Ischemic stroke: Interventional treatment + alteplase = new standard of care? (MR CLEAN)

In the early 1990s, the clot-busting drug alteplase (intravenous recombinant tissue plasminogen activator or rTPA) revolutionized stroke treatment when it was shown to significantly increase the chances of a good outcome after ischemic stroke when given in the first 4.5 hours since symptom onset. But alteplase is not a miracle drug. In a meta-analysis of 9 randomized trials, rTPA improved the chance of a good functional outcome (no significant disability at 3-6 months) by about 10% absolute (improvement from 23% to 33%) in those receiving it within 3 hours, and by 5% (from 30% to 35%) when given within 4.5 hours. Those are still pretty lousy odds, if you or your loved one is having the stroke. And that's if you get alteplase at all -- most ischemic stroke patients do not present in time, or have contraindications to rTPA (recent surgery, history of intracranial hemorrhage, or coagulation abnormalities). Several trials of alteplase have not shown benefit, and some observers have asserted that alteplase does not improve overall outcomes from ischemic stroke at all. One reason alteplase does not produce more consistently great outcomes is that rTPA has poor clot-busting effects in the anterior circulation at the origins of the internal carotid artery and other major intracranial arteries. These account for more than a third of strokes, and alteplase treatment is only successful about a third of the time for such lesions. Invasive interventional (intra-arterial) treatment can directly approach occluded vessels and achieve reperfusion, through local catheter-directed thrombolysis or mechanical thrombectomy (or both). Previous trials testing such interventions have been rendered obsolete by improvements in both interventional and drug treatments, and physician experience showed interventional approaches work where alteplase fails. Some housekeeping was due, prompting the MR CLEAN trial, published in the December 17 2014 New England Journal of Medicine. Authors randomized 502 patients at 16 centers in the Netherlands presenting within 6 hours of an ischemic stroke from an occlusion in the proximal anterior circulation to receive usual care (alteplase) or usual care plus arterial catheterization followed by catheter-directed thrombolysis and/or mechanical thrombectomy (at the discretion of the interventionalist). Before randomization, 90% of subjects received alteplase as usual care. After 90 days, 33% of the patients in the interventional arm were functionally independent (Rankin 0-2), compared to 19% receiving alteplase alone. More patients had visible reduction in occlusion of their lesion on imaging (75% vs 33%). Adding an interventional approach to alteplase may have increased later "aftershock" strokes, however: at 90 days, ~6% of patients receiving alteplase and intraarterial treatment had another stroke, while only 0.4% of those in the control arm did. Also, ~10% of patients undergoing inter-arterial treatment had complications: 9% were embolizations into other vascular territories, some resulting in neurologic deficits; 2.6% had vessel dissections or perforations. As noted above, despite these complications, the interventional approach resulted in a 14% absolute increase in functional independence. There were no differences in mortality or intracranial hemorrhage between groups. 24-hour availability of intra-arterial treatment for acute stroke requires staffing with multiple interventionally-trained physicians (neurologists, neuroradiologists, or neurosurgeons in the U.S.). There are not enough of these highly trained and expensive specialists to cover even a small minority of hospitals in the U.S., so this therapy will be practically limited to larger cities or academic medical centers. Make no mistake, though: MR CLEAN may be a practice-changer. With almost 700,000 ischemic strokes per year in the U.S., roughly 200,000 people per year would have proximal occlusions in the anterior circulation theoretically treatable with intra-arterial therapy. (Only about 1 in 20 people admitted with ischemic stroke actually received tPA at reporting centers in a registry 2003-2011, but the rate is increasing.) Expect MR CLEAN to trigger an expansion in interventional fellowship training programs, and an arms race among urban hospitals competing to offer 24/7 interventional stroke coverage. Validation is needed before certifying a new standard of care -- this was an unblinded (open label, pragmatic) trial, and we saw what happened with therapeutic hypothermia. Still, the high plausibility of the mechanism of benefit and the dire need for effective interventions in this common and devastating problem could justify a hasty adoption of this strategy. Based on MR CLEAN, wouldn't you want intra-arterial treatment for your family member if a skilled interventionalist were on duty?

Clinical Takeaway: Intra-arterial interventions (thrombolysis or mechanical thrombectomy) after alteplase improved outcomes from ischemic stroke caused by proximal occlusions in the anterior intracranial arterial circulation, as compared with alteplase alone, when performed within 6 hours of symptom onset.

Read more:

Olvert A. Berkhemer et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. (MR CLEAN trial). N Engl J Med online December 17, 2014.