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Is There Still a Role for Intravenous Heparin in Acute Stroke?: Yes

Is There Still a Role for Intravenous Heparin in Acute Stroke?: Yes INTRAVENOUS (IV) heparin was frequently considered a treatment option in acute ischemic stroke. However, only limitation of thrombus growth and facilitation of spontaneous endogenous thrombolysis are reasons to believe in its value in treating the index stroke. Most clinicians nowadays agree that the use of heparin, either IV or subcutaneously (SC), prevents deep venous thrombosis and pulmonary embolism.1However, the question remains whether heparin does prevent recurrent stroke. In view of the potential hemorrhagic complications and heparin-induced thrombocytopenia, early treatment with IV heparin has always been a matter of controversy. In 1994, the Stroke Council of the American Heart Association did not recommend heparin because data about safety and efficacy were insufficient and conflicting.1Nevertheless, in the absence of other acute treatment options and with proved primary and secondary preventive effects of oral anticoagulation in cardioembolic stroke, IV heparin was frequently applied in several parts of the world. Although such treatment was used for decades, the first placebo-controlled, randomized trial addressing full-dose unfractioned heparin treatment in acute stroke was the one performed by the Cerebral Embolism Study Group.2The study was terminated early because of excess mortality in the placebo arm. Later, statisticians and others claimed that the termination of the trial was premature and that there could be a type II error explaining the difference in early mortality. In another study, Duke and coworkers3found no significant difference between IV heparin and placebo in a small number of patients with presumably noncardioembolic stroke. From 1995 on, important studies on anticoagulation early after stroke have been published. In the Hong Kong Study, therapy with SC nadroparin calcium was safe and beneficial at 6 months (primary outcome variable) but not at 3 months or 10 days after stroke.4The larger follow-up Fraxiparine in Ischaemic Stroke Study, however, failed to replicate the positive aspects of the Hong Kong Study.5 In the Trial of ORG 10172 in Acute Stroke Treatment study, an intravenously administered heparinoid (danaparoid sodium) showed a positive response to treatment at 7 days, but not at 3 months (primary outcome variable). In this trial, the risk of recurrent stroke within 1 week was very low (1.2%) and was similar in different stroke subtypes. In post hoc analyses, patients with stroke from large-artery atherosclerosis (n=230) had a benefit from treatment with danaparoid. In the Trial of ORG 10172 in Acute Stroke Treatment, the factor Xa–adjusted use of the heparinoid was associated with an increased risk of extracranial and intracranial hemorrhage, especially in patients with large stroke.6 Particularly since the International Stroke Trial,7 treatment with heparin has increasingly come under fire. The International Stroke Trial used a high dose of twice-daily SC heparin, which in some patients probably led to systemic anticoagulation. However, there was no systematic assessment of the activated partial thromboplastin time to monitor anticoagulant effects. Certainly, the results of twice-daily SC heparin cannot be used as proof against full-dose IV heparin with proper monitoring of activated partial thromboplastin time, mandatory computed tomographic scanning before therapy, and formal exclusion criteria for anticoagulant treatment, such as severe cerebral microangiopathy, large cerebral infarcts, and uncontrolled severe hypertension. Because of the factorial design of the International Stroke Trial, many patients receiving either dose of heparin also received aspirin, which makes the assignment of complications to one part of the treatment probably more difficult than assumed. In the absence of blinding, there may be a bias toward assigning bleeding complications to the presumably more dangerous drug. All data reviewed so far stem from randomized trials. The inclusion of patients into such trials is based on detailed inclusion and exclusion criteria. Once patients are entered, the prescribed treatment follows, mostly with strict dosaging and treatment times. Clinical practice is different: treatment may be halted, reinstituted, or, most importantly, prematurely terminated if the supposed cause of stroke for which anticoagulation was chosen is not confirmed. There are few data about the safety of anticoagulation in a routine clinical setting. In the European Cooperative Acute Stroke Study I, the European trial of tissue plasminogen activator, it was up to the local investigators to use heparin 24 hours after stroke IV, SC, or not at all. In the placebo arm, treatment with or without heparin had no effect on the outcome. However, the safety results were surprising: hemorrhage rates were highest in the group without heparin and lowest in the full-dose IV group, while there were no significant differences in initial stroke severity, age, infarct size, or presumed stroke etiology between groups.8Could it be that clinicians are able to select patients with lower risk for cerebral hemorrhage? Where do we stand now? One of the most important lessons that can be learned from the recent trials is that the rate of early recurrence after ischemic stroke may be much lower than estimated. In view of the lower recurrence rate and the potential hazards, rapid administration of anticoagulants cannot be recommended as a general therapy in ischemic stroke, and it should certainly be avoided in patients with an increased risk of hemorrhage. We have become more cautious than in the past. We use IV heparin only for shorter periods, sometimes only 2 to 3 days. As soon as we can rule out all potential indications for anticoagulation, IV heparin is replaced by SC heparin or aspirin. In summary, we give it shorter and less frequently and we use a lower intensity than previously (eg, activated partial thromboplastin time, 50-70 seconds). What are the remaining relative indications for acute IV heparin at the present time? Our colleagues with special emphasis on evidence-based medicine would say: none, because there is no positive evidence, and there are some hints of danger. If one only considers prophylaxis of deep vein thrombosis, they are perfectly right: SC treatment will do it with even lower risk. We think that in the absence of contraindications against anticoagulation, IV heparin can be considered under the following conditions (with only grade 1 level of evidence): Proved or highly probable cardiac embolism Arterial dissection Symptomatic intracranial stenoses Deficiency of protein S, protein C, or antithrombin III until oral anticoagulation High-grade symptomatic internal carotid artery stenoses until surgery We really do not like those stroke articles that always start with mentioning that stroke is the third leading cause of death in Western countries (actually, it is number 2 now) and finish with stating that more data are needed and a controlled trial is warranted. So let us finish by saying that we need more data and that a blinded randomized, controlled, carefully monitored trial of full-dose IV anticoagulants against SC heparin or aspirin in clearly defined high-risk patients with an adequate sample size is needed. Sorry about that. Accepted for publication December 29, 1998. Reprints: Armin J. Grau, MD, Neurology Department, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany (e-mail: Armin_Grau@med.uni-heidelberg.de). References 1. Adams HPBrott TGCrowell RM et al. Guidelines for the management of patients with acute ischemic stroke: a statement for Healthcare Professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;251901- 1914Google ScholarCrossref 2. Cerebral Embolism Study Group, Immediate anticoagulation of embolic stroke: a randomized trial. Stroke. 1983;14668- 676Google ScholarCrossref 3. Duke RJBloch RFTurpie AGTrebilcock RBayer N Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: a randomized controlled trial. Ann Intern Med. 1986;105825- 828Google ScholarCrossref 4. Kay RWong KSYu YL et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995;3331588- 1593Google ScholarCrossref 5. Hommel Mfor the FISS bis Investigators Group, Fraxiparine in Ischaemic Stroke Study (FISS bis) [abstract]. Cerebrovasc Dis. 1998;8 (suppl 4) 64Google Scholar 6. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators, Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA. 1998;2791265- 1272Google ScholarCrossref 7. International Stroke Trial Collaborative Group, The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet. 1997;3491569- 1581Google ScholarCrossref 8. Willig VPawelec DMau JHöxter GHacke W Heparin effects in the European Cooperative Acute Stroke Study [abstract]. Stroke. 1997;28272Google Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Is There Still a Role for Intravenous Heparin in Acute Stroke?: Yes

Archives of Neurology , Volume 56 (9) – Sep 1, 1999

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References (13)

Publisher
American Medical Association
Copyright
Copyright © 1999 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.56.9.1159
Publisher site
See Article on Publisher Site

Abstract

INTRAVENOUS (IV) heparin was frequently considered a treatment option in acute ischemic stroke. However, only limitation of thrombus growth and facilitation of spontaneous endogenous thrombolysis are reasons to believe in its value in treating the index stroke. Most clinicians nowadays agree that the use of heparin, either IV or subcutaneously (SC), prevents deep venous thrombosis and pulmonary embolism.1However, the question remains whether heparin does prevent recurrent stroke. In view of the potential hemorrhagic complications and heparin-induced thrombocytopenia, early treatment with IV heparin has always been a matter of controversy. In 1994, the Stroke Council of the American Heart Association did not recommend heparin because data about safety and efficacy were insufficient and conflicting.1Nevertheless, in the absence of other acute treatment options and with proved primary and secondary preventive effects of oral anticoagulation in cardioembolic stroke, IV heparin was frequently applied in several parts of the world. Although such treatment was used for decades, the first placebo-controlled, randomized trial addressing full-dose unfractioned heparin treatment in acute stroke was the one performed by the Cerebral Embolism Study Group.2The study was terminated early because of excess mortality in the placebo arm. Later, statisticians and others claimed that the termination of the trial was premature and that there could be a type II error explaining the difference in early mortality. In another study, Duke and coworkers3found no significant difference between IV heparin and placebo in a small number of patients with presumably noncardioembolic stroke. From 1995 on, important studies on anticoagulation early after stroke have been published. In the Hong Kong Study, therapy with SC nadroparin calcium was safe and beneficial at 6 months (primary outcome variable) but not at 3 months or 10 days after stroke.4The larger follow-up Fraxiparine in Ischaemic Stroke Study, however, failed to replicate the positive aspects of the Hong Kong Study.5 In the Trial of ORG 10172 in Acute Stroke Treatment study, an intravenously administered heparinoid (danaparoid sodium) showed a positive response to treatment at 7 days, but not at 3 months (primary outcome variable). In this trial, the risk of recurrent stroke within 1 week was very low (1.2%) and was similar in different stroke subtypes. In post hoc analyses, patients with stroke from large-artery atherosclerosis (n=230) had a benefit from treatment with danaparoid. In the Trial of ORG 10172 in Acute Stroke Treatment, the factor Xa–adjusted use of the heparinoid was associated with an increased risk of extracranial and intracranial hemorrhage, especially in patients with large stroke.6 Particularly since the International Stroke Trial,7 treatment with heparin has increasingly come under fire. The International Stroke Trial used a high dose of twice-daily SC heparin, which in some patients probably led to systemic anticoagulation. However, there was no systematic assessment of the activated partial thromboplastin time to monitor anticoagulant effects. Certainly, the results of twice-daily SC heparin cannot be used as proof against full-dose IV heparin with proper monitoring of activated partial thromboplastin time, mandatory computed tomographic scanning before therapy, and formal exclusion criteria for anticoagulant treatment, such as severe cerebral microangiopathy, large cerebral infarcts, and uncontrolled severe hypertension. Because of the factorial design of the International Stroke Trial, many patients receiving either dose of heparin also received aspirin, which makes the assignment of complications to one part of the treatment probably more difficult than assumed. In the absence of blinding, there may be a bias toward assigning bleeding complications to the presumably more dangerous drug. All data reviewed so far stem from randomized trials. The inclusion of patients into such trials is based on detailed inclusion and exclusion criteria. Once patients are entered, the prescribed treatment follows, mostly with strict dosaging and treatment times. Clinical practice is different: treatment may be halted, reinstituted, or, most importantly, prematurely terminated if the supposed cause of stroke for which anticoagulation was chosen is not confirmed. There are few data about the safety of anticoagulation in a routine clinical setting. In the European Cooperative Acute Stroke Study I, the European trial of tissue plasminogen activator, it was up to the local investigators to use heparin 24 hours after stroke IV, SC, or not at all. In the placebo arm, treatment with or without heparin had no effect on the outcome. However, the safety results were surprising: hemorrhage rates were highest in the group without heparin and lowest in the full-dose IV group, while there were no significant differences in initial stroke severity, age, infarct size, or presumed stroke etiology between groups.8Could it be that clinicians are able to select patients with lower risk for cerebral hemorrhage? Where do we stand now? One of the most important lessons that can be learned from the recent trials is that the rate of early recurrence after ischemic stroke may be much lower than estimated. In view of the lower recurrence rate and the potential hazards, rapid administration of anticoagulants cannot be recommended as a general therapy in ischemic stroke, and it should certainly be avoided in patients with an increased risk of hemorrhage. We have become more cautious than in the past. We use IV heparin only for shorter periods, sometimes only 2 to 3 days. As soon as we can rule out all potential indications for anticoagulation, IV heparin is replaced by SC heparin or aspirin. In summary, we give it shorter and less frequently and we use a lower intensity than previously (eg, activated partial thromboplastin time, 50-70 seconds). What are the remaining relative indications for acute IV heparin at the present time? Our colleagues with special emphasis on evidence-based medicine would say: none, because there is no positive evidence, and there are some hints of danger. If one only considers prophylaxis of deep vein thrombosis, they are perfectly right: SC treatment will do it with even lower risk. We think that in the absence of contraindications against anticoagulation, IV heparin can be considered under the following conditions (with only grade 1 level of evidence): Proved or highly probable cardiac embolism Arterial dissection Symptomatic intracranial stenoses Deficiency of protein S, protein C, or antithrombin III until oral anticoagulation High-grade symptomatic internal carotid artery stenoses until surgery We really do not like those stroke articles that always start with mentioning that stroke is the third leading cause of death in Western countries (actually, it is number 2 now) and finish with stating that more data are needed and a controlled trial is warranted. So let us finish by saying that we need more data and that a blinded randomized, controlled, carefully monitored trial of full-dose IV anticoagulants against SC heparin or aspirin in clearly defined high-risk patients with an adequate sample size is needed. Sorry about that. Accepted for publication December 29, 1998. Reprints: Armin J. Grau, MD, Neurology Department, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany (e-mail: Armin_Grau@med.uni-heidelberg.de). References 1. Adams HPBrott TGCrowell RM et al. Guidelines for the management of patients with acute ischemic stroke: a statement for Healthcare Professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;251901- 1914Google ScholarCrossref 2. Cerebral Embolism Study Group, Immediate anticoagulation of embolic stroke: a randomized trial. Stroke. 1983;14668- 676Google ScholarCrossref 3. Duke RJBloch RFTurpie AGTrebilcock RBayer N Intravenous heparin for the prevention of stroke progression in acute partial stable stroke: a randomized controlled trial. Ann Intern Med. 1986;105825- 828Google ScholarCrossref 4. Kay RWong KSYu YL et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995;3331588- 1593Google ScholarCrossref 5. Hommel Mfor the FISS bis Investigators Group, Fraxiparine in Ischaemic Stroke Study (FISS bis) [abstract]. Cerebrovasc Dis. 1998;8 (suppl 4) 64Google Scholar 6. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators, Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA. 1998;2791265- 1272Google ScholarCrossref 7. International Stroke Trial Collaborative Group, The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet. 1997;3491569- 1581Google ScholarCrossref 8. Willig VPawelec DMau JHöxter GHacke W Heparin effects in the European Cooperative Acute Stroke Study [abstract]. Stroke. 1997;28272Google Scholar

Journal

Archives of NeurologyAmerican Medical Association

Published: Sep 1, 1999

Keywords: acute cerebrovascular accidents,intravenous heparin,heparin

There are no references for this article.