Determinants of IV heparin treatment in patients with ischemic stroke

W-P. Schmidt, MD; P. Heuschmann, MD; D. Taeger, MSc; H. Henningsen, MD; H-J. Buecker-Nott, MD; and K. Berger, MD

AbstractManagement of acute ischemic stroke with IV unfractionated heparin is subject to debate. The authors evaluated patient-related and institutional factors influencing its use in 42 hospitals. Cardioembolic stroke type, carotid stenosis, atrial fibrillation, and treatment in stroke units or intensive care units significantly increased the probability of use. However, there are large unexplained variations in IV heparin use among hospitals.
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The use of IV unfractionated heparin (UFH) to treat patients with acute ischemic stroke is a subject of debate.1,2 Treatment with IV heparin may prevent the recurrence of stroke in patients with completed events or offer a benefit for patients with defined stroke subtypes like cardioembolic stroke, largeartery occlusion, or carotid dissection.3 In contrast, the risk of adverse effects (e.g., intracranial bleeding) may outweigh potential benefits.4 Evidence from clinical trials is lacking. A Cochrane systematic review showed no net benefit for treatment with IV UFH in patients with ischemic stroke.5 In actual treatment guidelines, the routine use of urgent anticoagulation cannot be recommended.6 Although these reports and guidelines clearly do not support its use for patients with ischemic stroke, it is unknown to what extent this treatment is used in clinical practice. We assessed the frequency of IV application of heparin in patients with ischemic stroke and sought to determine patient-related and institutional factors influencing its use based on data from a large regional stroke register in Germany.
Methods. We used data from the Westfalen-Lippe Stroke Register, a regional data bank in the northwest of Germany.7 Between January 2000 and December 2001, 24 neurologic, 13 internal medicine, and 5 geriatric medicine departments in 42 hospitals participated on a voluntary basis. Patient information was documented anonymously and included sociodemographic characteristics, comorbidities, stroke type and severity, and details regarding the treating institution, the mode of admission, diagnostic and therapeutic procedures, and complications. The presented analysis was restricted to patients with ischemic stroke, and patients initially treated with thrombolytic therapy (n 198) were excluded from the analysis. Subtypes of ischemic stroke were classified according to the Trial of ORG 10172 in Acute Stroke Treatment criteria. IV heparin application was defined as treatment with UFH given IV and aiming at a 2- to 2.5-fold increase in the partial thromboplastin time (PTT). Subcutaneous application of heparin regardless of the dose was not included in this definition.

Data analysis was restricted to clinical centers that continuously documented 24 stroke patients per year. Age adjustments in univariate analysis of proportions were done with adjusted probabilities estimated in a logistic regression model; those for continuous variables were done using the adjusted means procedure following an analysis of variance model. Multivariable logistic regression was used to determine sociodemographic, institutional, and clinical factors influencing the IV administration of UFH.

Results. We included 7,657 patients with ischemic stroke (51% women) in this analysis (table 1). The patient proportions with macroangiopathic, microangiopathic, and cardioembolic stroke type were similar in this register. Hypertension was the most common comorbidity. Diabetes mellitus was present in approximately one-third of patients, and atrial fibrillation was noted in one-fifth of patients. Overall, 27.0% of the patients were treated with IV UFH, but treatment varied between 0 and 84% across centers. The application was significantly more common in patients admitted to neurologic departments (29.9%) than in those treated in departments of internal (16.9%) or geriatric medicine (4.7%). Table 2 shows patient-related and institutional determinants of the IV treatment with UFH. Patients admitted to stroke units or intensive care units had a higher probability to receive IV heparin treatment after adjustment for important confounders. The same applied for patients with atrial fibrillation, cardioembolic stroke etiology, and highgrade (70 to 99%) carotid stenosis (i.e., conditions assumed to bear a risk of embolism). In contrast, the chance of being treated with IV UFH decreased with increasing age. It was also lower for women and those with microangiopathic stroke type or a high Rankin score before the stroke event.

Discussion. The IV administration of UFH in patients with acute ischemic stroke is controversial.1-4 Wide variation in the use of this treatment between physicians and between institutions was reported 15

From the Institute of Epidemiology and Social Medicine (Drs. Schmidt, Heuschmann, and Berger, D. Taeger) and Department of Neurology (Dr. Henningsen), University of Muenster; Department of Neurology (Dr. Henningsen), Stdt. Krankenhaus Lneburg; and Chamber of Physicians Westfalen-Lippe (Dr. Buecker-Nott), Muenster, Germany. Supported by the Innovative Medical Research Fund (grant BE120123) of the Medical Faculty of the University of Muenster. Received February 20, 2004. Accepted in final form August 3, 2004. Address correspondence and reprint requests to Dr. Klaus Berger, Institute of Epidemiology and Social Medicine, University of Muenster, Domagkstrasse 3, 48149 Muenster, Germany; e-mail: bergerk@uni-muenster.de Copyright 2004 by AAN Enterprises, Inc. 2407

Table 1 Patient characteristics Total no. of patients Sociodemographic factors Women, % Age, y (median, interquartile range) Still working, % Nursing home resident, % Rankin Scale 3 upon admission,* % Ischemic stroke etiology, % Macroangiopathy Microangiopathy Cardioembolism Other/concurrent etiologies Unclear etiology Comorbidities, % Hypertension Diabetes mellitus Atrial fibrillation Carotid stenosis 70 History of stroke 72.8 32.0 20.8 6.7 19.0 23.0 19.8 18.7 10.7 27.8 50.9 72.7 (63.379.9) 13.9 6.7 67.5 7,657

* A Rankin Scale score 3 indicates a moderate to severe functional deficit.

years ago.8 Since then, evidence for a positive effect of this treatment is lacking. In a Cochrane review, the results of a meta-analysis showed no beneficial effect for the application of different types of heparin and any mode of application with respect to the endpoints death and dependency.5 Large randomized clinical trials have only been done with UFH given subcutaneously or with low molecular weight heparin. Their results cannot automatically be transferred to the IV application of heparin, both in terms of efficacy and side effects. However, the only two small randomized clinical trials on IV heparin treatment in acute stroke also showed no benefit.9,10 Overall, the studies on IV heparin treatment carried out thus far are not sufficient to rule out a possible detrimental role of this treatment. Despite the lack of recommendations in treatment guidelines and the lack of evidence from controlled clinical trials, IV heparin treatment is frequently used in this stroke register. Our analysis demonstrates a large variation in its application between participating centers and between different medical disciplines. Patients treated in stroke units or intensive care units had an increased probability to receive IV UFH. We observed a gender difference, with male patients receiving this treatment more often independent of age and stroke severity. Our results raise the question about the motivation and the aims of the treating physicians when

Table 2 Adjusted sociodemographic and clinical characteristics of patients with ischemic stroke, according to treatment status with intravenously applied heparin IV heparin treatment Yes, n 2,068 Age, y, median Female gender, % Rankin Scale 3 prior to acute event, % Rankin Scale 3 upon admission, % Hemiparesis, % Macroangiopathic stroke, % Cardioembolic stroke type, % Microangiopathic stroke, % Atrial fibrillation, % Diabetes mellitus, % Carotid stenosis 70%, % Hypertension, % Prior history of stroke, % Interval stroke onset/admission 3 h, % Treatment in stroke unit Treatment in intensive care unit 69.1 46.4 6.4 69.6 63.7 22.3 36.8 8.3 34.8 27.9 11.1 71.4 16.7 36.8 69.3 6.8 No, n 5,589 74.1 51.6 15.1 66.7 56.1 23.3 11.7 24.2 12.5 33.2 5.0 73.3 19.4 28.3 44.2 4.5

p* for difference 0.001 0.001 0.001 0.02 0.001 0.36 0.001 0.001 0.001 0.001 0.001 0.46 0.001 0.001 0.001 0.001

OR 0.70 0.77 0.56 1.16 1.14 1.05 2.62 0.39 1.74 0.86 2.41 1.16 0.88 1.14 2.72 2.78

95% CI 0.650.75 0.660.90 0.420.74 0.981.37 0.951.35 0.861.26 2.123.22 0.310.50 1.422.14 0.640.89 1.853.15 0.981.37 0.721.07 1.011.29 2.243.30 1.973.90

* Adjusted for age in years. Unadjusted. Per 10 year increase. Rankin Scale score 3 indicates a moderate to severe functional deficit.
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applying this treatment. Patients who had one or more condition that is generally accepted to have an embolic risk had a strong and significantly increased chance of being treated with IV heparin, perhaps reflecting the position of the treatments advocates.2,3 The gender difference cannot be explained by age, stroke type, or severity. There was also a difference in IV heparin application between different medical disciplines. One explanation may be that there are educational and training differences between disciplines in the organization of stroke management and care. Among the strengths of our study is the large number of included patients and hospitals from different medical specialties. The vast majority of participating hospitals were community hospitals and reflect routine clinical care of stroke patients. We carefully adjusted our analysis for important confounders, making residual confounding unlikely to explain the results. A limitation is the inability to assess PTT in each patient; instead, we relied on a clear definition of IV application of UFH aiming at a 2- to 2.5-fold increase of PTT. However, a misclassification of exposure because of the lack of PTT measurement or an insufficient PTT increase would have artificially decreased the treatment group and would have caused an underestimation of use and of the associations between single factors and treatment with heparin. We could not assess motivations and indications to use the treatment because we did not perform personal interviews with the treating physicians. Further evaluation of the reasons that physicians frequently manage acute ischemic stroke with IV UFH is warranted.
Acknowledgment
The authors thank the following hospitals for their contribution to this analysis: Departments of Neurology: Bathildis Krankenhaus, Bad Pyrmont; Bergmannsheil Bochum; St. Josef-Hospital, Bo-

chum; Knappschafts-Krankenhaus Bottrop; Evang. Krankenhaus, Castrop-Rauxel; Krankenhaus St. Elisabeth-Stift, Damme; Knappschaftskrankenhaus Dortmund; Stdtische Kliniken, Dortmund; Franziskus Hospital, Dlmen; Hans-SusemihlKrankenhaus, Emden; Evangelisches Krankenhaus Gelsenkirchen; Universittsklinik Greifswald; St. Johannes Hospital, Hagen; St. Marien-Hospital Hamm; Frederikenstift, Hannover; Gemeinschaftskrankenhaus Herdecke; Klinikum Lippe-Lemgo; Klinikum Minden; Universitt Mnster; Klinikum Osnabrck; St. Vincenz Krankenhaus, Paderborn; Christliches Krankenhaus, Quakenbrck; Elisabeth-Krankenhaus, Recklinghausen; Knappschafts-Krankenhaus Recklinghausen; Klinikum Wuppertal; Departments of Internal Medicine: St. Josef-Hospital BochumLinden; Stdt. Krankenhaus Marienhospital Arnsberg; Kreiskrankenhaus Diepholz; Kath. Krankenhaus West, Dortmund; Knappschaftskrankenhaus, Dortmund; Stdtische Kliniken Nord, Dortmund; St. Josefs-Hospital, Dortmund; Krankenhaus Bethanien, Dortmund; Evangelisches Krankenhaus, Hamm; St. Barbara Klinik Heesen; Krankenhaus Lbbecke; FranziskusHospital, Mnster; and Joseph-Hospital, Warendorf; and Departments of Geriatric Medicine: Httenhospital, Dortmund; Marienhospital, Herne; St. Marien Hospital, Vechta; and Marienhospital, Wattenscheid.

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