ExTRACT-TIMI 25: Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment

Luis Gruberg, MD, FACC

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

"The present study provides important data that may change current guidelines for the management of STEMI patients treated with thrombolytic therapy."

Presenter: Elliot M. Antman, MD (Brigham and Women's Hospital, Boston, Massachusetts)

Compared with unfractionated heparin (UFH), enoxaparin, a low-molecular-weight heparin, binds less avidly to plasma proteins, and therefore has increased bioavailability and duration of action. When coupled with antithrombin III, enoxaparin has weaker activity against thrombin, but unlike UFH, it has more potent inhibition of factor Xa. Also, due to its smaller molecular size, it may inactivate platelet-bound factor Xa and neutralize platelet factor 4. Furthermore, enoxaparin can be administered easily as either a subcutaneous or intravenous therapy and it is known to induce reliable anticoagulation without the need for further monitoring. Its use in patients with acute myocardial infarction undergoing a reperfusion strategy has not been evaluated, however.

The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction-Study 25 (ExTRACT-TIMI 25)[1,2] was designed to compare enoxaparin to UFH in patients with ST-elevation myocardial infarction (STEMI) who are eligible to receive fibrinolytic therapy. Investigators hypothesized that in STEMI patients treated with lytic therapy, the adjunctive use of enoxaparin would reduce all-cause mortality or nonfatal MI within 30 days as compared with UFH.[2]

Study Design

The prospective, multicenter, double-blind, double-dummy trial randomized patients within < 6 hours of initiation of STEMI treated with lytic therapy (streptokinase, tenecteplase, reteplase, and alteplase)[2] to receive enoxaparin or UFH.

In the enoxaparin arm, drug dosing was adjusted by patient age (< 75 vs ≥ 75 years) and renal function[2]:

  • Age < 75 years: enoxaparin 30 mg IV bolus followed by 1 mg/kg subcutaneous injection every 12 hours until hospital discharge

  • Age ≥ 75 years: No IV bolus and 0.75 mg/kg subcutaneous injection every 12 hours until hospital discharge

  • Creatinine clearance ≤ 30 mL/min 1 mg/kg every 24 hours

Patients randomized to UFH received 60 U/kg bolus followed by 12 U/kg for at least 48 hours.

Primary Efficacy Endpoint

Death or nonfatal MI at 30 days.

Primary Safety Endpoint

TIMI major bleeding.

Secondary Endpoint

Composite of all-cause mortality, nonfatal MI, and urgent revascularization.

Results

A total of 20,479 patients were randomized at 674 sites in 48 countries. Baseline clinical characteristics and administered medications were well matched between all patients (Table 1). The median time from symptom onset to initiation of lytic therapy was 3.2 hours, and 97.2% of patients received their assigned therapy within 30 minutes following lytic therapy.

Table 1. ExTRACT-TIMI 25: Baseline Characteristics (Intention-to-Treat Analysis)
Characteristic Patients
(n = 20,479)
Clinical
Median age (yrs) 59
Age ≥ 75 yrs (%) 12
Male gender (%) 77
Hypertension (%) 44
Hyperlipidemia (%) 18
Current smoker (%) 47
Diabetes (%) 15
S/P MI (%) 13
Anterior wall MI (%) 44
Creatinine clearance (mL/min)(median) 82
Killip class I (%) 89
TIMI score ≤ 3 (%) 64
TIMI score > 3 (%) 36
Medications
Streptokinase (%) 20
Fibrin-specific (%) 80
Aspirin (%) 95
Beta-blockers (%) 86
ACE inhibitor/ARB (%) 80
Statins (%) 70
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; MI = myocardial infarction; S/P = status-post; TIMI = thrombolysis in myocardial infarction

The primary endpoint of the study, death or nonfatal MI at 30 days, was significantly lower in patients randomized to enoxaparin (12.0% vs 9.9%), accounting for a 17% relative risk reduction (P < .0001) (Figure 1). The benefit was observed as early as 48 hours following therapy (5.2% vs 4.7%; P < .08).

Figure 1. ExTRACT-TIMI 25: Death or nonfatal myocardial infarction at 30 days and at 48 hours.

In addition, when the endpoint of urgent revascularization was included in the analysis, the difference between the 2 groups was even more pronounced in favor of enoxaparin at both 30 days and at 48 hours (Figure 2).

Figure 2. ExTRACT-TIMI 25: Net clinical benefit -- death/nonfatal myocardial infarction/ urgent revascularization at 30 days and at 48 hours.

Overall, use of enoxaparin was associated with an 8% reduction in 30-day mortality, a 33% reduction in nonfatal MI, and a 26% reduction in urgent revascularization rates (Figure 3). The benefit was seen in all groups, except in patients ≥ 75 years and in patients treated with streptokinase.

Figure 3. ExTRACT-TIMI 25: Death, nonfatal MI, and urgent revascularization at 30 days.

The benefits of enoxaparin, however, were somewhat offset by a significant increase in major bleeding complications (fatal and nonfatal) and in nonfatal major bleeding complications without an increase in intracranial bleeding (Figure 4).

Figure 4. ExTRACT-TIMI 25: Bleeding endpoints.

A summary of the results is presented in Table 2.

Table 2. ExTRACT-TIMI 25: Results
Endpoint UFH Enoxaparin RR (CI 95%) P
48 hrs
Death/nonfatal MI (%) 5.2 4.7 0.90 0.80-1.01 .08
Death (%) 3.8 3.7 0.98 0.85-1.12 .76
Nonfatal MI (%) 1.4 0.9 0.67 0.52-0.87 .002
Urgent revascularization 0.9 0.7 0.77 0.57-1.04 .09
Death/nonfatal MI/urgent revascularization (%) 6.1 5.3 0.88 0.79-0.98 .02
30 Days
Death/nonfatal MI (%) (primary endpoint) 12.0 9.9 0.83 0.77-0.90 < .001
Death (%) 7.5 6.9 0.92 0.84-1.02 .11
Nonfatal MI (%) 4.5 3.0 0.67 0.58-0.77 < .001
Urgent revascularization (%) 2.8 2.1 0.74 0.62-0.88 < .001
Death/nonfatal MI/urgent revascularization (%) 14.5 11.7 0.81 0.75-0.87 < .001
Bleeding at 30 days
Major bleeding (%) 1.4 2.1 1.53 1.23-1.89 < .001
Intracranial hemorrhage (%) 0.7 0.8 1.27 0.92-1.75 .14
CI = confidence interval; MI = myocardial infarction; RR = relative risk; UFH = unfractionated heparin
Conclusion

In patients receiving fibrinolysis for STEMI, treatment with enoxaparin throughout the index hospitalization is superior to treatment with UFH for 48 hours, but is associated with an increase in major bleeding episodes.

Viewpoint

ExTRACT-TIMI 25 provides important data that may change current guidelines for the management of STEMI patients treated with thrombolytic therapy. Although for some of us, fibrinolysis is a last-resort treatment for patients with acute MI, we have to remember that it continues to be the most common method of reperfusion used worldwide, and current guidelines recommend the use of UFH in these patients.

The protocol of the current study was well designed and specifically adjusted enoxaparin dosing to avoid excess bleeding complications in those patients at higher risk (eg, elderly patients and those with chronic renal failure). Nevertheless, its use was associated with an excess in major bleeding complications (but not in intracranial hemorrhage). Unfortunately, the elderly did not seem to benefit from this treatment. Of interest, enoxaparin was administered for the duration of the hospitalization, but the net benefit was already seen at 48 hours. Such findings may leave us questioning whether there is a need for such prolonged therapy.

References
  1. Antman EM, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin in ST elevation myocardial infarction patients treated with fibrinolysis. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 422-9.

  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.

Comments

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