Acute Ischemic Stroke Treatment 2015 by Esteban Cheng-Ching, MD

Dr. Cheng: Hi, I’m Esteban Cheng-Ching. I’m a neurointerventionalist and stroke neurologist, with the Clinical Neuroscience Institute at Premier Health. I’m going to talk today about acute ischemic stroke treatment and focus on the acute part with emphasis on the endovascular treatment. Treatment of acute ischemic stroke has suffered significant changes over the past six months, which has created a shift in the paradigm of treatment, a change that hasn’t been seen over a decade. And we’re gonna talk about these changes and about the chronological evolution of acute ischemic stroke treatment.

I have nothing to disclose. 

When we talk about acute ischemic stroke, I divide the treatment or the focus on the therapy in three stages. The first one is acute therapy with reperfusion. That’s what I’m gonna focus today. The second stage is etiology workup and secondary prevention, as well as prevention of complications. And the third stage is the phase of rehabilitation. All these three phases tend to overlap. 

We’re gonna talk today again about, about acute therapy. Stroke’s an important disease. It’s the fourth leading cause of death in the US and approximately 795,000 strokes occur per year. As I mentioned, acute stroke therapy has evolved over time beginning in 1995 with intravenous tPA therapy within three hours, subsequently extending the time window to four and a half hours. And then, with intra-arterial therapy; subsequently, we have negative intra-arterial therapy trials that were published, which held that widespread treatment with this therapy. And in 2015, this year, we have publication of subsequent, successful intra-arterial trials. 

In 1995, the NINDS tPA trial was published in the New England Journal. This study was the first study demonstrating, effectiveness of intravenous tPA within three hours from the onset of symptoms. It showed that patients given this treatment were 30% more likely to have minimal or no disability at three months. However, three hours is a short window and many patients were not being treated. It is not until 2008 that we have the ECASS III study demonstrating that intravenous tPA is effective up to four and a half hours. This study showed favorable outcome in patients receiving tPA up to four and a half hours with no significant increased risk in this patient population. 

Even though we have up to four and a half hours for treatment, the sooner we given the treatment the better. This graph demonstrates an increased odds of favorable outcome the earlier the tPA is administered. And as time passes, the favorable outcome decreases. So the sooner we give this treatment, the better.

Even though tPA showed to be effective for the large population of patients with stroke, there are a subset of patients who do not benefit completely from tPA. Patients with large vessel occlusions represent about a third of the anterior circulation strokes. These are patients with occlusions of the intracranial ICA, the M1 segment of the MCA, and the basilar artery. These are large vessels that do not recanalize with tPA. They’re generally resistant to tPA. With reperfusion or recanalization rates of 25% or less, these patients are the ones who have the bigger strokes and the worst outcomes with increased rates of mortality ranging from 27% up to 90% depending on the vessel that is affected. Large vessel occlusions, as I said, are not completely recanalized with tPA so an additional treatment is probably indicated. 

This is an example. This is a 46-year-old woman who presented with right hemiparesis and aphasia. The angiogram on the left demonstrates an occlusion in the M1 segment of the MCA. This patient did not recanalize and after the occlusion evolved, the patient had a big stroke with significant impact on her outcome with serious disability.

So large vessel occlusion strokes are a serious condition. And, as I mentioned, tPA does not recanalize these vessels completely. Intra-arterial therapy may play a role. 

This treatment also have evolved over time. The first study was published in 1999 with the PROACT II trial. In the 2000s, multiple devices were developed for mechanical thrombectomy – the MERCI device, the Penumbra device. And multiple registries were being done at that time. But, randomized trials did not appear until 2013 with negative results in which impacted the field significantly. And as I mentioned before, it’s not until this year when new data appears supporting intra-arterial therapy for stroke.

So I’m gonna talk about the several trials in a chronologic order. PROACT II was published in 1999. This study included patients with acute MCA strokes who presented within six hours from the onset of symptoms. These patients were randomized through intra-arterial urokinase given over two hours, plus heparin, versus a group that received only heparin. And it demonstrated that at 90 days, a modified ranking score of 0 to 2, which means functional independence, was achieved in 40% of patients with Pro-urokinase group, or the intra-arterial group versus 25% in the control group. Unfortunately, a second study was required for this treatment to be approved by the FDA and this second study was nor performed so this treatment did not take off.

In subsequent years, multiple devices were developed for mechanical thrombectomy. In the figure above, we see the MERCI device, which is a corkscrew like device thatgets deployed within the clot and removes the clot. The second figure below demonstrates the Penumbra device, which is a catheter that aspirates the clot. And these two devices are meant to recanalize vessels and they showed to be successful. However, the – however, the rates of recanalization were not optimal. 

The technology continues to evolve. In 2015, we have stent retrievers, which are stents attached to a wire which when deployed within the clot achieve mechanical thrombectomy with recanalization in rates up to 80 and 90%. These devices have been available for the past few years and are currently used most widely for stroke treatment. However, the stent retrievers were not available widely for these studies that were published in 2013 that were negative. 

This is a case example of a patient treated with a stent retriever device. This patient presented with an NIH Stroke Scale of 20, meaning a significant neurological deficit with the other angiogram on the left demonstrating an occlusion in the M1 segment of the left MCA. This angiogram in the picture is before the stent retriever. And after the recanalization with the stent retriever, we see the significant, reperfusion with all the vessels of the MCA appearing in the picture. This patient had improvement of NIH – from an NIH Stroke Scale of 20 to 4, which is minimal neurological deficits.

In 2013, as I mentioned, three studies were published. The first one is the SYNTHESIS Expansion trial, the second is the MR RESCUE, and the third is the IMS III. To understand these trials, we have to know what criteria to take into account when evaluating endovascular treatment for stroke. Here, we’re talking about large disabling strokes in which the index disease is large vessel occlusion. The treatment we are assessing has to be a treatment that has to be effective. Meaning that it has to open the blood vessels within the time period in which it will be beneficial. And the patient population that will benefit are those who will still have some brain to be saved. So these criteria needs to take into account to understand why these three trials were negative.

So the first study, that I mentioned was the SYNTHESIS Expansion. This study included 181 patients and randomized patients to intravenous tPA versus intra-arterial tPA, and concluded that intra-arterial therapy is not beneficial over medical therapy. However, in this study, there was no confirmation of large vessel occlusion, there was no report on the percentage of large vessel occlusion or recanalization rates. We don’t even know if the index disease was present.

The second study is the MR RESCUE. This study evaluated whether Penumbra based imaging is useful for patient selection in intra – for intra-arterial therapy. Penumbra based imaging is the perfusion study to assess how much tissue is damaged and how much tissue is at risk to be infarcted. So this study concluded that Penumbra based imaging is not useful and that intra-arterial therapy is not beneficial compared to medical therapy. However, the enrollment was very slow. Between 2004 and 2011, it included 127 patients. That is about one per month. That is only 64 in the intra-arterial arm and if we take into account that the recanalization rate was 25%, 16 of 64 patients using the MERCI device mainly. 

So can we really conclude that Penumbra based imaging is not useful based on only 16 recanalized patients with a device that did not open the occluded vessels? I don’t think we can conclude that.

The third study is the IMS III, which was a very well designed study. And from this study, we have learned a lot, which has helped the evolution of the treatments in the subsequent successful studies. IMS III included 656 patients randomized to endovascular treatment plus intravenous tPA versus intravenous tPA alone, and concluded that there was no benefit for endovascular therapy added to IV tPA. However, at the time IMS III was started, CTAs were not widely available in the ERs and therefore, only 33% of patients had CTAs. Subsequently, the addition of CTA was amended to the study so CTA was more widely used at the end of the study.

So can we conclude that there was an index disease in the other 66%? I don’t know if we can make this conclusion. Twenty percent of those patients in the intra-arterial arm didn’t have a large vessel occlusion. At the same time, this enrollment was very slow, as well, and expanded from 2006 up to 2012. The devices used were not effective devices with the majority of devices being the MERCI. Only five patients received stent retrievers. And the recanalization rate in this group ranged from 23% up to 44%, so not a good recanalization rate.

Several things we can learn from IMS III. One is that reperfusion was better in large vessel occlusion patients with intra-arterial therapy when compared to intravenous tPA. And with better recanalization, the functional outcome was better. So, for example, a TICI 0 score – TICI is the scale of recanalization, TICI 0 is no recanalization. TICI 0 was associated with 12.7% of good functional outcome. But a TICI 3, which is complete recanalization, was associated with good functional outcome in 71.4%. So the better recanalization, the better the functional outcome.

The second thing we can learn from the IMS studies – IMS I and IMS II – demonstrated a good relationship with time. And with every 30 minute delay, there was a 10% decrease in probability of good outcome. Same thing was seen in IMS III and significant delays were seen in IMS III as compared to the IMS I and II studies. In the subsequent post hoc analysis, the faster reperfusion was associated with better outcomes. So in reality, time is brain and the faster we act, the better the outcome. 

This paper published in the Stroke Journal in 2006 puts this into perspective in patients with large vessel occlusion strokes. For every minute that passes, we lose 1.9 million neurons. 

So for successful acute ischemic stroke endovascular treatment, we have to have certain criteria. We have to have a large vessel occlusion, we have to act fact, we have to use devices that work and open vessels, and the current devices are the stent retrievers, and we have to select the patients correctly. So these are patients with emergency large vessel occlusions, patients with small stroke at the time the procedure is started, (because a big stroke even if we recanalize the vessel, it will not necessarily improve from the recanalization), and patients who are candidates for this therapy should have some reasonable baseline function. And patients who are candidates for this therapy should have some reasonable baseline function. 

In 2014, the MR CLEAN study was present in the World’s Stroke Congress, and this is the first study that was positive for endovascular treatment for acute ischemic stroke demonstrating benefit. This study was subsequently published in the New England Journal, included 500 patients, 233 were in the intra-arterial group, and 267 in the control group. This study was done in, in the Netherlands and the enrollment occurred between December of 2010 and March of 2014. Patients in the study had anterior circulation strokes presenting within six hours and with a large vessel occlusion and the stent retrievers were used in up to 81.5% of the cases. The primary outcome of the study was the modified ranking scale at 90 days, meaning the functional outcome at 90 days. And a modified ranking of 0 to 2, or independence, was achieved in 32.6% in the patients who received intra-arterial therapy versus 19.1% in the control group with a significant difference between groups. The number needed to treat was 7 for independence and this basically represents that for every patient, every seven patients that we treat, we can achieve one patient being completely independent. A graph shown here demonstrates the difference between the Rankin scales in the intervention group and the control group. So a scale of Rankin of 0, 1, and 2, which is independent, was significantly more frequent in the intervention group as compared to the control group.

After MR CLEAN, we have certain conclusions. One is that intra-arterial treatment within six hours after a stroke is effective and safe for patients with large vessel occlusion, and this significantly impacts functional independence at three months. The presentation of this study led to stopping other endovascular acute ischemic stroke trials, which had to undergo interim analysis. This was like a falling domino phenomenon in which all the other studies were stopped or analyzed and demonstrated positive results. 

In the 2015 International Stroke Conference, three other studies were presented and published in the New England Journal of Medicine. The first one is the EXTEND IA, second is the ESCAPE, and the third is the SWIFT PRIME, and these three studies demonstrated positive results for intra-arterial therapy. 

EXTEND IA is the first one. This is a study from Australia and New Zealand. It included 70 patients – 35 in the intra-arterial group and 35 in the control group. It included only 70 patients because it was stopped earlier [stutter] secondary to the publication of the MR CLEAN study. In this group, all patients received intravenous tPA within four and a half hours, and had anterior circulation, large vessel occlusion strokes in the ICA terminus  M1 – or M2 segments. Endovascular treatment had to be initiated within six hours and they were selected based on CT perfusion with the RAPID software. I’m going to explain the RAPID software in the next slide but basically, what they were looking was a mismatch between the size of the perfusion deficit and the actual size of the stroke at the time of the study. And they were eligible if there was a mismatch between between this of 1.2 or by more than 10 cc, and a core infarct of less than 70 cc. 

This slide demonstrates a typical RAPID software sequence. The second line shows the ischemic core, or the infarcted tissue, in pink. And the third line demonstrates the area of perfusion deficit. And the mismatch between these two were the parameters used to select these patients. So a patient with a small infarct and a large perfusion deficit could be a great candidate for reperfusion therapy.

The EXTEND IA also looked at functional outcome at 90 days and the parameter was independent patients with a modified Rankin of 0 to 2. This was achieved in 71% of patients in the intra-arterial group versus 40% in the control group. The number needed to treat was 3.2, which is an impressive number. It means that for every three patients that treat, one patient will become independent. Another important parameter is that in the first 90 days, those patients treated with intra-arterial therapy were able to go home 64 days earlier. That is two months earlier that these patients can go home instead of being in the hospital or in a nursing home or in a rehab facility. And this represents significant impact emotionally, socially, and also, economically.

The graph shown before is the typical modified Rankin scale graph again showing that patients in the endovascular or intra-arterial group had modified Rankin of 0 and 1 significantly, more frequently or in a higher percentage than the tPA only group. 

The second study was ESCAPE study. And, this included 316 patients – 165 in the intra-arterial group and 150 in the control group. These patients had, had anterior circulation, large vessel occlusion strokes and, and the enrollment had to occur within 12 hours from the onset of symptoms. The selection of these patients was based on CT and multiphase CTA. And I’m gonna explain the multiphase CTA in the next slide. So for inclusion, they had to have a small core, an ASPECT score of 6 to 10. ASPECT score is used to assess the amount of tissue that has been damaged at the time the CT is obtained. A higher ASPECT score means a small stroke, a lower ASPECT score is a larger stroke. These patients also had to have moderate to good collaterals on the multiphase CTA with 50% or more of the MCA circulation with collaterals. And there was an emphasis on rapid treatment in this group of patients. 

So this slide, demonstrates the multiphase CTA. In the first slide, we see an MCA occlusion on the left MCA where the arrow is. And on the subsequent phases of the CTA, we see good collaterals in the rest of the MCA distribution. The second line shows an MCA occlusion, the left MCA, with intermediate collaterals in the multiphase CTA. And the third line shows an MCA occlusion with very poor collaterals in the territory of the MCA supplied by that vessel.

So in the ESCAPE study, patients with independence or a modified Rankin of 0 to 2 in 90 days, was achieved in 53% in the intra-arterial group versus 23.9% in the patients in the control group with a number needed to treat of 4. And the other important factor is that the mortality at 90 days was significantly lower in the intra-arterial group – 10.4% versus 19%. So this is the first study demonstrating reduced mortality in stroke patients. 

In the group of patients between six and 12 hours, there was a trend favoring the intra-arterial group. However, with only 49 patients, sample was small and no conclusions could be obtained from this. Again, the modified Rankin graph below shows that patients, in the intervention group achieved modified ranking scores of 0, 1, and 2 in a higher proportion as control compared to the control group.

The third study is the SWIFT PRIME study with 196 patients – again, randomized patients to intravenous tPA plus intra-arterial treatment with the stent retriever versus intravenous tPA in patients with anterior circulation large vessel occlusion treated within six hours. The study used for selection of patients was a CTA or MRI with the RAPID software looking at the target mismatch and number of profile. These patients had to have a small core infarct with a large hypo perfused region to be included in the study. And it showed that, a modified Rankin of 0 to 2 at 90 days was achieved in 60% of patients in the intra-arterial group versus 35% in the control group, which is a significant difference with the number needed to treat of 4 and a good recanalization rate of 88%. Again, the modified Rankin graph shows a higher proportion of patients with independence in the stent retriever group as compared to intravenous.

So all these three studies are different pieces of the puzzle and they led to eventually an  update in the guidelines for the early management of patients with acute ischemic stroke, which was published in June 29 of 2015, and endorsed by all the societies involved in the care of patients with stroke.

According to the current guidelines, patients with acute ischemic stroke should be evaluated for intravenous tPA and treated with this therapy if they’re candidates. All patients should also be evaluated immediately for endovascular treatment and endovascular treatment should be considered with the following criteria. In patients who have a baseline modified Rankin score of 0 to 1, in patients that received intravenous tPA within four and a half hours, patients with large vessel occlusion – meaning occlusion of the ICA intracranially or the M1 segment of the MCA – patients with ages of 18 or above, NIH Stroke Scale of 6 or more, ASPECT score of 6 or more, and in which the treatment can be started within six hours of symptom onset. These guidelines support the treatment of patients with acute ischemic stroke with endovascular treatment and acknowledge the importance to find these patients early and treat them rapidly, which will significantly impact their outcome and improve their functional independence in the long term.

I have a case that is gonna, show a patient with a large vessel occlusion, which was, treated successfully. This is a 70-year-old, man who presented with right hemiparesis and aphasia. On the left, we see an MRA demonstrated, an occlusion in the MCA. And an MRI shows a very small infarct. Even though he had significant deficits, the infarct was small, suggesting that the area of perfusion deficit was probably larger than the infarct that we see in the, iin the diffusion MRI. The patient was taken emergently to the angio suite. On the left, we see an AP view of an angiogram showing an occlusion in the MCA in the M1 segment with reduced, vessels in the MCA distribution. The image on your right is a lateral view demonstrating,  reduced vessels in the MCA distribution. 

These images demonstrate the catheters in the intracranial vessels. On the left, we can see the catheter with the stent retriever in the MCA. And after removal of the stent retriever, the angiogram on the right side shows significant reperfusion with good flow in that previously occluded MCA. 

This is the pre-treatment image is what I have shown you before, to compare to the post treatment image on this slide. And as we can see, the MCA is completely recanalized and the flow in the MCA is improved. This patient had a significantly, good outcome with a rapid recovery and was able to be discharged home.

This other case is a patient with 56-year-old is – who presented comatose, nonverbal, and quadriparetic. The suspicion was a posterior circulation stroke. The MRI only demonstrates a very small right cerebellar infarct despite the patient’s serious deficits. When the patient was taken to the angio suite, we see an occlusion in the basilar artery, which is shown in the image on the right. And on this slide, we can see that on the image on the left, the catheter’s in the basilar artery with a stent retriever across the occlusion with some partial flow. After removal of the stent retriever, removal of the thrombus, there is a complete recanalization of the basilar artery. The patient was initially comatose. After reperfusion, he had a dramatic recovery. On day two, he only had mild ataxia on the right upper extremity and on day three, he was discharged home, completely independent.

In summary, acute ischemic stroke is an emergency. Time is brain and we have to act fast. Intravenous tPA should be considered in all patients with acute ischemic stroke. This treatment can be administered really fast in the ER. And after this, all patients should be evaluated for the possibility of a large vessel occlusion. Endovascular treatment would be recommended if patients have a large vessel occlusion with acute ischemic stroke, which will significantly impact their functional independence and will have a morbidity-mortality benefit. 

Several questions remain for the future. The first one is, is anesthesia or conscious sedation the best way to treat these patients? We still don’t know this, and there are several ongoing studies looking into this question. 

Second question is which patients will benefit the most. So trying to select the patients better to improve their outcome and increase the possibility of administering this therapy to a wider population of patients, should be evaluated. And we still don’t know which is the best imaging technique to select these patients. What about those patients who present beyond the six-hour window from the onset of symptoms? And what about the wakeup strokes? As I said, several research studies are ongoing.

And thanks for listening.