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(Stroke. 2003;34:e45.)
© 2003 American Heart Association, Inc.

Research Reports

Oral Anticoagulation in Patients After Cerebral Ischemia of Arterial Origin and Risk of Intracranial Hemorrhage

From the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) Study Group.

Correspondence to Ale Algra, MD, Department of Neurology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Room D.01.335, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. E-mail a.algra{at}neuro.azu.nl

	Abstract

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Background and Purpose— In the recently published Warfarin Aspirin Recurrent Stroke Study (WARSS), a low-intensity anticoagulation regimen was used because of safety concerns. Such concerns are corroborated by the results of the Stroke Prevention in Reversible Ischemia Trial (SPIRIT), which was stopped early because of a high incidence of intracranial hemorrhage with a target international normalized ratio (INR) of 3.0 to 4.5. In the ongoing European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), an intermediate anticoagulation regimen (INR 2.0 to 3.0) is used.

Methods— We performed an interim analysis of the incidence of intracranial hemorrhage in ESPRIT.

Results— Thus far the overall rate of intracranial hemorrhage is 0.31% (95% CI, 0.18% to 0.52%) per year and 1.21% if all of these were in the anticoagulation group.

Conclusions— We conclude that anticoagulation with achieved INR of 2.0 to 3.0 is reasonably safe in patients with cerebral ischemia of arterial origin.

Key Words: anticoagulants • aspirin • cerebral ischemia • intracerebral hemorrhage

	Introduction

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Recently the results of the Warfarin Aspirin Recurrent Stroke Study (WARSS) were published.¹ This study investigated whether oral anticoagulation (international normalized ratio [INR] 1.4 to 2.8) is more effective than aspirin in the prevention of ischemic stroke or death after cerebral ischemia of arterial origin. In the early 1990s, at the design phase of the study, the investigators decided to use a low-intensity anticoagulation regimen because they were particularly concerned about the risk of intracranial hemorrhage. At a later stage these concerns were reiterated in correspondence about WARSS.²

The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) was a trial similar to WARSS except that the intensity of the oral anticoagulation was much higher, with a target range of INR 3.0 to 4.5.³ SPIRIT was terminated after its first interim analysis because of a statistically and clinically significant excess of major hemorrhages in the anticoagulated patients (relative risk, 9.3; 95% CI, 4.0 to 22) in comparison with the patients who received aspirin. The annual incidence of intracranial hemorrhage was 3.7% in the group on anticoagulants. In 1997 we started a new study, the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), with an intermediate intensity of anticoagulation. At the current stage of the trial we wished to study the incidence of intracranial hemorrhage after cerebral ischemia of arterial origin.

	Subjects and Methods

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ESPRIT is an open randomized clinical trial comparing (A) oral anticoagulation with a target INR between 2.0 and 3.0 or (B) the

See Editorial Comment, page e46

combination of aspirin (30 to 325 mg daily) and dipyridamole (400 mg daily) with (C) aspirin only (same dose).^4,5 The trial seeks to recruit 4500 patients with a mean follow-up of 3 years. Primary outcome is the composite of vascular death, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication. All outcome events are recorded at the central trial office, and a committee that has no information about treatment assignment adjudicates classification. An extracranial hemorrhage is defined as major if it results in death or hospital admission. All INR values are collected for patients allocated to anticoagulant treatment. With Rosen-daal’s method, we calculated the number of patient-years spent in each 0.5-U INR class.⁶

	Results

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As of November 19, 2002, 2191 patients had been enrolled in ESPRIT with a total follow-up time of approximately 4770 patient-years; 12 521 INR values had been recorded. The Figure shows the number of patient-years spent in each 0.5-U INR class for the patients allocated to anticoagulation. They spent 67.3% of their time within the target INR range, 21.8% above it, and 10.9% below it. The mean achieved INR was 2.6. At the same date, 15 intracranial hemorrhages had been recorded, resulting in an annual incidence of 0.31% (95% CI, 0.18% to 0.52%). In a worst-case scenario, these bleeds would all have occurred in the anticoagulation group, in which a total of 1235 patient-years had been accrued; the worst-case incidence would therefore be 1.21% per year (95% CI, 0.68% to 2.00%). By that time a total of 35 extracranial hemorrhages had been reported, resulting in an overall rate of 0.73% per year or 2.83% with the worst-case scenario. Five patients had 2 bleeding complications.

View larger version (23K): [in this window] [in a new window]   ESPRIT INR distribution.

	Discussion

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On the basis of the ESPRIT data, the most likely incidence of intracranial hemorrhage is between 0.31% and 1.21% annually in patients after cerebral ischemia of arterial origin anticoagulated with a target INR between 2.0 and 3.0. This incidence compares favorably with that of SPIRIT³ and is compatible with that of any major hemorrhage in the WARSS trial (3.4% per year); WARSS did not report on intracranial hemorrhage separately.¹ Rates for any major hemorrhage were 7.2% per year in SPIRIT and between 1.1% and 4.1% in ESPRIT. The worst-case scenario probably is an overestimation because the incidence of intracranial hemorrhage after aspirin treatment is in the order of 0.39% (95% CI, 0.22% to 0.80%) per year in similar patients.³ In a post hoc analysis in SPIRIT, the incidence of major hemorrhages in anticoagulated patients was approximately two thirds lower in those in whom the achieved INR ranged between 2.0 and 3.0 than in those in whom the target range of 3.0 to 4.5 was actually reached.³ In a direct comparison of data of anticoagulated patients from SPIRIT and the European Atrial Fibrillation Trial (which included patients with cerebral ischemia and atrial fibrillation), we found a 19-fold higher risk of intracranial hemorrhage among the patients with cerebral ischemia of presumed arterial origin if differences between the 2 patient groups were taken into account.^7,8 In an observational study of INR-specific incidence of ischemic and hemorrhagic events in patients with cerebral ischemia of arterial origin followed by the Leiden anticoagulation clinic, the optimal INR was between 2.5 and 3.5.⁹ Thus, we conclude that oral anticoagulation with a target (and achieved) INR of 2.0 to 3.0 is reasonably safe in patients with cerebral ischemia of arterial origin. Of course, conclusions about efficacy cannot be drawn until the end of the ESPRIT study.

	Acknowledgments

 
ESPRIT has been funded thus far by the Netherlands Heart Foundation (No. 97.026), University Medical Center Utrecht, UK Stroke Association, French Ministry of Health, Janivo Foundation, Aegon, and Netherlands Thrombosis Foundation.

Received October 10, 2002; revision received December 13, 2002; accepted December 18, 2002.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
1. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HPJ, Jackson CM, Pullicino P, for the Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001; 345: 1444–1451.[Abstract/Free Full Text]

2. Mohr JP, Thompson JL, Levin B, for the Warfarin-Aspirin Recurrent Stroke Study Group. Warfarin or aspirin for recurrent ischemic stroke. N Engl J Med. 2002; 346: 1170–1171. Correspondence.

3. 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.[CrossRef][Medline] [Order article via Infotrieve]

4. De Schryver EL, on behalf of the European/Australian Stroke Prevention in Reversible Ischaemia Trial Study Group. Design of ESPRIT: an international randomized trial for secondary prevention after non-disabling cerebral ischaemia of arterial origin. Cerebrovasc Dis. 2000; 10: 147–150.[CrossRef][Medline] [Order article via Infotrieve]

5. De Schryver EL. ESPRIT: protocol change. Cerebrovasc Dis. 2001; 11: 286.[CrossRef][Medline] [Order article via Infotrieve]

6. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993; 69: 236–239.[Medline] [Order article via Infotrieve]

7. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993; 342: 1255–1262.[Medline] [Order article via Infotrieve]

8. Gorter JW, for the Stroke Prevention In Reversible Ischemia Trial (SPIRIT) and European Atrial Fibrillation Trial (EAFT) Study Groups. Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Neurology. 1999; 53: 1319–1327.[Abstract/Free Full Text]

9. Torn M, Algra A, Rosendaal FR. Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk. Neurology. 2001; 57: 1993–1999.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) All Versions of this Article: 34/6/e45    most recent 01.STR.0000072275.34976.73v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by ESPRIT Search for Related Content PubMed PubMed Citation Articles by ESPRIT, Related Collections Secondary prevention Cerebrovascular disease/stroke Coumarins Intracerebral Hemorrhage Anticoagulants Antiplatelets Transient Ischemic Attacks