Heparin for Acute Stroke Treatment?

มีคำถามบ่อยๆ ถึงการใช้ Heparin ในการรักษา Acute ischemic stroke ครับ ผมก็ตอบไปหลายครับ แต่มาดู Werner Hacke เป็นบทความที่คัดลอกมาจาก Ask the Expert  ใน medscape ครับ

Question 

Is there any good evidence to support the use of heparin in the treatment of stroke?  

Response from Werner Hacke, MD, PhD 

Professor and Chairman, Department of Neurology, University of Heidelberg, Heidelberg, Germany 

The short answer is: No. There is no evidence at all for the use of heparin in the treatment of stroke. 

The longer answer is a bit more complicated. 

We have to distinguish among several types of heparin administration in the setting of acute stroke and consider the different possible goals, including the treatment and prevention of stroke and the prevention of deep vein thrombosis (DVT). 

First, with regard to administration, there is the traditional, full-dose acute IV anticoagulation with unfractionated heparin, which prolongs the aPTT. This method has been used extensively in the United States and parts of 

Western Europe for decades, despite the fact that only 1 very small and prematurely terminated clinical trial 

seemed to show some evidence for the usefulness of this acute treatment strategy. Unfortunately, thereafter, this 

approach — which has been used in millions of acute stroke patients per year — was never subjected to a formal 

modern randomized clinical trial. We hope that an investigator-driven trial called RAPID, which is about to begin at 

the end of this year in Europe, will correctly evaluate this classic treatment model for the first time. 

A second approach to administration is the use of unfractionated subcutaneous heparin. This approach was not so 

popular in the United States and mainland Europe, but it has been subjected to a large intervention trial, the 

International Stroke Trial (IST), with almost 20,000 patients enrolled. IST had a factorial design, in which either 

aspirin or 1 or 2 doses of subcutaneous heparin (2 times 5000 international units [IU] per day or 2 times 12,500 IU 

per day) or placebo was given to patients with acute stroke syndrome within 48 hours after stroke onset. In this 

trial, recurrence of stroke was slightly reduced with any type of subcutaneous heparin, but this benefit was 

outweighed by an increase in the incidence of symptomatic intracranial hemorrhage, resulting in essentially no 

benefit from treatment with subcutaneous heparin. Major criticisms of the IST included the absence of a CT scan 

before treatment onset in one third of the patients and failure to monitor aPTT in patients receiving 25,000 units 

per day of unfractionated heparin subcutaneously. Nevertheless, data from 20,000 patients are valid despite those 

critical remarks. 

Third, low-molecular-weight heparin has been used in several clinical trials. One pilot study seemed to show a 

superiority of subcutaneous low-molecular-weight heparin over placebo (Key, 1995). This benefit was only found 

after 6 months, but not after 3 months. Subsequent studies designed to replicate these encouraging data all 

failed. 

Fourth, a low-molecular-weight heparinoid was subjected to a stringent clinical trial, the Trial of ORG 10172 in 

Acute Stroke Treatment (TOAST). In this study, no benefit for the heparinoid-treated patients was found, although 

in a subgroup analysis, it seemed that patients with large stroke benefited more. 

Finally, it is well known that either fractionated or unfractionated subcutaneous heparin may prevent DVT and 

pulmonary embolism, but again, this is at the expense of a greater risk of bleeding.

Thus, so far there is no good evidence whatsoever for the use of any type of heparin treatment in the setting of 

acute stroke. 

Posted 08/19/2002 

Suggested Readings 

Adams HP Jr. Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke. 

2002;33:856-861. 

Adams HP Jr, Bendixen BH, Leira E, et al. Antithrombotic treatment of ischemic stroke among patients with 

occlusion or severe stenosis of the internal carotid artery: A report of the Trial of Org 10172 in Acute Stroke 

Treatment (TOAST). Neurology. 1999;53:122-125. 

Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin- 

controlled trial. Lancet. 2001;358:702-710. 

Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in patients with acute 

ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute 

Embolic Stroke Trial. Lancet. 2000;355:1205-1210. 

Counsell C, Sandercock P. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin 

for acute ischemic stroke (Cochrane review). Stroke. 2002;33:1925-1926. 

Gubitz G, Counsell C, Sandercock P, Signorini D. Anticoagulants for Acute Ischemic Stroke. The Cochrane 

Library, Issue 2, 2002. Oxford. 

Jonas S, Quartermain D. Low molecular weight heparin and the treatment of ischemic stroke. Animal results, the 

reasons for failure in human stroke trials, mechanisms of action, and the possibilities for future use in stroke. Ann 

N Y Acad Sci. 2001;939:268-270. 

Saxena R, Lewis S, Berge E, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients 

with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke. 2001;32:2333-2337. 

Sherman DG. Heparin and heparinoids in stroke. Review. Neurology. 1998;51(3 Suppl 3):S56-58. 

Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a 

randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment 

(TOAST) Investigators. JAMA. 1998;279:1265-1272. 

Van Aken H, Bode C, Darius H, et al. Anticoagulation: the present and future. Clin Appl Thromb Hemost. 

2001;7:195-204. 

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