Dr. Zamboni: This is true. In our first study, we tried to investigate the possibility of restoring the flow by a simple, conservative and safe methodology, which is venous angioplasty by balloon. Probably there are some presentations on the CCSVI condition where this kind of very simple procedure probably does not work properly, leading to the recurrence of CCSVI. In the case of future randomized control trials, my recommendation would be to understand and to subdivide in the follow-up the clinical results in people who had effective therapy for the CCSVI condition and people who did not have effective therapy for the condition. This is very important. Really, we are using a very simple device, and in some presentations of the condition it is not good enough to restore the flow or to fix the flow coming from the brain. We need to know exactly what the proportion is, because this was never done, and the proper tool again is to perform randomized control clinical trials.
The Chair: Thank you very much.
Senator Seth: Thank you, doctors. Such great knowledge has been given.
I must say that Senator Seidman has already asked such a vast question. MS is such a debilitating, progressive disease. The patients do suffer, and I think we need the clinical trial that you are going through so that we can achieve a good outcome and our patients can lead a normal life.
My question is for Dr. Laupacis. You have been at St. Michael's Hospital and you are on the Canadian Institutes of Health Research expert panel. You have concluded that there is a positive association between CCSVI and MS, but your results did not allow a definite conclusion to be reached. Please explain why not.
Dr. Laupacis: Let me make one correction at the beginning. Our research was funded by the Canadian Institute of Health Research, but I am not and have never been a member of the CIHR expert panel. The summaries of the world literature that my group does are forwarded to the expert panel, as well as other people, but I am not and never have been a member of that expert panel.
To answer the question, we did find when we looked at all of the 11 studies that many more studies found more CCSVI in people with multiple sclerosis than in healthy controls, and that is why we said that when you look at the average studies, or if you average the studies, there is more CCSVI in people with MS, but as I said, Dr. Zamboni's initial study found CCSVI in 100 per cent of the patients with MS and zero per cent of healthy controls. We had another study that found no CCSVI in any patients. Dr. Zivadinov, who trained with Dr. Zamboni, found results in the middle, around 56 per cent of patients with MS had CCSVI and around 30 per cent of people with healthy controls had CCSVI. When you have that degree of variability in the results of a test, it seems to me that we cannot be certain how to interpret the results. That is why our group concluded that, at least looking at ultrasound, we still do not know whether CCSVI is truly associated with MS and, in particular, what are the things about the ultrasound that make the results from one study to another so different.
Senator Seth: Dr. Zamboni, you have been doing quite extensive research. What have been the biggest obstacles to your research?
Dr. Zamboni: The main obstacle was to project the randomized control trial because, after our first observational study, we immediately asked to move forward by a randomized control trial, but this is a very expensive kind of study. We do not have, of course, something like a drug company or a device company on our back to push this kind of study or to fund it. It was very difficult to convince the political level and then partners to perform this study. It was a very long process. Also, to have a shared protocol by the interdisciplinary steering committee was a very long process, because we have neurologists, neuroradiologists, interventional radiologists and vascular surgeons, so different minds with a different way of thinking and way of describing the right protocol. It was a very long and very tough agreement to reach a shared protocol between the members of the steering committee.
Now this work is finished, and I look with faith to the possibility of performing this kind of study, because I believe that may be the answer to what we are looking for.
Senator Martin: I am keenly interested in looking at the risk factor and the percentages. From my own experience with my father, he fell into that small category of individuals who were always subject to these risks. Even if it is 1 or 2 per cent, I am so mindful of the impact, especially if it is so fatal. My question is regarding the process that was followed in Canada for the clinical trials that will be undertaken and how important the peer review process would be.
Dr. Zivadinov, I know that you were a member of the peer review selection committee. Would you speak about the thoughtfulness of that process and what you selected? You have all talked today about the importance of same outcome measures and how there is such disparity. Even within Italy, Dr. Zamboni opted out of the study by the MS society of Italy. These disparities are there. Would you speak about the peer-review process and what we have selected, and certain guarantees that our listening public, including ourselves, can have that what we are doing will be very important for our understanding?
Dr. Zivadinov: I was one of the eight members, I think, on the panel of CIHR who evaluated different proposals that have been sent. The proposal by British Columbia was one of the best because it was a meticulously planned training period for performing this type of procedure. It had a very good basis for diagnostics of CCSVI, which was done through the first funded study by the MS Society of Canada. They planned very well both the treatment arms, as well as treatment outcomes, in a detailed and standardized way, to be applied. It is also a multi-centre study, and it is important to show that this type of procedure can be done at different sites and not just in British Columbia. The investigators are well known in the field of multiple sclerosis. I think they assembled a great team, together with vascular surgeons.
One thing that Dr. Zamboni mentioned — with which I completely agree and which is why Buffalo produced so many studies — is that we are neurologists. I am in the Department of Neurology, and I definitely advise to all those people who are studying CCSVI and who are on the vascular side of the story that they cannot do it alone. They need to the participation of the neurologists who are experts in this disease. In our case, we needed the experts on the vascular side. That was something that was found in our centre, clearly, in Buffalo, and we had great teamwork.
To go back to this proposal, an important team has been awarded this study and I hope they will be able to answer some important questions.
Senator Martin: All of you have talked about how important it is to move toward standardization, harmonization and consensus, because it is a global effort and arena, where there are so many jurisdictions undertaking their own trials. For Canada, would you say that going forward we have enough communication and exchange of information such that we will be looking at greater standardization and harmonization?
The Chair: I will remind our committee that a large part of that has been answered, so if you will focus on it. All speakers, especially Dr. Zamboni, talked about the need to bring it together.
I wonder, Dr. Zivadinov, if you could pull that together.
Dr. Zivadinov: As probably many MS patients are watching us today, it is important to give the message that I repeated over and over. While patients might be impatient to get the treatment immediately, I would agree with my colleagues that we need to show whether the treatment is appropriate and effective. That is why we need to do this trial and why we need to wait until these trials are done. The last thing everyone in this room wants is to learn that the treatment might be harmful, at any level, from side effects, to serious adverse events, to treatment outcomes.
Senator Dyck: Thank you, gentlemen, for your wonderful, very scientific presentations this morning. It shows that we really are in the infancy stage of understanding the role of CCSVI in MS. I want to focus my questions on the bill before us today, particularly with regard to two aspects of the bill.
Dr. Zivadinov, you mentioned that MS patients are watching us. It is clear that MS patients have gone for CCSVI treatment, and some of them are being refused treatment. The bill proposes that we ensure that there is follow-up care for persons who seek treatment or who have had treatment for CCSVI, in or outside of Canada.
My question to all of our presenters this morning is the following: Do you agree that that should be set up? The second part is whether you agree that we need to have a national registry that tracks individuals who have received this, in the event that there are adverse side effects and those kinds of things.
Dr. Zivadinov: I completely agree with the bill. I think it is not ethical, first of all, that assessment of the treatment outcome is refused or rejected.
Second, absolutely, you need a national registry. You need to see how these patients are doing. In short, absolutely yes to both questions.
Dr. Laupacis: I, for sure, agree that it is totally inappropriate for people in the health care system not to see patients who have had the procedure elsewhere and not to provide them care. I would hope that we do not need a national strategy for that but that the provincial health care systems and the physicians who work in them will simply do that.
A registry would obviously provide useful information, particularly about serious long-term side effects. As I said before, I am skeptical that a registry will provide much information about the benefits of treatment, and I think for that we need a randomized trial. Here I have on my hat as a person who is a general internist and sees people with cystic fibrosis and any number of diseases. I think a registry will cost a lot of money. We need to carefully think about, if we put a registry together, what information will be collected and how we can ensure that we collect it reliably. I am not sure it is quite that straightforward, and we need to think about the equity for many patients with other diseases as well.
Dr. Zamboni: I think that, in general, the registry is a very good tool. However, in this case I think it cannot help very much because we do not know exactly what are the procedures performed outside. Sometimes I look to reports and note that the azygous vein, for instance, is never treated. However, in my experience, with this vessel there are a lot of abnormalities that need to be treated, especially for motor disability.
The registry is very good if you have a shared protocol of treatment outside. Otherwise, I think in this phase it is better to move rapidly to RCT.
Senator Enverga: Thank you to all our presenters today. I appreciate your coming here. I know this topic is getting some international attention, and it is so important for all our MS friends out there.
A few months ago, the U.S. Food and Drug Administration issued an alert about the potential dangers of CCSVI. Dr. Siskin, an expert from Albany, recently said:
Although the studies published to date seem to provide the necessary support for the off-label use of these devices in clinic practice, they do not adequately answer the safety and efficacy concerns raised by the FDA and neurology community.
Could you please comment on the FDA's warning and on Dr. Siskin's recommendation?
Dr. Laupacis: My interpretation of what the FDA said is that there are some rare but serious side effects of venoplasty, and I think we all agree with that. I would agree with Dr. Zivadinov that this procedure should be done as part of randomized trials.
Dr. Zivadinov: I agree. I think the FDA had to come in advance and say you cannot put the devices that are not approved for this type of pathology, and I think it was the right thing to do.
It will be very helpful that there will be more order after this decision, but I do not think that the decision will in any way decrease the ability to conduct trials on CCSVI. As a matter of fact, just to give you an idea, when we have any investigational drug we always apply to FDA for an investigational new drug, and whether we get approval depends on when, why and how, so this is nothing strange.
Dr. Zamboni: I believe that the FDA takes into account more than 20,000 procedures that were performed with devices that were sold in the absence of any safety study sponsored by the companies. Therefore, the warning is more to the company because they sell devices and do not perform any kind of separate study and do not pay for and support trials to assess the safety of their devices. In my opinion, the warning is not for the investigators; it is for the companies.
Senator Enverga: Do you have a plan to work with the FDA at this point?
Dr. Zivadinov: We are finishing our study. It was an early design, but we definitely registered our study with the ClinicalTrials.gov.
Senator Eggleton: My question for Dr. Zamboni is a follow-up to what Senator Merchant asked about earlier. As a preamble, we have to bear in mind that while these clinical trials are going on people will still seek this procedure. People with MS cannot get this procedure done in Canada and they are going abroad to get it, and we are hearing a lot of stories about that.
Senator Merchant mentioned the statistic that after venoplasty the narrowing recurs in the months after treatment in between 30 and 40 per cent of patients.
What can be done about that? People get their hopes up and go and get the procedure done. Many of them come back talking about the wonderful new abilities they have to do things. They are so enthusiastic, and then this narrowing can recur in a number of cases.
What can be done about it? Does it mean a further procedure or does more discretion have to be used in who gets the procedure to start with? Maybe some people are getting it who should not be getting it.
What do you suggest? People will try to get the procedure even while we are waiting for the clinical trials to be concluded.
Dr. Zamboni: We watch our cases of reoccurrences very carefully. We discovered that there are two conditions that can be preoperatively detected with adequate and deeper investigation that clearly predict the best candidates for venous angioplasty with respect to people who need other kinds of treatment for CCSVI.
For instance, there are two frequent conditions linked with ineffective treatment — because mostly it is not recurrence; it is simply ineffective treatment; the balloon is not enough. One condition is an entrapment and compression of the jugular vein by muscles in the neck, especially the digastric and the omohyoid muscles. That can be temporarily solved by the balloon angioplasty, but it recurs because the abnormal anatomical relationship between the muscle and the vein is not permanently solved.
The second is a very long intraluminal obstructive septum that cannot be disrupted by the inflation of a balloon and simply recurs after the vein regains the previous cross-sectional area. This condition can be seen before the treatment, and someone who performs careful preoperative assessment can see it and give correct indications to people who want this kind of treatment.
Dr. Zivadinov: It is critical to establish monitoring screening tools after the treatment to determine whether the restenosis recurs. These must not be invasive because you will not put your patient through catheter venography every month as it is, we all agree, certainly not a simple procedure.
The use of Doppler in trained hands is a very good tool, but yes, the restenosis occurs. We have no experience with reapplying the procedure, but from what I read and review I think it is very dangerous and I do not recommend a reopening if the first treatment did not work, because you could even collapse the vein with a second procedure. From what I understand, most of the safety issues that happened in open label are from repetition of the procedure.
Senator Eggleton: I have a specific question about something I need education on. We are talking about endovascular treatment, but my impression is venoplasty and stenting are both that kind of treatment. Are all the statistics and information we are talking about completely with regard to venoplasty as opposed to stenting?
Dr. Zivadinov: That is an excellent question. I would say that if you exclude stents, the prevalence of serious adverse events would dramatically decrease, because most of the serious adverse events have been linked to the use of them. From the beginning neither Dr. Zamboni nor us have recommended the use of stents for this condition.
The problem with the venoplasty is obviously, as has been said, the atrial fibrillation and the non-efficacy and repeat of restenosis. The prevalence is probably much lower without stents.
I wish to make another important point. The arteries should always be open to bring blood to the brain, but with veins it is a different condition. When you are in an upright position, the jugular veins are closed because the vertebral system is draining mostly the brain. Therefore, by artificially changing the status of the vein, not in a physiological manner by using stents, you are altering a normal condition. Why should someone have an open jugular vein in an upright position? There is more to learn about how the treatment should be done.
The Chair: On behalf of the committee, I wish to say that it is remarkable for us to have such a level of expertise covering the various ranges of such a new and emerging concept and the potential application of the concept and its implications.
You have been exceedingly helpful in explaining to our committee the serious and complex issues that go into the medical side of what is actually going on. You have given us the ability to interpret your remarks in a way that will be helpful to us in dealing with this question.
I was impressed by the fact that all three of you stressed the critical importance of the double-blinded clinical trial study with clearly defined measures and, hopefully, some international consensus on what to look for and to contribute, as Senator Martin has suggested. Perhaps a conclusion can be reached more quickly than if we have a series of studies.
I also thought it was important that you raised the issue of risk factor. We have been dealing with this in respect of the drug side and have heard about numerous people who died from the use of Tsyabri, for example. It is clearly important to identify the risk factor — how many serious adverse effects occur per patient treated at the same level.
It has come up several times, so I looked into the details of the drug. Tsyabri apparently is applied to MS, Crohn's disease and some other areas. In all patients studied, for those who have all three conditions the risk ratio is 1.1 per cent. That falls within the range you were discussing. It was helpful to us that you made the point that it is the risk factor and not the number of events that is important. It is how you interpret those risks against the issue.
Dr. Zamboni, I cannot tell you how much our committee appreciates the degree of effort you took on a holiday in your country to travel considerable distance to appear as a witness today. Some of us think that auto travel in Italy is not necessarily the easiest thing to achieve and on holiday it is probably extra special. We thank you not only as the person whose name is associated with the issue that we are studying but also for making such an extraordinary effort.
Dr. Laupacis, it was difficult for you to be available for this meeting. Fortunately, you were able to appear and to stay throughout; it is appreciated.
Dr. Zivadinov, you drove from Buffalo to Canada and took a flight to get here this morning.
I do not think it is possible for me, on behalf of the committee, to thank all of you enough for being here. You have contributed enormously to our understanding of the issue.
(The committee adjourned.)