Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Tissue plasminogen activator improved clinical outcome after acute ischemic stroke

ACP J Club. 1996 May-June;124:58. doi:10.7326/ACPJC-1996-124-3-058


Source Citation

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333:1581-7.


Abstract

Objective

To assess the effectiveness of intravenous recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke who participated in a 2-part study.

Design

3-month, randomized, double-blind, placebo-controlled trial.

Setting

8 clinical centers and affiliated hospitals in the United States.

Patients

624 patients (mean age 76 y, 58% men, 65% white) who had had an acute ischemic stroke and no evidence of intracranial hemorrhage. Exclusion criteria included recent stroke or surgery, history of intracranial hemorrhage, elevated blood pressure, possible subarachnoid hemorrhage, recent gastrointestinal or urinary tract hemorrhage, recent arterial puncture at a noncompressible site, seizure at stroke onset, receipt of anticoagulants or heparin in the preceding 48 hours and an elevated partial thromboplastin time, prothrombin time > 15 seconds, platelet counts < 100 000/mm3, or glucose concentrations < 2.7 mmol/L or > 22.2 mmol/L. Data were complete for all but 1 patient in part 1 (24-h follow-up) and 4 patients in part 2 (3-mo follow-up).

Intervention

Patients were stratified by clinical center and time from onset of stroke to start of treatment (0 to 90 or 91 to 180 min), and allocated to alteplase (recombinant tPA), 0.9 mg/kg of body weight (n = 144 in part 1; n = 168 in part 2), or to placebo (n = 147 in part 1; n = 165 in part 2).

Main Outcome Measures

For part 1, a 4-point improvement over baseline values of the National Institutes of Health stroke scale (NIHSS) within 24 hours of stroke onset. For part 2, the 3-month clinical outcome using a global statistic derived from scores on the Barthel index, the modified Rankin scale, the Glasgow outcome scale, and the NIHSS.

Main Results

In part 1, the groups did not differ for improvement by ≥ 4 points in the NIHSS score at 24 hours (47% vs 39%, P = 0.2). In part 2, 60 minutes of treatment with tPA led to more patients with minimal or no disability at 3 months than did placebo (50% vs 38%, P = 0.03). {This absolute risk improvement of 12% means that 8 patients would need to be treated with tPA (rather than placebo) for 1 additional patient to have minimal or no disability, 95% CI 5 to 87; the relative risk improvement was 31%, CI 3% to 68%.}* Similar clinical and statistical observations were made using the Rankin scale, the Glasgow outcome scale, and the NIHSS. Symptomatic intracerebral hemorrhage occurred in 6.4% of patients who received tPA and in 0.6% of patients who received placebo (P < 0.001 for the combined analysis). The global test statistic gave an odds ratio of 1.7 for a favorable outcome in patients who received tPA (CI 1.2 to 2.6, P = 0.008).

Conclusion

Intravenous recombinant tPA given within 3 hours of an acute ischemic stroke increased the proportion of patients with minimal or no neurologic and functional disability at 3 months.

Source of funding: National Institute of Neurological Disorders and Stroke.

For article reprint: Dr. J.R. Marler, National Institute of Neurological Disorders and Stroke, Federal Building, Room 800, 7550 Wisconsin Avenue, Bethesda, MD 20892, USA. FAX 301-480-1080.

*Numbers calculated from data in article.


Commentary

Low-molecular-weight heparin was effective in reducing poor outcome at 6 months in ischemic stroke

The results of these two well-designed and -executed trials oblige us, as clinicians and as a society, to re-examine the way in which we care for patients with acute ischemic stroke. For clinicians, a key question not answered by these studies is whether these promising new treatments are better than those currently being used. Typically, clinicians do not avoid all antithrombotic agents as was done for the first 24 hours in the tPA study and for the first 10 days in the LMWH study. Were patients in the placebo groups in these studies put at an unfair disadvantage? Without much evidence to support the practice, aspirin has been used to treat patients with acute ischemic stroke. Some information on its possible efficacy comes from a recently suspended clinical trial (MAST-I) in which patients received within 6 hours of stroke onset either intravenous streptokinase, 300 mg/d of buffered aspirin, both, or neither (1). In MAST-I, which used the same 6-month outcome measures as the LMWH study, 39% of the 153 patients who received aspirin alone had a favorable outcome compared with 32% of the 156 who received neither drug. The absolute difference of 7% was not statistically significant. If this effect of aspirin were real and if an aspirin arm had been included in the current trials, it would have diminished or possibly eliminated the significant benefit of the more expensive and complex treatments.

Further information to help clinicians decide which is the safest and most effective treatment for acute ischemic stroke should be forthcoming, and trials are currently being done to evaluate further thrombolytics (tPA), anticoagulants (heparinoids), and antiplatelet agents (aspirin) (2). In the meantime, clinicians should not assume that the benefits seen in the tPA and LMWH studies apply to different regimens, even of similar drugs. Other recent trials of thrombolytics have been negative (1, 3), and the benefits achieved with LMWH were not seen in a previous trial of unfractionated heparin (4).

Finally, neither the clinician who gives nor the patient who receives tPA or LMWH should expect an immediate benefit. In the short term, patients who received tPA faced a 10-fold increased risk for a symptomatic intracranial hemorrhage before an improved outcome was seen at 3 months. For LMWH, the short-term risk was lacking, but the wait was longer, with outcomes that were significantly better at 6 months but not at 3 months.

For society, a key question is how much are we willing to invest to reduce the morbidity of ischemic stroke? Interestingly, the tPA study has received more attention in the media and certainly in an accompanying editorial (5) than the LMWH study. The tPA study with its time window of 3 hours provides support for implementing a system whereby patients are rapidly identified after stroke onset and transported to the hospital for treatment—the heart attack paradigm or "brain attack." The LMWH study with its time window of 48 hours—most patients being randomized between 24 and 48 hours—suggests that this system may not be absolutely necessary. Given the investment required and the chance that funds may be diverted from other means such as prevention to reduce the burden of stroke, further studies are needed before we can conclude that very early evaluation and treatment are prerequisites for a favorable outcome. Instead, these systems may be important to implement, not because we now have the answer but because they will facilitate our answering the question of which way is best for treating patients with ischemic stroke.

Will Longstreth, MD
Harborview Medical CenterSeattle, Washington, USA


References

1. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial—Italy (MAST-I) Group. Lancet. 1995;346:1509-14.

2. Major Ongoing Stroke Trials. Stroke. 1995;26:1978-82.

3. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-25.

4. Duke RJ, Block RF, Turpie AG, Trebilcock R, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med. 1986;105:825-8.

5. del Zoppo GJ. Acute stroke—on the threshold of a therapy? [Editorial]. N Engl J Med. 1995;333:1632-3.