Published online before print December 19, 2002, doi: 10.1161/01.STR.0000047036.77466.E8
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(Stroke. 2003;34:230.)
© 2003 American Heart Association, Inc.
Controversies in Stroke |
Resolved: Heparin May Be Useful in Selected Patients With Brain Ischemia
From the Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Mass.
Correspondence to Louis R. Caplan, Beth Israel Deaconess Medical Center, Dept of Neurology, Dana 779, 330 Brookline Ave, Boston, MA 02215-5400. E-mail lcaplan{at}caregroup.harvard.edu
Key Words: heparin • ischemia • stroke, ischemic • thrombi
Theoretical Utility of Heparins
Heparin reduces development of erythrocyte-fibrin thrombi that form in regions of vascular stasis especially within the heart, in severely stenosed arteries sometimes engrafted on white thrombi, in acute arterial occlusions as fresh tails on existing thrombi, and within extremity and pelvic veins. Unfortunately, heparin use can be associated with severe bleeding, especially if not closely monitored.
Optimal Testing of Heparin Effectiveness and Safety
Heparin should not be indiscriminately used in all brain ischemia patients. Bleeding complications will outweigh therapeutic benefit. Unfortunately, randomized trials have not adequately studied heparins in patients with conditions likely to respond to treatment. Reported trials lumped patients with brain ischemia together without diagnostic investigations defining etiology, stroke subtypes, or vascular lesions.
Worsening and new neurologic deficits can develop when thrombi form, propagate, and embolize. Stroke worsening, even when thrombi are present, occurs in only 20% to 33% of ischemic strokes. Even when anticoagulants are stopped because of hemorrhage in prosthetic heart valve patients, recurrent embolism rarely occurred during the next 10 days.1 Most cardioembolic recurrences do not occur during the first week after an embolus.2 Worsening in patients with atherothrombotic large artery occlusive disease is due to perfusion failure often unrelated to changes in occlusive thrombi.3 Randomized trials to effectively determine heparin utility must be (1) eclectic and include only patients in whom brain and cardiac and vascular imaging show high-risk cardiac and artery-to-artery embolic brain infarcts and in patients with documented severe extracranial or intracranial large artery occlusive disease; (2) powered to account for clinical worsening and/or new brain infarcts in less than one third of patients; and (3) closely monitored to ensure infrequent bleeding. No available trials even remotely meet these criteria. In the International Stroke Trial (IST), the largest heparin trial, vascular and cardiac imaging were not reported, some patients had no brain imaging before treatment, heparin was given subcutaneously while elsewhere heparins are usually given intravenously, and levels of anticoagulation were not always closely monitored.4 Heparin effectively prevented pulmonary embolism.4
Available Data
Acute Ischemic Stroke
In the TOAST trial, a low-molecular-weight heparinoid was given within 24 hours of acute ischemic strokes, by continuous intravenous infusion for 7 days with dose adjustments after 24 hours according to anti-Xa factor activity.5 Danaparoid treatment was effective in patients diagnosed clinically as having large artery atherosclerosis in whom heparinoid reduced recurrent strokes during the 7 days of infusion, and rates of favorable and very favorable outcomes were significantly higher in patients given heparinoid compared with placebo.5 Danaparoid was effective in patients with large artery atherosclerosis who had severe cervical internal carotid artery (ICA) stenosis.6 Heparinoid-treated patients with ICA stenosis had significantly more favorable and very favorable outcomes. A study of heparin given within 5 hours after anterior circulation strokes showed that heparin could be given safely with minimal bleeding.7
Cardiogenic Embolism
Early anticoagulation of patients with atrial fibrillation-related strokes can be safe and effective.8,9 Chamorro et al treated patients with atrial fibrillation-related cardioembolic strokes with intravenous or subcutaneous heparin as soon as CT excluded brain hemorrhage.10 The 74 patients treated within 6 hours had better recovery than the 157 treated between 6 and 48 hours. Patients with recurrent strokes had lower mean APTT ratios than those without recurrence.
Dural Sinus and Cerebral Venous Thrombosis (CVT)
Case reports and reviews showed that patients did not worsen or develop new hemorrhages after heparin. Among 82 heparin-treated patients, there were no deaths, and 77% of patients recovered completely.11 Among 79 patients given anticoagulants, 94% improved and survived while only half of 157 patients not given anticoagulants survived.12
Meta-analysis of 2 trials13,14 showed an absolute risk reduction in mortality of 14% and a relative risk reduction of 70% in heparin-treated patients. Einhaupl et al planned a 60-patient study, but interim analysis after the first 20 was so positive for heparin that the study was terminated.13 Severity scores in the heparin-treated group were much improved over placebo. Among 102 patients with CVT (43 with intracerebral hemorrhages), those not treated with heparin fared worse and had higher mortality.13 In a double-blind, placebo-controlled multicenter trial, CVT patients treated with low-molecular-weight heparin had better outcomes than those given placebo.15 No new symptomatic brain hemorrhages occurred.
Conclusions
(1) Heparins should not be indiscriminately given to all acute brain ischemia patients. (2) The efficacy of heparins has been inadequately tested in patients with defined stroke subtypes and occlusive vascular lesions. (3) More trials are needed testing heparins in patients whose cardio-cerebrovascular lesions are clarified by modern brain and vascular imaging. (4) Heparins effectively prevent venous thrombosis and pulmonary embolism. (5) Knowledge of thromboembolism pathophysiology and clinical experience leads to the theory that heparins will prevent red thrombus development, propagation, and embolism. (6) Until more definitive trials are performed, I use heparins in patients with: large artery occlusions and severe stenosis; cardiogenic embolism with a high acute recurrence risk; dural sinus and cerebral venous thrombosis.
Footnotes
Section Editors: Geoffrey A. Donnan, MD, FRACP, and Stephen M. Davis, MD, FRACP
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1. Phan TG, Koh M, Wijdicks EFM. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol. 2000; 57: 1710–1713.
2. Cerebral Embolism Task Force. Cardiogenic brain embolism. Arch Neurol. 1986; 43: 71–84.
3. Caplan LR. Worsening in ischemic stroke patients: is it time for a new strategy? Stroke. 2002; 33: 1443–1445.
4. International Stroke Trial Collaboration Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute stroke. Lancet. 1997; 349: 1569–1581.[CrossRef][Medline] [Order article via Infotrieve]
5. 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; 279: 1265–1272.
6. Bendixen BH, Adams HP, Leira EC, et al. Responses to treatment with a low molecular weight heparinoid or placebo among patients with acute ischemic stroke secondary to large artery atherosclerosis. Neurology. 1998; 50: A345.
7. Camerlingo M, Casto L, Censori B, Ferraro B, Gazzaniga GC, Cesana B, Mamoli A. Immediate anticoagulation with heparin for first-ever ischemic stroke in the carotid artery territories observed within 5 hours of onset. Arch Neurol. 1994; 51: 462–467.
8. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: a randomized trial. Stroke. 1983; 14: 668–676.
9. Chamorro A, Vila N, Saiz A, Alday M, Tolosa E. Early anticoagulation after large cerebral embolic infarction. Neurology. 1995; 45: 861–865.
10. Chamorro A, Vila N, Ascaso C, Blanc R. Heparin in acute stroke with atrial fibrillation: clinical relevance of early treatment. Arch Neurol. 1999; 56: 1098–1102.
11. Ameri A, Bousser M-G. Cerebral venous thrombosis. Neurol Clin. 1992; 10: 87–111.[Medline] [Order article via Infotrieve]
12. Jacewicz M, Plum F. Aseptic cerebral venous thrombosis. In: Einhaupl K, Kempski O, Baethmann A, eds. Cerebral Sinus Thrombosis: Experimental and Clinical Aspects. New York, NY: Plenum; 1990: 157–170.
13. Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, Haberl RL, Pfister HW, Schmiedek P. Heparin treatment in sinus venous thrombosis. Lancet. 1991; 338: 597–600.[CrossRef][Medline] [Order article via Infotrieve]
14. Meister W, Einhaupl K, Villringer A, et al. Treatment of patients with cerebral sinus and vein thrombosis with heparin. In: Einhaupl K, Kempski O, Baethmann A, eds. Cerebral Sinus Thrombosis: Experimental and Clinical Aspects. New York, NY: Plenum; 1990: 225–230.
15. de Bruijn SFTM, Stam J, for the Cerebral Venous Sinus Thrombosis Study Group. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral venous sinus thrombosis. Stroke. 1999; 30: 484–488.
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