REVIEW ARTICLE An Overview of Acute Stroke Therapy Past, Present, and Future Marc Fisher, MD; Wolf Schaebitz, MD he effort to develop effective therapies for acute ischemic stroke achieved several im- portant successes during the past decade, but also many disappointing failures. The 2 primary successes were related to thrombolysis. The first was the NINDS rt-PA (Na- tional Institute of Neurological Disorders and Stroke Recombinant Tissue-Type Plas- Tminogen Activator) trial reported in 1995. This study demonstrated that initiation of intravenous (IV) rt-PA within 3 hours after the onset of acute ischemic stroke significantly improved outcome at 3 months.1 This study led to the approval of rt-PA initiated within 3 hours of stroke onset as the only currently available acute stroke therapy. The second major success was the demonstration that intra-arterial prourokinase initiated within 6 hours of stroke onset in patients with angio- graphically documented proximal middle cerebral artery (MCA) occlusion also improved out- come at 3 months.2 A third marginally positive acute stroke trial used ancrod, a defibrinogenating agent derived from Malaysian pit vipers.3 Ancrod initiated within 3 hours after stroke onset also improved 3-month outcome but to a lesser degree than either rt-PA initiated within 3 hours or prourokinase initiated within 6 hours. These successful acute stroke therapy trials were out- weighed by a large number of neuroprotective trial failures. Currently, not one of many purported neuroprotective therapies assessed in pivotal clinical trials has demonstrated unequivocal, statis- tically significant improvement in clinical outcome.4 The neuroprotective trials all included pa- tients who presented with a stroke 3 hours after onset, and the therapies used for each patient failed for myriad reasons that will be explored in detail. In this overview of the current status and terventions, a treatment strategy likely to future direction of acute stroke therapy, we lead to maximal improvement in the great- will discuss in detail the current situation est number of stroke patients. of thrombolytic therapy for acute ische- mic stroke, reviewing the results of pub- THROMBOLYTIC THERAPY FOR lished clinical trials, postmarketing expe- ACUTE ISCHEMIC STROKE rience with rt-PA given within the 3-hour window, and future directions of how to po- The NINDS rt-PA trial was the first acute tentially expand this window for IV throm- ischemic stroke trial to unequivocally dem- bolytic therapy. The status of various neu- onstrate that this disorder could be ben- roprotective therapies for acute ischemic efited by any therapeutic intervention.1 In stroke will be reviewed and potential new this trial, 624 carefully selected patients neuroprotective strategies previewed. were randomly and blindly assigned to Last, we attempt to envision likely ap- therapy with rt-PA (0.9 mg/kg) or pla- proaches toward multiple therapeutic in- cebo within 3 hours of stroke onset. Half of the patients were treated within 90 min- From the Departments of Neurology, University of Massachusetts Medical School, utes of onset, an accomplishment by the Worcester (Dr Fisher), and University of Heidelberg, Heidelberg, Germany investigators participating in the trial. The (Dr Schaebitz). Dr Fisher serves as a paid consultant to Bristol-Myers Squibb. patients treated with rt-PA had an abso- (REPRINTED) ARCH INTERN MED/ VOL 160, NOV 27, 2000 WWW.ARCHINTERNMED.COM 3196 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Postmarketing Studies of Intravenous rt-PA Studies Compared With the NINDS Trial* NINDS Trial Modified Rankin Median Age, y, Median Time Score 0-1 at Symptomatic Study Patients, No. NIHSS Mean ± SD to Treat, min 90 Days, % Mortality, % ICH, % NINDS, placebo1 165 15 66 ± 13 90 26 21 1 NINDS, rt-PA (part 2)1 168 14 69 ± 12 90 39 17 7 Chiu et al7 30 14 ± 8 66 ± 15 157 30 23 7 Egan et al8 33 17 NA 157 36 18 9 Tanne et al9 75 NA 66 ± 15 NA 34 (At discharge) 11 3 Wang et al10 14 15.4 ± 2 (15-88) NA 57 7 7 Grond et al11 100 12 63 ± 11 124 40 12 5 Albers et al12 296 13 68 ± 13 165 35 (Day 30) 12 4 *rt-PA indicates recombinant tissue-type plasminogen activator; NINDS, National Institute of Neurological Disease and Stroke; NIHSS, National Institutes of Health Stroke Scale Score; ICH, intracerebral hemorrhage; and NA, not available. lute improvement rate of 11% to 13% this time point may not be of proven study, the median baseline NIHSSs at 90 days when compared with the efficacy. were 12 and 13, while in the NINDS placebo patients on various out- Several postmarketing studies of trial the median baseline NIHSS in the come measures that evaluated both IV rt-PA are now available.7-15 Pa- placebo group was 14 in part 1 and neurologic and functional status. tients were included in these stud- 15 in part 2. In other acute stroke tri- The patients treated with rt-PA had ies using the general guidelines for als where the baseline NIHSS was 11, a symptomatic intracerebral hem- treatment used in the NINDS trial. the percentage of patients achieving orrhage rate of 6.4% (almost half the The most important inclusion crite- a Rankin score of 0-1 approximates patients died) within 36 hours of on- rion was initiation of therapy within 37%13 and when the baseline NIHSS set, while the rate was only 0.6% in 3 hours of stroke onset. Most of the was 13, 29% achieved this out- the placebo group. Despite this early studies encompassed relatively small come.14 Comparing the outcomes in hemorrhagic risk, the 90-day mor- numbers of patients, ranging from 14 the study by Grond and colleagues tality rate was 17% in the rt-PA to 75 (Table). However, several and the STARS study with those of a group and 21% in the placebo group. larger studies are available, includ- placebo group that had a similar de- Subsequent analysis of the study data ing the study reported by Grond and gree of baseline severity demon- demonstrated that early computed colleagues11 of 100 patients and the strates an absolute improvement rate tomographic (CT) demonstration of STARS (Standard Treatment With of 3% to 6%, not the approximately extensive edema or hypodensity, his- Activase to Reverse Stroke) study of 12% absolute rate of improvement tory of diabetes mellitus, and el- 296 patients.12 The median time from observed with rt-PA treatment in the evated baseline National Institutes stroke onset to initiation of rt-PA NINDS trial. The postmarketing stud- of Health Stroke Scale Score (NIHSS) therapy ranged from 124 minutes in ies do, however, provide some en- were predictors of poor outcome.5 the study by Grond and colleagues couraging data about the rate of The use of rt-PA was associated with to 165 minutes in the STARS study. symptomatic intracerebral hemor- improved outcome in all stroke sub- The percentage of patients achiev- rhage. The percentage of patients ex- types included in the study, in pa- ing a modified Rankin score of 0-1, periencing this serious complica- tients across the broad range of base- the results defined as a favorable out- tion of thrombolysis ranged from 0% line stroke severity, and in all age come in the NINDS trial, ranged to 19% with only 2 studies observ- groups. The initial analysis of the from 34% to 57%; although, in sev- ing double-digit rates of intracere- study data did not distinguish a dif- eral of the reports, day 90 data were bral hemorrhage. In the 2 largest ference in benefit of rt-PA related to not provided. studies, the intracerebral hemor- time-of-treatment initiation. How- On the surface, the rates of rhage rates were only 4% to 5%. It ever, in a subsequent analysis that favorable functional outcome dem- therefore appears that expanding IV adjusted for baseline severity of the onstrated in these postmarketing rt-PA use into general practice is not neurologic impairment, an earlier studies appear to be quite good, sur- associated with a substantially in- time to initiation of therapy was as- passing in some studies the 39% 0-1 creased risk of intracerebral hemor- sociated with a more favorable out- Rankin rate at 90 days seen in the rhage, if the guidelines for patient se- come, demonstrating an inverse lin- NINDS trial. These results must be lection used in the NINDS trial are ear relationship between time to treat interpreted cautiously because the followed. and the odds ratio of a favorable out- baseline severity of the patients Studies evaluating the efficacy of come.6 The confidence interval for treated in these postmarketing stud- IV rt-PA beyond the 3-hour time win- a favorable outcome crossed 1 in pa- ies were not as severe as in the NINDS dow were conducted. The first clini- tients treated beyond 2 hours 40 trial. For example, in the 2 largest cal trial to evaluate IV rt-PA up to 6 minutes after stroke onset, suggest- postmarketing studies, the study by hours after stroke onset was the Eu- ing that treatment initiated beyond Grond and colleagues and the STARS ropean Cooperative Acute Stroke (REPRINTED) ARCH INTERN MED/ VOL 160, NOV 27, 2000 WWW.ARCHINTERNMED.COM 3197 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Study (ECASS-1).14 Patients were ran- One other large IV rt-PA study, the fully selected patients and should ini- domly and blindly assigned to rt-PA Alteplase Thrombolysis for Acute tiate additional attempts to success- (1.1 mg/kg) or placebo within the Non-Interventional Therapy in Is- fully expand the time window for IV 6-hour period after acute stroke on- chemic Stroke (ATLANTIS), evalu- thrombolysis in acute ischemic set in the MCA territory.