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TWO
THROMBOLYTIC THERAPIES MAY BE BETTER THAN ONE
PHILADELPHIA—Stroke management is advancing to the point where it may soon be possible for patients with acute ischemic stroke to be treated with not one but two thrombolytic therapies. The benefits of combined therapies will include, it is hoped, extension of the current three-hour treatment window. This is the consensus emerging from a number of increasingly promising studies assessing the strategy of combining intravenous tissue plasminogen activator (t-PA) with intra-arterial t-PA. In the latest series, the largest reported so far, recanalization was achieved within two hours from the start of intra-arterial infusion in nearly two thirds of patients (14/22), with minimal bleeding and good early functional outcome.
Encouraged by the strong recanalization rates and clinical outcomes, as well as by “acceptable” hemorrhage rates, lead investigator Jeffrey L. Saver, MD, reported that he is optimistic about the future of combined therapy. Dr. Saver, who is an Associate Professor of Neurology at the University of California, Los Angeles (UCLA), presented his team’s results at the 53rd Annual Meeting of the American Academy of Neurology.
“This could be a major step forward,” he said in a follow-up interview. “The advantages of the combined intravenous/intra-arterial approach will likely be substantial compared to either modality alone.”
THE PROS AND CONS OF CURRENT TREATMENT MODES
The traditional approach to thrombolytic therapy has been to give t-PA either intravenously—still the only thrombolytic treatment for acute stroke approved by the Food and Drug Administration—or intra-arterially, which remains investigational. Each approach has its advantages and disadvantages, Dr. Saver noted. Intravenous administration can be done quickly after clinical screening and a computed tomography (CT) or magnetic resonance imaging scan. But only a small amount of the administered drug ever arrives at the clot, and there is systemic exposure to the drug.
With intra-arterial administration, more drug reaches the clot, thus achieving higher recanalization rates. One drawback, however, is the long lag between the CT scan and the time angiography is performed and the catheter required for intra-arterial infusion is placed. In prior studies, this delay has averaged about one hour and 20 minutes, Dr. Saver reported.
The idea behind combining both methods of administration “is to give some intravenous t-PA up front, to get some thrombolytic activity initiated, and then to proceed directly to intra-arterial thrombolysis,” he said. “If there’s still a clot by the time you arrive on-site with the catheter, then go ahead and give the more definitive endovascular treatment.” Dr. Saver hopes that this approach can combine the advantages of quick systemic delivery and high on-clot concentration of lytic agent while avoiding the disadvantages of the two approaches.
In the UCLA study, the average time from the start of intravenous to the start of intra-arterial thrombolysis was one hour and 41 minutes. There were two sets of patients: those who presented to the UCLA Medical Center, where both the intravenous and intra-arterial were started (within one hour and two minutes of each other on average), and those who had intravenous therapy started elsewhere and then were transported to UCLA, where the intra-arterial was started. “There was an extra delay from being transported, and for these patients the average time interval from intravenous to intra-arterial was two hours and 32 minutes,” Dr. Saver said.
Overall, however, the intra-arterial infusion in these patients was begun at four hours and 52 minutes from onset—faster than the average time in the PROACT II study, one of two major trials that demonstrated the safety and efficacy of intra-arterial thrombolytic therapy.
Because intravenous t-PA is approved for use only within three hours from symptom onset, a benefit of combining the approaches is that it allows more of the drug to be started much later—in effect, extending the treatment window.
OUTLOOK FOR THE FUTURE
Although the availability of sites capable of intra-arterial thrombolysis remains an issue, Dr. Saver believes it will become less of an obstacle to the general acceptance of combined therapy. Because intra-arterial delivery of t-PA is complicated and requires endovascular experts, it will probably be available only at specialized stroke centers in the foreseeable future. “But it’s feasible to set up a hub-and-spoke network, where patients would present to a nearby primary stroke center and have an intravenous dose begun and then be transported to a central comprehensive center to have more definitive intra-arterial treatment given if needed,” Dr. Saver postulated.
Dr. Saver looked ahead to the upcoming International Management of Stroke Trial, which will compare patients on combined thrombolysis to a matched historical control from the National Institute of Neurological Disorders and Stroke intravenous t-PA trial. “If the results look good, the same research team will roll over into a Phase III trial comparing intravenous to combined intravenous/intra-arterial,” he said.
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—Fred Balzac
Suggested Reading
1. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. JAMA. 1999;282:2003-2011.
2. Jahan R, Duckwiler GR, Kidwell CS, et al. Intra-arterial thrombolysis for treatment of acute stroke: experience in 26 patients with long-term follow-up. AJNR Am J Neuroradiol. 1999;20:1291-1299.
3. Kidwell CS, Saver JL, Mattiello J, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol. 2000;47:462-469.
4. Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: emergency management of stroke (EMS) bridging trial. Stroke. 1999;30:2598-2605.
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