Low Molecular Weight Heparinoid, ORG 10172 (Danaparoid), and Outcome After Acute Ischemic Stroke - TOAST

Description:

TOAST is a randomized, double-blind, placebo-controlled trial to test whether a low molecular heparinoid (ORG 10172) increases the likelihood of a favorable outcome at 3 months following acute ischemic stroke.

Hypothesis:

The low molecular heparinoid ORG 10172 may improve outcomes at both 7 days and 3 months following acute ischemic stroke more than placebo.

Study Design

Study Design:

Patients Screened: 25624
Patients Enrolled: 1281
Mean Follow Up: 3 months
Mean Patient Age: Mean of 65
Female: 40

Patient Populations:

  • 18-85 years old
  • Acute or progressing ischemic stroke with symptoms present for more than 1 hour but less than 24 hours
  • Prestroke modified Barthel Index of 12 or more

Exclusions:

  • Resolution of neurologic symptoms
  • An isolated mild neurologic deficit
  • Stroke less than 24 hours old with recent progression, coma, or mass effect on baseline CT
  • Intracranial blood on CT
  • CT evidence of nonvascular cause of symptoms
  • Active bleeding
  • Major surgery within the previous 24 hours
  • Abnormal baseline coagulation studies
  • Mean blood pressure greater than 130 mm Hg
  • Major organ failure
  • Known vasculitis or infective endocarditis
  • Complex medical illness or terminal illness
  • Confounding neurologic disease
  • Allergy to heparin
  • Prior participation in TOAST
  • Women who are pregnant or lactating

Primary Endpoints:

Favorable outcome at 3 months, defined as a score of I or II on the Glasgow Outcome Scale and a score of 12-20 on the modified Barthel Index.

Secondary Endpoints:

  • Favorable outcome at 7 days
  • Reducing recurrent stroke within 7 days
  • Halting worsening of neurologic deficits within 7 days
  • Reducing mortality at 7 days and 3 months

Drug/Procedures Used:

  • 7-day course of ORG 10172 titrated to maintain an anti-factor Xa level of 0.6-0.8.
  • placebo

Concomitant Medications:

Concomitant use of aspirin, heparin, warfarin, ticlopidine and NSAIDs was prohibited during this period

Principal Findings:

  • At 3 months, 482 (75.2%) of patients randomized to ORG 10172 vs. 467 (73.7%) of those in the placebo group had a favorable neurologic outcome, p=0.49
  • At 7 days 376 (59.2%) of those in the ORG 10172 vs. 344 (54.3%) of those in the placebo group had favorable neurologic outcomes, p=0.07
  • 215 (33.9%) in the ORG 10172 vs. 176 (27.8%) of the placebo group had very favorable neurologic outcome at 7 days, p=0.01
  • Serious intracranial bleeding events occurred in 14 patients given ORG 10172 vs. 4 patients in placebo group, p=0.05)

Interpretation:

Among patients with acute ischemic stroke, treatment with ORG 10172 (Danaparoid) demonstrated no significant difference in favorable neurologic outcomes at 3 months compared with placebo. Patients randomized to the ORG 10172 group had a significantly higher rate of very favorable outcomes at 7 days. There was, however, a significant association of ORG 10172 administration and serious intracranial bleeding within 10 days.

References:

The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). Low Molecular Weight Heparinoid, ORG 10172 (Danaparoid), and Outcome After Acute Ischemic Stroke. JAMA,1998; 279:1265-1272.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: Dermatan Sulfate, Heparinoids, Stroke, Chondroitin Sulfates, Heparin, Heparitin Sulfate, Factor Xa


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