MR-CLEAN & the New Golden Age

I, among many others, have been highly skeptical of thrombolytic therapy and its role in the treatment of acute ischemic stroke.  As has been well-documented, a few trials were positive, many were neutral, and a few were stopped early for harm or futility.  To most of us, this indicates a therapy for whom only a small subset of those treated are ideal candidates for benefit, and the margin between benefit and harm is razor thin.

In my previous posts, I’ve sighed wistfully at the hope of The Next Big Thing in stroke treatment – local endovascular therapy, akin to percutaneous coronary intervention.  However, each major endovascular trial published in the New England Journal last year failed to demonstrate benefit.

MR-CLEAN is different.  MR-CLEAN is rather unambiguously positive.  To be zero or minimally disabled?  The endovascular intervention is favored 12% to 6%.  “Functionally independent”, a modified Rankin Scale of 0-2, favors endovascular intervention 33% to 19%.  A number needed to treat of, apparently, ~8 for independence is nothing to scoff at.

But why?  It’s very similar to IMS-3, which was stopped early due to futility.  Patients are about the same age.  The comparator – usual care, typically tPA – is the same.  Median NIHSS is about the same.  The differences are quite subtle.  Patients were randomized earlier in IMS-3 compared with MR-CLEAN, with the implication IMS-3 includes patients whose natural course was superior, whereas MR-CLEAN enrolled “non-responders”.  The other difference, and the one you’ll hear by far the most frequently, is that MR-CLEAN utilized modern stent retrievers, rather than such killing machines as the MERCI device.  Newer, as you’ve always been taught, is better.

But, clearly, there’s something else we simply cannot splice out of these data.  Patients in MR-CLEAN did awful.  Recall NINDS, where a tPA cohort with a median NIHSS of 14 resulted in 39% attaining mRS 0-1.  In IMS-3, intravenous tPA with a median NIHSS 16 resulted in 26% mRS 0-1.  In MR-CLEAN, intravenous tPA with a median NIHSS of 18 resulted in 6% mRS 0-1.  Patients in MR-CLEAN did recanalize at a greater rate than those in IMS-3, 58% vs. 23-44%, owing to the improved performance of modern retrievers.  In a world where definitively opening the vessel, where reperfusion means time=brain, this makes sense.  But, like NINDS, the positive results do not seem so much to result from the intervention, but rather from the control group simply doing unwell.

As the embargo lifts, I’m sure this post is one of a tiny minority wondering if this is fool’s gold.  If you think of p-values like likelihood ratios, as initially intended, the presence of multiple prior neutral evaluations makes the bar for success that much higher in follow-up trials.  These are excellent results, results I’d like to believe in, but the totality of evidence to date requires they be validated.

I wholeheartedly expect they will not.  Prepare for the full onslaught of hype regarding endovascular therapy for stroke.

“A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke”

6 thoughts on “MR-CLEAN & the New Golden Age”

  1. My mother was treated in May 2012 in a Dublin hospital, with a Stryker Trevo stentretriever device, without informed consent. The family, when they asked clinical questions, were treated by the hospital, and continue to be treated, in an abominable fashion.

    The woman is now seriously disabled requiring 24 hour care and a major lawsuit is pending.

    We suspect, from our investigations over the last two years, that many patients have been treated with these devices, with poor causal outcome, and unreported.

  2. What do you mean by this statement?

    But, like NINDS, the positive results do not seem so much to result from the intervention, but rather from the control group simply doing unwell.

  3. Many folks contest the NINDS data on the basis of a feeling the control cohort had poorer outcomes than would expect, even beyond just the baseline imbalances.

    In MR-CLEAN here, only 6% of the tPA cohort achieved mRS 0-1. Even the IMS-3 cohort with NIHSS >20 saw 11% achieve mRS 0-1, and the median NIHSS here is lower. It's always a challenge to compare enrollment cohorts, but 6% is unexpectedly low – and favors the comparison. MR-RESCUE, SYNTHESIS, IMS-3, and ICARO-3 (as you'll see tomorrow) were all neutral, so these results should be highly suspect until confirmed.

  4. You missed another key difference – CTA positivity was required for MR CLEAN. This is a dramatically different cohort than the other studies you cite(both IV and IA), which relied on NIHSS scores for their inclusion, with many non large vessel occlusions randomized (i.e. lacunar strokes, small vessel distal occlusions, and TIA's) which have much better outcomes and dilute the poor outcomes of LVO's as seen in MR CLEAN. Other important issues you do cite are revascularization rates improving – big issue for all prior studies on first generation devices – 25 to 40% TICI 2b-3. MR CLEAN is better at approx 60% with newer generation devices. Still a long way to go, but I think this is an important first step in confirming "successful reperfusion" of "large vessel occlusions" will "improve clinical outcomes" over current standards (iv-TPA or nothing). Still need better revasc, patient selection, and alternative/innovative strategies to make more progress. I don't disagree with healthy skepticism of iv tPA and IAT trials, and that confirmation is needed. Some progress in this deadly disabling stroke subtype is better than none.

  5. Fair points, for sure, and part of why it's difficult to compare cohorts across trials due to differing eligibility criteria. And, perhaps, a very narrow cohort of proximal large-vessel occlusion is reasonable for IAT. However, ICARO-3 is all ICA occlusions with median NIHSS 16, and the tPA-only cohort there had 18.2% mRS 0-1. I stand by my puzzlement over the tPA-only cohort in MR-CLEAN doing so poorly.

  6. Just speculating, but ICA occlusions might have an inherently more favourable prognosis due to more extensive collateral circulation compared to MCA occlusions which made up the biggest group in the Mr Clean trial?

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