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”