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In acute ischemic stroke...NINDS* pivotal study shows

Patients treated with Activase were 30% more likely to have minimal to no disability at 3 months vs placebo†

The efficacy profile of Activase was established in the pivotal National Institute of Neurological Disorders and Stroke (NINDS) study1

NINDS Safety study

  • *
  • Activase=144; placebo=147.
  • †
  • Defined as a 4-point improvement in the NIHSS score from baseline values or complete resolution of the neurologic deficit.
  • ‡
  • Activase=168; placebo=165.
  • §
  • According to scores on the Barthel Index, the Modified Rankin Scale, the Glasgow Outcome Scale, and the National Institutes of Health Stroke Scale.1
  • ||
  • Based on a Modified Rankin Scale score of 0 or 1 (minimal or no disability).
  • Reference: 1. NINDS. N Engl J Med. 1995;333:1581-1587.

The efficacy profile of Activase was established in the pivotal National Institute of Neurological Disorders and Stroke (NINDS) study (NINDS 1995)

  • The NINDS study was carried out in 2 parts: Part 1 (N=291) assessed changes in neurologic deficits 24 hours after the onset of stroke, whereas part 2 (the pivotal study; N=333) assessed clinical outcomes at 3 months, according to scores on the Barthel Index, the Modified Rankin Scale, the Glasgow Outcome Scale, and the National Institutes of Health Stroke Scale1
  • The favorable outcome is defined as a Modified Rankin Scale score of 0 or 1 (minimal or no disability)
    • – In Part 2, 39% of patients treated with Activase experienced favorable outcomes, compared with 26% of patients in the placebo group (P=0.019)
    • – 6.4% of patients treated with Activase experienced symptomatic intracerebral hemmorrhage (SICH), compared with 0.6% of patients in the placebo group (P<0.001)
    • – 17% of patients treated with Activase died, compared with 21% in the placebo group. This was not a statistically significant difference (P=0.30)

3 months: more patients recover with minimal or no disability(1)

  • *
  • NINDS=National Institute of Neurological Disorders and Stroke.

Favorable outcome=Barthel, 95 or 100; Modified Rankin, 0 or 1; Glasgow, 1; NIHSS, <1.
P value is based on a global scale.

Part 2 of a randomized, double-blind, placebo-controlled study (N=333) conducted by NINDS of patients at 3 months after being treated for ischemic stroke with intravenous recombinant tissue plasminogen activator (n=168) or placebo (n=165) within 3 hours of onset.

  • †
  • A global test statistic was used to assess clinical outcome, according to the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and NIHSS. Part 1 of the study (n=291) tested results within 24 hours of stroke onset.



The NINDS t-PA Stroke Trial - Safety Outcome

  • 1
  • Within trial follow-up period. Symptomatic ICH was defined as the occurrence of sudden clinical worsening followed by subsequent verification of ICH on CT scan. Asymptomatic ICH was defined as ICH detected on a routine repeat CT scan without preceding clinical worsening.
  • 2
  • Fisher's Exact Test


NINDS study design: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study was a randomized, double-blind, placebo-controlled study of patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator (t-PA) or placebo.
The NINDS trial was conducted in two parts. The primary endpoint in Part 1 (N=291) was a demonstration of clinical activity in the Activase group, as defined by an improvement of 4 points over baseline values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. This endpoint was not met; no significant difference in outcome was seen between groups at 24 hours. The endpoint in Part 2 (N=333) was a global test statistic to assess clinical outcome at three months, according to scores on the Barthel Index (BI), Modified Rankin Scale (MRS), Glasgow Outcome Scale (GOS), and NIHSS. In Part 2, the endpoint was confirmed (global odds ratio for a favorable outcome, 1.7; 95% confidence interval, 1.2-2.6).

  • Outcomes reflect data reported in Figure 2 of Part 2 of the NINDS study, applied to this hypothetical patient population1
  • Assignment to disability levels is based on average percentage per group on all 4 assessment scales (NIHSS, Barthel Index, Modified Rankin Scale, and Glasgow Outcome Scale)

This hypothetical representation of 16 patients treated with Activase (t-PA) vs 16 patients treated with placebo is based on NINDS results at 3 months.1

Net clinical benefit

In this illustration, 1 of the mortalities in the Activase (t-PA) group could be due to SICH.

Patients treated with Activase (t-PA)   Patients treated with placebo
Patients with symptomatic intracranial hemorrhage (SICH)†

In NINDS, when eligible patients were treated with Activase (t-PA) compared with placebo1:

  • More ischemic stroke patients sustained minimal to no disability (31% vs 20%†)
  • Fewer had moderate-to-severe disability (52% vs 59%†)
  • There was no statistically significant difference in overall mortality (17% vs 21%; P=0.30)
  • The rate of SICH among patients treated with Activase (t-PA) was 6.4% vs 0.6% with placebo (P<0.001) at 36 hours
    • – Approximately half of the patients experiencing SICH had nonfatal outcomes at 36 hours
    • – 55% (11 of 20) of patients treated with Activase (t-PA) and 50% (1 of 2) of patients given a placebo
  • *
  • Defined by the National Institutes of Health Stroke Scale (NIHSS) score compared to baseline.
  • †
  • Based on NIHSS score comparison; trend consistent across remaining 3 outcome scales.

Why choose to reperfuse?

  • Activase (t-PA) may help reverse neurologic impairment*
  • More acute ischemic stroke patients recover with minimal or no disability at 3 months and 1 year4,5

* Defined by the National Institutes of Health Stroke Scale (NIHSS) score compared to baseline.



  • 11% to 13% absolute increase in favorable outcomes for Activase (t-PA) at 3 months vs placebo1
    • – There was an 11% absolute (55% relative) increase in the number of patients receiving Activase (t-PA) with an NIHSS score of 0 or 1; a 12% absolute (32% relative) increase in the number of patients with minimal or no disability based on a score of 95 or 100 on the Barthel Index; and 13% absolute increases in the numbers of patients with favorable outcomes based on the Modified Rankin and Glasgow Outcome Scales, all vs placebo
  • Treatment is not recommended after 3 hours of acute ischemic stroke symptom onset or in patients with minor neurologic deficit or with rapidly improving symptoms

1 year: neurologic benefits confirmed(2)

Adapted from Kwiatkowski TG et al. N Engl J Med. 1999;340:1781.

Note: NIHSS scores were unavailable at 6 and 12 months because follow-up assessments were conducted by telephone.

Favorable outcome=Barthel, 95 or 100; Modified Rankin, 0 or 1; Glasgow, 1.

A 1-year follow-up study of outcome data for the 624 patients enrolled in the original 2-part NINDS study, using intent-to-treat analysis (26 patients missing at 12-month assessment considered to have unfavorable outcomes). There were 312 patients in each group, those treated for ischemic stroke with t-PA.

A favorable outcome was defined as minimal or no disability as measured by the Barthel Index, the Modified Rankin Scale, and the Glasgow Outcome Scale.

  • 11% to 13% absolute increase in neurologic recovery for Activase (t-PA) at 1 year vs placebo2
    • – There was a 12% absolute (32% relative) increase in the number of patients receiving Activase (t-PA) with minimal or no disability based on a score of 95 or 100 on the Barthel Index; a 13% absolute (46% relative) increase in the number with minimal or no disability based on a score of 0 or 1 on the Modified Rankin Scale; and an 11% absolute (34% relative) increase in the number with minimal or no disability based on a score of 1 on the Glasgow Outcome Scale

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Independent reviews support findings from NINDS

  • Follow-up analyses demonstrated that original NINDS study outcomes were not biased by baseline imbalances (eg, NIHSS score, severity, age), a previous misconception4,5

  • After consideration of baseline imbalances, favorable outcomes were more likely in patients treated with Activase (t-PA) in original trials at 3 months (OR 1.9; 95% CI, 1.5–2.9)4

Indication
Activase (Alteplase) is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage (see CONTRAINDICATIONS).

Important Safety Information
Activase therapy in patients with AIS is contraindicated in certain situations (eg, suspicion of subarachnoid hemorrhage on pretreatment evaluation, recent (within 3 months) intracranial or intraspinal surgery, history of intracranial hemorrhage, uncontrolled hypertension at time of treatment, active internal bleeding, known bleeding diathesis (eg, current use of oral anticoagulants, administration of heparin within 48 hours of onset of stroke, platelet count <100,000) (see CONTRAINDICATIONS for full list).

The most common complication during Activase therapy is bleeding. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately. Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

The risks of Activase therapy may be increased and should be weighed against the anticipated benefits in certain conditions. [See WARNINGS in full prescribing information].

  • Patients with severe neurological deficit (eg, NIHSS >22) at presentation. There is an increased risk of intracranial hemorrhage in these patients.
  • Patients with major early infarct signs on a computerized cranial tomography (CT) scan (eg, substantial edema, mass effect, or midline shift).

Treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.

Orolingual angioedema has been observed in postmarketing experience in patients treated with Activase for AIS. Patients should be monitored during and for several hours after infusion for signs of orolingual angioedema.

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References:
1.
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587.
2.
Kwiatkowski TG, Libman RB, Frankel M, et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. N Engl J Med. 1999;340:1781-1787.
3.
NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke: subgroup analysis of the NINDS t-PA stroke trial. Stroke. 1997;28:2119-2125.
4.
Ingall TJ, O'Fallon WM, Asplund K, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke. 2004;35:2418-2424.
5.
Kwiatkowski TG, Libman R, Tilley BC, et al. The impact of imbalances in baseline stroke severity on outcome in the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator stroke study. Ann Emerg Med. 2005;45:377-384.