Similar Result With Endovascular Therapy vs tPA in Cervical ICA Stroke

Susan Jeffrey

February 14, 2014

SAN DIEGO, California — A new case–control study finds no difference in the rate of favorable outcome after an acute cervical internal carotid artery (ICA) occlusion when patients received standard treatment with intravenous (IV) thrombolytic therapy out to 4.5 hours after symptom onset compared with endovascular therapy offered up to 6 hours after symptoms began.

Endovascular therapy was associated with a higher rate of intracranial hemorrhage (ICH), but the increase did not translate to higher mortality, the researchers, led by Maurizio Paciaroni, MD, Santa Maria della Misericordia University Hospital in Perugia, Italy, reported. "In fact, this rate was significantly lower in the endovascular treated group, compared to patients treated with IV tPA," Dr. Paciaroni pointed out. The number of patients with severe disability and death was similar between groups, he added.

"In view of the nonrandomized design of this study, these results should be interpreted with caution," he concluded. "In future, we look forward to confirming these results in a larger randomized study."

The results, from the ICARO-3 study, were presented here at the International Stroke Conference (ISC) 2014.

Case–Control Design

The aim of this case–control study was to compare intra-arterial (IA) therapy, either mechanical therapy or IA tPA offered to patients up to 6 hours after symptom onset, with systemic IV tPA given within 4.5 hours of symptom onset.

Dr. Maurizio Paciaroni

Cases were consecutive patients treated with endovascular therapy at 1 of 37 stroke units in the United States, Europe (most in Italy), and Asia between 2010 and 2013. Controls were selected from a series of 418 consecutive patients treated with IV tPA, matched to cases for age, sex, and severity of stroke. Patients with so-called tandem occlusions, affecting the extracranial ICA and the middle cerebral artery, were also included.

Before treatment, ICA occlusions were diagnosed with carotid ultrasonography, computed tomographic (CT) angiography, magnetic resonance angiography (MRA), or angiography. "Physicians were free to follow treatment procedures for IV or IA according to the clinical picture and/or neuroradiological reports," Dr. Paciaroni noted.

Matching was done in the absence of any information about the patients' final outcomes. Inclusion and exclusion criteria followed the SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) criteria, except the age limit at 80 years, he said. Cases received IA thrombolysis that was, when necessary, combined with or substituted for mechanical clot disruption and/or retrieval, he noted. Patients who received both IA and IV thrombolysis were included with the cases.

The primary efficacy outcome was disability at 90 days measured using the modified Rankin scale (mRS) and dichotomized into favorable outcome (mRS score, 0 to 2) or unfavorable outcome (mRS score, 3 to 6). Safety outcomes were mortality at 90 days, any intracranial bleeding, fatal intracranial bleeding, and other adverse events.

There were 324 patients in each group; risk factors were balanced between groups and the median National Institutes of Health Stroke Scale (NIHSS) score was 16, meaning patients had severe strokes, he said. All patients who had IA procedures had the occlusion confirmed with angiography, while patients receiving IV tPA were diagnosed mostly by ultrasonography and CT angiography.

Tandem occlusions were present in 13% of the IA group and 13% of the IV tPA group for whom CT angiography or MRA images were available. IA procedures were varied, including in some cases stenting, and combinations of IV, IA, and mechanical approaches.

On the primary efficacy endpoint, they found that despite a 5% absolute increase in favorable outcome with the IA approach, the difference between the 2 treatments was not statistically significant.

Table 1. ICARO-3: Primary Efficacy Outcome

Endpoint Procedures, n (%) IV tPA, n (%) OR (95% CI), Adjusted Analysis P Value
Favorable outcome (mRS score, 0 - 2) 105 (32.4) 89 (27.4) 1.25 (0.88 - 1.79) .1

CI = confidence interval; OR, odds ratio.


Any ICH and fatal ICH were more common with IA procedures than with IV tPA, but overall mortality was lower. The percentage of patients with severe disability or death (mRS score, 5 – 6) was similar between groups.

Table 2. ICARO-3: Safety Outcomes

Endpoint IA Procedures IV tPA OR (95% CI) P Value
Any ICH, n (%) 120 (37.0) 56 (17.3) 2.82 (1.95 - 4.06) .0001
Fatal ICH, n (%) 19 (5.9) 7 (2.2) 3.31 (1.30 - 8.40) .01
Death, n (%) 57 (17.6) 75 (23.1) 0.61a (0.40 - 0.93) .022
mRS score, 5 - 6 (%) 30.5 32.4 .67

aAdjusted analysis.


Mechanical procedures, alone or in combination with IA or IV thrombolysis had a greater rate of good outcome and lower mortality, with "acceptable" rates of fatal and intracranial hemorrhage compared with IV tPA, he noted.

Looking at causes of death, the only significant differences between groups was that malignant edema was more common with IV tPA (9.0% vs 4.1%; P = .01), and hemorrhagic transformation was more common with IA procedures (5.8% vs 2.2%; P = .01).

"Regarding the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes and atrial fibrillation, the common odds ratio resulted being 1.15 and it was not statistically significant," Dr. Paciaroni said (95% CI, 0.86 - 1.54; P = .33).

Running Theme?

Asked to comment on these findings, Larry B. Goldstein, MD, professor of medicine (neurology) at Duke University, Durham, North Carolina, pointed out that large ICA occlusions don't seem to respond as well to thrombolytic therapy, probably because of the larger clot burden. "That's been one of the arguments for trying to use endovascular therapy for those patients in particular," he told Medscape Medical News.

Dr. Larry B. Goldstein

ICARO-3 was a case–control study evaluating the outcomes of patients with ICA occlusions treated endovascularly compared with patients who were treated with standard IV tPA, he noted. "And the bottom line, looking at the data, is that firstly, there was no difference in patient outcome, so the 2 seemed to perform similarly."

There also appeared to be an increase in bleeding in those receiving endovascular treatment, Dr. Goldstein pointed out. "The problem with this is that it's a case–control, retrospective analysis," he said. "A variety of different treatment regimens was used, a variety of endovascular approaches were used, and internal carotid artery occlusions may just be very, very difficult to treat, no matter how we try to approach them.

"What this didn't do, however — which is what one would hope for — is show that the endovascular approach would result in better patient outcomes compared to intravenous tPA," he concluded. "This seems to be a theme that keeps coming up — yes, we can identify subgroups of patients who might not respond as well to IV tPA as we would like, but endovascular therapy, so far, hasn't proven to be better for those patients than just standard tPA."

Last year at this meeting, 3 major phase 3 trials, SYNTHESIS, MR-RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy), and IMS-III (Interventional Management of Stroke III), all showed no incremental benefit of endovascular therapy.

International Stroke Conference (ISC) 2014. Abstract LB9. Presented February 13, 2014.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.