SEMINARS IN THROMBOSIS AND HEMOSTASIS-VOLUME 17, NO.4, 1991
Heparins and Stroke: Is There a Place for Low Molecular Weight Heparins? s.
The management of ischemic stroke, whether acute or progressing, continues to be a major challenge for neurologists. Acute ischemic stroke is usually defined as an embolic or thrombotic occlusion of an artery leading to the brain, followed by secondary ischemic injury. A stroke is considered acute when the symptoms have been present for less than 24 hours. When an ischemic stroke has been static for more than 24 hours and can no longer be considered acute, it is extremely unlikely that it will respond to any intervention, medical or surgical. Progressing stroke is defined as an event in which neurologic worsening occurs as a result of the ischemic process. Such worsening, which usually occurs in a "stuttering" fashion, may be reported by the patient or more frequently observed directly by medical personnel. Deterioration after hospitalization may occur in about half of these patients. 1 It is most frequent during the first 24 hours and extremely rare after 48 hours. 2 Progression of neurologic symptoms is unpredictable and the attending physician should assume that any patient with an ischemic stroke can deteriorate during the first 24 hours after admission. Consequently, for any treatment to be effective it must be instituted as early as possible after the onset of symptoms. The mechanism by which a stroke progresses is not clearly established and probably represents a combination of factors. 3 However, the development of cerebral edema is considered to be the most frequent cause of deterioration in the patient's condition. Unfortunately, no therapy that interferes with the development of edema or the metabolic effects of ischemia has been proven effecti ve in patients with ischemic stroke.
From the Department of Neurology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas. Reprint requests: Dr. Fields, The University of Texas, M. D. Anderson Cancer Center-Box 211,1515 Holcombe Blvd., Houston, Texas 77030.
FIELDS, M.D.
Recurrent embolism, which can cause deterioration among patients in whom the stroke is the result of cardiogenic emboli, is most common during the first week after stroke. 3 Although the risk of recurrent embolism has not been clearly established, one report suggests that it might be high as 25%.4 Moreover, lysis of the intraluminal clot a few hours after arterial occlusion may produce distal embolization, resulting in additional ischemic injury, or extension of the intraluminal clot can induce further occlusion of the artery and result in failure of the collateral circulation. Because acute or progressing ischemic stroke is caused, for the most part, by thrombotic or embolic occlusions of arteries perfusing the brain, treatment that directly attacks the clot or prevents further propagation of clot and thereby helps restore circulation makes good sense. Although antithrombotic or thrombolytic drugs may improve cerebral perfusion and thereby result in clinical improvement, the results thus far have been inconclusive in the small clinical trials and anecdotal reports that have appeared in the literature. Drugs that conceivably might be useful in the treatment of patients with acute or progressing ischemic strokes are: 1. 2. 3. 4. 5. 6.
Heparin Low molecular weight heparins/heparinoids Ancrod Streptokinase/urokinase Tissue plasminogen activator Single-chain urokinase plasminogen activator
Studies of the last four categories have been extremely limited and in each the risk of intracerebral hemorrhage remains a grave concern. Heparin is the drug most frequently prescribed for treatment of patients with acute or progressing ischemic stroke and its administration to patients has been recommended for the past 10 years by many experts in
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
371
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WILLIAM
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
cerebrovascular disease.5-9 In a recent article, neurologists from four academic services reported its use in 73% of patients with large artery atherothrombotic strokes, 54% with cardioembolic strokes, 31% with lacunar infarctions, and 38% with strokes of undetermined etiology.10 Despite this wide use of heparin, its role in the management of ischemic stroke is still controversial. The regimen of heparin administration in patients with ischemic stroke has not been standardized, but the method most commonly used is a constant intravenous infusion, at an hourly dose of 800 to 1000 U/hour. Continuous infusion is considered safer than intermittent bolus doses of the drug. 11,12 The maintenance dosage is adjusted by the results of the activated partial thromboplastin time (APTT) with the usual therapeutic range at 1.5 to 2.0 times control values. Most neurologists endeavor to maintain an APTT of approximately 60 seconds.13 A low-dose regimen, similar to that used to prevent deep vein thrombosis, is unlikely to be effective. The only large-scale trials employing anticoagulants in patients with stroke were conducted nearly 30 years ago. The results were often disastrous because of the risk of fatal intracranial bleeding. During that era, it was impossible to distinguish cerebral hemorrhage from cerebral infarction in many cases without doing a lumbar puncture. However, even this method of diagnosis frequently failed to make the distinction because the bleeding was confined to the brain parenchyma; blood had not escaped into the cerebrospinal fluid pathways. Anticoagulation under such circumstances was fraught with grave danger. It has only been possible since the advent of new imaging techniques such as computed tomography and magnetic resonance imaging that one can make a definitive diagnosis of cerebral hemorrhage without the need for an invasive procedure. In spite of more sophisticated diagnostic methods, heparin therapy is still accompanied by potentially lifethreatening complications.14 In one recent report intracranial hemorrhages complicating heparin infusion occurred in 16% of patients with progressing stroke.15 Moreover, hemorrhagic transformation of a cerebral infarct can occur in up to 40% of patients within 2 weeks of the stroke.16,17 The Cerebral Embolism Study Group concluded that asymptomatic hemorrhagic transformation can occur without heparin, but major intracranial hemorrhages are more likely to be observed during concomitant heparin administration.18 The risk of hemorrhage within the brain is increased among patients with cardioembolic stroke, those who are seriously ill, those who have major neurologic deficits, and those who have large multilobar infarctions demonstrated by computed tomography. Advanced age or coexisting hypertension can also increase the risk of intraparenchymal bleeding. In this
latter group of patients with cardioembolic strokes, early recurrent embolism appears to be a serious risk.4,19 A small randomized trial undertaken by the Cerebral Embolism Study Group suggested that the risk of hemorrhage with heparin therapy, however serious, might be less than the risk of recurrent embolism.20 Heparin-induced thrombocytopenia can be a mild reaction occurring during the first 48 hours of the infusion or a more serious event that develops later after initiation of therapy, usually between 5 and 10 days. 21-23 Thrombocytopenia is a direct effect of the heparin; its incidence and severity seem unrelated to whether porcine or bovine heparin is used.24 During the last few years, several investigators prospectively evaluated heparin in the treatment of acute cerebral ischemia in uncontrolled studies. Either continued progression or no improvement was observed despite an adequate level of anticoagulation.24,25 These studies included all types of stroke and in no specific cohort was the heparin clearly effective. The indications and contraindications for early anticoagulation in such patients have been the subject of a recent extensive review.27 At the present time, heparin has not been established as either effective or ineffective in the management of patients with acute or progressing ischemic stroke. It may be potentially useful, but a large-scale clinical trial using modern methodology and including an adequate number of subjects needs to be undertaken. Nevertheless, the physician in practice may wish to consider the administration of heparin to a patient with acute or progressing ischemic stroke. If heparin is used, the most reasonable regimen would appear to be a continuous intravenous infusion following a loading bolus dose. Fractionation of heparin into low molecular weight heparins or heparinoids has made possible a dissociation between the antithrombotic and the anticoagulant effects of the drug. 28,29 Conceivably, the employment of these agents may prove to be ideal, since they should be able to prevent propagation of a thrombus or recurrent embolism without complication by hemorrhage. Low molecular weight heparins have a selective antithrombotic effect by inhibiting Factor Xa without some of the other actions of heparin and they prevent thrombosis and fibrin formation at least as well as conventional heparin. Hemorrhage associated with reversible platelet aggregation independent of antithrombin III is lacking with these compounds, unlike heparin. In addition, these agents do not have the antiplatelet aggregation or thrombocytopenic effects of conventional heparin and thereby mitigate the "white clot" syndrome and resultant risk for further cerebral ischemia.29,30 Deep vein thrombosis (DVT) in the lower extremities occurs in about half of patients with acute ischemic stroke, and pulmonary embolism accounts for about 5%
Downloaded by: Universite Laval. Copyrighted material.
372
of deaths. The aforementioned heparinoid substances, lacking the hazards of more established anticoagulants, raise the question of DVT prophylaxis for these patients. Recent advances in noninvasive diagnostic techniques, which enable one to detect DVT early, and the development of these relatively safe heparinoid agents emphasize the need for a prophylactic study of these complications in patients with ischemic stroke.31 The low molecular weight anticoagulant most widely studied thus far by neurologists is the heparinoid Org 10172.32 This agent prevents thrombin formation primarily by inhibition of Factor Xa; it does not affect platelets. It has been used to prevent DVT in a series of patients with recent stroke, only one of whom had hemorrhagic complications.33 This same heparinoid compound has also been employed successfully in the prevention of pulmonary embolism in patients with intracranial hemorrhage.34 Low molecular weight heparinoids and heparins, like conventional heparin, require a constant intravenous infusion. Moreover, they have a minimal effect on the APTT. Their activity is measured by the degree of inhibition of clotting Factor Xa. Investigators at Duke University and the University of Iowa recently performed a dose escalation study of the heparinoid Org 10172 in 27 patients with acute or progressing ischemic stroke.35 Five dose levels, as measured by inhibiting Factor Xa (0.2 to 1.0 U/ml) were studied. The drug was found to be safe, and further examination of the possible efficacy of Org 10172 in a dosage necessary to achieve an anti-Factor Xa level of 0.8 U/ml was believed to be warranted. A study of large dose infusions of Org 10172 in another 58 patients followed,36 with essentially the same result. Therapy with this agent appears to be at least equal in efficacy to heparin and is probably less risky. Further studies in stroke patients of the efficacy of low molecular weight heparin anticoagulants, either alone or in combination with other drugs, are definitely indicated.
REFERENCES 1. Britton M, A Roden: Progression of stroke after arrival at hospital. Stroke 16:629-632, 1985. 2. Duke RJ, AG Turpie, RF Bloch, et al: Clinical trial of low-dose subcutaneous heparin for the prevention of stroke progression. Natural history of acute partial stroke and stroke-in-evolution. In: Reivich M, HI Hurtig, (Eds): Cerebrovascular Diseases. Raven Press, New York, 1983, pp 399-405. 3. Irino T, M Watanabe, M Nishide, et al: Angiographic analysis of acute cerebral infarction followed by "cascade"-like deterioration of minor neurological deficits. What is progressing stroke? Stroke 14:363-368, 1983. 4. Koller RL: Recurrent embolic cerebral infarction and anticoagulation. Neurology (NY) 32:283-285, 1982.
373
5. Millikan C: Anticoagulant treatment to prevent cerebral infarction. Med Clin North Am 63:897-904, 1979. 6. Yatsu FM, JP Mohr: Anticoagulation therapy for cardiogenic emboli to brain. Neurology (Cleve) 32:274-275, 1983. 7. Weksler BB, MP Lewin: Anticoagulation in cerebral ischemia. Stroke 14:658-663, 1983. 8. Dyken ML: Anticoagulant and platelet antiaggregating therapy in stroke and threatened stroke. Neurol Clin 1:223-242, 1983. 9. Miller VT, RG Hart: Heparin anticoagulation in acute brain ischemia. Stroke 19:403-406, 1988. 10. Foulkes MA, PA Wolf, TR Price, et al: The Stroke Data Bank. Design, methods and baseline characteristics. Stroke 19:547-554, 1988. 11. Salzman EW, D Deykin, RM Shapiro, et al: Management of heparin therapy. Controlled prospective trial. N Engl J Med 292:1046-1050, 1975. 12. Glazier RL, EB Crowell: Randomized prospective trial of continuous vs intermittent heparin therapy. JAMA 236:1365-1367, 1976. 13. Alberts MJ, EW Massey, D Dawson: A multicenter study of anticoagulation parameters when using heparin and warfarin. Arch Neurol 44:1229-1231, 1987. 14. Ramirez-Lassepas M, MR Quinones: Heparin therapy for stroke. Hemorrhagic complications and risk factors for intracerebral hemorrhage. Neurology (Cleve) 34:114-117, 1984. 15. Bogousslavsky J, F Regli: Anticoagulant-induced intracerebral bleeding in brain ischemia. Evaluation in 200 patients with TIA's, emboli from the heart and progressing stroke. Acta Neurol Scand 74:464-471, 1985. 16. Calandre L, Ortega J Fernandez, F Bermejo: Anticoagulation and hemorrhagic infarction in cerebral embolism secondary to rheumatic heart disease. Arch Neurol 41:1152-1154, 1984. 17. Hornig CR, W Dorndorf, AL Agnoli: Hemorrhagic cerebral infarction. A prospective study. Stroke 17:179-185, 1986. 18. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke. Brain hemorrhage and management options. Stroke 15:779-789, 1984. 19. Furlan AJ, SJ Cavalier, RE Hobbs, et al: Hemorrhage and anticoagulation for nonseptic embolic brain infarction. Neurology (NY) 32:280-282, 1982. 20. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke. A randomized trial. Stroke 14:668-676, 1983. 21. Ansell J, D Deykin: Heparin-induced thrombocytopenia and recurrent thromboembolism. Am J Hematol 8:325-332, 1980. 22. King DJ, JG Kelton: Heparin-associated thrombocytopenia. Ann Intern Med 100:535-540, 1984. 23. Kelton JG: Heparin-induced thrombocytopenia. Haemostasis 16:173-186, 1986. 24. Ansell JE, JM Price, S Shah, et al: Heparin-induced thrombocytopenia. What is its real frequency? Chest 88:878-882, 1985. 25. Dobkin BH: Heparin for lacunar stroke in progression. Stroke 14:421-423, 1983. 26. Haley EC Jr, NF Kassell, JC Torner: Failure of heparin to prevent progression in progressing ischemic infarction. Stroke 19:10-14, 1988. 27. Yatsu FM, RG Hart, JP Mohr, et al: Anticoagulation of embolic strokes of cardiac origin. An update. Neurology (Cleve) 38:314— 316, 1988. 28. Fareed J: Heparin, its fractions, fragments and derivatives. Some new perspectives. Semin Thromb Hemost 11:1-9, 1985. 29. Hirsh J, F Ofosu, M Buchanan: Rationale behind the development of low molecular weight heparin derivatives. Semin Thromb Hemost 11:13-16, 1985. 30. Salzman EW: Low molecular weight heparin. Is small beautiful? N Engl J Med 315:957-959, 1986.
Downloaded by: Universite Laval. Copyrighted material.
HEPARINS AND STROKE—FIELDS
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
31. Bornstein NM, JW Norris: Deep vein thrombosis after ischemic stroke: Rationale for a therapeutic trial. Arch Phys Med Rehabil 69:955-958, 1988. 32. TenCate H, CP Henny, JW TenCate, et al: Randomized doubleblind, placebo-controlled safety study of a low molecular weight heparinoid in patients undergoing transurethral resection of the prostate. Thromb Haemost 57:92-96, 1987. 33. Turpie AGG, MN Levin, J Hirsh, et al: Double-blind randomized trial of Org 10172 low-molecular-weight heparinoid in prevention of deep vein thombosis in thrombotic stroke. Lancet 1:523-526, 1987.
34. TenCate H, CP Henny, HR Boiler, et al: Use of a heparinoid in patients with hemorrhagic stroke and thromboembolic disease. Ann Neurol 15:268-270, 1984. 35. Biller J, EW Massey, JR Marler, et al: A dose escalation study of Org 10172 (low molecular weight heparinoid) in stroke. Neurology (Cleve) 39:262-265, 1989. 36. Massey EW, J Biller, JN Davis, et al: Heparinoid Org 10172 in stroke (Abst). Ann Neurol 24:130, 1988.
Downloaded by: Universite Laval. Copyrighted material.
374
Heparins and Stroke: Is There a Place for Low Molecular Weight Heparins? s.
The management of ischemic stroke, whether acute or progressing, continues to be a major challenge for neurologists. Acute ischemic stroke is usually defined as an embolic or thrombotic occlusion of an artery leading to the brain, followed by secondary ischemic injury. A stroke is considered acute when the symptoms have been present for less than 24 hours. When an ischemic stroke has been static for more than 24 hours and can no longer be considered acute, it is extremely unlikely that it will respond to any intervention, medical or surgical. Progressing stroke is defined as an event in which neurologic worsening occurs as a result of the ischemic process. Such worsening, which usually occurs in a "stuttering" fashion, may be reported by the patient or more frequently observed directly by medical personnel. Deterioration after hospitalization may occur in about half of these patients. 1 It is most frequent during the first 24 hours and extremely rare after 48 hours. 2 Progression of neurologic symptoms is unpredictable and the attending physician should assume that any patient with an ischemic stroke can deteriorate during the first 24 hours after admission. Consequently, for any treatment to be effective it must be instituted as early as possible after the onset of symptoms. The mechanism by which a stroke progresses is not clearly established and probably represents a combination of factors. 3 However, the development of cerebral edema is considered to be the most frequent cause of deterioration in the patient's condition. Unfortunately, no therapy that interferes with the development of edema or the metabolic effects of ischemia has been proven effecti ve in patients with ischemic stroke.
From the Department of Neurology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas. Reprint requests: Dr. Fields, The University of Texas, M. D. Anderson Cancer Center-Box 211,1515 Holcombe Blvd., Houston, Texas 77030.
FIELDS, M.D.
Recurrent embolism, which can cause deterioration among patients in whom the stroke is the result of cardiogenic emboli, is most common during the first week after stroke. 3 Although the risk of recurrent embolism has not been clearly established, one report suggests that it might be high as 25%.4 Moreover, lysis of the intraluminal clot a few hours after arterial occlusion may produce distal embolization, resulting in additional ischemic injury, or extension of the intraluminal clot can induce further occlusion of the artery and result in failure of the collateral circulation. Because acute or progressing ischemic stroke is caused, for the most part, by thrombotic or embolic occlusions of arteries perfusing the brain, treatment that directly attacks the clot or prevents further propagation of clot and thereby helps restore circulation makes good sense. Although antithrombotic or thrombolytic drugs may improve cerebral perfusion and thereby result in clinical improvement, the results thus far have been inconclusive in the small clinical trials and anecdotal reports that have appeared in the literature. Drugs that conceivably might be useful in the treatment of patients with acute or progressing ischemic strokes are: 1. 2. 3. 4. 5. 6.
Heparin Low molecular weight heparins/heparinoids Ancrod Streptokinase/urokinase Tissue plasminogen activator Single-chain urokinase plasminogen activator
Studies of the last four categories have been extremely limited and in each the risk of intracerebral hemorrhage remains a grave concern. Heparin is the drug most frequently prescribed for treatment of patients with acute or progressing ischemic stroke and its administration to patients has been recommended for the past 10 years by many experts in
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
371
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SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
cerebrovascular disease.5-9 In a recent article, neurologists from four academic services reported its use in 73% of patients with large artery atherothrombotic strokes, 54% with cardioembolic strokes, 31% with lacunar infarctions, and 38% with strokes of undetermined etiology.10 Despite this wide use of heparin, its role in the management of ischemic stroke is still controversial. The regimen of heparin administration in patients with ischemic stroke has not been standardized, but the method most commonly used is a constant intravenous infusion, at an hourly dose of 800 to 1000 U/hour. Continuous infusion is considered safer than intermittent bolus doses of the drug. 11,12 The maintenance dosage is adjusted by the results of the activated partial thromboplastin time (APTT) with the usual therapeutic range at 1.5 to 2.0 times control values. Most neurologists endeavor to maintain an APTT of approximately 60 seconds.13 A low-dose regimen, similar to that used to prevent deep vein thrombosis, is unlikely to be effective. The only large-scale trials employing anticoagulants in patients with stroke were conducted nearly 30 years ago. The results were often disastrous because of the risk of fatal intracranial bleeding. During that era, it was impossible to distinguish cerebral hemorrhage from cerebral infarction in many cases without doing a lumbar puncture. However, even this method of diagnosis frequently failed to make the distinction because the bleeding was confined to the brain parenchyma; blood had not escaped into the cerebrospinal fluid pathways. Anticoagulation under such circumstances was fraught with grave danger. It has only been possible since the advent of new imaging techniques such as computed tomography and magnetic resonance imaging that one can make a definitive diagnosis of cerebral hemorrhage without the need for an invasive procedure. In spite of more sophisticated diagnostic methods, heparin therapy is still accompanied by potentially lifethreatening complications.14 In one recent report intracranial hemorrhages complicating heparin infusion occurred in 16% of patients with progressing stroke.15 Moreover, hemorrhagic transformation of a cerebral infarct can occur in up to 40% of patients within 2 weeks of the stroke.16,17 The Cerebral Embolism Study Group concluded that asymptomatic hemorrhagic transformation can occur without heparin, but major intracranial hemorrhages are more likely to be observed during concomitant heparin administration.18 The risk of hemorrhage within the brain is increased among patients with cardioembolic stroke, those who are seriously ill, those who have major neurologic deficits, and those who have large multilobar infarctions demonstrated by computed tomography. Advanced age or coexisting hypertension can also increase the risk of intraparenchymal bleeding. In this
latter group of patients with cardioembolic strokes, early recurrent embolism appears to be a serious risk.4,19 A small randomized trial undertaken by the Cerebral Embolism Study Group suggested that the risk of hemorrhage with heparin therapy, however serious, might be less than the risk of recurrent embolism.20 Heparin-induced thrombocytopenia can be a mild reaction occurring during the first 48 hours of the infusion or a more serious event that develops later after initiation of therapy, usually between 5 and 10 days. 21-23 Thrombocytopenia is a direct effect of the heparin; its incidence and severity seem unrelated to whether porcine or bovine heparin is used.24 During the last few years, several investigators prospectively evaluated heparin in the treatment of acute cerebral ischemia in uncontrolled studies. Either continued progression or no improvement was observed despite an adequate level of anticoagulation.24,25 These studies included all types of stroke and in no specific cohort was the heparin clearly effective. The indications and contraindications for early anticoagulation in such patients have been the subject of a recent extensive review.27 At the present time, heparin has not been established as either effective or ineffective in the management of patients with acute or progressing ischemic stroke. It may be potentially useful, but a large-scale clinical trial using modern methodology and including an adequate number of subjects needs to be undertaken. Nevertheless, the physician in practice may wish to consider the administration of heparin to a patient with acute or progressing ischemic stroke. If heparin is used, the most reasonable regimen would appear to be a continuous intravenous infusion following a loading bolus dose. Fractionation of heparin into low molecular weight heparins or heparinoids has made possible a dissociation between the antithrombotic and the anticoagulant effects of the drug. 28,29 Conceivably, the employment of these agents may prove to be ideal, since they should be able to prevent propagation of a thrombus or recurrent embolism without complication by hemorrhage. Low molecular weight heparins have a selective antithrombotic effect by inhibiting Factor Xa without some of the other actions of heparin and they prevent thrombosis and fibrin formation at least as well as conventional heparin. Hemorrhage associated with reversible platelet aggregation independent of antithrombin III is lacking with these compounds, unlike heparin. In addition, these agents do not have the antiplatelet aggregation or thrombocytopenic effects of conventional heparin and thereby mitigate the "white clot" syndrome and resultant risk for further cerebral ischemia.29,30 Deep vein thrombosis (DVT) in the lower extremities occurs in about half of patients with acute ischemic stroke, and pulmonary embolism accounts for about 5%
Downloaded by: Universite Laval. Copyrighted material.
372
of deaths. The aforementioned heparinoid substances, lacking the hazards of more established anticoagulants, raise the question of DVT prophylaxis for these patients. Recent advances in noninvasive diagnostic techniques, which enable one to detect DVT early, and the development of these relatively safe heparinoid agents emphasize the need for a prophylactic study of these complications in patients with ischemic stroke.31 The low molecular weight anticoagulant most widely studied thus far by neurologists is the heparinoid Org 10172.32 This agent prevents thrombin formation primarily by inhibition of Factor Xa; it does not affect platelets. It has been used to prevent DVT in a series of patients with recent stroke, only one of whom had hemorrhagic complications.33 This same heparinoid compound has also been employed successfully in the prevention of pulmonary embolism in patients with intracranial hemorrhage.34 Low molecular weight heparinoids and heparins, like conventional heparin, require a constant intravenous infusion. Moreover, they have a minimal effect on the APTT. Their activity is measured by the degree of inhibition of clotting Factor Xa. Investigators at Duke University and the University of Iowa recently performed a dose escalation study of the heparinoid Org 10172 in 27 patients with acute or progressing ischemic stroke.35 Five dose levels, as measured by inhibiting Factor Xa (0.2 to 1.0 U/ml) were studied. The drug was found to be safe, and further examination of the possible efficacy of Org 10172 in a dosage necessary to achieve an anti-Factor Xa level of 0.8 U/ml was believed to be warranted. A study of large dose infusions of Org 10172 in another 58 patients followed,36 with essentially the same result. Therapy with this agent appears to be at least equal in efficacy to heparin and is probably less risky. Further studies in stroke patients of the efficacy of low molecular weight heparin anticoagulants, either alone or in combination with other drugs, are definitely indicated.
REFERENCES 1. Britton M, A Roden: Progression of stroke after arrival at hospital. Stroke 16:629-632, 1985. 2. Duke RJ, AG Turpie, RF Bloch, et al: Clinical trial of low-dose subcutaneous heparin for the prevention of stroke progression. Natural history of acute partial stroke and stroke-in-evolution. In: Reivich M, HI Hurtig, (Eds): Cerebrovascular Diseases. Raven Press, New York, 1983, pp 399-405. 3. Irino T, M Watanabe, M Nishide, et al: Angiographic analysis of acute cerebral infarction followed by "cascade"-like deterioration of minor neurological deficits. What is progressing stroke? Stroke 14:363-368, 1983. 4. Koller RL: Recurrent embolic cerebral infarction and anticoagulation. Neurology (NY) 32:283-285, 1982.
373
5. Millikan C: Anticoagulant treatment to prevent cerebral infarction. Med Clin North Am 63:897-904, 1979. 6. Yatsu FM, JP Mohr: Anticoagulation therapy for cardiogenic emboli to brain. Neurology (Cleve) 32:274-275, 1983. 7. Weksler BB, MP Lewin: Anticoagulation in cerebral ischemia. Stroke 14:658-663, 1983. 8. Dyken ML: Anticoagulant and platelet antiaggregating therapy in stroke and threatened stroke. Neurol Clin 1:223-242, 1983. 9. Miller VT, RG Hart: Heparin anticoagulation in acute brain ischemia. Stroke 19:403-406, 1988. 10. Foulkes MA, PA Wolf, TR Price, et al: The Stroke Data Bank. Design, methods and baseline characteristics. Stroke 19:547-554, 1988. 11. Salzman EW, D Deykin, RM Shapiro, et al: Management of heparin therapy. Controlled prospective trial. N Engl J Med 292:1046-1050, 1975. 12. Glazier RL, EB Crowell: Randomized prospective trial of continuous vs intermittent heparin therapy. JAMA 236:1365-1367, 1976. 13. Alberts MJ, EW Massey, D Dawson: A multicenter study of anticoagulation parameters when using heparin and warfarin. Arch Neurol 44:1229-1231, 1987. 14. Ramirez-Lassepas M, MR Quinones: Heparin therapy for stroke. Hemorrhagic complications and risk factors for intracerebral hemorrhage. Neurology (Cleve) 34:114-117, 1984. 15. Bogousslavsky J, F Regli: Anticoagulant-induced intracerebral bleeding in brain ischemia. Evaluation in 200 patients with TIA's, emboli from the heart and progressing stroke. Acta Neurol Scand 74:464-471, 1985. 16. Calandre L, Ortega J Fernandez, F Bermejo: Anticoagulation and hemorrhagic infarction in cerebral embolism secondary to rheumatic heart disease. Arch Neurol 41:1152-1154, 1984. 17. Hornig CR, W Dorndorf, AL Agnoli: Hemorrhagic cerebral infarction. A prospective study. Stroke 17:179-185, 1986. 18. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke. Brain hemorrhage and management options. Stroke 15:779-789, 1984. 19. Furlan AJ, SJ Cavalier, RE Hobbs, et al: Hemorrhage and anticoagulation for nonseptic embolic brain infarction. Neurology (NY) 32:280-282, 1982. 20. Cerebral Embolism Study Group: Immediate anticoagulation of embolic stroke. A randomized trial. Stroke 14:668-676, 1983. 21. Ansell J, D Deykin: Heparin-induced thrombocytopenia and recurrent thromboembolism. Am J Hematol 8:325-332, 1980. 22. King DJ, JG Kelton: Heparin-associated thrombocytopenia. Ann Intern Med 100:535-540, 1984. 23. Kelton JG: Heparin-induced thrombocytopenia. Haemostasis 16:173-186, 1986. 24. Ansell JE, JM Price, S Shah, et al: Heparin-induced thrombocytopenia. What is its real frequency? Chest 88:878-882, 1985. 25. Dobkin BH: Heparin for lacunar stroke in progression. Stroke 14:421-423, 1983. 26. Haley EC Jr, NF Kassell, JC Torner: Failure of heparin to prevent progression in progressing ischemic infarction. Stroke 19:10-14, 1988. 27. Yatsu FM, RG Hart, JP Mohr, et al: Anticoagulation of embolic strokes of cardiac origin. An update. Neurology (Cleve) 38:314— 316, 1988. 28. Fareed J: Heparin, its fractions, fragments and derivatives. Some new perspectives. Semin Thromb Hemost 11:1-9, 1985. 29. Hirsh J, F Ofosu, M Buchanan: Rationale behind the development of low molecular weight heparin derivatives. Semin Thromb Hemost 11:13-16, 1985. 30. Salzman EW: Low molecular weight heparin. Is small beautiful? N Engl J Med 315:957-959, 1986.
Downloaded by: Universite Laval. Copyrighted material.
HEPARINS AND STROKE—FIELDS
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
31. Bornstein NM, JW Norris: Deep vein thrombosis after ischemic stroke: Rationale for a therapeutic trial. Arch Phys Med Rehabil 69:955-958, 1988. 32. TenCate H, CP Henny, JW TenCate, et al: Randomized doubleblind, placebo-controlled safety study of a low molecular weight heparinoid in patients undergoing transurethral resection of the prostate. Thromb Haemost 57:92-96, 1987. 33. Turpie AGG, MN Levin, J Hirsh, et al: Double-blind randomized trial of Org 10172 low-molecular-weight heparinoid in prevention of deep vein thombosis in thrombotic stroke. Lancet 1:523-526, 1987.
34. TenCate H, CP Henny, HR Boiler, et al: Use of a heparinoid in patients with hemorrhagic stroke and thromboembolic disease. Ann Neurol 15:268-270, 1984. 35. Biller J, EW Massey, JR Marler, et al: A dose escalation study of Org 10172 (low molecular weight heparinoid) in stroke. Neurology (Cleve) 39:262-265, 1989. 36. Massey EW, J Biller, JN Davis, et al: Heparinoid Org 10172 in stroke (Abst). Ann Neurol 24:130, 1988.
Downloaded by: Universite Laval. Copyrighted material.
374
