Lower-Dose Heparin With Fibrinolysis
Lower-Dose Heparin With Fibrinolysis
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 Æ 9B: 1.87% Æ 1.07%, GUSTO-IIa Æ IIb: 0.92% Æ 0.71%, TIMI 10B: 2.80% Æ 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.
Intracranial hemorrhage (ICH) remains the most feared complication of fibrinolytic therapy and is associated with a mortality rate of 50% to 70%; the majority of survivors have significant disability. To preserve the modest reduction in net clinical benefit (death or disabling stroke) achieved with fibrinolytic therapy over placebo, it is important to minimize ICH associated with fibrinolysis. Several factors influence the risk of ICH, including the fibrinolytic regimen and dose; patient characteristics, including age, sex, weight, race, blood pressure, and history of stroke; and the antithrombotic agent.
Data supporting the use of intravenous heparin in combination with recombinant tissue plasminogen activator (alteplase, TPA) are drawn mostly from small angiographic studies or inferred from comparisons between trials. Three trials have demonstrated improved infarct artery patency at late time points (18 to 81 hours) with the addition of intravenous heparin to TPA. This benefit, however, was not evident at 90 minutes in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 3 trial. There are no direct comparisons of the different doses or routes of administration of heparin as an adjunct to TPA in large mortality trials. However, indirect evidence from studies of TPA with delayed subcutaneous heparin compared with immediate intravenous heparin suggest that the advantage of TPA over streptokinase may in part be dependent on the method and timing of heparin administration. Subcutaneous heparin administered 4 to 12 hours after TPA did not lower early mortality rates relative to streptokinase in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto Miocardico (GISSI)-2 and International Study of Infarct Survival (ISIS)-3 trials. However, intravenous heparin administered simultaneously with accelerated TPA was superior to streptokinase in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-1 study.
Last, an overview demonstrated that the addition of intravenous heparin to TPA resulted in modest reductions in death (5 of 1000), reinfarction (3 of 1000), and pulmonary embolism (1 of 1000). On the basis of the above data, current practice guidelines recommend that intravenous heparin be used in combination with accelerated TPA for the treatment of acute myocardial infarction. The optimal dose of heparin (if any) as an adjunct to fibrinolytic therapy with the newer bolus fibrinolytic agents has not been well studied in clinical trials.
Our working hypothesis was that early (<3-hour) excessive anticoagulation associated with higher doses of heparin increased the risk of ICH in patients with acute myocardial infarction treated with fibrinolytic agents. The objectives of this study were to compare the rates of ICH, risk factors, and initial heparin regimens in recent clinical trials studying accelerated TPA and the newer bolus agents.
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 Æ 9B: 1.87% Æ 1.07%, GUSTO-IIa Æ IIb: 0.92% Æ 0.71%, TIMI 10B: 2.80% Æ 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.
Intracranial hemorrhage (ICH) remains the most feared complication of fibrinolytic therapy and is associated with a mortality rate of 50% to 70%; the majority of survivors have significant disability. To preserve the modest reduction in net clinical benefit (death or disabling stroke) achieved with fibrinolytic therapy over placebo, it is important to minimize ICH associated with fibrinolysis. Several factors influence the risk of ICH, including the fibrinolytic regimen and dose; patient characteristics, including age, sex, weight, race, blood pressure, and history of stroke; and the antithrombotic agent.
Data supporting the use of intravenous heparin in combination with recombinant tissue plasminogen activator (alteplase, TPA) are drawn mostly from small angiographic studies or inferred from comparisons between trials. Three trials have demonstrated improved infarct artery patency at late time points (18 to 81 hours) with the addition of intravenous heparin to TPA. This benefit, however, was not evident at 90 minutes in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 3 trial. There are no direct comparisons of the different doses or routes of administration of heparin as an adjunct to TPA in large mortality trials. However, indirect evidence from studies of TPA with delayed subcutaneous heparin compared with immediate intravenous heparin suggest that the advantage of TPA over streptokinase may in part be dependent on the method and timing of heparin administration. Subcutaneous heparin administered 4 to 12 hours after TPA did not lower early mortality rates relative to streptokinase in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto Miocardico (GISSI)-2 and International Study of Infarct Survival (ISIS)-3 trials. However, intravenous heparin administered simultaneously with accelerated TPA was superior to streptokinase in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-1 study.
Last, an overview demonstrated that the addition of intravenous heparin to TPA resulted in modest reductions in death (5 of 1000), reinfarction (3 of 1000), and pulmonary embolism (1 of 1000). On the basis of the above data, current practice guidelines recommend that intravenous heparin be used in combination with accelerated TPA for the treatment of acute myocardial infarction. The optimal dose of heparin (if any) as an adjunct to fibrinolytic therapy with the newer bolus fibrinolytic agents has not been well studied in clinical trials.
Our working hypothesis was that early (<3-hour) excessive anticoagulation associated with higher doses of heparin increased the risk of ICH in patients with acute myocardial infarction treated with fibrinolytic agents. The objectives of this study were to compare the rates of ICH, risk factors, and initial heparin regimens in recent clinical trials studying accelerated TPA and the newer bolus agents.