Endovascular Breakthrough*

Breakout

By now, most interested people are well-aware of the MR CLEAN results; if not, you can read the article here. Following are just a few thoughts and observations:

One thing that caught my eye is that the absolute difference between endovascular therapy and conservative care with respect to the (secondary) outcome of achieving a modified Rankin scale (mRS) score of 0-2 was ~ 13%. This is the same effect size that IV tPA had on the (secondary) outcome of achieving a mRS of 0-1 in the pivotal NINDS study. Put another way, the number needed to treat (NNT) with IV tPA vs. placebo to save a subject from any disability is the same NNT with endovascular intervention vs. tPA alone to save a subject from slight disability (8 subjects). I thought it interesting how similar those effect sizes are.

Next, the risk of symptomatic intracerebral hemorrhage (sICH) in the control arm (91% of whom received IV tPA) was 6.4%. Again, this is exactly the sICH risk in the pivotal NINDS trial and is very similar to other trials. It’s remarkable how consistent that finding is.

Third, there are some parallels between the early failures of IV tPA and the early failures of endovascular therapy. Multiple early studies of IV thrombolysis for acute ischemic stroke were negative. They used inferior drugs (streptokinase) and long time windows (5-6 hours, with most subjects being randomized toward the later part of the windows). Eventually, the NINDS tPA study group hit upon an important innovation: They required that about half of the subjects be randomized within 1.5 hours. If a study site had a run of 1.5 – 3 hour randomizations, they had to halt enrollment until they got some subjects within the 1.5 hour window. This ensured that sites really worked hard to treat people quickly rather than dally “because we still have over an hour to go”. Turns out that tPA benefit is exquisitely time-sensitive.

Similarly, early endovascular trials used a drug not currently in use (pro-urokinase, although this was actually a positive trial) or substandard tPA dosing, enrolled subjects without an identified vascular occlusion, used less-efficacious embolectomy devices, and had long onset-to-treatment times. Moreover, recruitment was often very sluggish, possibly because the patients felt to be most likely to benefit from endovascular treatment were treated off-study. MR CLEAN rectified all of those issues.

Fourth, I think that MR CLEAN vindicates both the cautious and the enthusiastic schools of thought regarding endovascular treatment. It’s easy to see how strong endovascular proponents would feel vindicated–we finally have a really well-done randomized controlled trial showing the robust clinical benefit they always believed in. But looking back on the purported reasons for the earlier studies’ negative results also vindicates those of us who were more cautiously optimistic (as I have always considered myself to be). If one accepts the proposition that earlier failures were due to factors such as immature technology, then the current success doesn’t show that those technologies were beneficial all along–it shows that only in this newer era of stent retrievers is endovascular therapy truly beneficial.

Finally, a few words about the other major trials not yet published. Several ongoing endovascular studies have halted enrollment, with interim analyses occasioned by the favorable MR CLEAN results either pending or showing clear benefit. The ethical argument for this is that we should not be randomizing subjects to conservative care once we know that endovascular care is beneficial. However, there are important reasons to continue randomization. One is that our estimate of the overall effect size will be more precise if we have a larger sample. Another argument in favor of completing the trials is that it will allow for more robust subgroup analyses. While it’s great to finally have compelling data in support of a beneficial stroke treatment, it would be even better to have a finely-grained understanding of exactly who benefits and by how much.

Take carotid endarterectomy (CEA) for symptomatic disease, for example. I wasn’t around back then, but I was taught that strong supporters were vociferous in their insistence that CEA is beneficial and that randomizing subjects was unethical. Indeed, NASCET substantiated this belief, but also provided rich data sets that taught us the differential benefits (or lack thereof) according to degree of stenosis, time from stroke/TIA to randomization, patient gender, presence of contralateral occlusion, presence of tandem stenosis, etc. It’s very gratifying to know that we’re moving into an era of expanded therapeutic options for acute ischemic stroke, but many important questions remain to be answered about endovascular therapy: Is there a differential effect according to patient age? Gender? Location of occlusion? Is recanalization beneficial out to 8 hours? 12 hours? What role should perfusion imaging play? How about ASPECTS scores? DWI? Assessment of vascular collaterals? These questions will be much harder to address if we stop all trial enrollments and return to relying on lower-quality retrospective data.

Still, it’s a very exciting time in the stroke world–I’m sure this year’s conference in Nashville will be humming. Wish I could go, but someone’s got to mind the fort . . .


* OK, so the game pictured is Atari’s Breakout, not “Breakthrough”, but close enough. If you’re in the age range where you used to play such Atari games for hours on end, and you can afford to blow off the rest of your day, go to Google image search and type “Atari Breakout”. Or just click on the picture 🙂

About Justin A. Sattin

I'm a vascular neurologist and residency program director. I created this blog in order to share some thoughts with my resident and other colleagues, and to foster my own learning as well.
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3 Responses to Endovascular Breakthrough*

  1. Ahsan Sattar says:

    Thanks a lot Dr. Sattin for such an interesting and timely post. I totally agree that there are a lot more questions that remain to be answered. I feel like, as a community, we might have lost the true equipoise of standard medical treatment versus endovascular treatment after MR CLEAN results (two more randomised trials have been halted due to interim analysis in favor of endovascular, ESCAPE & Extend IA). To continue enrolling in such trials, how does one obtain a well informed consent with the knowledge of these results? After the NINDS tPA trial it was considered unethical to design/enroll patients in a trial in which tPA was not offered to one cohort. By the same toke, it might be very hard to continue enrolling is such trials. I would definitely like to have more data and more therapeutic options for stroke patients as you eluded. Some of the questions like patient selection based on perfusion, CTA collateral should be answered after ESCAPE and SWIFT Prime are published (SWIFT Prime is also positive per some non-reliable Covidian reps).

    Stent retrievers work great, but that doesnt mean the previous generation suctioning devices did not work. Large segment clots, saddle emboli and carotid terminus clots are still better treated with Penumbra ACE suctioning than by stent retrievers in my limited experience. The goal is to open the blood vessel as fast as possible. Some of the other reasons why IMS 3 was a negative study:

    1. Inclusion criteria did not include a large vessel occlusion (25 % of patients in IMS 3 had lacunar strokes)

    2. Very slow enrollment as a lot of patients (good candidates) were treated outside the trial, hence the results did not have consecutive enrollment. MR CLEAN sites rectified this problem by reimbursing only if they participated in the trial.

    Next year ISC would be historical. Hope to catch some of you there.

    Ahsan

  2. Dave Weisman says:

    I was also struck by the parallels between initial tPA trials and the new IA trials. But of course that’s a scary thought. Because as soon as IV tPA came out, it was misused and patients suffered predictable and terrible complications. We’ve already seen abuses without a shred of data to support these procedures. Now I worry that we’ve provided a bedrock of data to support leaning forward in these cases. My only solace is that IMSIII provided some lines of play. But will this be enough of a line? The current data supports interventions in only a small population of stroke patients.

    As far as this trial, I also look with political eyes. The Dutch trial was rapid because they ONLY pulled clots out of people in a trial. They treated an unproven experimental procedure as an unproven experimental procedure, first testing it, then finding it supported, using it. This is a failure of our regulatory agencies especially when compared to a better version.

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