Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes.

Abstract

Thrombolytic agents hold theoretical promise as therapy for cerebral infarction. This study was designed to evaluate the safety of tissue plasminogen activator, to accomplish urgent patient treatment, and to estimate potential efficacy of tissue plasminogen activator. Following neurological evaluation and computed tomography of the brain, patients with acute ischemic stroke were evaluated and treated with intravenous tissue plasminogen activator under an open-label, dose-escalation design within 90 minutes from symptom onset. End points examined included symptomatic and asymptomatic intracranial hematoma, systemic hemorrhage, and neurological outcome at 2 hours, 24 hours, and 3 months. Seventy-four patients were treated within 90 minutes of symptom onset over seven dose tiers of tissue plasminogen activator, ranging from 0.35 mg/kg to 1.08 mg/kg. Intracranial hematoma with associated neurological deterioration occurred in three patients and was related to increasing doses of tissue plasminogen activator (p = 0.045). Intracranial hematoma did not occur in any of the 58 patients treated with less than or equal to 0.85 mg/kg. Major neurological improvement occurred in 22 patients (30%) at 2 hours from the initiation of tissue plasminogen activator and in a total of 34 patients (46%) at 24 hours, but major neurological improvement was not related to increasing doses of tissue plasminogen activator or to stroke type. Patients with acute stroke can be evaluated and treated within 90 minutes. Tissue plasminogen activator for acute ischemic infarction is not without risk, but the potential for clinical benefit justifies a randomized clinical trial. To date, differences in hemorrhagic risk or neurological benefit of tissue plasminogen activator for particular ischemic stroke types are not apparent.

Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Stroke Is Better Than Low Doses

“…Safety analysis demonstrated that SICH seldom occurred in doses of ≤0.85 mg/kg. 3,4 The NINDS trial, ECASS III trial, and the metaanalysis of them had provided strong evidence for the overall net benefit of standard-dose IV-tPA (0.9 mg/kg, max 90 mg/kg) in AIS within 4.5 hours after symptom onset. 1,2,13 In ECASS, a high dose (1.1 mg/kg) of tPA was tested for AIS within 6 hours from the onset of symptoms, but the occurrence of large parenchymal hemorrhages in the tPA-treated group was significantly more frequent than placebo group.…”

“…SICH was defined as (1) per SITS-MOST, 11 a type 2 intracranial hemorrhage (blood clot >30% of the infarct area, with substantial space occupation) on the 24 to 36 hours follow-up imaging scan after the treatment, combined with a neurological deterioration of >4 points on the NIHSS from the baseline or the lowest NIHSS score between the baseline and 24 hours after thrombolysis or death; (2) per original NINDS study, 1 a hemorrhage that was not seen on a previous cerebral tomographic scan and there had subsequently been either a suspicion of hemorrhage or any decline in neurological status; (3) per European Cooperative Acute Stroke Study (ECASS) II study, 12 any intracranial bleeding, with>4 points worsening on NIHSS score.…”

“…1 This standard dose of tPA was chosen based on the findings of 2 pilot dose-escalation studies, which only enrolled small numbers of subjects (94 cases) in each dose tier. 3,4 There has never been any randomized clinical trial to test different doses of tPA in AIS. Therefore, there is controversy on the optimal dose of tPA.…”

Lessons learned from multicenter randomized clinical trials with intravenous thrombolysis for acute ischemic stroke

“…In ECASS 1, a dose ranging study did not show any evidence of a dose response in regard to efficacy 29 ; therefore, a dose similar to acute myocardial infarction (MI) doses was used. In the NINDS trial, dose-ranging studies 16,17 found a dose effect in regard to safety, that higher dose produced more ICHs. This is consistent with thrombolysis trials for acute myocardial infarction in which overdosing, especially in those with low body mass, is a well-established risk factor for ICH.…”

Lessons learned from multicenter randomized clinical trials with intravenous thrombolysis for acute ischemic stroke

“…Local and superselective intra-arterial approaches with relatively low complication rates and high recanalization rates appear promising. [3][4][5][6][7][8][9] The initial studies of IV thrombolysis [10][11][12][13][14][15][16][17] for acute stroke accumulated sufficient data to justify further largescale randomized, double-blinded, placebo-controlled studies. During the 1990s, seven large randomized trials of IV thrombolysis have been reported.…”