Original Contributions Low Molecular Weight Heparinoid, ORG 10172 (Danaparoid), and Outcome After Acute Ischemic Stroke A Randomized Controlled Trial The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators Context.—Anticoagulation with unfractionated heparin is used commonly for ANTICOAGULATION with unfrac- treatment of acute ischemic stroke, but its use remains controversial because it has tionated heparin commonly is used to not been shown to be effective or safe. Low molecular weight heparins and hepa- treat persons with acute ischemic 1 rinoids have been shown to be effective in preventing deep vein thrombosis in per- stroke. However, the use of heparin re- mains controversial because it is not es- sons with stroke, and they might be effective in reducing unfavorable outcomes fol- 2-6 lowing ischemic stroke. tablished as safe or effective. A recent open trial demonstrated a modest effect Objective.—To test whether an intravenously administered low molecular from subcutaneously administered hep- weight heparinoid, ORG 10172 (danaparoid sodium), increases the likelihood of a arin in preventing recurrent stroke favorable outcome at 3 months after acute ischemic stroke. within 14 days but no improvement in Design.—Randomized, double-blind, placebo-controlled, multicenter trial. outcomes.7 Thus, whether an intrave- Setting and Participants.—Between December 22, 1990, and December 6, nously administered anticoagulant that 1997, 1281 persons with acute stroke were enrolled at 36 centers across the United would act more rapidly would be effec- States. tiveremainsunanswered.Thesearchfor Intervention.—A 7-day course of ORG 10172 or placebo was given initially as alternative medications that possess the a bolus within 24 hours of stroke, followed by continuous infusion in addition to the antithrombotic characteristics of hepa- best medical care. Doses were adjusted in response to anti–factor Xa activity. rin but have a lower propensity for bleeding or thrombocytopenia led to the Main Outcome Measures.—Favorable outcome rated as the combination of a development of low molecular weight Glasgow Outcome Scale score of I or II and a modified Barthel Index of 12 or greater heparins and heparinoids. A clinical trial on a scale of 0 to 20 at 3 months or 7 days; very favorable outcome was recorded recently showed a lower rate of unfavor- for the combination of a Glasgow Outcome Scale of I and a Barthel Index of 19 or able outcomes at 6 months after stroke 20 at 3 months or 7 days. following the administration of the low Results.—At 3 months, 482 (75.2%) of 641 persons assigned to treatment with molecular weight heparin, nadroparin, ORG 10172 and 467 (73.7%) of 634 patients treated with placebo had favorable butnosignificantdifferenceswerenoted outcomes (P=.49); 49.5% and 47%, respectively, of patients in each group had very at 10 days or 3 months.8 favorable outcomes at 3 months. At 7 days, 376 (59.2%) of 635 persons given ORG ORG 10172 (danaparoid sodium [Or- 10172 and 344 (54.3%) of 633 receiving placebo had favorable outcomes (P=.07). garan]) is a mixture of glycosaminogly- cans with a mean molecular weight of For the same interval, 215 (33.9%) of 635 persons given ORG 10172 and 176 5500 d that is isolated from porcine in- (27.8%) of 633 persons administered placebo had very favorable outcomes (P=.01; testinal mucosa. The anti–factor Xa ac- odds ratio, 1.36; 95% confidence interval, 1.06-1.73). Within 10 days of onset of tivity of ORG 10172 is attributed to its treatment, serious intracranial bleeding events occurred in 14 patients given ORG heparan sulfate component,9 which has a 10172 (15 events) and in 4 placebo-treated patients (5 events) (P=.05). high affinity for antithrombin III. It is Conclusion.—Despite an apparent positive response to treatment at 7 days, not inactivated by endogenous heparin- emergent administration of the antithrombotic agent, ORG 10172, is not associated neutralizing factors such as histidine- with an improvement in favorable outcome at 3 months. richglycoproteinorplateletfactor4,and JAMA. 1998;279:1265-1272 it has virtually no effect on platelet func- tion. It has minimal effects on the acti- vated partial thromboplastin time, pro- thrombin time, or thrombin time.10 The From the Publications Committee for the Trial of ence, Amsterdam, the Netherlands, May 29, 1997, and ORG 10172 in Acute Stroke Treatment (TOAST) In- at the 23rd International Joint Conference on Stroke and drug has low cross-reactivity to antibod- vestigators. Cerebral Circulation, Orlando, Fla, February 7, 1998. ies correlated with heparin-induced A complete list of the local principal investigators and Reprints: Harold P. Adams, Jr, MD, Division of Cere- thrombocytopenia, and it is used to treat coordinators and members of study committees ap- brovascular Diseases, Department of Neurology, Uni- pears at the end of this article. versity of Iowa College of Medicine, 200 Hawkins Dr, persons at high risk for thrombosis Presented in part at the Sixth European Stroke Confer- Iowa City, IA 52252 (e-mail: [email protected]). who have a history of heparin-induced JAMA, April 22/29, 1998—Vol 279, No. 16 ORG 10172 (Danaparoid) and Acute Ischemic Stroke—TOAST Investigators 1265 ©1998 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a Johns Hopkins University User on 07/02/2012 The primary outcome was a favorable Patients Screened outcome at 3 months after stroke, de- n=25 624 fined as a score of I or II on the Glasgow Ineligible Patients Outcome Scale and a score of 12 to 20 on n=23 720 17-19 Eligible Patients the modified Barthel Index. The in- n=1904 tention-to-treat (ITT) analysis required Consent Not Obtained that the patient have at least 1 postbase- n=623 Enrolled Patients line assessment of the Glasgow Outcome n=1281 Scale and Barthel Index. The study was designed to detect an improvement of ORG 10172 Placebo 20% with treatment (from an assumed n=646 n=635 base rate of 50%) with 90% power. Safety Analyses Safety Analyses Prespecified secondary hypotheses ITT Analyses n=638 ITT Analyses n=628 included a favorable outcome at 7 days, n=641 n=634 reducing recurrent stroke within 7 days, Premature Termination Premature Termination halting worsening of neurologic deficits of Study Drug of Study Drug within 7 days, and reducing mortality at n=94 n=87 7 days and 3 months. After a trial of thrombolytic therapy demonstrated a Follow-up at 3 Months Follow-up at 3 Months benefit in improving very favorable out- 20 Alive, Agreed to Follow-up n=591 Alive, Agreed to Follow-up n=583 comes after stroke, the TOAST inves- Dead n=44 Dead n=38 tigators added analyses evaluating simi- Alive, Refused Follow-up Visit n=7 Alive, Refused Follow-up Visit n=8 lar responses (defined as a combination Alive, Lost to Study n=2 Alive, Lost to Study n=1 of a Glasgow Outcome Scale score of I Lost to Study, Unknown Status n=2 Lost to Study, Unknown Status n=5 and a Barthel Index score of 19 or 20) at 7 days and 3 months. Neurologic wors- ening was assessed by evaluating differ- The populations were reported in TOAST (Trial of ORG 10172 [(danaparoid sodium, low molecular weight heparinoid] in Acute Stroke Treatment). The ITT (intention-to-treat) data were collected from persons who ences between the day 7 and baseline had at least 1 postbaseline outcome assessment. Postbaseline primary efficacy (Glasgow Outcome Scale scores of the NIHSS.21 Patients whose and Barthel Index scores) data were not provided by 5 patients assigned to treatment with ORG 10172 and day 7 NIHSS score was 4 or more points 1 patient treated with the placebo. These 6 patients were excluded from the ITT analysis. The safety analy- less than baseline or was 0 were classi- ses involve data collected from persons who received any amount of the study drug or placebo. fied as improved, a score that was within thrombocytopenia.11 It is also used for a stroke less than 24 hours old even with 3 points of baseline was considered un- prophylaxis against deep vein thrombo- recent progression, coma, mass effect changed, and a score of 4 or more addi- sis.12 Pilot studies examined the safety (shift of midline structures) on baseline tional points or death was rated as andpotentialutilityofORG10172inper- computed tomogram (CT), intracranial worse. sons with acute ischemic stroke.13,14 blood on a CT, CT evidence of a nonvas- Subtypes of acute ischemic stroke Based on the results of these projects, cular cause of symptoms, active bleed- were also a prespecified end point. Clas- the Trial of ORG 10172 in Acute Stroke ing, major surgery in the previous 24 sification was based on a central-blinded Treatment (TOAST) was performed to hours, another illness that required an- evaluationassessingtheclinicalfindings test the efficacy of the drug in improving ticoagulation, were currently receiving and the results of brain imaging and an- outcomes among persons with acute is- heparin or warfarin, received thrombo- cillary diagnostic tests, such as carotid chemic stroke. lytic therapy in the previous 24 hours, duplex or echocardiography. Categories active bleeding, abnormal baseline co- were large-artery atherosclerosis, car- METHODS agulation studies, mean blood pressure dioembolism, small-artery occlusion, other determined cause, or undeter- Design greater than 130 mm Hg, major organ 22 failure, known vasculitis or infective en- mined cause. TOAST was a randomized, double- docarditis, a complex medical illness or Safety analyses assessed events ex- blind, placebo-controlled multicenter terminal illness, confounding neurologic perienced by any treated patient subcat- trial conducted from December 1990 to disease, allergy to heparin, prior partici- egorized by the time of onset and in- December 1996 that treated persons pation in TOAST, or were participating cluded adverse experiences that occurred within 24 hours of the onset of acute is- in another clinical trial.