MR CLEAN-NO IV: No Advantage to Skipping tPA Before Stroke Thrombectomy
There may be scenarios where foregoing IV thrombolytics make sense, but most centers can stick with the guidelines, experts say.
For patients who present to a thrombectomy-capable center, a direct trip to endovascular therapy does not improve functional outcomes compared with the guideline-recommended approach of giving IV thrombolytics before the procedure, the MR CLEAN-NO IV trial shows.
In the study—designed to assess the superiority of the more-direct approach and not noninferiority like other recent trials—there was no difference between groups in terms of the ordinal modified Rankin Scale (mRS) score at 90 days, Yvo Roos, MD, PhD (Amsterdam UMC, University of Amsterdam, the Netherlands), reported during the virtual International Stroke Conference 2021 last week. Roughly half of patients in each group were functionally independent (mRS 0 to 2) at that time point.
“The MR CLEAN-NO IV trial did not show any superiority nor noninferiority of direct endovascular treatment over the combination treatment with alteplase and endovascular treatment,” Roos said, noting that hemorrhage rates also were similar in the two arms.
Later in the same session, Raul Nogueira, MD (Emory University School of Medicine, Atlanta, GA), presented results from the SHRINE collaboration, which pooled patient-level data from two prior trials of direct thrombectomy versus IV thrombolysis plus endovascular therapy, DEVT and SKIP, both of which were published earlier this year in JAMA. The analysis fell short of establishing the noninferiority of skipping IV alteplase (Activase; Genentech) before the intervention.
“Overall, these studies suggest that use of intravenous thrombolysis remains a viable strategy prior to mechanical thrombectomy,” American Stroke Association spokesperson Philip B. Gorelick, MD (Michigan State University, Grand Rapids), commented to TCTMD in an email. “However, there may be clinical scenarios whereby one may wish to individualize the treatment decision.”
MR CLEAN-NO IV
The publication of the original MR CLEAN trial in December 2014 heralded the arrival of mechanical thrombectomy as a safe and effective treatment for patients with acute ischemic strokes caused by large-vessel occlusions. Several more positive trials soon followed, with a focused guideline update recommending thrombectomy for select patients not far behind.
Recommendations continue to call for the administration of IV thrombolysis in eligible patients before endovascular therapy, though there’s uncertainty about whether that’s necessary. Data from the HERMES collaboration, which pooled patient-level data from five major thrombectomy trials, showed that the procedure significantly improved functional outcomes regardless of whether IV alteplase was administered beforehand.
In addition, three recent randomized trials conducted in Asia—DIRECT-MT, DEVT, and SKIP—showed similar thrombectomy outcomes when IV alteplase was not administered, although SKIP was unable to establish the noninferiority of the approach, a result attributed to higher-than-expected rates of recanalization and favorable outcomes.
Gorelick explained that arguments in favor of IV thrombolysis before thrombectomy touch on the possibilities of either establishing substantial reperfusion without the need for further intervention or softening the clot and making it easier to extract during thrombectomy. Potential downsides, on the other hand, include risks of hemorrhage and of delays to thrombectomy.
MR CLEAN-NO IV, performed at two centers in France, two in Belgium, and 16 in the Netherlands, provides more data to inform this discussion. Trial investigators randomized 539 patients who had acute ischemic strokes caused by large-vessel occlusions in the anterior circulation and who presented to a thrombectomy-capable center.
Functional outcomes did not differ between trial arms, and the only secondary efficacy outcome that did—median NIHSS score after 5 to 7 days or discharge—favored the administration of IV alteplase before the procedure.
The mortality rate was numerically higher in the patients who did not receive IV alteplase, although the difference was not significant (20.5% vs 15.8%; OR 1.39; 95% CI 0.84-2.30). There was no difference between the direct and combination arms in terms of any intracranial hemorrhage (35.9% vs 36.4%; OR 0.99; 95% CI 0.70-1.41) or symptomatic ICH (5.9% vs 5.3%; OR 1.31; 95% CI 0.61-2.84).
After pooling results of MR CLEAN-NO IV and the previous three Asian trials, there was no difference between approaches for achievement of functional independence (mRS 0 to 2) at 90 days (OR 1.04; 95% CI 0.83-1.29).
The SHRINE collaboration analysis combining patient-level data from DEVT and SKIP included a total of 438 patients randomized to thrombectomy with or without prior IV thrombolysis.
Nogueira and colleagues performed a noninferiority analysis to assess the impact of skipping IV thrombolysis on the achievement of functional independence at 90 days. The point estimate favored the streamlined approach (adjusted OR 1.27; 95% CI 0.84-1.92), but the criteria for noninferiority were not met (P = 0.06). There were no differences between groups for any of the other measures of functional status at 90 days, or for assessments of successful reperfusion or early clinical response, either.
Symptomatic ICH was numerically, but not significantly, higher in the IV thrombolysis plus thrombectomy arm (9.0% vs 6.5%; P = 0.49). The rate of any ICH, however, was significantly greater with the addition of alteplase (39.4% vs 26.3%; P = 0.004), as was the rate of puncture complications (4.1% vs 0.5%; P = 0.03).
Survival at 90 days was high at about 87% in both groups.
A Call for Individualized Decision-making
Leading into his presentation, Nogueira underscored that results from all of these types of trials apply only for situations in which patients present directly to a thrombectomy-capable center—or “mother ship”—with a fast workflow and immediate availability of the neuroendovascular team. In any other scenario, “we must continue to provide IV tPA to all eligible patients,” he said, noting, too, that none of these trials evaluated use of IV tenecteplase (TNKase; Genentech).
He issued a call for a more-tailored approach to choosing when IV thrombolysis should or should not be used before thrombectomy.
“I think the overall data shows bridging [with IV alteplase] is neither dangerous nor a panacea,” Nogueira said. “And I think the overall results highlight the importance of departing from polarized decision-making [and moving] to precision medicine. The critical question should not be, ‘Should you be giving or not giving alteplase to all [large-vessel occlusion] mother-ship patients?’ But rather, ‘Who are the specific patients that benefit from bridging versus not when they present to a mother ship?’”
Nogueira pointed out that a SHRINE subgroup analysis hinted that leaving off IV thrombolysis might be particularly beneficial in three groups—those with expected onset-to-puncture times above 3 hours, with intracranial internal carotid artery occlusions, or with atrial fibrillation.
Gorelick agreed that direct thrombectomy might be preferred in those three groups. On the other hand, he commented, “for those who are longer distances or times away from a hub center that performs mechanical thrombectomy, intravenous thrombolysis should be performed, if it can be done so safely.”
Roos Y. Intravenous thrombolysis followed by endovascular thrombectomy versus direct endovascular thrombectomy: a randomized controlled trial. Presented at: ISC 2021. March 18, 2021.
Nogueira RG. Systemic thrombolysis randomization in endovascular stroke therapy (SHRINE) collaboration. Presented at: ISC 2021. March 18, 2021.
- MR CLEAN-NO IV was part of the CONTRAST consortium, which is supported by Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, and by the Brain Foundation Netherlands, Medtronic, Health~Holland, and Top Sector Life Sciences. AMC and Erasmus MC received additional unrestricted funding for the execution of MR CLEAN NO-IV from Stryker European Operations BV.
- Roos reports being a shareholder of NICO.LAB.
- Nogueira reports receiving honoraria from Anaconda, Genentech, Biogen, and Prolong Pharmaceuticals; having other relationships with Stryker Neurovascular, Medtronic, Cerenovus, and Phenox; receiving other research support from Sensome and Corindus Vascular Robotics; serving as a speaker for IschemaView; and holding stock in Brainomix, Viz-AI, Corindus Vascular Robotics, Vesalio, and Ceretrieve.
- Gorelick reports no relevant conflicts of interest.