Thoughts on the MR CLEAN study (thrombectomy in acute stroke)

[soulofmpatel]

I just wanted to hear everybody's thoughts on the MR CLEAN study published in the NEJM

MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands

http://www.nejm.org/doi/full/10.1056/NEJMoa1411587

I know that all of the subgroup analysis and details of the study will be released at the ISC shortly, and the word on the street is that there are multiple other successful thrombectomy trials in acute stroke. These results with be announced with unthwarted enthusiasm. People will call for a new era in stroke treatment.

I should preface this by saying that I am not a stroke specialist. You may or may not remember my posts in prior threads regarding IMS3 and MR rescue. My general feeling based on experience with innumerable unsuccessful thrombectomy procedures (and rare successful cases) is relatively straight-forward:

1) Early reperfusion in a patient with impending infarction with no significant early infarct on NC CT can be beneficial, and when this happens, the patient improves on the table or shortly afterwards.
2) Reperfusion of infarcted tissue is deleterious. It worsens edema, possibly extends the infarct as the edema tamponades collaterals, and causes complications, extended hospital stay, et cetera.

This is the only reasonable explanation for the data in IMS3 and MR rescue, as these trials had excellent recanalization results, and the patients were reasonably selected-the procedure must have caused undocumented deleterious effects which negate the benefits. Undoubtedly, patients were included in those trials who improved on the table after intervention. This was either 1) sufficiently rare as to be diluted by unsuccessful cases or 2) negated by undocumented side effects of the procedure. If a patient has a slight extension of the infarct due to reperfusion injury and ends up being modified rankin 4 instead of 3 at 90 days, this does not show up as an adverse event in the trial data.

There is a lot of wishful thinking in the field of stroke, and stroke neurologists or interventional radiologists will often take credit for a patient's delayed improvement (i.e. natural history). I have literally heard an interventional radiologist take credit for a patient's improvement during inpatient rehab-as though their handiwork somehow helped the physical therapist. People seem to forget that it is not uncommon for patients to significantly improve over time with conservative treatment only. They also tend to believe that an unsuccessful procedure was a "wash" and at least did not harm the patient so long as there was no significant post-procedural hemorrhage.

Anyways, I found out that the median ASPECTS score for the non contrast CT in the MR CLEAN study in the thrombectomy group was 9. In other words, these patients had essentially stone-cold normal CTs.

there are a few things I do not know...

1) Was the NC CT done at the time of tPA or at the time of randomization (which was significantly later)?
2) Was subgroup analysis done based on ASPECTS score?
3) was the subgroup at 5-6 hours for groin puncture time also positive?

Because the benefit in the trial was modest, perhaps we should make the cutoff ASPECTS 10 (no sign of infraction on CT) and the time cutoff < 5 hours (groin puncture time), although I am a proponent of tissue over time.

I call for a warning against extending the results of the study beyond what they actually show and performing potentially harmful procedures on patients unlikely to benefit from them. Let us not forget the big picture. If I were to rank stroke treatments/preventatitive measures based on their overall ability to prevent neuronal injury and stroke morbidity in the general population, it would be something like this:

#1) broccoli
2) sodium restriction
3) the treadmill
4) smoking cessation
5) Physical therapy
6) lisinopril
7) aspirin
8) coumadin
9) plavix
10) aggrenox
11) simvastatin

tPA and thrombectomy are definitely far below these treatments in terms of their overall efficacy and importance as they will only be used on the minority of stroke patients and with modest success. You will never hear a nursing home attendant say "you know...we haven't gotten a lot of stroke patients since they made thrombectomy the standard of care."

...but if we could get people to make significant lifestyle changes and to control vascular risk factors, we could cut down on stroke morbidity enourmously.

-soul of m patel

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[Hank Rearden]

The main theory behind why IMS-III and the other trials were negative is that they were using outdated technology. The vast majority of the subjects in IMS-III had thrombectomy with the MERCI clot retriever. This device has recalanization rates in the 50-60% range whereas the stentrievers have rates in the 70-80% range (don't quote me on these numbers). It is my understanding that the stentrievers are also less likely to shower distal emboli.

Your theory on reperfusion into infarcted tissue is not quite accurate - it is not always deleterious. Reperfusion is only deleterious if it leads to ICH. Whether or not this occurs depends on the length of time / severity of ischemia. Ischemia damages the blood vessel wall - the longer this is going on the more likely the patient is to experience hemorrhagic conversion upon reperfusion. Let's say you have a subject with a small hypodensity on CT, but much larger perfusion deficit on CTP over the motor strip and they are only 1-2 hrs out from symptom onset. If you can quickly recanalize that vessel they are very unlikely to bleed. If you don't recanalize, the patient is at high risk for stroke expansion over the next 72 hrs.

Saying that the effect of embolectomy in MR-CLEAN was "modest" is also inaccurate. They reported a risk reduction of 13.5% which is on par with the original NINDS tPA trial. An effect that large is extremely rare.

Now that I've pumped up MR-CLEAN, I will say I agree with many of your points. I too am skeptical that those with groin puncture in the 5-6 hr range received much benefit. This is only 1 trial - we need others to validate the results. While MR-CLEAN has certainly increased the number of patients going for these procedures I don't think it's going to open the floodgates for neuro-IR in stroke. These procedures remain very time sensitive and are only indicated for large vessel occlusion.

 

[TUGM]

In general, I agree with the above statements. I also have significantly less experience than you (seemingly) veteran neurologists. I think that as technology advances and selection criteria is fine-tuned, the endovascular modality will definitely find its place. At this time, the number of patients who are eligible for intervention remain quite small - essentially just large vessel occlusions and posterior circulation occlusions, w/in the time frame of 6 hours. To become standard of care, we need more positive trials, better technology, and faster door-to-groin times (that's what she said).

Obviously, I agree that primary prevention can lead to decreased incidence and prevent stroke. However, in my inexperience, I am unaware of any data that suggests improved outcomes in stroke in patient's who are relatively "healthier" to begin with. Intervention deals with what we can do to salvage the brain AFTER the stroke has already occurred.

 

[soulofmpatel]

The main theory behind why IMS-III and the other trials were negative is that they were using outdated technology.

I disagree with the "main theory." My hypothesis is that reperfusing infarcted tissue is deleterious, negating the benefit of the procedure done in patients who are better candidates.

The vast majority of the subjects in IMS-III had thrombectomy with the MERCI clot retriever. This device has recalanization rates in the 50-60% range whereas the stentrievers have rates in the 70-80% range (don't quote me on these numbers). It is my understanding that the stentrievers are also less likely to shower distal emboli.

So why didn't those 50-60% of patients do any better clinically?

Your theory on reperfusion into infarcted tissue is not quite accurate - it is not always deleterious. Reperfusion is only deleterious if it leads to ICH.

Source?

This does not make any sense. The IMS3 data clearly show that the risk of hemorrhage with embolectomy is not sufficient to explain the lack of benefit. If you are not causing harm, it doesn't matter if you are only recanalizing in 60% of cases-there should still be some benefit.

Let's say you have a subject with a small hypodensity on CT, but much larger perfusion deficit on CTP over the motor strip and they are only 1-2 hrs out from symptom onset.

I don't think there is any evidence that CT perfusion is helpful given the MR-rescue data. There will always be a huge mean transit time wedge in the at-risk territory. Why not just use the infarction-clinical symptoms mismatch? Acquiring and analyzing the CT perfusion scan wastes time while neurons die. I've had innumerable cases with a huge mismatch on multimodal imaging with poor outcomes. If it's me with a huge clinical deficit and a normal CT (ASPECTS 10), just do the procedure.

Saying that the effect of embolectomy in MR-CLEAN was "modest" is also inaccurate. They reported a risk reduction of 13.5% which is on par with the original NINDS tPA trial. An effect that large is extremely rare.

I disagree. 13.5% is a modest benefit, and the benefit of tPA is also modest. If tPA and thrombectomy stopped existing, it would make almost no difference in terms of the big picture of stroke morbidity. If everyone started eating a healthier diet, quit smoking, exercised regularly, and controlled vascular risk factors, it would make a big difference.

I don't think it's going to open the floodgates for neuro-IR in stroke. These procedures remain very time sensitive and are only indicated for large vessel occlusion.

I hope you are right. My cynical view is that incentives ultimately drive treatment decisions. If insurance companies reimburse for it, people will perform it.

-soul

 

[soulofmpatel]

Intervention deals with what we can do to salvage the brain AFTER the stroke has already occurred.

Yes...I understand. I by no means meant to suggest that we should ignore acute stroke treatment entirely. We should try to improve care at all time-points in all patients. I still stand by my claim that broccoli is a better stroke treatment than tPA by a factor of at least 10:1 (adjudicated by total volume of brain saved from infarction).

By the way, can someone in Nashville give us an update?

-soul

 

[TUGM]

And the evidence gathers? ESCAPE showing some interesting results.

 

[gonogo]

Yes, both ESCAPE and EXTEND-IA were just published in NEJM, showing decreased mortality in stroke and increase rate of return to functional independence following a stroke when endovascular treatment is performed.

 

[TUGM]

Tack on SWIFT PRIME to the list... results have yet to be release officially, I believe. Exciting times.

 

[Notch3]

RACE also going on in France. From I last read, that study will be even larger and is still recruiting!

SWIFT PRIME is American based with Savor as its PI at UCLA. Can only imagine what will happen when the >3rd generation endovascular devices are developed.

 

[deathmerchant]

Its true that most old studies were not positive and the recent ones and upcoming are/will be modestly positive; which just tells us one thing' that we are missing some link'. But if any of u have seen/managed a patient with completely occlusive 'ICA terminus with MCA/ACA' thrombus, and a full RMCA syndrome and who gets Intervention with recanalization and complete resolution of symptoms in 3 hrs- u will not be so skeptical . If someone I loved had a stroke, I would go ahead and do intervention. It wont be long before we find out the true inclusion and exclusion criterias and change the game.

 

[TUGM]

Its true that most old studies were not positive and the recent ones and upcoming are/will be modestly positive; which just tells us one thing' that we are missing some link'. But if any of u have seen/managed a patient with completely occlusive 'ICA terminus with MCA/ACA' thrombus, and a full RMCA syndrome and who gets Intervention with recanalization and complete resolution of symptoms in 3 hrs- u will not be so skeptical . If someone I loved had a stroke, I would go ahead and do intervention. It wont be long before we find out the true inclusion and exclusion criterias and change the game.

In general, I agree with you. But we cannot and should not take anecdotal outcomes and generalize them as evidence, especially when lives and loved ones' functionalities are at stake. (I'm not saying that this is what you're suggesting, I'm just engaging in discourse). Anyone who has been following these SDN discussions on acute stroke therapy knows that I am an enthusiastic and hopeful follower, and I guarantee, no one here is more ecstatic at the recent results as I am. I am even more enthusiastic about research and evidenced-driven medicine, whatever that may mean for acute ischemic stroke, and I think that most clinicians SHOULD feel the way I do, at least to a certain extent. These new positive trials are a giant step forward and in the right direction - we must continue to gather the evidence, so as to offer our patients safe, effective treatments without putting them at unnecessary risk.

 

[TUGM]

That being said, I also think that now would be an excellent time for re-organization of stroke care for improved triage and timely therapeutic intervention. AND FOR THE LOVE OF GOD, FELLOWSHIP PROGRAMS, PLEASE MOVE TOWARDS ACCREDITATION - mainly for the sake of regulation of training and limiting the number of trainees.

 

[xaelia]

Just don't forget the key features of the new endovascular trials are two-fold:
• Better devices with reliable recanalization.
• Strict imaging selection criteria of patients with small infarct cores and significant collateral perfusion.

That tPA is junk is the best-kept secret of the AHA/ASA and its corporate partners – only a fraction of tPA candidates actually have early, sustained recanalization at a greater rate than spontaneous, and patients have a highly variable amount of clinically important salvageable tissue. Patient selection needs to be more than just NCCT and time-of-onset – one of the trials enrolled up to 12 hours and didn't require tPA pre-treatment, and still showed benefit in that cohort. We need do be doing more CTA and perfusion imaging to select patients both as non-candidates and as candidates for endovascular treatment.

 

[typhoonegator]

The outcome for tPA trials was 3 month mRS, not "early recanalization". And they were positive.

I'm happy to admit that I'm not entirely certain the mechanism by which tPA improves outcomes. Early recanalization is one such possible mechanism, but as you point out, the rates of spontaneous radiographic recanalization on tPA is not particularly high.

 

[xaelia]

The outcome for tPA trials was 3 month mRS, not "early recanalization". And they were positive.

Well, NINDS and ECASS III were.

ECASS, ECASS II, ATLANTIS, IST-3 ... not exactly.

But, the totality of the evidence is there is a cohort for whom thrombolysis is likely to confer benefit. And a bunch who are a wash. And a few who are harmed. I just tend to fall on the side of "better selection" given the bias in the underlying data, not "more more more".

 

[soulofmpatel]

I'm happy to admit that I'm not entirely certain the mechanism by which tPA improves outcomes. Early recanalization is one such possible mechanism, but as you point out, the rates of spontaneous radiographic recanalization on tPA is not particularly high.

Are you seriously suggesting that tPA may benefit patients in ways other than recanalizing the lesion which is about to cause permanent infarction of tissue?

For either tPA or thrombectomy, if you don't recanlize the lesion and reperfuse tissue PRIOR to infarction, you are not benefiting the patient. Moving the lesion distally can also be beneficial. Dead brain doesn't benefit from tPA. collateral vessels don't benefit form tPA. tPA does not regrow brain tissue. tPA is not neuroprotective.

In a successful treatment leading to recanalization, the patient will improve rapidly (i.e. within minutes or a few hours). Any improvement beyond 48 hours has nothing to do with the intervention. I love how interventional radiologist love to take credit for the work of physical therapists when they present their cases.

A lot of people get confused with the NINDS data and think that the benefit of IV tPA is somehow delayed (because mRS at 3 months was positive but mRS at 24 hours was negative). What is happening here is that successful tPA cases (recanlization or distal mobilization of thrombus leading to less infarction) are being negated by the increased rated of intracranial hemorrahges. People with symptomatic ICHs are more likely to improve than people with large infarctions over 3 months.

 

[soulofmpatel]

Well, NINDS and ECASS III were.

ECASS, ECASS II, ATLANTIS, IST-3 ... not exactly.

But, the totality of the evidence is there is a cohort for whom thrombolysis is likely to confer benefit. And a bunch who are a wash. And a few who are harmed. I just tend to fall on the side of "better selection" given the bias in the underlying data, not "more more more".

Exactly. I feel it is reasonable to presume that NINDS an ECASSIII were somewhat lucky given the vast number of negative trials, so the actual benefit of IV tPA is likely less than what we would presume it to be.

Again, IV tPA and thrombectomy are modestly effective treatments which only benefit a small number of stroke patients.

Broccoli is a much better stroke treatment because it benefits the vast majority of potential stroke patients (excluding traumatic dissections, genetic hypercoagulable states, and other non-lifestyle related strokes). Also, it helps to prevent various other terrible diseases (DM2, HTN, CAD) and is inexpensive, readily available, and does not require a highly trained specialist.

 

[typhoonegator]

Are you purposefully using the term recanalization? Because I've seen plenty of recanalizations that did "improve rapidly".

 

[Hank Rearden]

One theory that has been thrown out regarding why the benefits of IV-tPA at 3 months seem to go beyond what you might expect with the modest recanalization rates is upregulation of MMP-9. IV-tPA upregulates MMP-9. In the acute phase this is bad because MMP-9 acts as a protease that can break down the neurovascular unit and increase rates of hemorrhagic conversion. Later in the stroke recovery process, however, MMPs break down the protein matrix that supposedly locks many of your synaptic connections in place. Upregulating MMP's during recovery might help "remove the brakes" on neural plasticity, allowing more neural outgrowth. I admit that this theory seems far fetched, especially since the half life of tPA is so short and the neural repair process is thought to start around 3 days post-CVA.

http://stroke.ahajournals.org/content/38/2/748.long

 

[typhoonegator]

Are you seriously suggesting that tPA may benefit patients in ways other than recanalizing the lesion which is about to cause permanent infarction of tissue?

I seriously am. And I'm not alone. But I applaud your confidence.

 

[deathmerchant]

Exactly. I feel it is reasonable to presume that NINDS an ECASSIII were somewhat lucky given the vast number of negative trials, so the actual benefit of IV tPA is likely less than what we would presume it to be.

Again, IV tPA and thrombectomy are modestly effective treatments which only benefit a small number of stroke patients.

Broccoli is a much better stroke treatment because it benefits the vast majority of potential stroke patients (excluding traumatic dissections, genetic hypercoagulable states, and other non-lifestyle related strokes). Also, it helps to prevent various other terrible diseases (DM2, HTN, CAD) and is inexpensive, readily available, and does not require a highly trained specialist.

We are talking about 'acute treatment' here not 'prevention'; also 'broccolis' are not even the best preventive measure. drinking water daily beats it may be

 

[typhoonegator]

Let's not forget about exposure to sunlight! Vitamin D might just be at the root of all disease!

 

[Neurologo]

Yes, both ESCAPE and EXTEND-IA were just published in NEJM, showing decreased mortality in stroke and increase rate of return to functional independence following a stroke when endovascular treatment is performed.

Let's not forget that all 3 studies (ESCAPE, EXTEND IA, SWIFT PRiME) were much smaller studies all funded by one same Covidien solitaire device manufacturer and that they were too eagerly terminated prematurely before we had a chance to fully assess true risks. Also all three had wide confidence intervals surrounding their point estimates.

I should also point out that the study centers could only recruit on average 2 patients per month meaning we are talking about only very few acute strokes cases. Can we justify paying for a neuro IR and setting up CT perfusion for such few potential cases even if one can prove confidently that endovascular intervention is clearly superior.

I forgot the name of another recent endovascular study in Italy or Spain that was truncated due to negative results. I will post it later. Perhaps some of you may know.

My point: a lot needs to be investigated still before being excited and the true epidemiological impact of these interventions is actually small.

 

[typhoonegator]

History repeats itself. Your point about the number of cases, and the justification of cost was widely circulated in 1996 after the NINDS trial was released. Treatment effect was small, and how were we going to get all these patients to scan so quickly, and who was going to pay to have a stroke doc on call to determine candidacy, etc. Not saying your points aren't valid, but it is funny to see the parallels.

The wide confidence intervals are due to statistical power, which by default was low due to the premature termination. That in itself is not nefarious, the results were on the positive side regardless, and remember that the DSMB's job is to determine the risk/benefit ratio to patients in the study -- not to society at large. Once they saw that patients in the control arm were getting a statistically inferior treatment, there wasn't much else they could do. I agree that it would have been nice to understand the more infrequent risk events and how they impact the overall effect of treatment, but we can still get that information moving forward, although the genie is clearly out of the bottle at this point.

I think it's OK for people to be excited within reason so long as they stick to the right devices for the right patients as defined by study inclusion criteria, and avoid mission creep. Open-label registries of patients treated with these procedures are necessary both to assess the real-world applicability of the study results, and identify risks with better fidelity over time. And you're certainly right, this is not a panacea.

 

[soulofmpatel]

The new Endovascular Interventions for reference purposes:

1. Patients eligible for intravenous r-tPA should receive intravenous
r-tPA even if
endovascular treatments are being considered (Class I; Level of
Evidence A). (Unchanged
from the 2013 guideline)
2. Patients should receive endovascular therapy with a stent retriever
if they meet all the
following criteria (Class I; Level of Evidence A). (New recommendation):
(a) prestroke mRS score 0 to 1,
(b) acute ischemic stroke receiving intravenous r-tPA within 4.5 hours of onset
according to guidelines from professional medical societies,
(c) causative occlusion of the internal carotid artery or proximal MCA (M1),
(d) age ≥18 years,
(e) NIHSS score of ≥6,
(f) ASPECTS of ≥6, and
(g) treatment can be initiated (groin puncture) within 6 hours of symptom onset
3. As with intravenous r-tPA, reduced time from symptom onset to
reperfusion with
endovascular therapies is highly associated with better clinical
outcomes. To ensure
benefit, reperfusion to TICI grade 2b/3 should be achieved as early as
possible and within
6 hours of stroke onset (Class I; Level of Evidence B-R). (Revised
from the 2013 guideline)
4. When treatment is initiated beyond 6 hours from symptom onset, the
effectiveness of
endovascular therapy is uncertain for patients with acute ischemic
stroke who have
causative occlusion of the internal carotid artery or proximal MCA
(M1) (Class IIb; Level
of Evidence C). Additional randomized trial data are needed. (New
recommendation)
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5. In carefully selected patients with anterior circulation occlusion who have
contraindications to intravenous r-tPA, endovascular therapy with
stent retrievers
completed within 6 hours of stroke onset is reasonable (Class IIa;
Level of Evidence C).
There are inadequate data available at this time to determine the
clinical efficacy of
endovascular therapy with stent retrievers for those patients whose
contraindications are
time-based or nontime based (eg, prior stroke, serious head trauma, hemorrhagic
coagulopathy, or receiving anticoagulant medications). (New recommendation)
6. Although the benefits are uncertain, use of endovascular therapy
with stent retrievers may
be reasonable for carefully selected patients with acute ischemic
stroke in whom treatment
can be initiated (groin puncture) within 6 hours of symptom onset and
who have causative
occlusion of the M2 or M3 portion of the MCAs, anterior cerebral
arteries, vertebral
arteries, basilar artery, or posterior cerebral arteries (Class IIb;
Level of Evidence C). (New
recommendation)
7. Endovascular therapy with stent retrievers may be reasonable for
some patients <18 years
of age with acute ischemic stroke who have demonstrated large vessel
occlusion in whom
treatment can be initiated (groin puncture) within 6 hours of symptom
onset, but the
benefits are not established in this age group (Class IIb; Level of
Evidence C). (New
recommendation)
8. Although the benefits are uncertain, use of endovascular therapy
with stent retrievers may
be reasonable for patients with acute ischemic stroke in whom
treatment can be initiated
(groin puncture) within 6 hours of symptom onset and who have
prestroke mRS score of
>1, ASPECTS <6, or NIHSS score <6 and causative occlusion of the internal carotid artery
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or proximal MCA (M1) (Class IIb; Level of Evidence B-R). Additional
randomized trial
data are needed. (New recommendation)
9. Observing patients after intravenous r-tPA to assess for clinical
response before pursuing
endovascular therapy is not required to achieve beneficial outcomes and is not
recommended. (Class III; Level of Evidence B-R). (New recommendation)
10. Use of stent retrievers is indicated in preference to the MERCI
device. (Class I; Level of
Evidence A). The use of mechanical thrombectomy devices other than
stent retrievers may
be reasonable in some circumstances (Class IIb, Level B-NR). (New
recommendation)
11. The use of proximal balloon guide catheter or a large bore distal
access catheter rather than
a cervical guide catheter alone in conjunction with stent retrievers
may be beneficial (Class
IIa; Level of Evidence C). Future studies should examine which systems
provide the
highest recanalization rates with the lowest risk for nontarget
embolization. (New
recommendation)
12. The technical goal of the thrombectomy procedure should be a TICI
2b/3 angiographic
result to maximize the probability of a good functional clinical
outcome (Class I; Level of
Evidence A). Use of salvage technical adjuncts including
intra-arterial fibrinolysis may be
reasonable to achieve these angiographic results, if completed within
6 hours of symptom
onset (Class IIb; Level of Evidence B-R).(New recommendation)
13. Angioplasty and stenting of proximal cervical atherosclerotic
stenosis or complete
occlusion at the time of thrombectomy may be considered but the
usefulness is unknown
(Class IIb; Level of Evidence C). Future randomized studies are needed.
14. Initial treatment with intra-arterial fibrinolysis is beneficial
for carefully selected patients
with major ischemic strokes of <6 hours’ duration caused by occlusions
of the MCA (Class
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I; Level of Evidence B-R). However, these data derive from clinical
trials that no longer
reflect current practice, including use of fibrinolytic drugs that are
not available. A
clinically beneficial dose of intra-arterial r-tPA is not established,
and r-tPA does not have
FDA approval for intra-arterial use. As a consequence, endovascular
therapy with stent
retrievers is recommended over intra-arterial fibrinolysis as
first-line therapy (Class I;
Level of Evidence E). (Revised from the 2013 guideline)
15. Intra-arterial fibrinolysis initiated within 6 hours of stroke
onset in carefully selected
patients who have contraindications to the use of intravenous r-tPA
might be considered,
but the consequences are unknown (Class IIb; Level of Evidence C).
(Revised from 2013
guideline)
16. It might be reasonable to favor conscious sedation over general
anesthesia during
endovascular therapy for acute ischemic stroke. However, the ultimate
selection of
anesthetic technique during endovascular therapy for acute ischemic
stroke should be
individualized based on patient risk factors, tolerance of the
procedure, and other clinical
characteristics. Randomized trial data are needed (Class IIb; Level of
Evidence C). (New
recommendation)
Imaging
1. Emergency imaging of the brain is recommended before initiating any
specific treatment
for acute stroke (Class I; Level of Evidence A). In most instances,
nonenhanced CT will
provide the necessary information to make decisions about emergency management.
(Unchanged from the 2013 guideline)
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2. If endovascular therapy is contemplated, a noninvasive intracranial
vascular study is
strongly recommended during the initial imaging evaluation of the
acute stroke patient but
should not delay intravenous r-tPA if indicated. For patients who
qualify for intravenous
r-tPA according to guidelines from professional medical societies,
initiating intravenous rtPA
before noninvasive vascular imaging is recommended for patients who have not had
noninvasive vascular imaging as part of their initial imaging
assessment for stroke.
Noninvasive intracranial vascular imaging should then be obtained as
quickly as possible
(Class I; Level of Evidence A). (New recommendation)
3. The benefits of additional imaging beyond CT and CTA or MR and MRA,
such as CT
perfusion or diffusion- and perfusion-weighted imaging, for selecting
patients for
endovascular therapy are unknown (Class IIb; Level of Evidence C).
Further randomized,
controlled trials may be helpful to determine whether advanced imaging paradigms
employing CT perfusion, CTA, and MRI perfusion and diffusion imaging, including
measures of infarct core, collateral flow status, and penumbra, are
beneficial for selecting
patients for acute reperfusion therapy who are within 6 hours of
symptom onset and have
an ASPECTS <6. Further randomized, controlled trials should be done to determine
whether advanced imaging paradigms using CT perfusion and MRI
perfusion, CTA, and
diffusion imaging, including measures of infarct core, collateral flow
status, and penumbra,
are beneficial for selecting patients for acute reperfusion therapy
who are beyond 6 hours
from symptom onset. (New recommendation)
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Systems of Stroke Care
1. Patients should be transported rapidly to the closest available
certified primary stroke
center or comprehensive stroke center or, if no such centers exist,
the most appropriate
institution that provides emergency stroke care as described in the
2013 guidelines (Class
I; Level of Evidence A). In some instances, this may involve air
medical transport and
hospital bypass. (Unchanged from the 2013 guideline)
2. Regional systems of stroke care should be developed. These should
consist of consisting
of:
(a) Healthcare facilities that provide initial emergency care
including administration of
intravenous r-tPA, including primary stroke centers, comprehensive
stroke centers, and
other facilities.
(b) Centers capable of performing endovascular stroke treatment with
comprehensive
periprocedural care, including comprehensive stroke centers and other healthcare
facilities, to which rapid transport can be arranged when appropriate
(Class I; Level of
Evidence A). (Revised from the 2013 guideline)
3. It may be useful for primary stroke centers and other healthcare
facilities that provide initial
emergency care including administration of intravenous r-tPA to
develop the capability of
performing emergency noninvasive intracranial vascular imaging to most
appropriately
select patients for transfer for endovascular intervention and reduce
time to endovascular
treatment (Class IIb; Level of Evidence C). (Revised from the 2013 guideline)
4. Endovascular therapy requires the patient to be at an experienced
stroke center with rapid
access to cerebral angiography and qualified neurointerventionalists.
Systems should be
designed, executed and monitored to emphasize expeditious assessment
and treatment.
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Outcomes on all patients should be tracked. Facilities are encouraged
to define criteria that
can be used to credential individuals who can perform safe and timely
intra-arterial
revascularization procedures (Class I; Level of Evidence E). (Revised
from the 2013
guideline)

 

[soulofmpatel]

One theory that has been thrown out regarding why the benefits of IV-tPA at 3 months seem to go beyond what you might expect with the modest recanalization rates is upregulation of MMP-9. IV-tPA upregulates MMP-9. In the acute phase this is bad because MMP-9 acts as a protease that can break down the neurovascular unit and increase rates of hemorrhagic conversion. Later in the stroke recovery process, however, MMPs break down the protein matrix that supposedly locks many of your synaptic connections in place. Upregulating MMP's during recovery might help "remove the brakes" on neural plasticity, allowing more neural outgrowth. I admit that this theory seems far fetched, especially since the half life of tPA is so short and the neural repair process is thought to start around 3 days post-CVA.

http://stroke.ahajournals.org/content/38/2/748.long

I am skeptical.

 

[typhoonegator]

I am skeptical.

You should be! We all should be! But pleiotropy is hard to find unless you look for it.