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Treatment of Acute Ischemic
Stroke with Heparin

Hans-Christoph Diener, MD

Department of Neurology, University of Essen, Essen, Germany

WHY SECONDARY PREVENTION?
   Secondary prevention is defined as treatments or procedures to prevent another ischemic cerebral accident after a TIA or a first stroke. Among the 80-85% of patients who survive a stroke the risk of recurrent stroke is between 5 and 15% in the first year with the highest risk in the first few weeks after the acute event (1-3). The risk of a recurrent stroke or a stroke following a TIA is higher in patients with multiple vascular risk factors and patients who in addition to a TIA or stroke already suffer from coronary heart disease or peripheral arterial disease. The risk is higher after TIA in the cerebral circulation than following amaurosis fugax (4).

   Treatment should be based on the nature, location, and severity of the causative lesion. The causes can be vascular (stenosis, plaques, or occlusion of extracranial and intracranial large arteries, or disease of small penetrating arteries), cardiac (causing embolism or systemic hypoperfusion) or hematologic causing hypercoagulability. The mechanism of ischemia has to be clarified (hemodynamic versus embolic). All patients with TIAs and strokes should be evaluated for the underlying causes of the ischemia and appropriate treatment aimed at the etiology. Unfortunately in the past few systematic studies of brain ischemia based on etiology were performed. Exceptions are studies of treatment for patients with atrial fibrillation and carotid stenosis.

   There are 4 different types of prophylaxis for patients with cerebral ischemia:

· Treatment of vascular risk factors

· Modification of coagulation functions in order to prevent the formation, propagation, and embolization of white platelet-fibrin thrombi and red erythrocyte-fibrin thrombi. The commonest drugs used are those that affect platelet functions (e.g. aspirin, ticlopidine, clopidogrel, aspirin plus dipyridamole, GPIIb/IIIa antagonists) and standard anticoagulants (heparin, heparinoids, LMWH, coumadin). The standard anticoagulants are more effective at preventing red clots while the drugs that affect platelet function are active against white thrombi.

· Reperfusion: These treatments aim to prevent occlusion of brain supplying arteries with severe occlusive changes but not thrombosed. Reperfusion can be obtained by direct surgery (endarterectomy) or stenting with or without angioplasty.

· Augmentation of brain blood flow. This can be performed by increasing blood volume and/or blood pressure and by using agents that increase flow in the affected or collate
ral arteries.

THROMBUS INHIBITION
   Thrombus formation at the site of advanced atherosclerotic disease is the cause of most initial and recurrent strokes. The physiologic goal of secondary prevention is the long-term inhibition of thrombus formation, which can be accomplished by inhibition of platelet aggregation and anticoagulation. Unfortunately, chronic anticoagulant therapy is limited by a high incidence of adverse effects, particularly hemorrhage and the attendant need for routine dose monitoring. Nevertheless, low-dose oral warfarin (INR 3.0) is effective in preventing embolic TIA and stroke associated with atrial fibrillation in patients with a recent history of TIA or minor ischemic stroke (5).

ANTICOAGULANTE IN EARLY STROKE PREVENTION
   The role of anticoagulation in the early phase after an ischemic stroke was investigated in six trials (6-11). Subcutaneous administration of heparin was investigated in the International Stroke Trial (IST)(8). In one part of the study which included 19,435 patients with suspected acute ischemic stroke unfractionated heparin was administered subcutaneously in doses of either 5000 IU bid or 12.500 IU bid and compared to "avoid heparin". The primary endpoint was mortality within the first 2 weeks and mortality and morbidity after 6 months. Combining the two heparin groups showed no difference in mortality within the first 14 days. Mortality was 9% (n=876) in the heparin group amd 9.3% (n=905) in the non-heparin group. Patients on heparin had significantly fewer recurrent ischemic strokes within the first two weeks (2.9% versus 3.8%). This positive effect was counterbalanced by a higher incidence of intracranial hemorrhages in the heparin groups (1.2% versus 0.4%) yielding no overall benefit. The high-dose heparin group suffered more systemic bleeding and hemorrhagic strokes and had a significantly increased risk of death or nonfatal stroke at 14 days. Patients with identified cardiac sources of cerebral embolism were not investigated in the IST trial. In the subgroup of patients with atrial fibrillation, however, the benefit of heparin was not superior to its risk.

   Low molecular heparin was investigated in a small-randomised trial in Hong Kong (9). This trial included 308 stroke patients treated within 48 hours with two doses of nadroparin or placebo for 10 days. Outcomes were not different after 3 months. The risk of death or dependency was reduced in the heparin groups after 6 months. The trial was underpowered in terms of number of patients. This result could not be reproduced in a much larger trial with fraxiparine (FISS bis). The trial is only published in abstract form (12). FISS bis, however, showed, that low-dose heparin reduces deep vein thrombosis and pulmonary embolism in patients with ischemic stroke.

   The TOAST trial investigated the low molecular weight heparinoid danaparoid in 1,281 patients with ischemic stroke (6). Patients were treated within 24 hours of stroke onset for 7 days with danaparoid or placebo. Overall, there was no significant benefit of danaparoid after 3 months. Only a subgroup of patients with large artery atherosclerosis seemed to benefit.

   The TOPAS study was performed to study the safety and efficacy of the low molecular weight heparin certoparin, in a randomized, double-blind, dose-finding multicenter trial in patients with acute ischemic stroke. 404 patients were randomized to four treatment groups within 12 hours of stroke onset: 3000 U anti-factor Xa (U aXa) certoparin once daily, 3000 U aXa twice daily, 5000 U aXa twice daily and 8000 U aXa twice daily. The primary efficacy variable was the proportion of patients reaching a favorable functional outcome (Barthel Index >90 points) at 3 months. Computed tomography was performed at trial entry, after 7 days and on clinical deterioration. The proportion of patients with Barthel Index >90 was not different between treatment arms (61.5% vs 60.8% vs 63.3% vs. 56.3%, intent-to-treat population). European Stroke Scale scores improved in all treatment groups within the first 14 days to a similar extent. During the follow up of 6 months, patients with restroke/ transient ischemic attack were 11.0% vs. 5.9% vs. 9.7% vs. 13.0%. Overall mortality was only 7.4%. Two parenchymal cerebral hematomas and 1 extracranial bleeding occurred in the low dose treatment group vs. 1/0 in the next higher dose group vs. 2/0 in the next dose group 3 vs. 4/5 in the group with the highest dose. During certoparin treatment, only one deep vein thrombosis was observed, but no pulmonary embolism. In conclusion, dose increase of certoparin up to 8000 U aXa twice daily did not improve the functional outcome of patients with ischemic stroke. Severe bleeding tended to be more frequent in the highest dose group only.

   A study from Norway investigated whether heparinoids might be useful in patients who have atrial fibrillation and suffered an acute ischemic stroke (11). In this randomised, double blind trial 160 mg acetylsalicylic acid (ASA) were compared with 100 IU/kg dalteparin bid. The study included 449 patients. Patients who were already anticoagulated, with severe strokes, or onset of symptoms >30 hours were excluded. Nineteen patients (8.5%) in the dalteparin group suffered a recurrent stroke compared to 17 (7,5%) in the ASA group. There were no differences between the 2 treatment groups for cerebral bleeding, progressive stroke, death, acute myocardial infarction or pneumonia. The same was true for impairment, disability and neurological symptoms after 3 months (Barthel-Index, Rankin-scale, Scandinavian Stroke Scale). This study indicates, that low-dose heparin is not effective for the prevention of early stroke recurrences in patients with a presumed cardiac source of embolism.

   With the available knowledge from prospective trials full-dose heparin or heparinoids cannot be recommended for patients with acute ischemic strokes. Whether subgroups of patients with cardiac source of embolism or progressive stroke would benefit is not known. Low-dose low-molecular heparin prevents deep vein thrombosis and pulmonary embolism.

ANTICOAGULANTS IN SECONDARY STROKE PREVENTION
   The role of anticoagulants as secondary prevention in patients with cardiac related stroke was investigated in only one large, randomized trial. The EAFT trial assessed the efficacy or oral anticoagulation for secondary prevention of noncardioembolic stroke compared high-intensity oral anticoagulation (INR 3.0-4.5) with aspirin 30 mg per day(13) in 1316 patients with TIA or minor ischemic stroke. The study was stopped prematurely by the Safety Committee because of a significant increase in the rate of major bleeding complications including cerebral hemorrhages in the anticoagulation group. The ongoing Warfarin Aspirin Recurrent Stroke Study (WARSS) compares a lower INR of 1.4 to 2.8 with 325 mg aspirin. Data are not yet available. At the present time, anticoagulation with an INR between 3.0 and 4.5 cannot be recommended in patients with noncardiac TIA or stroke. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study was a retrospective trial in patients with 50-99% stenosis of an intracranial artery. Sixty-three patients received 325 mg aspirin and 88 were anticoagulated with warfarin (14). There was a significantly lower incidence of vascular events in the warfarin-treated group but an increased incidence of major hemorrhagic complications. A larger prospective randomized trial is under way.

REFERENCES

1. Dennis M, Bamford J, Sandercock P, Warlow C. The prognosis of transient ischemic attacks in the community. The Oxfordshire Community Stroke project. Stroke 1991;21:848-853.

2. Hankey GJ, Warlow CP, Slattery J. The prognosis of transient ischaemic attacks. J Neurol 1990;237:142.

3. Wilterdink JL, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol 1992;49:857-863.

4. The Amaurosis Fugax Study Group. Current management of amaurosis fugax. Stroke 1990;21:201-208.

5. EAFT Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255-1262.

6. The Publications Committee for the Trial ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (Danaparoid), and outcome after acute ischemic stroke. JAMA 1998;279:1265-1272.

7. Hommel M, for the FISS bis Investigators Group. Fraxiparine in ischemic stroke study (FISS bis). Cerebrovasc Dis 1998;8 (Suppl 4):19.

8. 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;349:1564-1565.

9. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995;333:1588-1593.

10. Diener HC, Ringelstein RB, von Kummer R, Langohr HD, Bewermeyer H, Langraf H, et al. Treatment of acute ischemic stroke with the low molecular weight heparin certoprain. Stroke 2001;32:22-29.

11. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular- weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000;355:1205-1210.

12. Hommel M, for the FISS bis Investigators Group. Fraxiparine in ischaemic stroke study (FISS bis). Cerebrovasc Dis 1998;8(Suppl 4):63.

13. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857-865.

14. Chimowitz M, Kokkinos J, Strong J, Brown M, Levine S, Silliman S, et al. The warfarin-aspirin symptomatic intracranial disease study. Neurology 1995;45:1488-1493.

 

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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