Treatment of Acute Ischemic Stroke With the Low-Molecular-Weight Heparin Certoparin
Results of the TOPAS Trial
Background and Purpose—To study the safety and efficacy of the low-molecular-weight heparin certoparin, we performed a randomized, double-blind, dose-finding multicenter trial in patients with acute ischemic stroke (Therapy of Patients With Acute Stroke [TOPAS]).
Methods—We randomized 404 patients to 4 treatment groups within 12 hours of stroke onset: 3000 U anti–factor Xa (aXa) certoparin once daily (treatment group 1); 3000 U aXa twice daily (group 2); 5000 U aXa twice daily (group 3); and 8000 U aXa twice daily (group 4). The primary efficacy variable was the proportion of patients reaching a favorable functional outcome (Barthel Index ≥90 points) at 3 months. CT was performed at trial entry, after 7 days, and on clinical deterioration.
Results—The proportion of patients with Barthel Index ≥90 was not different between treatment arms (61.5%, 60.8%, 63.3%, and 56.3% in the 4 groups, respectively; 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, percentages of patients with recurrent stroke/transient ischemic attack were 11.0%, 5.9%, 9.7%, and 13.0% in the 4 groups, respectively. Overall mortality was only 7.4%. Two parenchymal cerebral hematomas and 1 extracranial bleeding episode occurred in treatment group 1 versus 1 and 0 in group 2, 2 and 0 in group 3, and 4 and 5 in group 4, respectively. During certoparin treatment, 1 deep vein thrombosis but no pulmonary embolism was observed.
Conclusions—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.
Acute intervention for ischemic stroke is currently the subject of intensive clinical research, including thrombolytic agents to restore perfusion, neuroprotective agents to limit neuronal damage, and anticoagulants for early secondary prevention.1 2 At present, no proven treatment strategy exists except the intravenous application of recombinant tissue plasminogen activator (rtPA), as suggested by the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study and European Cooperative Acute Stroke Study (ECASS) trials.3 4 5 However, thrombolytic drugs may be given only to a well-defined patient population and within a very short time interval after onset of stroke symptoms.6 The intention to use antithrombotic agents, particularly heparins, in the treatment of acute ischemic stroke is to inhibit clot propagation, prevent reembolization, and facilitate clot lysis.7 8 9 10 However, the benefit of heparin treatment is unproved and remains controversial, especially with regard to the risk of major bleeding. In the randomized, double-blind Fraxiparin in Ischemic Stroke Study (FISS), Kay et al11 treated ischemic stroke patients with 2 doses of the low-molecular-weight (LMW) heparin nadroparin in comparison to placebo. They found that 45% of the patients in the high-dose nadroparin group, 52% in the low-dose nadroparin group, and 65% in the placebo group died or became dependent at 6 months. At 3 months, no difference was detected. In rates of hemorrhagic complication, no significant difference between the treated patients and those given placebo was observed. In the FISS-bis trial, the previous results were not confirmed.12 Additionally, the large-scale International Stroke Trial (IST), which allocated stroke patients to low- or medium-dose unfractionated heparin (UFH) and/or aspirin, as well as the Trial of ORG10172 in Acute Stroke Treatment (TOAST) study, which compared a heparinoid with placebo, showed no improvement in the functional outcome of patients.13 14 15
However, LMW heparins are distinct from heparin, with different pharmacological and biological profiles. Therefore, it was the purpose of the present dose-finding study to assess whether certoparin had an acceptable risk and was able to influence the functional outcome of patients with acute ischemic stroke.
Subjects and Methods
The Therapy of Patients With Acute Stroke (TOPAS) trial was performed in 57 centers in Germany. The study was approved by all local institutional ethics committees and was performed according to the Declaration of Helsinki.
Inclusion and Exclusion Criteria
Eligible patients were men and women aged 18 to 85 years who had a clinical diagnosis of an acute ischemic cerebral infarction involving the carotid or vertebrobasilar territory manifested clinically as stable moderate to severe paresis of an arm or a leg or both. The severity of the underlying stroke was defined by the European Stroke Scale (ESS) between 30 and 85 points (see below). Investigators who rated the patients were trained in use of the ESS. Patients must have been treated within 12 hours of symptom onset. Patients were excluded if it was not possible to perform CT for any reason or if they had CT-documented signs of intracerebral hemorrhage, subarachnoid hemorrhage, or any other structural brain disease. After enrollment of 111 patients, CT exclusion criteria were extended to hypodensity exceeding a third of the middle cerebral artery (MCA) territory to reduce the risk of parenchymal cerebral hematoma. Other exclusion criteria included the following: unstable neurological deficit within the last 60 minutes before start of treatment; previous neurological deficits that might hinder the ability to detect improvement from the current stroke event; acute or unstable cardiovascular disease (including consistent blood pressure >220 mm Hg systolic or >120 mm Hg diastolic or <90 mm Hg systolic or <60 mm Hg diastolic); major illnesses (such as major infection; active, recurrent, or metastatic cancer; severe hepatic or renal disease); primary hemorrhagic events within the last 12 months; known thrombocytopenia or coagulopathy within the last month; severe diabetic retinopathy; known allergy; or hypersensitivity to heparins. Pregnant or breast-feeding women were not included. All patients must be able to be compliant with the protocol, and appropriate informed consent was obtained. During the treatment period, other UFH or LMW heparins, oral anticoagulants, antiplatelet drugs, or hemorheological drugs were not allowed; administration of aspirin was allowed after the combined data of the IST and Chinese Acute Stroke Trial (CAST) showed a small benefit of aspirin.13 16
Randomization and Treatment Protocol
To avoid any imbalances between the treatment groups according to the severity of the underlying stroke, randomization was stratified by stroke territory (carotid/vertebrobasilar). Patients were randomly assigned to subcutaneous injections of 3000 U anti–factor Xa (aXa) certoparin once daily, 3000 U aXa certoparin twice daily, 5000 U aXa certoparin twice daily, and 8000 U aXa certoparin twice daily. A dosage of 3000 U aXa certoparin once daily corresponds to the prophylactic dose used to prevent thromboembolic complications after abdominal or hip operations. A dosage of 8000 U aXa certoparin twice daily corresponds to the dose necessary to treat a manifested deep vein thrombosis. The duration of treatment with study medication was 12 to 16 days. At each center, eligible patients were randomly assigned to the treatment group by means of sequential patient numbers. In the case of emergency, investigators had access to sealed code envelopes containing treatment allocation.
CT was performed at baseline before randomization, routinely at day 7 to 8 after stroke onset, and in each patient in case of clinical deterioration or any suspicion of intracranial hemorrhage. An independent neuroradiologist evaluated all CT scans blinded to any clinical information, time of stroke onset, and treatment. Hemorrhagic transformation of brain tissue was classified by radiological criteria according to Pessin et al17 as hemorrhagic infarction and parenchymal cerebral hematoma. The extent of ischemic edema on baseline CT was categorized as small (≤33% of MCA territory) and large (>33% of MCA territory) according to the ECASS trial.4 The volumes of infarctions on follow-up CT were measured with the formula for irregular volumes.
The primary objective used in this trial was the proportion of patients with favorable functional outcome as assessed by the modified Barthel Index obtained at 3 months after stroke.18 A favorable outcome was defined as a score ≥90 points. Patients who died were scored with the worst possible score in this scale. Secondary end points included Barthel Index score at 6 months after stroke, Rankin Scale score at 3 and 6 months, and volume of cerebral infarction and classification of brain swelling measured by a 7- to 8-day follow-up head CT scan. The patient’s level of impairment was evaluated with the ESS, a neurological scale consisting of 14 items selected for their specificity and their prognostic value. Its concurrent validity was correlated with other neurological scales.19
A bleeding episode was classified as major if it met 1 of the following criteria: retroperitoneal or gastrointestinal, leading directly to death, clinically apparent and leading to a transfusion of ≥2 units of packed cells, or clinically apparent and associated with a fall in hemoglobin level of 2 ≥g/dL. Intracranial bleedings were termed severe if they were classified as parenchymal hemorrhage by central CT evaluation. All other bleeding episodes were classified as minor. During the study all severe bleedings were reported to an independent external statistician, who had access to the treatment code and who informed the steering committee if there was an unacceptable risk to continue the study.
Certoparin is a LMW heparin produced by chemical cleavage of UFH with isoamyl nitrite.20 LMW heparins inhibit thrombin as well as coagulation factor Xa, and therefore the anticoagulant potency of LMW heparins can be measured by their aXa activity.
For the primary analysis of this trial, a monotonically ascending dose-response relationship was assumed, ie, increasing doses of study medication should result in a better outcome of patients. A hierarchical step-down procedure for pairwise treatment comparisons was planned, ie, the comparison of the highest-dose group versus the lowest-dose group should be followed by the comparison of the second highest versus the lowest, if and only if the first step led to null hypothesis rejection, and so on. Because this method corresponds to a closed test procedure, the same nominal α level could be applied at each step, keeping the multiple type I error at a 1-sided level of 0.025. Fisher’s exact test was performed for confirmatory testing.
The sample size estimation was based on a treatment difference of 15% in the response rate as assumed to be clinically relevant. Assuming the most conservative case (57.5% versus 42.5%) led to a total number of 184 patients per group for 80% power. Overall, 200 patients per group should be included.
An interim analysis was planned after 100 patients per group, adjusting α to 0.005 for the interim analysis and 0.022 for the final analysis.21 Stopping without rejection of the null hypothesis was foreseen in case the treatment difference between the highest and the lowest dose would be <5% in favor of the highest.
Before unblinding of the interim analysis data, the blinded review committee (principal investigator, project leader, trial statistician) defined the patient samples. For safety analysis, all patients who were administered at least 1 dose of medication should be included. The intent-to-treat population should consist of all patients who were not excluded by decision of the blinded review committee. Since a last observation carried forward approach was considered not applicable for primary efficacy analysis, patients should have been excluded from this analysis if the target parameter was not assessed and the reason for this was considered to not be drug related.
Appropriate statistical methodology was applied for analysis of baseline comparability and secondary parameters. This included descriptive statistics and treatment group comparisons by χ2 tests, F tests from ANOVA, and nonparametric methods.
From December 1996 through December 1998, >7500 patients were screened for inclusion. The most frequent reasons for initial exclusion were the time interval from stroke onset to treatment >12 hours (25.7%), ESS at baseline outside the required range of between 30 and 85 points (23.8%), age outside the required range of between 18 and 85 years (7.7%), necessity for full heparinization (7.5%), and hemorrhagic stroke (7.2%). Four hundred four patients were randomized and included in the safety sample: 99 patients received 3000 U aXa certoparin once daily (as well as an additional syringe with placebo) (treatment group 1), 102 patients received 3000 U aXa certoparin twice daily (group 2), 103 patients received 5000 U aXa certoparin twice daily (group 3), and 100 patients received 8000 U aXa certoparin twice daily (group 4) (Table 1⇓). Four patients were found to be ineligible for the intent-to-treat population (1 patient was without proven signs of stroke, and in 3 patients full heparinization was clinically indicated). Therefore, the intent-to-treat population included 98, 102, 103, and 97 patients in groups 1 through 4, respectively. From these, the following 13 patients had to be excluded because the last observation carried forward approach was not applicable: 5 patients withdrew their informed consent, 3 patients failed to return for scheduled visits, and an additional 5 patients could not be considered for efficacy analysis because of the reasons stated in Table 1⇓. Accordingly, the primary efficacy criterion was available for 387 patients (96, 97, 98, and 96 patients in groups 1 through 4, respectively).
Demographics and baseline characteristics were well balanced between the 4 treatment groups (Table 2⇓). In particular, stroke severity (see Table 4⇓) and the time between symptom onset and treatment were evenly distributed, and therefore all groups were absolutely comparable. Centers were encouraged to enroll patients as soon as possible, and therefore the mean time to treatment was 7.2 hours (median, 6.75 hours).
Table 3⇓ lists CT findings at baseline and at day 7 to 8. More patients with hypodensity >33% of the MCA territory at baseline were present in the treatment group receiving 5000 U aXa certoparin twice daily. At day 7 to 8, the mean infarct volume in this group was increased accordingly compared with other treatment groups.
Stroke severity at baseline was characterized by the ESS score (Table 4⇓); mean ESS score at baseline was 62.9 points (median, 64.0 points). Neurological recovery was similar in all study groups. Clinical improvement was greatest within the first 7 days, with a parallel course of the mean ESS values throughout the trial. There were no differences in the absolute increase in the ESS scores over time between the 4 treatment groups.
Table 5⇓ shows functional outcome at 3 months. The treatment groups were not different with respect to the proportion of patients with a favorable functional outcome (Barthel Index ≥90) as the predefined primary efficacy criterion. Additionally, no significant difference in the mean Barthel Index score was noted.
The overall fatality rate was 7.4%. Three fatal intracranial bleedings occurred during treatment, 5 deaths resulted from local mass effects as a consequence of the underlying stroke, and 2 patients died of cardiac events (Table 6⇓). No between-group differences were observed. During follow-up, deaths were more frequently seen in the highest-dose treatment group. However, causes of death were quite divergent, and a reasonable attribution to the initial study medication was not possible.
Recurrent ischemic strokes and transient ischemic attacks were diagnosed in 40 patients (9.9%) during the entire trial (Table 7⇓). Twenty recurrent strokes/transient ischemic attacks were observed during the treatment period and 20 during the follow-up. Under treatment with certoparin, 1 patient developed a deep vein thrombosis but no pulmonary embolism. In 6 patients venous thrombotic complications were detected during the follow-up period, in which patients were not anticoagulated and therefore not protected against thrombosis.
Intracranial and extracranial bleeding complications occurred during the treatment with certoparin and thereafter (Table 8⇓). Severe bleeding complications appeared more frequently in the highest-dose group. CT showed parenchymal hemorrhage in 9 patients (2.2%) during the treatment period and in 1 patient 6 weeks later. The cerebral hematoma was fatal in 3 patients. One patient did not clinically deteriorate despite the cerebral hematoma. Other adverse events were equally distributed between the treatment groups. No heparin-induced thrombocytopenia was reported. Two patients received aspirin concomitant with certoparin, and 7 patients received aspirin for short times. None of these 9 patients had a bleeding complication.
Heparin is a potent anticoagulant that prevents thrombus propagation or recurrent embolism and helps to maintain collateral channels so that blood can reach the ischemic area.7 8 9 Compared with UFH, LMW heparins display improved bioavailability and a more predictable dose response. Reduced incidences of heparin-induced thrombocytopenia and severe bleeding have been reported.20 22 23 As distinguished from other LMW heparins, certoparin is administered at a fixed dose independently of the patient’s body weight. Despite its widespread use, the efficacy of heparin for the treatment of acute ischemic stroke is still controversial: the possible benefit of heparins must be weighed against the increased risk of intracranial and extracranial bleeding. TOPAS was a dose-finding study testing the range between the prophylactic dosage used to prevent perioperative/postoperative thrombosis and the therapeutic dosage recommended to treat manifested deep vein thrombosis. In TOPAS, no correlation between the dose of a LMW heparin and an improvement of neurological or functional outcome was observed, which is in agreement with recently presented clinical trials. The time to treatment from stroke onset to the first application of certoparin was only 7.2±2.7 hours in TOPAS, which is a short time span compared with FISS-bis and TOAST (approximately 15 hours in both) or IST, in which 63% of the patients were not treated before 12 hours.12 13 15 Patient populations seem to be similar. Severity of stroke, however, is hard to compare because different neurological scales were chosen. Nevertheless, the mean ESS score of 62.9 points in TOPAS represents stroke patients with medium severity. In the open IST study, the main outcome events “death from any cause within 14 days” and “combined death and dependency” did not show differences between the groups treated with and without heparin.13 Additionally, administration of the heparinoid ORG 10172 (danaparoid) in TOAST or the use of the LMW heparin nadroparin in FISS-bis failed to demonstrate any benefit of anticoagulation for the therapy of acute ischemic stroke.12 15 In all these trials, however, anticoagulants increased the incidences of severe bleeding but also reduced the incidence of deep vein thrombosis or pulmonary embolism. Overall fatality was remarkably low in TOPAS (7.4%). Fatality rates within the placebo groups of other stroke trials ranged between 6% and 27%.3 4 5 11 12 15
Spontaneous hemorrhagic transformation of ischemic brain tissue is a common phenomenon.24 The extent of parenchymal hypoattenuation as detected by CT within 6 hours of stroke onset is associated with the risk of postischemic cerebral hematoma.25 26 We therefore decided in the early study period to change the study protocol and to exclude patients with parenchymal hypoattenuation exceeding one third of the MCA territory. This decision may have contributed to a low rate of parenchymal hemorrhage (2.2%), which was in the range of the placebo groups of other stroke trials (0.6% to 6.5%).3 4 5 12 15 27 Patients with the highest dose of certoparin, however, showed a trend for more intracranial and extracranial bleeding complications. We therefore regard only doses of certoparin up to 5000 U aXa to be safe in patients with acute ischemic stroke.
Stroke patients are at high risk for venous thrombosis because of immobilization. At the first investigator meeting, most centers declined to participate in a placebo-controlled trial. It was therefore not possible to compare certoparin with placebo. During the treatment with certoparin, even in the low-dose group no pulmonary embolism was observed, and only 1 patient developed deep vein thrombosis, in agreement with other heparin trials. It should be considered, however, that we did not search systematically for deep vein thrombosis or pulmonary embolism because these events were not defined as study end points.
Anticoagulants failed to improve the neurological or functional outcome in ischemic stroke patients. It may be possible that the time window until the start of treatment must be further reduced to show an impact of heparin. A benefit of heparin in stroke patients can perhaps be shown in specified patient populations, such as those with cerebral sinus thrombosis or progressive or cardioembolic stroke.28 However, in TOPAS only a few patients with suspected cardioembolic stroke were included because high-dose heparin was an accepted indication in these patients when the trial was performed. Therefore, we cannot exclude the possibility of a benefit by using high-dose certoparin in this subset of patients. The recently published Heparin in Acute Embolic Stroke Trial (HAEST) did not show an advantage of the LMW heparin dalteparin compared with aspirin in patients with acute ischemic stroke and atrial fibrillation.29 Nevertheless, antithrombotic treatment of stroke among patients with occlusion or severe stenosis of the internal carotid artery may improve functional outcome, as was recently shown by Adams et al.30 However, until now a benefit of heparin for treatment of acute ischemic stroke was not proven, and high doses of heparin lead to an increased risk for severe bleeding. On the other hand, prophylaxis of venous thrombosis is an absolute medical need in stroke patients.
This trial had a low mortality because patients with milder strokes were included. The mean ESS score in this study was 62 to 64, whereas, for example, in the multinational lubeluzole trial the ESS score at baseline was 40. The lubeluzole trial had a mortality of 21%.31
In conclusion, none of the studied 4 doses of certoparin was superior to others in affecting the clinical outcome of patients with ischemic stroke. Compared with other stroke populations, the rate of fatality and bleeding complications was remarkably low. These observations suggest that a dose of 3000 U aXa certoparin may be safe in patients with stroke and effective in preventing venous thromboembolism.
Steering Committee: H.C. Diener, Universitätsklinikum Essen (principal investigator); E.B. Ringelstein, Universität Münster; R. von Kummer, Universität Dresden; D. Welzel, Universität Regensburg; M. Gräve, G. Weidinger, Novartis, Nürnberg. Central CT Reader: R. von Kummer, Universität Dresden. External Safety Committee: H. Schäfer, H. Prinz, Universität Marburg. Statistics and Data Management: M. Gräve, B. Wolf, Novartis, Nürnberg. Head of Monitoring Group: R. Ross, Novartis, Nürnberg. Project Coordination and Logistics: I. Brenner, U. Fleischer, E. Igelhaut, K. Krause, J. Brom, Novartis, Nürnberg.
The following investigators and clinical centers participated in TOPAS. The number of patients enrolled at each center is given in parentheses, and main investigators are italicized.
Klinikum Fulda (38): H.D. Langohr, G. Ickenstein, C. Bender. Städtisches Krankenhaus Köln-Merheim (26): H. Bewermeyer, B. Raffelsieper, W. Müller, U. Merten. Wenckebach-Krankenhaus Berlin (26): H. Landgraf, E. Becker, S. Schneider, C. Jung, J. Kaufmann. Neurologische Universitätsklinik Mannheim (26): M. Hennerici, O. Mielke, S. Behrens, L. Timpe, M. Fritinger, K. Szabo, C. Eschenfelder. Universitätsklinikum Göttingen (19): W. Paulus, S. Wischer, M. Sommer, C. Doberenz. Klinikum Aschaffenburg (19): R. Schneider, B. Silberbach, J. Dorr. St Josef-Krankenhaus Moers (17): H-W. Scharafinski, D. Sanner. Klinikum Mannheim (16):J. Harenberg, L. Piazolo, U. Hoffmann. Klinikum Minden (14): O. Busse, J. Phillips, J. Glahn, T. Baumann. Bergmannsheil Bochum (14): M. Tegenthoff, U. Weyen. Universität Jena (14): C. Weiller, C. Dettmers, C. Terborg, R. van Schayck, M. Rijntjes. Universität Mainz (12): B. Tettenborn, S. Meckes, V. Kuhl, M. Eicke. Klinikum Remscheid (12): W. Pencz, V. Stiefken, H-J. Kindl, M. Splittgerber. Humboldt Universität Charité/Universitätsklinikum Rudolf Virchow Berlin (11): K. Einhäupl, T. Trottenberg, F. Masuhr, W. von Pannwitz. Klinikum Süd Nürnberg (11): H-W. Greiling, B. Borcherding, G. Kroczek, E. Glaser. Städtische Krankenanstalten Karlsruhe (10): K.F. Druschky, J. Schneider, H. Rickmann. Asklepios-Klinik Bad Salzhausen (9):G.-M. von Reutern, O. Betting, J. Allendörfer. Universität Dresden (9): H. Reichmann, G. Gahn. Klinikum Ludwigsburg (8):W. Roos, H. Lohner. Universitätsklinikum Benjamin Franklin Berlin (8): P. Marx, A. Frommholz. Städtisches Krankenhaus Pforzheim (8):D. Dörstelmann, J. Fäßler, M. Kaltenmaier. Universität Rostock (8): R. Benecke, A. Kloth, R. Knoblich. Universität Münster (7): E.B. Ringelstein, A. Holling. Krankenhaus Elisabeth Herzberge Berlin (7): H. Zettler, A. Kauert, A. Ecke. Universitätsklinikum Bonn (5): A. Hartmann, F. Hamzei. Klinikum Frankfurt/Oder (5):K. Freier, F. Hamilton. St Josefs-Hospital Bochum (5): T. Büttner, T. Postert, S. Meves. Klinikum Neubrandenburg (4): B. Bauer. Kreiskrankenhaus Rastatt (4): H. Keller, C. Fahr. Universitätsklinikum Essen (3):H.C. Diener, C. Eichten, C.E. Ehrenfeld. Universität Kiel (3): G. Deuschl, P. Zunker. Katholisches Krankenhaus Essen (3):H. Gerhard, A. Rogozinski, S. Kolks. Winterbergkliniken Saarbrücken (3): K-H. Grotemeyer, S. Houy, K. Leinenbach. Krankenhaus Weilmünster (3): C.R. Hornig, M. Adelmann, J. Bonnert, M. Hotz, B. Zentgraf. Klinikum Wuppertal-Barmen (3): J.R. Jörg, I. Blaeser. Bürgerhospital Stuttgart (3): H. Wiethölter, E. Schmid. Klinikum Lippe-Detmold (2):U. Tebbe, E. Flicker. Marien-Hospital Düsseldorf (2):W. Steinke, R. Roβmann, G. Kersting. Universität Tübingen (1): J. Dichgans, A.M. Eichhorn, M. Fetter. St. Lukas Klinik Solingen (1): H.K. Leopold, A. Schuster. Klinikum Ludwigshafen (1):K. Lowitzsch, G. Zech, C. Menges. Universitätsklinik Magdeburg (1): C-W. Wallesch, M. Görtler. Klinikum Erfurt (1): M. von Maravic. Universitätsklinik Regensburg (1):U. Bogdahn, R. Schladetzki. Fachklinik für Neurologie Dietenbronn (1): J. Reeß.
This study was supported by a grant from Novartis Pharma GmbH, Nürnberg, Germany. We gratefully thank H.K. Breddin for his advice in all questions regarding coagulation and hemostasis.
A list of TOPAS trial participants is given in the Appendix.
- Received July 10, 2000.
- Revision received August 31, 2000.
- Accepted September 7, 2000.
- Copyright © 2001 by American Heart Association
Alberts GW, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 1998;114(suppl):683S–698S.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne M, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–1025.
Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352:1245–1251.
Zivin JA. Thrombolytic stroke therapy: past, present, and future. Neurology. 1999;53:14–19.
Sandercock PAG, van den Belt AGM, Lindley RI, Slattery J. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. J Neurol Neurosurg Psychiatry. 1993;56:17–25.
Hommel M, for the FISS bis Investigators Group. Fraxiparine in Ischaemic Stroke Study (FISS bis): 7th European Stroke Conference; May 27–30, 1998; Edinburgh, UK. Cerebrovasc Dis. 1998;suppl 4:19. Abstract 64.
Hantson L, de Weerdt W, de Keyser J, Diener HC, Franke C, Palm R, Van Orshoven M, Schoonderwalt R, De Klippel N, Herroelen L, Feys H. The European Stroke Scale. Stroke. 1994;25:2215–2219.
Jeske W, Wolf H, Ahsan A, Fareed J. Pharmacologic profile of certoparin. Exp Opin Invest Drugs. 1999;8:315–327.
Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1998;114(suppl):489S–510S.
del Zoppo GJ, von Kummer R, Hamann G. Ischemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry. 1998;65:1–9.>
Larrue V, von Kummer R, del Zoppo G, Bluhmki E. Hemorrhagic transformation in acute ischemic stroke. Stroke. 1997;28:957–960.
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 sinus thrombosis. Stroke. 1999;30:484–488.
Adams HP Jr, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, Clarke RW, Hansen MD. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the trial of ORG 10172 in acute stroke treatment (TOAST). Neurology. 1999;53:122–125.