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rt-PA, tissue plasminogen activator; ICH, intracranial hemorrhage.

rt-PA, tissue plasminogen activator; ICH, intracranial hemorrhage.

Intravenous rt-PA: 0-3 Hours After Stroke Onset

The current use of IV rt-PA for acute stroke thrombolysis is based on the NINDS rt-PA study, a two-part randomized, double blind, placebo-controlled trial.24 This trial was preceded by two open-label, dose-escalation safety studies that suggested that treatment within 180 minutes of stroke onset, and rt-PA dosages no higher than 0.95 mg/kg, was safe and effective.25,26

The NINDS rt-PA study was divided into two parts. NINDS part I included 291 patients and NINDS part II included 333 patients. In both parts, acute ischemic stroke patients presenting within 3 hours of symptom onset were randomized to placebo versus treatment with the human rt-PA Alteplase (Activase). The dose was 0.9 mg/kg (maximum dose 90 mg), with 10% of the total dose given as a bolus and the remaining 90% infused over 60 minutes. Inclusion and exclusion criteria for both parts are listed in Table 3.2. These criteria are now the standard clinical criteria used to determine IV rt-PA eligibility in acute stroke patients.

The primary outcome of NINDS part I was early clinical improvement by 24 hours, defined as complete resolution of the stroke symptoms or an improvement in the National Institute of Health Stroke Scale (NIHSS) score by 4 or more points. There was no difference in early clinical improvement in the rt-PA group compared to the placebo group (relative risk 1.2, 95% CI 0.9-1.6, p = 0.21).

The primary outcome of NINDS part II was a favorable outcome at 3 months, as assessed by four commonly used assessment scales: the Barthel Index (BI), modified Rankin Scale (mRS), Glasgow Outcome Scale (GOS), and NIHSS. A

TABLE 3.2 Inclusion and Exclusion Criteria for Treatment with Intravenous Tissue Plasminogen Activator2.

Inclusion Criteria Exclusion Criteria

Clearly defined time of onset <3 h Stroke or head trauma within 3 months Measurable stroke-related deficit Major surgery within 14 days

No intracranial hemorrhage on CT History of intracranial hemorrhage

SBP > 185 mm Hg or DBP >110 mm Hg Rapidly improving or minor symptoms Symptoms suggestive of subarachnoid hemorrhage Gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 21 days Arterial puncture at a noncompressible site within the previous 7 days Seizure at stroke onset

Anticoagulant or heparin use <48 h before onset with elevated partial-thromboplastin time Prothrombin time >15 s Platelet count <100,000/mm3 Glucose concentration <50 mg/dL or >400 mg/dL

aBased primarily on the study protocol of the 1995 NINDS rt-PA study.24 Many centers would also exclude patients with known documented endocarditis or aortic dissection, and those with CT hypoattenuation in more than one third of the middle cerebral artery territory.39 There are insufficient data to support the use of rt-PA for ischemic stroke in pregnancy or in the pediatric population (age <18 years).

global endpoint was derived from the individual scales with the use of scale-specific cut-points that were defined as a favorable outcome. NINDS part II found that IV rt-PA-treated patients were more likely to have a favorable outcome on each of the assessment scales (p = 0.02-0.03, Fig. 3.2). When the results from the four scales were combined into the global test statistic, the odds ratio (OR) for a favorable outcome in the rt-PA group, compared to the placebo group, was 1.7 (95% CI 1.2-2.6, p = 0.0008). The absolute percent differences between rt-PA and placebo across the four assessment scales ranged from 11% to 13% (Fig. 3.2), There was a 12% absolute increase in the number of patients with minimal or no disability in the rt-PA group, using the global statistic, which corresponds to a number needed to treat (NNT) of 8.3.

Combined analysis of parts I and II of the NINDS study confirmed the effect of IV rt-PA on favorable outcome at 3 months. There was no difference in mortality (17% for rt-PA group vs. 21% for placebo, p = 0.30). There was, however, an increase in symptomatic intracerebral hemorrhage (sICH) in the rt-PA-treated group (6% vs. 0.6% in the placebo group, p < 0.0001) during the first 36 hours poststroke. Among those with sICH, the 3-month mortality rate was 61%. Therefore, the improvement in 3-month stroke outcomes in the rt-PA group and the overall lack of increased mortality compared to placebo occurred despite the excess mortality from sICH in the rt-PA group. A secondary analysis showed that a group difference in favorable outcome, favoring the IV rt-PA group, was still present at 1 year.27

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