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Title:   Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-Thrombolysis in Myocardial Infarction (TIMI) Study 25—Elderly Patients Substudy¹

Objective:  The primary objective of ExTRACT-TIMI 25 was to determine whether enoxaparin is more effective than unfractionated heparin (UFH) in reducing 30-day all-cause mortality and nonfatal myocardial infarction (MI) in patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy.²

Substudy objective: Elderly patients are at increased risk for adverse effects of fibrinolytic and antithrombotic therapy. Therefore, the objective of the Elderly Patients Substudy was to determine whether using a reduced dose of enoxaparin in patients aged >=75 years would reduce the frequency of adverse events while maintaining efficacy.¹

Study design:  randomized, active control, double-blind, double-dummy, parallel group, multinational trial

Drug names:  enoxaparin, streptokinase, tenecteplase, alteplase, reteplase, UFH

Drug types:  low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), thrombolytic agents

Patient population:  Patient population: ExTRACT-TIMI 25 recruited patients aged >=18 years who had STEMI, defined as ischemic symptoms at rest lasting >=20 minutes occurring <=6 hours before randomization; ST-segment elevation of >=0.1 mV in 2 limb leads or >=0.2 mV in >=2 contiguous precordial leads or left bundle branch block. Patients were scheduled for reperfusion therapy with streptokinase, tenecteplase, alteplase, or reteplase.²

Treatment regimens: All patients were treated with aspirin and were randomized to receive enoxaparin or UFH. Enoxaparin treatment continued for 8 days or until hospital discharge, whichever came first. UFH infusion lasted at least 48 hours and could be continued at the discretion of the treating physician. In patients aged <75 years, enoxaparin treatment was begun with a 30-mg IV bolus injection and continued in a dose of 1.0 mg/kg subcutaneously every 12 hours. Patients aged >=75 years did not receive the bolus injection and were treated with enoxaparin 0.75 mg/kg. Patients with an estimated creatinine clearance <30 mL/min received enoxaparin 1 mg/kg every 24 hours. UFH administration was started with an IV bolus injection of 60 U/kg (maximum 4000 U) and continued with an IV infusion of 12 U/kg/hour (maximum 1000 U/hour). Adjustments were made to the infusion according to the activated partial thromboplastin time.²

End points: The primary end point of ExTRACT-TIMI 25 was death or nonfatal recurrent MI at 30 days.²

Results: ExTRACT-TIMI 25 recruited 2532 patients aged >=75 years and 17,947 patients aged <75 years. In patients aged <75 years, death or recurrent MI occurred in 9.9% of UFH patients and 7.9% of enoxaparin patients (absolute risk difference [ARD] = 2.0%; P < 0.0001). In patients aged >=75 years, death or recurrent MI occurred in 26.3% of UFH patients and 24.8% of enoxaparin patients (ARD = 1.5%; P_int = 0.10). The number of patients needing to be treated to prevent a single event was similar in the 2 age groups: 50 in younger patients and 67 in older patients.¹

Major bleeding was similar in the elderly (UFH 2.9% vs enoxaparin 3.3%, P = 0.53), but higher with enoxaparin in younger patients (UFH 1.1% vs enoxaparin 1.9%, P < 0.0001). Rates of intracranial hemorrhage were similar between the 2 treatment groups in both older patients (UFH 1.7% vs enoxaparin 1.6%, P = 0.85) and younger patients (UFH 0.5% vs enoxaparin 0.7%, P = 0.06).¹

Conclusions: In the overall ExTRACT-TIMI 25 trial, enoxaparin administered throughout hospitalization was found to provide greater efficacy than UFH administered for 48 hours in reducing the 30-day incidence of death or nonfatal recurrent myocardial infarction. Although more bleeding occurred in enoxaparin-treated patients, the net clinical benefit from enoxaparin treatment was superior to that from UFH treatment.

This substudy found that a reduced-dose regimen in elderly patients maintained the efficacy of enoxaparin treatment while reducing the magnitude of the relative increase in major bleeding, including intracranial hemorrhage. Therefore, the enoxaparin dosing strategy used in ExTRACT-TIMI 25 is preferred to standard UFH treatment in both older and younger patients with STEMI undergoing fibrinolysis.

Place in therapy: Fibrinolysis is the most commonly used initial treatment for STEMI, and adjunctive antithrombotic therapy is an essential component of the procedure. In previous trials of patients with STEMI undergoing fibrinolysis, enoxaparin treatment reduced the incidence of ischemic events but increased the risk of major bleeding, including intracranial hemorrhage, particularly in elderly patients, and thus did not provide a net clinical benefit compared with UFH treatment.³ In ExTRACT-TIMI 25, the reduced enoxaparin dosage used in elderly patients reduced the risk of bleeding, such that there were no statistically significant differences between the enoxaparin group and the UFH group in major bleeding, intracranial hemorrhage, or death from major bleeding. Enoxaparin therapy was associated with a 1.5% absolute reduction in risk for death or nonfatal recurrent MI at 30 days relative to UFH.¹

Thus, adjunctive therapy with enoxaparin provides a consistent treatment benefit in older and younger STEMI patients receiving fibrinolysis and is preferred to UFH in all age groups. These data demonstrate that effective regimens for optimal fibrinolytic and antithrombotic therapy for patients with STEMI can be safely modified for elderly patients to achieve significant clinical benefit. Results of the ExTRACT-TIMI 25 trial clearly demonstrate that enoxaparin is superior to UFH in STEMI patients undergoing fibrinolytic therapy, and this substudy demonstrates that these results can be applied to older patients.

As a result of the favorable outcomes achieved with reduced enoxaparin dosing in the elderly subjects in ExTRACT-TIMI 25, enoxaparin prescribing information was changed to include the following dosing recommendation⁴:

For treatment of acute ST-segment elevation myocardial infarction in geriatric patients >=75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses).

References:

1. White HD, Braunwald E, Murphy SA, et al. Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25. Eur Heart J. 2007;28:1066-1071.

2. Antman EM, Morrow DA, McCabe CH, et al, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:1477-1488.

3. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation. 2003;108:135-142.

4. Lovenox® [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2007.