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


Therapeutics

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

ACP J Club. 1996 May-June;124:59. doi:10.7326/ACPJC-1996-124-3-059


Source Citation

Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995 Dec 14;333:1588-93.


Abstract

Objective

To determine the effectiveness of low-molecular-weight heparin (LMWH) in patients with acute ischemic stroke.

Design

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

Setting

4 hospitals in Hong Kong.

Patients

308 patients (mean age 67 y, 58% men) who were diagnosed with acute stroke in the preceding 48 hours. Exclusion criteria were age > 80 years, intracranial hemorrhage, transient neurologic deficits, sustained hypertension, major neurologic or systemic illness, recent major operation or tendency toward bleeding, receipt of anticoagulant therapy or necessity of such therapy for valvular heart disease, or known hypersensitivity to heparin. 6-month follow-up was 99%.

Intervention

Patients were allocated to subcutaneous injections of LMWH, 4100 anti-factor Xa IU of nadroparin calcium in 0.4 mL of solution every 12 hours (high-dose) (n = 102); LMWH alternated with placebo every 12 hours (low-dose) (n = 101); or placebo injections every 12 hours (n = 105). The treatment was administered for 10 days. Oral aspirin, 100 mg daily, was given after the treatment period unless contraindicated.

Main Outcome Measures

Poor outcome (death or dependency in daily activities) at 6 months. Secondary outcomes were death, hemorrhagic transformation of the infarct, other complications at 10 days, and poor outcome at 3 months.

Main Results

At the 6-month follow-up, 10 days of high-dose LMWH led to fewer poor outcomes than did placebo (45% vs 65%, P = 0.005). {This absolute risk reduction of 20% means that 5 patients would need to be treated with LMWH (rather than placebo) for 10 days to prevent 1 additional poor outcome, 95% CI 3 to 18; the relative risk reduction was 30%, CI 10% to 46%.}* The difference for low-dose LMWH compared with placebo did not reach statistical significance (52% vs 65%, {P = 0.09}*). At 10 days, patients who received high-dose LMWH, low-dose LMWH, or placebo did not differ for death, hemorrhagic transformation of the infarct, or complications (P for trend = 0.84, 0.19, and 0.14, respectively). At 3 months, the 3 groups did not differ for poor outcome (P = 0.12).

Conclusion

In patients who had had an acute ischemic stroke, LMWH given at a dosage of 4100 anti-factor Xa IU twice daily was effective in reducing death or dependency at 6 months.

Sources of funding: Chinese University of Hong Kong and Sanofi Recherche.

For article reprint: Dr. R. Kay, Department of Medicine, Prince of Wales Hospital, Shatin, Hong Kong. FAX 852-2637-5876.

*Numbers calculated from data in article.


Commentary

Tissue plasminogen activator improved clinical outcome after acute 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.