20 Cerebrovascular Disease C ARDIOLOGY N EWS • May 2005 MRI Buys Time for of Acute

BY MITCHEL L. ZOLER ed imaging by MR to identify pa- cluding patients from the study was that Philadelphia Bureau tients with at least a 20% mismatch they had gone beyond the 9-hour window. between the two. The mismatch is The U.S. study’s primary end point was N EW O RLEANS — The presence of a a marker for patients with a signifi- the rate of symptomatic, intracranial he- favorable pattern of cerebral perfusion on cant penumbra region in their brain, morrhage (sICH), which occurred in none magnetic resonance imaging may tell physi- tissue that might be salvageable by of the patients. In the prior European cians which patients with acute ischemic thrombolytic therapy because it is study, one sICH occurred among 15 pa- stroke stand to benefit from thrombolysis still viable despite being hypoper- tients treated with 90 mcg/kg and none NIVERSITY even hours after the onset of symptoms. fused. “Most patients who made it U among 15 patients treated with 125 Findings from two phase II studies us- to MR were eligible,” he said. mcg/kg. Thus, the overall rate of sICH in ing MRI show that some patients were The other novel feature of both these two studies at these two doses was able to safely receive a thrombolytic drug the European and U.S. studies was ASHINGTON 1 among 59 treated patients, a 1.7% rate as long as 9 hours after the onset of their the thrombolytic drug used: W that was lower than the 6% rate with TPA stroke symptoms. Results from the most desmoteplase, a plasminogen acti- in routine practice, noted Dr. Furlan at the recent of these studies were reported at vator derived from vampire-bat sali- ENTER AT conference, sponsored by the American the 30th International Stroke Conference. va. Desmoteplase has several po- C Stroke Association.

“These are the first trials to test the hy- tential advantages over tissue TROKE In the European study, 30 patients re- pothesis that selecting patients with fa- (TPA). In an- S ceived substantially higher doses of vorable imaging patterns can extend treat- imal studies, desmoteplase showed desmotoplase, and they had a 27% rate of NTERNET ment beyond the current 3-hour window,” no neurotoxicity, and it did not ac- I sICH. In this higher-dose group, the low- said Anthony J. Furlan, M.D., head of the tivate -amyloid, a process that’s A large infarct is clearly visible in the middle est desmotoplase dose associated with in- section of stroke and neurologic intensive been linked to an increased risk of cerebral artery of an 18-year-old woman. tracranial hemorrhage was 294 mcg/kg. care at the Cleveland Clinic and principal intracranial hemorrhage. The new study was not powered to investigator of the new study. Results from Desmoteplase also has very high speci- cipal investigator in these and ongoing show significant differences in clinical out- the prior, European, study were published ficity and selectivity for fibrin and a long studies. comes. The reperfusion rate was 38% in in January (Stroke 2005;36:66-73). serum half-life of 4 hours. This last prop- The U.S. study involved enrollment of the control group, 18% in the 90-mcg/kg “If this hypothesis is borne out, it could erty means that it can be given as a bolus 37 patients who all met the entry MR cri- group, and 53% in the 125-mcg/kg group. have an enormous impact on how we use dose and may also help prevent acute re- teria. After randomization, 14 patients Improved clinical outcomes at 90 days thrombolytic therapy for stroke,” he occlusion of newly opened arteries. were treated with 90 mcg/kg were seen in 25% of those in the placebo added. “It has the potential to at least Desmoteplase is being developed in the desmoteplase, 15 received 125 mcg/kg group, 29% of those in the low-dose arm, triple the number of acute stroke patients United States by Forest Laboratories and desmoteplase, and 8 received placebo. The and 60% of those in the high-dose arm. who are eligible for thrombolytic therapy.” in Europe by PAION, a German drug average time to treatment was 7 hours. Al- There was no reduction of safety or effi- Like the study done in Europe, Dr. company. Dr. Furlan is a consultant to though patients could enter treatment as cacy in the patients treated 6-9 hours after Furlan’s research used a combination of both companies, and he received com- long as 9 hours after the onset of their their stroke onset, compared with those perfusion-weighted and diffusion-weight- pensation from both for acting as a prin- stroke symptoms, the top reason for ex- treated 3-6 hours after onset. I Lower Dose of TPA May Is Better Than for Suffice for Acute Stroke Intracranial Arterial Stenosis Patients BY MICHELE G. SULLIVAN ology at Columbia University, New York. BY MITCHEL L. ZOLER ral center for further evaluation, Dr. Mid-Atlantic Bureau Dr. Chimowitz and his associates report- Philadelphia Bureau Rymer and her associates reported in a ed on the trial’s final analysis that included poster at a conference sponsored by the igh-dose aspirin is just as effective as war- 569 patients with symptomatic intracranial N EW O RLEANS — A lower-than- American Stroke Association. Hfarin in treating intracranial arterial arterial stenosis who were randomized to ei- usual intravenous dose of tissue plas- Dr. Rymer and her colleagues iden- stenosis, and appears much safer, Marc Chi- ther warfarin 5 mg daily or aspirin 650 mg minogen activator may still be effective tified 83 patients who received the 0.6- mowitz, M.B., and colleagues have reported. twice daily. for treating patients with acute stroke, mg/kg dose only in the MABSI data- “The common practice of administering The patients’ mean age was about 63 according to a review of 83 patients. base, as well as another 50 patients warfarin rather than aspirin for sympto- years; about 61% were men. All had a his- “A low dose of 0.6 mg/kg was safe who received a 0.6-mg/kg dose initial- matic intracranial arterial stenosis is not sup- tory of either stroke or transient ischemic and effective,” Marilyn M. Rymer, ly that was later followed by intraarte- ported by the results of this trial,” said Dr. attack caused by 50%-90% stenosis of a M.D., and associates reported in a rial treatment with 0.3 mg/kg of TPA Chimowitz of Emory University, Atlanta. major intracranial artery. The mean fol- poster at the 30th International Stroke to assess in-hospital mortality and pa- Enrollment in the Warfarin-Aspirin low-up was 1.8 years. Conference. tients’ NIH Stroke Scale (NIHSS) score Symptomatic Intracranial Disease (WASID) The primary outcome—stroke, brain he- The usual dose of intravenous tissue at discharge. This analysis used a dis- trial ended early because of the high rate of morrhage, or death from vascular causes plasminogen activator (TPA) is 0.9 charge NIHSS of 4 or less and 2 or less serious adverse events in the warfarin pa- other than stroke—occurred in 22% (62) of mg/kg, based on the regimen’s safety as criteria for good outcomes. tients. In addition to being safer for pa- the aspirin patients and 21.8% (63) of the and efficacy in the original thrombolyt- The in-hospital mortality rates were tients, the researchers said, aspirin therapy warfarin patients. Myocardial infarction or ic therapy trial by the National Institute 6% in the 83 patients treated with 0.6 did not require constant monitoring of in- sudden death occurred significantly more of Neurological Disorders and Stroke mg/kg of TPA only and 12% in all 133 ternational normalized ratios (INRs) and often in the warfarin group than in the as- (NINDS) and reported in 1995, accord- patients in the MABSI database. The 90- treatment of warfarin-associated bleeding. pirin group (7.3% vs. 2.9%). ing to Dr. Rymer, medical director of day mortality rates were 17% in the Aspirin also is much cheaper, they noted (N. The overall rate of death was significant- the stroke center at Saint Luke’s Hospi- original NINDS trial and 16% in the Engl. J. Med. 2005;352:1305-16). ly higher in the warfarin group than in the tal in Kansas City, Mo., and colleagues. IMS trial. Ralph Sacco, M.D., an investigator in the aspirin group: 5.9% (17) vs. 4.3% (12). How- The idea of treating patients initial- At hospital discharge, 71% of the pa- Northern Manhattan Stroke Study, noted in ever, chance probably accounted for some of ly with a 0.6-mg/kg IV dose began tients who received just the 0.6-mg/kg an interview that the WASID trial’s findings the deaths that were higher in the warfarin with the Interventional Management of dose had an NIHSS of 4 or less, and add to existing data to dispel beliefs about group, especially the six cancers. Major he- Stroke (IMS) trial, which reserved a 63% had a score of 2 or less. In the en- the benefit of warfarin for certain stroke morrhages occurred significantly more often 0.3-mg/kg dose for subsequent in- tire MABSI group, 62% had discharge populations. in the warfarin group (8.3% vs 3.2%). traarterial delivery. Hospitals in the Mid scores of 4 or less and 48% had scores The conclusion that warfarin provides no Dr. Sacco noted that warfarin is “clearly in- America Brain and Stroke Institute of 2 or less. In the NINDS and IMS stud- survival benefit over aspirin, but confers dicated” for cardioembolic stroke. “This has (MABSI) regional network now rou- ies, NIHSS were measured 90 days after added risk, is more expensive, and requires in- been made clear in multiple studies, which tinely use the 0.6-mg/kg dose of intra- treatment; 31% and 28% of patients, re- tensive monitoring, should reshape its were actually so positive that they were the venous TPA, and then send the patient spectively, had scores of 1 or 0 at that risk/benefit profile for some patients, said Dr. springboard for these other studies looking by ambulance to a hospital or a refer- time, the investigators reported. I Sacco, professor of neurology and epidemi- at warfarin in different populations.” I

Pages 20a—20bŅ