Various approaches have been undertaken to limit the acute and long-term effects of stroke. These include thrombolysis (systemic or direct intra-arterial), pharmacologic interventions to limit secondary stroke insults, and modulation of cerebral metabolism. With the exception of early thrombolysis in thrombotic stroke (<3h), none of these has been shown to be effective, been universally accepted, or made a large impact on stroke outcome [1]. One of the current keys therefore remains stroke prevention through control of hypertension and appropriate anticoagulation of patients with atrial fibrillation (~4% of patients over the age of 65 and 15% over 75).

In 1996 after the National Institute of Neurological Disorders (NINDS) trials 1 and 2, the Food and Drug Administration approved the use of systemic tissue plasminogen activator (t-PA) within 3 hours of the onset of acute thrombotic or ischemic stroke. Unfortunately <5% of stroke patients qualify for this therapy. Therefore, the search continues to identify effective therapies that can be instituted with less morbidity (hemorrhagic stroke development after lytic therapy) and at a later time. Furthermore, although restoring blood flow to ischemic brain is important, it does not address the multiple neurochemical changes that lead to progressive cell insult and neuronal death. To that end, a host of pharmacologic modulators including glutamate antagonists, nitric oxide transduction inhibitors, free radical scavengers, ion channel antagonists, anti-inflammatory agents and antibodies, growth factor agonists, and others have been investigated as means to improve survival and quality of life after a cerebral vascular accident (CVA).

These two JAMA studies address differing approaches to the use of lytic therapy in the thrombotic strokes that comprise about 80% of CVAs. Thrombotic strokes develop most commonly in the distribution of the middle cerebral artery (MCA). Occlusion of the carotid arteries is the second most common site of thrombotic insult.

Six previous trials administering systemic lytic therapy up to 6 hours after CVA failed to show benefit. The heterogeneous nature of stroke pathology has been cited as a major cause of this poor outcome. The PROACT (prolyse in acute cerebral thromboembolism) II study evaluated the intra-arterial infusion of higher doses of recombinant prourokinase (r-pro-UK; 9 mg vs. the 6 mg used in PROACT I) in a homogeneous population of patients who suffered MCA insults only [2]. In contradistinction to other studies, PROACT I and II looked only at patients suffering MCA strokes, and PROACT II included the most severe stroke victims studied to date. Slightly over 12,000 patients were screened in this open label, randomized multicenter study. Just under 500 underwent screening cerebral angiograms at a median of 4.5 h after insult with 180 patients randomized to receive r-pro-UK or placebo (121 received drug plus i.v. heparin while 59 were controls on i.v. heparin only). The two groups were reasonably well matched. Treated patients had a higher incidence of hemorrhagic events after therapy when compared to control and not all treated patients had complete recanalization of the MCA. However, the PROACT II treatment group had a significantly improved clinical outcome (~15% better) at 90 days when compared to controls.

The ATLANTIS study was a randomized, controlled study of r-TPA (alteplase) performed as a multicenter study [3]. It included 547 patients treated between 3 to 5 hours after the onset of stroke. Roughly half received 0.9mg/kg of t-PA, the remainder placebo. The groups were again well matched. Unfortunately, there was no benefit at 90 days for CVA patients given t-PA within 3 to 5 hours of insult. There was a significantly higher hemorrhagic stroke rate in t-PA treated patients (~7%, but this was not higher than the incidence in the earlier NINDS trials) and a trend toward higher mortality. Of note, patients in this study had milder strokes than PROACT and others. Whether that had an effect on outcome in that there was better spontaneous recovery is open to debate.

The PROACT II and ATLANTIS studies were expensive and time-consuming, taking 2.5 and 4.5 years, respectively, to complete. Consistent with other lytic trials and studies with the defibrinogenating agent Ancrod, neither study improved survival. However, intra-arterial r-pro-UK did improve the 90-day quality of life. This approach requires a sophisticated multidisciplinary care of stroke patients with a dedicated interaction of emergency room physicians, neurologists, interventional radiologists, and technical support.

So where does this leave us? Stroke is a heterogeneous disease. Clot busting is not the answer for all thrombotic strokes and it does not appear to improve survival. However, in a subset of patients within a specific time frame, it does improve the quality of life for survivors. Improvements in microcatheter technology, mechanical clot removal techniques, and thrombolysis may lead to faster and more complete recanalization of the MCA and even better patient outcomes. There are still various issues that remain unresolved. How do we get the right patient to a stroke center in a timely fashion and institute therapy? How do we effectively identify patients who have viable, ischemic brain after stroke? What other pharmacologic therapies will improve stroke survival and post-stroke viability? Stay tuned!

1. Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work. Stroke 1999; 30:180-182).