In patients with acute ischemic stroke, endovascular therapy does not provide better outcomes than systemic intravenous (IV) thrombolysis, despite being more effective at opening obstructed vessels, according to findings presented February 6, 2013, at the International Stroke Conference in Honolulu, HI. Results from the randomized SYNTHESIS Expanded trial were simultaneously published online ahead of print in the New England Journal of Medicine.

Investigators led by Alfonso Ciccone, MD, of Carlo Poma Hospital (Mantua, Italy), randomized 362 patients with acute ischemic stroke presenting within 4.5 hours of onset to endovascular therapy (intra-arterial thrombolysis with recombinant tPA, mechanical clot disruption or retrieval, or a combination; n = 181) or IV tPA (n = 181).

No Difference in Primary Outcome

In the 90-day intention-to-treat analysis, patients receiving endovascular-treatment and IV tPA showed similar rates of disability-free survival, the trial’s primary outcome (defined as a modified Rankin score of 0 or 1; 30.4% vs. 34.8%; crude OR 0.82; 95% CI 0.53-1.27; P = 0.37), indicating that endovascular therapy did not meet the criterion for superiority. Adjustment for key variables including age, sex, initial stroke severity, and presence or absence of baseline atrial fibrillation yielded an odds ratio of 0.71 (95% CI 0.44-1.14; P = 0.16). Moreover, there was no difference in mortality between the endovascular and IV tPA groups (14.4% vs. 9.9%; P = 0.22).

In addition, safety outcomes within 7 days of treatment were similar between the 2 groups (table 1).

Table 1. Safety Outcomes at 1 Week

^a Defined as an increase of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS).

Multiple subgroup analyses showed that the effect of treatment on the primary outcome did not depend on factors such as time to treatment, stroke cause or territory, and center volume, even after adjustment for age, sex, initial stroke severity, and presence or absence of atrial fibrillation at baseline. Only NIHSS score (< 11 vs. ≥ 11) showed an interaction, with the lower score favoring IV tPA (OR 0.57; 95% CI 0.27-1.20; P for interaction < 0.001).

“This trial does not show that endovascular therapy achieves superior outcomes as compared with intravenous thrombolysis, and our findings do not provide support for the use of the more invasive and expensive endovascular therapy over intravenous treatment,” Dr. Ciccone and colleagues conclude.

Each Strategy Has a Role

In a telephone interview with TCTMD, L. Nelson Hopkins, MD, of University at Buffalo Neurosurgery (Buffalo, NY), characterized the trial as out of date due to substantial improvements in endovascular technology over the approximately 5 years since its inception.

Moreover, the investigators’ conclusion regarding endovascular therapy “represents a misunderstanding of the facts,” he said. Both systemic tPA and endovascular treatment are part of the therapeutic “toolbox” for stroke, and each has a role to play, Dr. Hopkins commented. “If a patient falls within the 4.5-hour window [since symptom onset], does not have a major vessel occlusion, and has a relatively low stroke score, then IV tPA is a good therapy,” he said. “But if the patient doesn’t improve rapidly, you’re doing them a real disservice if you don’t go get the clot out [mechanically]. There are reams of data showing that revascularization provides better long-term results. [And on the other side,] the percentage of cases in which IV tPA can reopen a major artery is relatively low.”

Endovascular Therapy in Trial Outdated

Dr. Hopkins’s main criticism of the trial is that about two-thirds of patients in the endovascular arm received local tPA infusion but only catheter and wire manipulation of the clot. “That is not really endovascular therapy,” he asserted. “And less than 20% received anything close to what we would call a modern-day approach—that is, a clot retriever.”

He also faulted the investigators for not using modern diagnostic techniques to screen patients. As a result, in some cases IV tPA may have been given when vessel occlusion was not the source of symptoms, he indicated. On the other hand, endovascular therapy may have been used to remove clots when the brain tissue served by the culprit vessel was no longer viable, making the treatment appear ineffective when in fact it was futile to begin with.

In a telephone interview with TCTMD, Harry J. Cloft, MD, of the Mayo Clinic (Rochester, MN), observed that clinicians are becoming increasingly alert to the phenomenon of ‘futile recanalization,’ in which patients are revascularized even when brain tissue downstream of the clot does not have sufficient collateral circulation to maintain viability.

Currently, it is difficult to identify those patients, he noted. “But if we get to the point where we can clearly identify the patients who are or are not going to benefit from recanalization, then these trials, and endovascular therapy in particular, will look a lot better,” Dr. Cloft said. “Right now we have way too many patients in these studies who have already infarcted their brain.”

Dr. Hopkins agreed. “You don’t revascularize people if they have a large volume of dead brain,” he said, “and the best way to tell that is by measuring blood volume in the area with CT angiography and CT perfusion.”

Currently, several trials, including SWIFT PRIME and PENUMBRA 3D, are under way comparing systemic tPA with up-to-date endovascular technology, Dr. Hopkins reported, adding that the current study is “of historical interest only.”

Study Details

The study arms were generally well matched with regard to baseline characteristics, except for atrial fibrillation, which was more common in the IV tPA group (16% vs. 8%; P = 0.02) and dissection as the cause of the stroke, which was more frequent in the endovascular therapy group (8% vs. 2%; P = 0.03).

The most widely used endovascular devices were Solitaire (ev3/Covidien, Irvine, CA; 18 patients), Penumbra System (Penumbra, Alameda, CA; 9 patients), Trevo (Concentric/Stryker, Mountain View, CA; 5 patients), and Merci (Concentric/Stryker; 5 patients).

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