Overhauls are atypical in medicine. Reforms are not sweeping, but gradual consensus-building efforts. But if there is a landmark study with the ability to shake things up like they haven’t been shook in 20 years, MR CLEAN is it.
MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) was the first recent study with modern techniques to show a benefit for catheter-based treatments for acute stroke patients. The data confirm the practice of rapidly evaluating and treating the severe stroke patients with techniques to remove the thrombus from the blood vessel, and should allow advances in development of systems of care around these most severe of strokes.
Here, Practical Neurology™ speaks with Yvo Roos, MD, PhD, a co-principal investigator, to learn more about the study.
Prior to the release of the study, can you give us a little bit of background on the stroke field and some of the attitudes towards this procedure? The SYNTHESIS Extension Trial, IMS-III and MR RESCUE really didn’t show any benefit with endovascular therapy in addition to or instead of TPA.
Dr. Roos: I think when we look back, several studies in the last decade had shown already that with the catheter treatments, the device treatments, you could open up the arteries, you could open up the blood vessels and remove the clot in a higher percentage by using thrombolytic therapy, by dissolving the clot with medication. So, that had already been shown. And I think what we saw over the last decade was that there were many believers who said, well, the therapy that we need is a therapy that opens up the vessel and then that must be worthwhile for our patients. We saw that several centers already started using this as a routine treatment, although there was no proven clinical benefit. And then we had the three trials, which were published last year in the New England Journal of Medicine, which were for many people working in this field a real disappointment. They were neutral; they didn’t show any benefit in the clinical condition of the patients after three months.
Maybe we shouldn’t call it a disappointment, maybe that’s too strong, but let’s say that I think the three publications pointed us to an important idea: that we are not treating simple pipes in a house. We’re not working as plumbers, but we’re working with patients, and things in patients always work out a little bit different than they work out when you’re doing tubing, and that’s what we saw last year. And, of course, when we look back and we look at the differences between our own trial and the trials that were published last year, we can see that there are huge differences and we can understand why our trial is a positive trial and why the three others were neutral.
Do you think the MR CLEAN study eliminated the previous concerns?
Dr. Roos: As I said, there are differences between the studies. For instance, when you take a look at the previous studies, they were set up a couple of years ago and many of them used a very rigid study setup, which meant that only certain devices were allowed to be used; devices which were already there when the trials were being developed. And in the meantime there was a development in the stents that, for instance, was a huge improvement. Over the last decade we saw that the percentage of patients in which the blood vessel could be opened with catheter treatment was initially only 50 percent; it then raised to 80, 90 percent. So, there was indeed a quality improvement in the catheters that could be used.
And one of the big differences was that we used a very pragmatic design. We said when we were developing the trial we are going to use devices which are at that moment state of the art. We allowed that new devices could be introduced during the study setup and during the study. The only thing we said is that we wanted the devices to have an FDA approval or a CE mark, and we wanted the people who were working with the devices to demonstrate that they had experience working with such a device. They had to have already been treating at least five patients with devices like that before they could include patients in our study.
That was a huge difference, being pragmatic in our study setup against the more rigid setup in the older studies. When we designed the trial we said this is going to be a trial where most patients are treated with a mechanical thrombectomy removing the blood clot. And we thought when we designed the trial that only a minority of the patients would be treated with intra-arterial thrombolytic medication. That’s why when we were designing the trial, we said we want patients to be selected with a CT angiogram, and we want that before patients are randomized to the trial that the blood vessel is shown on the CTA. In the other trials patients could be included based on clinical signs and symptoms without a proven blocked vessel. So, the group we have in our study is, in fact, a selected patient group that could really benefit from endovascular treatment. That’s also a huge difference from the other studies.
And finally, when you look at the times between symptom onset and treatment, we see that we, although we are now very fast, and I think must be faster in the future, now we have shown that it’s clinically beneficial for the patients. But you see that in our trial on average, patients who are being treated earlier than they were in some of the other trials. And like we say always, “time is brain.” Treating patients earlier, the chance of a good recovery is higher.
What are your thoughts on where the results could be improved upon even further in future trials or even the real world clinical setting?
Dr. Roos: That’s a good question. The interesting thing is that when we presented our results last October in Istanbul at the World Stroke Conference, we heard after that that many ongoing trials were halted and planned an interim analysis earlier than expected because of our results. We had been told that already two of them have stated that they have also positive results. We haven’t seen the results actually and, we are waiting for those results to be presented, we understood, at the international stroke conference in February, in Nashville. We’re very anxious to see whether they show similar results to our trial. That would be great because if it’s true that there are already two other trials with positive results, I think that then we have three trials showing the same results and I think then it is clear that there is benefit for the patients, and there is no need to do other trials. But we have to wait.
Can you comment on the degree to which this population represented a real world setting despite being a rigorous RCT providing contemporary level 1 data?
Dr. Roos: I think that being a very pragmatic design, this is a real world study, and this is a very important issue here you’re focusing on. I think that’s very important. When you compare our study to the previous study, I think that you have to say it the other way around. For instance, when you take a look at the MR RESCUE trial, there was a patient selection based on MRI imaging, a very complex imaging procedure that can’t be done everywhere, and it takes time. When you take a look at our trial, because of its pragmatic design, this is something that can be done in every intervention center without any problem. So, these are real world results.
I think what we need to do, and I don’t know the exact situation in the United States, but something we have to do over here in the Netherlands is that we are now talking to our smaller community hospitals, and discussing whether they can do the CT angiograms or whether they will be sending just their patients to the intervention centers so that there the CTAs can be done.
I think that the best thing would be, if possible, to have the smaller hospitals, when they are still treating their patients with intravenous tPA, that they can also do the CT angiogram. They can then select the patients to be treated in the intervention center and then send them straight on after the initiation of the IV treatment to the intervention center. That’s the thing that we are working right on in the Netherlands, and I expect that similar things must be done in the United States.
What do you think will be the impact of the data regarding the increase in interventional procedures, and possibly even the interest in entering the neurointerventional specialties, where at least in America there aren’t too many docs right now in that specialty?
Dr. Roos: I think that there is going to be a huge change, and I think it will change everything. We have to be careful with that. We have to be sure that the patient must be treated initially with intravenous treatment. That’s for sure the first step; intravenous thrombolysis is the cornerstone. The first step we must take by treating patients with ischemic strokes, that’s clear. But after that, now we know that if a patient has a blocked vessel, and especially when the vessel is blocked in the distal carotid artery or proximal in the circulation of the brain, we know that in those patients intravenous thrombolytic treatment has a relatively low chance of opening up the vessel, and especially those are the patients which can hugely benefit from the endovascular treatments with the mechanical thrombectomy. We have to focus that those patients can be sent on and be treated as quickly as possible.
This will mean that there will have to be interventional centers [near] the intravenous centers. And there must be 24/7 doctors available who can do the procedure. Again, I don’t know the situation exactly in the United States, but I know that over here in the Netherlands that most of the doctors who are doing the procedure are radiologists—neuroradiologists, in fact—but we also had a neurosurgeon working and doing the interventions, and we had a neurologist doing the intervention.
I think that everybody who is dedicated to do this job and is working in the field of this kind of patient—a neurologist or neurosurgeon—that he or she can learn to do this procedure. And I know that in the United States there are even some cardiologists doing the intervention and, of course, they have huge experience working endovascularly with those patients with ischemic heart disease. I think when they are willing to take interest in patients with an ischemic stroke and to discuss their patients with a neurologist, and they are willing to learn the difference between the cerebral circulation and the cardiac circulation, there is nothing wrong with a cardiologist doing the procedure. I think it all has to do with the dedication of the doctor and the team.
In what ways might the data unify several specialties or even divide them?
Dr. Roos:What I’ve seen over here in the Netherlands is that there used to be some kind of wall between, for instance, interventional cardiology and interventional radiology. And, I am a neurologist myself, and my only thing is that I want the best care for my patients. And like I said before, I think that if every doctor that is willing to be trained to learn this procedure, and he or she is working together in a team, that would be great.
I’m hoping, but I don’t know what’s going to happen. I’m hoping that this will be a patient group where doctors can work together so it will not divide the groups but will bring them together. I think that’s really necessary, because even more important than in patients with ischemic heart disease, is the timing of the treatment. When we are talking about patients with ischemic heart diseases, timing is also crucial, let’s be clear about that. But the difference is in a cardiac patient, is that he or she has a larger or smaller infarction of the heart, which means in real life that the patient has more or less difficulty walking up the stairs, for instance.
When we’re talking about this patient group, the patients with the ischemic stroke, the difference can be whether a patient spends the rest of his life in a nursing home or he or she can go home and walk, talk, and be able to care for him or herself. That’s a huge difference that we can achieve with this treatment. So, I hope that doctors and nurses and institutions are going to work together, and develop regional protocols in how these patients can be treated as soon as possible. I think and I really hope that this is going to work.
Is there anything you wanted to add?
Dr. Roos: We find it also very important that we have shown that the treatment is not only working in a certain group of patients, it’s working in younger patients, and it’s working in older patients. It’s working in patients with a large clinical deficit coming into the hospital, but also working in patients with less clinical neurological deficit. It’s working in all the patients who have been predefined. We were interested in whether the treatment would do something. In the all the subgroups we predefined, it’s showing more or less the same results, it’s showing that it’s working, so that’s really, really important.
Yvo Roos, MD, PhD is a neurologist at Academic Medical Center in Amsterdam.