Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage

Am Heart J. 2001 May;141(5):742-50. doi: 10.1067/mhj.2001.114975.


Background: The optimal heparin dose as an adjunct to fibrinolysis and its role in causing intracranial hemorrhage (ICH) is unclear.

Methods: We reviewed the heparin regimens and rates of ICH in 3 sets of recent fibrinolytic trials: (1) studies with accelerated recombinant tissue plasminogen activator (TPA, alteplase) plus intravenous heparin, in which the heparin regimen was changed during the course of the trial; (2) phase III trials with accelerated TPA plus intravenous heparin; and (3) trials of new single-bolus fibrinolytic agents.

Results: Lower rates of ICH were observed among studies of accelerated TPA that reduced the heparin dose mid-trial (TIMI 9A --> 9B: 1.87% --> 1.07%, GUSTO-IIa --> IIb: 0.92% --> 0.71%, TIMI 10B: 2.80% --> 1.16%). Rates of ICH with accelerated TPA gradually increased from GUSTO-I (0.72%) in 1990 to 1993 to ASSENT-2 (0.94%) in 1997 to 1998. However, this trend was reversed in InTIME-II, which used the lowest heparin dose and most aggressive activated partial thromboplastin time monitoring and observed an ICH rate of 0.64% with accelerated TPA. Lower ICH rates were also observed when the heparin dose was reduced with single-bolus tenecteplase (TNK-TPA) and lanoteplase.

Conclusions: Nonrandomized comparisons with accelerated TPA suggest that lower doses of intravenous heparin are associated with lower rates of ICH. This observation also appears to apply to single-bolus TNK-TPA and novel plasminogen activator. A lower-dose, weight-adjusted heparin regimen (60 U/kg bolus; maximum, 4000 U; 12 U/kg per hour infusion; maximum, 1000 U/h) with earlier monitoring of activated partial thromboplastin time is currently recommended in the revised American College of Cardiology/American Heart Association myocardial infarction guidelines and should be used in clinical practice.

Publication types

  • Comparative Study
  • Meta-Analysis

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Fibrinolytic Agents / administration & dosage*
  • Fibrinolytic Agents / adverse effects
  • Heparin / administration & dosage*
  • Heparin / adverse effects
  • Humans
  • Incidence
  • Injections, Intravenous
  • Intracranial Hemorrhages / blood
  • Intracranial Hemorrhages / chemically induced
  • Intracranial Hemorrhages / epidemiology*
  • Intracranial Hemorrhages / prevention & control
  • Male
  • Middle Aged
  • Myocardial Infarction / drug therapy
  • Prognosis
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Survival Rate
  • Thrombolytic Therapy / adverse effects
  • Thrombolytic Therapy / methods*
  • Tissue Plasminogen Activator / administration & dosage*
  • Tissue Plasminogen Activator / adverse effects
  • United States / epidemiology


  • Anticoagulants
  • Fibrinolytic Agents
  • Heparin
  • Tissue Plasminogen Activator