Heparin for acute stroke treatment?
Heparin for acute stroke treatment?
Is there any good evidence to support the use of heparin in the treatment of stroke?
William Reichert, MD
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.
Question
Is there any good evidence to support the use of heparin in the treatment of stroke?
William Reichert, MD
Response From the Expert
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.
Source...