Kenneth P. Madden

The rtPA (Alteplase) 0- to 6-Hour Acute Stroke Trial, Part A (A0276g) Results of a Double-Blind, Placebo-Controlled, Multicenter Study

BACKGROUND AND PURPOSE The Thrombolytic Therapy in Acute Ischemic Stroke Study, which started in August of 1991, was designed to assess the efficacy and safety of intravenous rtPA (alteplase) in patients with acute (0 to 6 hours) ischemic stroke. In October 1993 enrollment was halted because of Safety Committee (DMSB) concerns. In December 1993 the time window was changed to 0 to 5 hours, and it was decided to restart enrollment as a separate study (part B). We report here the results of the original study (part A), focusing on evaluating the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset. METHODS This investigation was a phase II, placebo-controlled, double-blind, randomized study utilizing 0.9 mg/kg IV rtPA or placebo over 1 hour, which was conducted at university and community sites in North America. Except for time to treatment, enrollment criteria were very similar to those of the NINDS rtPA stroke study. Primary efficacy end points were the number of patients with a decrease of 4 or more points on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours and day 30, along with infarct volume at day 30. Secondary end points included mortality and functional recoveries on the Barthel Index and Modified Rankin scale at days 30 and 90. RESULTS A total of 142 patients were enrolled at 42 sites in North America, including 22 <3 hours (15%) and 46 between 5 and 6 hours (32%). The groups were well matched on baseline characteristics, including NIHSS (mean of 13 for both). For the primary end points, a higher percentage of rtPA patients had a 4-point improvement at 24 hours (placebo 21%, rtPA 40%; P=0.02); however, this early effect was reversed by 30 days, with more placebo patients having a 4-point improvement (75%) than patients treated with rtPA (60%, P=0.05). Treatment with rtPA significantly increased the rate of symptomatic intracerebral hemorrhage within 10 days (11% versus 0%, P<0.01) and mortality at 90 days (23% versus 7%, P<0.01). CONCLUSIONS This study found no significant rtPA benefit on any of the planned efficacy end points at 30 and 90 days in patients treated between 0 and 6 hours after stroke onset. These negative results apply to patients treated after 3 hours, because only 15% of the patients were enrolled before 3 hours. The risk of symptomatic intracerebral hemorrhage was increased with rtPA treatment, particularly in patients treated between 5 and 6 hours after onset. These results do not support the use of intravenous rtPA for stroke treatment >3 hours after onset.

Prehospital and Emergency Department Delays After Acute Stroke The Genentech Stroke Presentation Survey

Background and Purpose Patient delays in seeking treatment for stroke and delays within the Emergency Department (ED) are major factors in the lack of use of thrombolytic therapy for stroke. The Genentech Stroke Presentation Survey was a multicentered prospective registry of patients with acute stroke. The study was designed to characterize prehospital delays and delays within the ED. Methods Patients with stroke symptoms presenting to 48 EDs participating in a clinical trial of acute stroke therapy were enrolled prospectively. A 1-page data form was completed from patient interviews and medical records. Results A total of 1207 subjects were entered into the study. Ninety-four percent of the 721 subjects with complete data had a diagnosis of stroke or transient ischemic attack, 13% were black, 50% were female, and 67% were aged >65 years. The median time from symptom onset to ED arrival was 2.6 (interquartile range 1.2 to 6.3) hours. The median time from ED arrival until CT scan completion was 1.1 (0.7 to 1.8) hours, and the total delay time (symptom onset until CT scan completion) had a median of 4.0 (2.3 to 8.3) hours. Patients who arrived by emergency medical services had significantly shorter prehospital delay times and times to CT scan. Age, race, sex, and educational level did not appear to affect prehospital delay times. Conclusions Despite its limitations, this large geographically diverse study strongly suggests that the use of emergency medical services is an important modifiable determinant of delay time for the treatment of acute stroke.

Dose Escalation Study of the NMDA Glycine-Site Antagonist Licostinel in Acute Ischemic Stroke

BACKGROUND AND PURPOSE Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke. METHODS In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale. RESULTS Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated. Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models. A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients. CONCLUSIONS A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients. Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists.

Effect of gamma-aminobutyric acid modulation on neuronal ischemia in rabbits.

BACKGROUND AND PURPOSE Antagonists of excitatory neurotransmitters are effective in limiting ischemic damage to the brain and spinal cord, but use in clinical stroke may be limited by side effects. Agonists of inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), may provide similar neuroprotection with less severe side effects. This study examines the effect of an agonist and antagonist of the GABA-A receptor on neuronal ischemic damage. METHODS Either muscimol (a GABA-A agonist) or bicuculline (a GABA-A antagonist) was administered intravenously to groups of rabbits exposed to reversible spinal cord ischemia induced by temporary occlusion of the infrarenal aorta. The duration of occlusion for individual animals was varied, providing a range of ischemia for each experimental group. The group P50 represents the duration (in minutes) associated with 50% probability of resultant permanent paraplegia. Neuroprotection was demonstrated if a drug prolonged the P50 compared with the control group. RESULTS The P50 of the control group was 26.3 +/- 2.0 minutes. Treatment with intravenous muscimol at 5 mg/kg significantly prolonged the P50 (32.4 +/- 1.3; P = .01). Treatment with intravenous bicuculline at 0.1 mg/kg significantly shortened the P50 (20.6 +/- 1.5; P = .03). The physiological and apparent behavioral effects of the drugs at these doses did not appear substantial. CONCLUSIONS Pharmacological manipulation of the GABA-A receptor may offer another avenue of therapy for central nervous system ischemia, possibly with less severe associated physiological side effects than other effective drugs.

Keep the Three Hour TPA Window: The Lost Study of Atlantis

The recent fanfare surrounding the reporting of the ECASS III results leads to the inference that intravenous recombinant tissue plasminogen activator (rt-PA) is conclusively beneficial beyond 3 hours and that ECASS III must be the first large trial to study this population; we feel both of these conclusions are erroneous for the following reasons. Between 1993-1998 the Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial was conducted in 140 U.S. sites to investigate the efficacy of rt-PA given between 3-5 hours post-stroke onset with over 600 patients enrolled. This trial was sponsored by Genentech, the statistician was an employee of Genentech, and the Steering Committee were all investigators. Despite all of these ‘‘positive biases’’ the trial was completely negative on all primary and secondary endpoints with a 7% rate of symptomatic cerebral hemorrhage. In addition to these negative results, additional findings suggesting that IV rt-PA is not beneficial after 3 hours comes from the NINDS trial itself. In an analysis of the 0-90 minutes patients versus 91-180 minute patients Marler et al found increased odds of 3 month favorable outcome in patients treated under 90 minutes. A graphic analysis showed the odds ratio of improvement started at 4 for patients at 60 minutes, then dropped throughout the next 2 hours hitting 1, or no predicted benefit at 3 hours. Based on the negative results of ATLANTIS, Genentech halted further stroke studies in the U.S. beyond 3 hours with the exception of research efforts focusing on identifying selective patients through image advances. In contrast to these negative U.S. results, ECASS III concluded that there was a benefit when rt-PA was administered between 3-4.5 hours. A comparison of the two trials reveals many similarities with a few important differences. Both trials were of similar size and used nearly identical inclusion and exclusion criteria including using initial CTs to exclude patients with major early stroke changes. That the populations were very similar is supported by the identical stroke severity seen in the placebo