How many times have you spoken with interventional radiology and heard about the latest and greatest endovascular treatment for acute ischemic stroke? If they had their way, treatment for stroke will be treated just like STEMI and patients will be taken away to angiography suites. The physiology seems to make sense, remove the clot and improve perfusion, or does it? Up until now, evidence has come mostly from a “physicians experience”, non-randomized trials, or outcomes looking at revascularization rather than hard clinical end-points like neurologic function using a modified-rankin scale. The first, to my knowledge, of a published RCT comparing intravenous tPA vs. IA thrombolysis with threombectomy has been published in the NEJM.
1. Why is this topic important?
Several non-randomized trials and cohort studies have suggested that thrombectomy and revascularization after acute ischemic stroke improves outcomes for patients with large vessel occlusions. Up until this point no randomized controlled trials comparing the current standard of care (IV tPA) with mechanical embolectomy has been undertaken.
2. What does this study attempt to show?
This study attempts to identify whether there is improved survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6 with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms and 6 indicating death) at 3 months after acute ischemic stroke.
Patients were randomized within the 4.5-hour time frame if they had symptoms of a stroke and a head CT without signs of an ICH. Patients were randomized to one of two arms:
1. Intra-arterial thrombolysis with the option for mechanical thrombectomy.
2. Intravenous thrombolysis as previously described (NINDS and ECASS).
If patients were outside the time window of 4.5 hours they were excluded. Due to operator delays patients who were randomized to IA tPA could still receive treatment up to 6 hours as long as they were randomized prior to the 4.5 hour mark.
The interventionalist could instill up to 0.9 mg/kg (or 90mg) of IA tPA (the dose given IV) and not higher. They could use a mechanical device if the operator believed it was indicated. If upon angiography there was no identifiable thrombus the operator could instill tPA into the region that was presumably affected, if clinically warranted. If the patient had no neurologic deficit, or rapidly improving symptoms then the operator did not have to proceed with angiography.
3. What are the essential findings?
Between February 1, 2008 and April 16th 2012, 362 patients were enrolled. 181 patients in the IA +/- thrombectomy arm, and 181 in the IV tPA (control) arm. Baseline characteristics were similar (table 1). Average NIHSS was 13.
Of the 181 patients assigned to endovascular therapy, 15 did not receive the treatment (6 because of clinical improvement, 3 because of a lack of evidence of occlusion on angiography, 3 because of dissection, 1 because of an unknown bleeding diathesis, 1 because of a groin hematoma, 1 because of delayed availability of the interventionalist.) 3 procedures were interrupted due to equipment complications.
In total 165 patients underwent endovascular treatment. 109 had IA thrombolysis, and 56 had a device deployed. The median dose of tPA was 40mg.
Primary outcome at 90 days is show in figure 1. 30.4% of patients undergoing thrombectomy survived without disability, and 34.8% of patients in the IV tPA group survived without disability, OR 0.82 (95% CI 0.53-1.27; P=0.37).
At 90 days 26 patients in the endovascular treatment group (14.4%) and 18 in the intravenous (9.9%) group had died.
On secondary analysis, stratifying for time to randomization, age, NIHSS, stroke territory did not affect odds ratio as NONE favored the endovascular treatment. Overall treatment with IV tPA was favored (figure 2).
4. How is patient care impacted?
In patients with acute ischemic stroke, this study represents the first relatively large randomized controlled trial comparing thrombectomy to intravenous tPA. IV tPA is cheaper, less labor intensive and appears to have similar and possibly improved efficacy compared with endovascular therapy. The trial does not support the routine use of interventional procedures for acute ischemic stroke.
Previously the consensus was that endovascular therapy was superior to IV tPA alone due to increased recanalization rates seen in previous trials. This theory made clinical sense, improve flow and save the ischemic penumbra. However, several studies just released in the NEJM refute this contention.
5. Is this an area of controversy?
As always it is. The interventionalists will argue that t IV tPA can be followed by endovascular therapies for patients who do not achieve recanalization. Also, “the latest and greatest” retrieval devices will be argued to improve outcomes as these older devices were more “rudimentary.”
This study also does not even question the utility of tPA in acute ischemic stroke as apparently that bus has left the station, despite many randomized trials demonstrating harm. Although I don’t think it is quite dead yet, Endovascular therapy may be added to the same bin as many other interventions before it: Vioxx, Xigris, Avandia, Diehtylstilbestrol…
6. Major Limitations of the study?
The study is a well completed randomized controlled trial. However, several limitations still exist.
First, there were inconsistencies in what types of interventions were performed. Several patients randomized to the interventional arm got both IA tPA and thrombectomy while others received IA tPA alone. Also, the dosing of IA tPA was also not standardized, and this could potential confound the results. The authors acknowledge this when they state this is a pragmatic trial as there is no standard of IA tPA or when to deploy a mechanical device, as this is mostly based on operator experience.
In addition, it is possible that patients with angiography defined acute ischemic stroke in a large vessels may have greater benefit, as that was not part of the inclusion criteria in this trial. Only 1/3 of patients had a large vessel atherosclerosis or cardiogenic embolism as the cause (the rest were small-vessel and other). Therefore whether or not more benefit would be derived from obtaining a CTA and identifying these patients first is questionable. The authors argue that the CTA adds significant time delays to an already time sensitive situation and that the probability that a CTA adds significant benefit is “unlikely”.
Lastly some interventionalists ask for systemic thrombolysis first, and then complete thrombectomy afterwards. Whether this approach is more efficacious can not be ascertained by this study.
Take home points!
1. Intra-arterial thrombolysis in acute ischemic stroke without systemic thrombolysis does not offer improved neurologic survival compared to systemic thrombolysis for acute ischemic stroke.
OF note several trials were all presented on Feburary 8th 2013 at the international stroke conference, ALL WERE NEGATIVE. Abstracts provided below.
MR RESCUE- Kidwell and colleagues completed a randomized controlled trial in 118 patients within 8 hours after the onset of large-vessel, anterior-circulation strokes comparing mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14). Conclusion: A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care.
IMS III trial- In patients with moderate-to-severe acute ischemic stroke who received intravenous t-PA within 3 hours after symptom onset, Broderick et al randomly assigned eligible patients to receive additional endovascular therapy or not, in a 2:1 ratio. The study was stopped early because of futility after 656 participants had undergone randomization. The proportion of participants with a modified Rankin score of 2 or less (indicating functional independence) at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA alone; absolute adjusted difference, 1.5 % points; 95% CI 6.1 to 9.1). Mortality was unchanged at 90 days ( endovascular-therapy: 19.1% versus intravenous t-PA 21.6%; P=0.52), as was the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). Also, there were there no significant differences for the predefined subgroups of patients with an NIHSS score of >20 or <20. Conclusion: Additional endovascular therapy after intravenous t-PA was not associated with improved outcomes in acute ischaemic stroke.
Ciccone et al. Endovascular treatment for Acute Ischemic Stroke. NEJM. 2013; 1-10.
UNTIL NEXT TIME!