Quite literally, in fact, considering the timing of the publication of MR-CLEAN – and, now, the triple fall-out from those results.
Due to the positive findings presented by the MR-CLEAN investigators in December 2014, three other ongoing major endovascular trials used this opportunity to check their results early. ESCAPE, EXTEND-IA, and SWIFT-PRIME – all products of the Covidien Solitaire FR clinical trial machine – ceased recruitment and looked to see if they’d met statistical measures of efficacy. Obviously, if you’re reading about all three of these trials here today – presented at the International Stroke Conference yesterday – they all found the results they hoped. ESCAPE and EXTEND-IA were published simultaneously in the NEJM, while SWIFT-PRIME is still in the manuscript drafting stages.
The more robust of the two trials is ESCAPE, whose original target enrollment was 500 patients based on a primary outcome of “ordinal shift analysis” on the modified Rankin scale. The important feature of all these new endovascular trials is the eligibility population: proximal, large-vessel occlusions with imaging-based evidence of moderate-to-good collateral supply surrounding a small infarct core. In this particular trial, it was proximal internal carotid or middle cerebral artery trunk, an ASPECTS of 6 to 10, and 50% or more filling of the local pial arterial circulation. Interestingly, this trial enrolled patients with symptoms out to 12 hours from onset – and did not require pretreatment with intravenous alteplase before intervention.
Ignoring their “ordinal shift analysis” nonsense that only serves to distort the effect size, the key results that matter are these: in the 316 patients enrolled, mRS 0-2 was 53.0% in the endovascular cohort and 29.3% in the control cohort. Deaths were improved to 10.4% from 19.0%, despite a small increase in sICH of 3.6% to 2.7%. 3 patients suffered access site hematomas and one retriever perforated the middle cerebral artery. Pretty good, frankly, for a cohort with a median NIHSS of 16. Interestingly, 45 patients underwent endovascular intervention without receiving alteplase, and 58% achieved mRS 0-2 – although 20% died.
EXTEND-IA was a much smaller trial, targeting only 100 patients, with coprimary outcomes of reperfusion and NIHSS improvement at 24 hours. Again, these investigators targeted proximal occlusions with radiographic evidence of salvageable “ischemic penumbra”. They stopped at 70 patients, again, because they’d met their own complex statistical criteria for efficacy. All patients in this trial received alteplase within 4.5 hours prior to endovascular intervention. Finally, yet again, ignoring their specific primary outcomes, the result of interest: mRS 0-2 was achieved by 71% in the endovascular group compared with 40% in the alteplase-only group. Deaths were improved to 9% from 20%, although this did not reach statistical significance owing to the small sample size. Reperfusion and infarct region growth at 24 hours also favored the endovascular cohort, as did the measures of early neurologic improvement.
There are many tiny oddities worth picking over in these trials – and, no doubt, their data will be picked over for further clues and hypotheses. SWIFT-PRIME was similarly positive, but those data were not yet available for full review. And, finally, we will all have to come to terms with the early termination of all these trials based on MR-CLEAN. The sponsor, obviously, is ready to make endovascular treatment the (profitable) standard of care. However, the full enrollment from these trials would have provided additional information regarding potentially dangerous subgroups. One hopes there will be ongoing endovascular registries going forward to identify any such patterns.
The key take-home, however, is endovascular therapy for acute stroke has probably finally arrived. After a decade-and-a-half of generally failed trials, it seems the devices and patient selection have finally improved to the point of clinical utility. For patients with collateral flow and one of these accessible lesions, it seems clear this therapy should be provided – and neither time of onset or tPA use matter as much as viable brain tissue. But the obvious key, as shown in MR-CLEAN, is patient selection – ESCAPE only managed to enroll 1.4 patients per month per center, while EXTEND-IA screened 7,798 stroke patients over two years to come up with 70. This therapy is very much so not for everyone – though, no doubt, Covidien hopes it will become so beyond the eligibility population identified here.
But, for the first time ever, if I were to have one of these specific types of heavily disabling strokes, this is probably the first advanced stroke intervention I’d willingly choose.
“Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection”
http://www.nejm.org/doi/full/10.1056/NEJMoa1414792
“Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1414905
As no senior medical professional, or medical device manufacturer, seems willing to come clean to the public or health journalists about the devastating risks of this experimental operation, here is the prescriptive information from one of the leading manufacturers to neurointerventionists:
"Procedures requiring percutaneous catheter introduction should not be attempted by
physicians unfamiliar with possible complications which may occur during or after the
procedure. Possible complications include, but are not limited to, the following: air embolism; hematoma or hemorrhage at puncture site; infection; distal embolization; vessel spasm, thrombosis, dissection, or perforation; emboli; acute occlusion; ischemia; intracranial
hemorrhage; false aneurysm formation; neurological deficits including stroke; and death."
All three of the trial results published this week were funded by one particular manufacturer of the one of the devices, and the lead investigators of each disclosing relationships to said company. At least one of these three trials operated on a "deferral of consent" basis, thereby sidestepping the disclosure of the above risks to patients and their representatives, and the first lawsuits in respect of this technology (the newest models) are underway. The true extent of the deployment of these devices, and non-consensual causal injuries, at one particular trial site, is under investigation.
Mechanical clot retrieval for stroke is a commercial project, not a philanthropic one. We are entering a perilous period for patient safety in emergency rooms.
I think these trials are exciting, as well as acknowledging that they must be interpreted with caution.
The above commenter mentions "devastating risks" – the risks from a large vessel occlusion stroke are pretty clear as well, and the outcomes pretty dismal.
As for the packet insert legal disclaimer, similar risks are mentioned on any IR equipment, ranging from carotid stenting to PICC lines. Similar risks are found on the packet insert for an aspirin.
The fact that the trials were manufacturer funded is well documented, and must be remembered. However a significant amount of medical data is manufacturer funded. They have a clear interest in promoting their devices, and as such the studies they fund must be scrutinised carefully. However the trials in question seem pretty well designed, albeit two of them have relatively small numbers due to being stopped early.
These three trials are promising, but by no means definitive. All three were positive. The trials with the tighter selection criteria (EXTEND-IA, for example) showed much more positive results. tPA is next to useless in this cohort of patients. Shouldn't trials like this be viewed positively, and encourage many more trials to further investigate both this technique and who will benefit most from it?
""However the trials in question seem pretty well designed, albeit two of them have relatively small numbers due to being stopped early"
This is an important point, and many trials are stopped early. It's a damn if you do damned if you don't situation.
One problem is that it is akin to stopping a horse race when your horse is ahead. Still you don't necessarily know how the race would have ended. The maths of this are not that it is mathematically impossible another outcome would have occurred. ANd there is some literature warning against early stoppage of trials.
I don't know whether all due precautions were taken in these trials. Letting this to methodology experts.
It is unclear as to whether or not all patients who underwent the treatment at one trial centre, were included in the data.
It is also well known on the ground that this procedure, if attempted and recanalization fails, leaves the patient in a worse condition than if the operation had not been attempted atall.
"It is also well known on the ground that this procedure, if attempted and recanalization fails, leaves the patient in a worse condition than if the operation had not been attempted atall."
Does this not just mean that if we can't do anything for these patients with a severe stroke, they have a horrendous outcome? Is this not an argument for intervening in the first place? Certainly the rates of symptomatic intracranial haemorrhage and complications related to the procedure in the trials were on the order of 2%.
I am curious why there is this small subset of the EM community fixed on finding reasons not to treat stroke? The magnitude of the effect in this trial is more dramatic than just about any intervention in any branch of medicine. I just find it sad to hear EM physicians sound disappointed about dramtically positive trials to treat stroke. Clearly not thinking about the patients best interests. Confident doing nothing is better??? Please make sure you have a card in wallet so I know when I see you hemiplegic and aphasic I can ship you straight to the nursing home.
I think you oversimplify the issue. It is entirely reasonable to continue a quest for evidence in the setting of a heterogenous disease process and a therapy based on an inconsistently efficacious therapy with serious adverse effects. As we can see from these endovascular trials, the benefit is now emerging due to two factors: radiographically demonstrated potentially viable brain tissue and reliable, sustained reperfusion. tPA is being pushed for greater and greater cohorts likely to have fewer patients capable of benefit, and it is clearly overhyped in its ability both to open the occluded vessel and to keep it from re-occluding. To say we wouldn't want tPA for hemiparesis and aphasia is incorrect. But, if the infarct core is not surrounded by salvageable tissue, tPA cannot help us. We ought to be doing significant additional work narrowing the tPA eligibility cohort, as the endovascular trials have been doing, to prevent harms, rather than do as Genentech would prefer us and give to all comers indiscriminately.