Intravenous tissue plasminogen activator (IV tPA) is generally effective in a wide range of patients with acute stroke,1,2 and can be administered in nearly any acute care hospital, at least theoretically, because no advanced resources are necessary.3 IV tPA is therefore the best option for most patients. However, one of the major lessons learned from the pivotal NINDS trial1 establishing the efficacy of IV tPA for acute stroke was that, despite aggressive therapy, the majority of patients were still left disabled or dead. New strategies are desperately needed to improve outcome. IV tPA is essentially a “one size fits all” treatment, based only on clinical presentation and CT of the brain, not visualization of the target thrombus. Recanalization rates of major occlusions may be relatively low, possibly <25%. Further, up to 20% of patients have clinical deterioration following improvement with IV tPA, most often due to reocclusion,4 though collateral failure, reperfusion injury, edema, and other explanations have been proposed.5 Clinicians are therefore left to ask, “What more could be done?”
Intra-arterial (IA) thrombolysis is effective,6 but remains an unapproved, off-label treatment for acute stroke. Potential advantages of IA thrombolysis include direct visualization of the acute large vessel thrombus, the ability to individualize the dose and location of drug delivery based on specific features of the clot, and possibly more complete clot lysis. Recanalization, the most critical determinant of good clinical outcome,6 can be verified during IA treatment as a marker of procedural success. Unfortunately, IA thrombolysis takes much longer to initiate than IV thrombolysis, particularly during off hours, and is only available in a relatively small number of specialized centers. Clinicians who use IA therapy have to deal with the question, “How can we get patients to tertiary centers and start treatment sooner?”
The Interventional Management of Stroke (IMS) Study sought to combine the advantages of these two methods, improving time to initiation of treatment with IV tPA, then bridging to more directed treatment and possibly more complete recanalization with IA thrombolysis. After initial treatment with low dose (0.6 mg/kg) IV tPA alone, only ≈5% of patients appeared to have partially or completely recanalized. Of 62 patients subsequently given IA tPA for major arterial occlusions, recanalization (TIMI 2 or 3 flow) was achieved in 56% of patients. There was no placebo arm in the IMS study, so comparisons were made to patients in the NINDS tPA trial. The safety profile of the combined approach was comparable to that of standard dose IV tPA. The efficacy results may at first seem unimpressive despite the high rate of recanalization; outcome with combined IV/IA therapy was clearly better than with placebo, but only equivalent to or perhaps modestly better than IV tPA alone. Is this aggressive and resource-intensive intervention necessary if the results are similar to IV tPA by itself? The limitations of the historical cohort used for this comparison must be considered in answering this question. Patients in the IMS study had persistent major vascular occlusions despite early IV tPA treatment and probably greater clot burden than those treated in the NINDS trial, had more atrial fibrillation (possibly contributing to larger embolic occlusions), and were treated later, but still tended to have better outcomes. Thus, the IMS results are promising, and suggest the possibility of greater efficacy over IV tPA alone.
If ultimately proven effective, combining IV/IA thrombolysis in practice will be logistically challenging. To traverse existing technology and resource gaps, IV treatment may start at community hospitals, followed by transfer to comprehensive stroke centers for IA lysis. However, there are too few interventional neuroradiologists to provide this treatment everywhere, and neurologists, cardiologists, and surgeons may be called on to be trained in this technique.
One great achievement of the IMS trial was its completion in record time, about three times faster than expected. This amazing pace, particularly at the top enrolling centers, attests to the benefits of regionally organized stroke care in improving access to acute therapy. However, it may have been relatively easy to obtain informed consent for participation in this study since there was neither a placebo arm nor randomization. Subsequent trials will likely require randomization to compare therapeutic strategies, and obtaining consent will likely become more difficult. The Prolyse in Acute Cerebral Thromboembolism (PROACT-II) trial took over 2 and a half years to enroll 180 patients,6 and a comparison of IV/IA versus IV thrombolysis alone would probably need about 400 patients in each arm to demonstrate superiority of the combined approach.
The NINDS tPA trial revolutionized acute stroke therapy, but it is clear that IV tPA alone is not enough. The IMS study has now set the standard for testing other interventions that might augment the efficacy of tPA, such as combinations of thrombolysis with glycoprotein IIb/IIIa antagonists, direct thrombin inhibitors, external or local ultrasound, mechanical clot retrieval or maceration, neuroprotective strategies, and others. We can probably improve on a good thing, and there is more than one way to lyse a clot.
The NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997; 28: 2119–2125.
Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002; 59: 862–867.
Grotta JC, Welch KM, Fagan SC, Lu M, Frankel MR, Brott T, Levine SR, Lyden PD. Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke. 2001; 32: 661–668.
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F, for the PROACT Investigators. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA. 1999; 282: 2003–2011.