Endovascular therapy for patients with acute ischemic stroke is currently an area of intense investigation. An Accreditation Council for Graduate Medical Education–approved training pathway was developed to train physicians for endovascular treatment of cerebrovascular diseases, including ischemic stroke.28
Training criteria and standards of performance for endovascular stroke treatment are summarized in a consensus document.17,29
The American Stroke Association has given qualified endorsement of intra-arterial fibrinolysis, despite its lack of scientifically proven efficacy in >1 trial. Intra-arterial fibrinolysis has been studied in several randomized trials and numerous case series but proven according to FDA standards in only 1 trial using prourokinase, a drug no longer available.4
Thus, intra-arterial fibrinolysis has the status of community standard in many locales, but remains an off-label application of any available fibrinolytic agent requiring further experimental proof of safety and efficacy for on-label application. Similarly, 2 devices have been granted US FDA approval with an indication for mechanical stroke thrombectomy, but no thrombectomy device has yet been scientifically proven to improve patient outcomes.
It has been recognized for nearly 20 years that intravenous fibrinolysis is less likely to recanalize large cerebral artery occlusions. Intravenous fibrinolysis is time-consuming, and the action of fibrinolytic agents may take ≥2 hours.30
Occlusions in more proximal locations, including the intracranial internal carotid artery and proximal middle cerebral artery, are more resistant to intravenous delivery of lytic agents, with only 8% to 12% probability of early recanalization.31
In contrast, intra-arterial administration of fibrinolytic agents has been shown to significantly increase the chances of recanalization.4
Although intra-arterial fibrinolysis has been used for nearly 3 decades and has shown apparent benefit in case series, Prolyse in Acute Cerebral Thromboembolism II (PROACT II)4
is the only randomized trial to date on the safety and efficacy of intra-arterial fibrinolysis in acute ischemic stroke. In this study, 12 323 stroke patients were evaluated to identify 180 eligible patients with proximal middle cerebral artery occlusions (1.4% of screened patients). Patients were randomized to treatment with intra-arterial prourokinase with intravenous heparin versus intravenous heparin alone. More than 10 years later, 66% recanalization and 40% good neurological outcomes achieved in PROACT II remain the yardstick by which newer endovascular methods are judged. Although higher rates of recanalization have been accomplished in more recent trials, 40% favorable neurological outcomes and 25% mortality remain the standard for new devices and techniques even a decade later ().
The EKOS MicroLysUS infusion catheter (EKOS Corp, Bothell, WA) was designed to augment intra-arterial fibrinolysis by creating local convection currents at the site of occlusion using low-intensity, high-frequency ultrasound. This facilitates diffusion of the lytic agent into the thrombus, increasing its effective surface area of interaction. A phase I trial reported preliminary results in 14 patients with 60% recanalization at 60 minutes despite treatment of large clot burdens in some patients.32
The device was tested again in Interventional Management of Stroke (IMS) II33
with promising results (), and is an option for use in the NINDS rt-PA-funded IMS III trial,34
which is currently enrolling at 60 stroke centers worldwide.
The data on intra-arterial fibrinolysis for vertebrobasilar occlusion are limited. Mostly because neurological outcomes are abysmal without treatment, review of the literature generally supports potential benefit even as long as 18 to 24 hours after symptom onset.5
A meta-analysis of multiple case series comparing intravenous with intra-arterial fibrinolysis for acute vertebrobasilar stroke in 422 patients showed marginally better recanalization rates with intra-arterial therapy (65% versus 53%; P
=0.5), good neurological outcomes in 22% to 24% of patients, but no clear difference in efficacy between the 2 modalities.35
Similar findings were demonstrated in 400 patients in the Basilar Artery International Cooperative Study (BASICS) trial.24
Lee et al31
performed a meta-analysis of randomized, controlled trials evaluating intra-arterial fibrinolysis for acute ischemic stroke. To date, PROACT II remains the only randomized, controlled trial of intra-arterial fibrinolysis to show a statistically significant clinical benefit.4
Four other trials demonstrated trends in favor of intra-arterial fibrinolysis, but were inadequately powered to demonstrate statistically significant improvement in neurological outcomes. For this reason, meta-analysis of combined data on 395 patients from 5 trials provides a strong indication of statistically significant good (odds ratio, 2.05; 95% confidence interval, 1.33 to 3.14; P
=0.001) and excellent (odds ratio, 2.14; 95% confidence interval, 1.31 to 3.51; P
Lee et al31
noted an interesting discrepancy between recanalization of occluded cerebral arteries and clinical outcomes. Intra-arterial fibrinolysis was associated with an absolute increase in the rate of partial or complete vessel recanalization (46.8%) over placebo therapy. Yet, the rate of recanalization is 3 times higher than the absolute increase in good (14.8%) or excellent (13.0%) clinical outcomes. Although recanalization and reperfusion are presumably benefits of intra-arterial fibrinolysis,36
these authors speculate that the disparity is due to either limitations in the outcome measurement tools to adequately detect real clinical improvement in stroke victims or completion of stroke injury before revascularization and reperfusion.31
The gap between recanalization and clinical improvement becomes more pronounced during the evaluation of mechanical revascularization studies performed up to 8 hours after stroke onset ( and ). Ultimately, this issue must be addressed for endovascular stroke therapies to succeed. Patient selection for treatment still needs to be defined, which may be the role for advanced brain viability imaging.
Figure 1 Higher rates of recanalization, approaching 90% in the Penumbra Pivotal Trial, do not correspond with similar rates of clinical improvement after treatment as measured by the modified Rankin scale (mRS) at 90 days. NIHSS indicates National Institutes (more ...)