European Heart Journal Advance Access originally published online on June 11, 2007
European Heart Journal 2007 28(13):1566-1573; doi:10.1093/eurheartj/ehm179
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Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis
1 TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 350 Longwood Avenue, 1st Floor, Boston, MA 02115, USA
2 Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
3 Department of Cardiovascular Diseases, Pontificia Universidad Catolica, Santiago, Chile
4 Fundacion Favaloro, Buenos Aires, Argentina
5 Coronary Care Unit, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico
6 H. Gregorio Maranon, Madrid, Spain
7 Institute of Cardiology, Kiev, Ukraine
8 Enschede, The Netherlands
Received 19 December 2006; revised 7 April 2007; accepted 13 April 2007; online publish-ahead-of-print 11 June 2007.
* Corresponding author. Tel: +1 617 525 6865; fax: +1 888 249 5261; E-mail address: rgiraldez{at}partners.org
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Abstract |
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Aims: We compared outcomes of ST-elevation myocardial infarction (STEMI) patients randomized to a strategy of either enoxaparin or unfractionated heparin (UFH) to support fibrinolysis.
Methods and results: In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial, 20 479 patients undergoing fibrinolysis for STEMI with a fibrin-specific agent (N = 16 283) or streptokinase (SK) (N = 4139) were randomized to enoxaparin throughout their hospitalization or UFH for at least 48 h. The primary end point of death or nonfatal recurrent MI through 30 days occurred in 12.0% of patients in the UFH and 9.8% in the enoxaparin groups when treated with fibrin-specific lytics [odds ratioadjusted (ORadj) 0.78; 95% CI 0.70–0.87; P < 0.001] and 11.8 vs. 10.2%, respectively, when treated with SK (ORadj 0.83; 95% CI 0.66–1.04; P = 0.10; Pinteraction = 0.58). Major bleeding rates including intracranial hemorrhage within the fibrin-specific cohort were 1.2 and 2.0% in the UFH and enoxaparin groups, respectively (P < 0.001) and 2.0% in UFH and 2.4% in enoxaparin patients in the SK cohort (P = 0.16). Interaction tests between antithrombin- and lytic-type were non-significant (P = 0.20). Death, nonfatal MI, or major bleeding was significantly reduced with enoxaparin in the fibrin-specific cohort (ORadj 0.82; 95% CI 0.74–0.91; P < 0.001) and favoured enoxaparin in the SK cohort (ORadj 0.89; 95% CI 0.72–1.10; P = 0.29; Pinteraction = 0.53).
Conclusion: The benefits of an enoxaparin strategy over UFH were observed in both SK and fibrin-specific-treated STEMI patients. Therefore, an enoxaparin strategy is preferred over UFH to support fibrinolysis for STEMI regardless of lytic agent.
Key Words: STEMI • Enoxaparin • Fibrin-specific lytics • Streptokinase
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Introduction |
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Fibrinolysis remains the leading re-perfusion strategy around the world for patients with ST-elevation myocardial infarction (STEMI). Despite several advantages, including development of fibrin-specific lytics and bolus-administered agents, the benefits of fibrinolysis are compromised when re-occlusion of successfully re-perfused infarct arteries occurs.1
The generation of thrombin via the coagulation cascade is pivotal in the formation of fibrin strands and activation of platelets at the site of a ruptured vulnerable plaque. Local production of thrombin is also paradoxically increased by the action of fibrinolytic agents.2 Enzymatically active thrombin plays a key role in re-occlusion following successful coronary re-perfusion, providing the rationale for adjunctive anticoagulant therapy in STEMI patients undergoing fibrinolysis.
Unfractionated heparin (UFH) is an anti-coagulant that has been widely used in the treatment of STEMI for >40 years. Investigations have confirmed the benefits of UFH combined with fibrinolytic therapy.3–5 The addition of UFH to fibrinolysis with streptokinase (SK) has been demonstrated to reduce death and reinfarction,3 whereas in combination with fibrin-specific agents UFH is believed to help achieve and maintain coronary arterial patency.4,5 Low-molecular-weight heparins, such as enoxaparin, are an attractive potential replacement for UFH because of the convenient subcutaneous route of administration and reliable anticoagulation effects, eliminating the need for therapeutic monitoring.
The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial demonstrated that a strategy of adjunctive anticoagulant therapy with enoxaparin for the duration of the index hospitalization was superior to the standard two-day UFH regimen in patients with STEMI treated with fibrinolytic therapy.6 However, little information is available regarding the efficacy and safety of enoxaparin across a range of available lytics agents.7,8 In the ExTRACT-TIMI 25 trial, alteplase, tenecteplase, reteplase, or SK was administered to STEMI patients at the discretion of the treating physician, and 30-day outcomes were evaluated. We report a pre-specified subgroup analysis conducted to determine the efficacy and safety of the administration of a strategy of enoxaparin compared with UFH stratified by the type of lytic therapy used in the trial.
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Methods |
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Patient population and study protocol
The design of the ExTRACT-TIMI 25 trial has been reported previously.9 In brief, patients aged
18 years presenting within 6 h of the onset of symptoms of STEMI scheduled to undergo fibrinolysis were treated with a fibrinolytic agent (alteplase, tenecteplase, reteplase, or SK) selected by the treating physician and administered according to the package insert for the treatment of STEMI. Patients were to receive aspirin (recommended dose of 150–325 mg in a nonenteric formulation orally or 500 mg intravenously on the first day and 75–325 mg daily thereafter for at least 30 days). Clopidogrel could be added to aspirin at the treating physician's discretion. Patients were randomly assigned in a 1:1 ratio to receive enoxaparin or UFH in a double-blinded fashion with a double-dummy design. UFH or matching placebo was given as an i.v. bolus of 60 U kg–1 (maximum 4000 U) followed by a continuous infusion at 12 U kg–1 h–1 (maximum 1000 U h–1) initiated within 15 min after the bolus and continued for at least 48 h. The dose of UFH was adjusted to maintain an activated partial thromboplastin time of 1.5–2.0 times the control value. The enoxaparin dosing regimen was adjusted according to the patient's age and renal function, as described elsewhere.9 The subcutaneous enoxaparin regimen was continued until hospital discharge or for a maximum of eight days. Patients were monitored for clinical outcomes and adverse events either in person or by telephone during their hospitalization and through day 30.
Outcomes
The primary efficacy end point of the trial and of this analysis was the composite of all-cause mortality or nonfatal recurrent MI in the first 30 days after randomization. The main, secondary end point was the composite of death from any cause, nonfatal reinfarction, or recurrent myocardial ischemia leading to urgent revascularization in the first 30 days. The primary safety end point was TIMI major bleeding. All-cause mortality, nonfatal reinfarction, or a nonfatal episode of major bleeding was a pre-specified net clinical benefit end point. The definition of the end points has been described previously.9
Statistical analysis
The population used for the statistical analysis included patients randomized in the trial and treated with fibrinolytic therapy. The comparison of baseline characteristics between patients treated with fibrin-specific lytics vs. SK was performed using t-tests or Wilcoxon rank sum tests for normally or non-normally distributed continuous variables, respectively, and 
2 tests were applied for categorical variables. All efficacy comparisons were analysed according to the intention-to-treat principle. The 2 test was used to compare the primary and secondary end points in the UFH and enoxaparin groups stratified by each of the four fibrinolytic agents used in the trial. All safety analyses were performed according to the treatment actually received by the patient. Multivariable analyses for the evaluation of efficacy, safety, and composite end points stratified by lytic type included components of the TIMI risk score such as age, weight, anterior location of the MI, previous angina, history of hypertension or diabetes, time to fibrinolysis and systolic blood pressure, heart rate, and Killip class upon admission. Adjustment was also performed for the different regions of the world as local practice might influence outcomes. The five regions selected for this adjustment were (i) North America, (ii) South America, (iii) Australia, Asia, and Africa, (iv) Western Europe, and (v) Eastern Europe (reference). A univariate regression model was performed for the assessment of the interaction between randomized therapy and fibrinolytic treatment. A P-value of <0.05 was the threshold for nominal significance for all end points.
Analyses were done with Stata/SE version 9.2 (StataCorp).10
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Results |
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A total of 20 479 patients with STEMI were included in the intention-to-treat population. Overall, 16 283 (79.7%) patients were treated with fibrin-specific lytics and 4139 (20.3%) received SK. A total of 57 patients in the intention-to-treat population were not treated with fibrinolytic therapy and therefore were not considered in this analysis. Of the patients who received fibrin-specific agents, 11 175 (68.6%) patients were treated with alteplase, 3986 (24.5%) with tenecteplase, and the remainder 1122 (6.9%) were treated with reteplase.
Baseline characteristics stratified by the category of lytic are shown in Table 1. Patients who received SK were older and had a higher prevalence of diabetes. In-hospital medical therapy was comparable in both cohorts. Patients in both groups were treated according to contemporary guidelines and received aspirin (95.2%), beta-blockers (85.8%) and inhibitors of the renin-angiotensin system (79.7%).
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Efficacy outcomes stratified by lytic |
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The rate of the primary efficacy end point (death or nonfatal MI) in the fibrin-specific cohort at 30 days was 12.0% in patients treated with UFH compared with 9.8% in the enoxaparin group [odds ratioadj (ORadj) 0.78; 95% CI 0.70–0.87; P < 0.001; Table 2 and Figure 1]. A strategy of enoxaparin also significantly reduced the rates of recurrent MI in the fibrin-specific cohort (4.6 vs. 3.1%; ORadj 0.68; 95% CI 0.57–0.80; P < 0.001). The benefit of enoxaparin strategy observed in the primary end point and its components for the fibrin-specific cohort was also present for the alteplase, tenecteplase, and reteplase cohorts analysed separately (Table 3). In patients who received SK, the primary end point occurred in 11.8% of those receiving UFH and 10.2% of those treated with enoxaparin (ORadj 0.83; 95% CI 0.66–1.04; P = 0.10). A significant 31% reduction in the adjusted OR of nonfatal reinfarction was observed in the SK cohort treated with enoxaparin (3.8 vs. 2.7%; P = 0.05) (Table 2). A test for interaction between antithrombin group and fibrin-specific vs. SK cohorts was non-significant for the composite primary end point (P = 0.58; Figure 1).
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Analysis of the time course of the treatment effect of enoxaparin shows that the rates of the primary end point death or recurrent MI were significantly reduced in the fibrin-specific cohort on the first day of therapy (ORadj 0.81; 95% CI 0.67–0.98; P = 0.03; Figure 2A). In the SK cohort, the point estimate favoured the enoxaparin strategy by day 3, and increased progressively during the course of therapy (Figure 2B).
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A strategy of enoxaparin also significantly reduced the secondary end point of all-cause mortality, nonfatal MI, or urgent revascularization in both lytic cohorts compared with UFH (Table 2 and Figure 3). Interaction tests between anticoagulant groups and fibrin-specific vs. SK cohorts were non-significant for the secondary end point (P = 0.60) (Figure 3). Episodes of recurrent myocardial ischemia leading to urgent target vessel revascularization were significantly decreased by enoxaparin both in patients who received fibrin-specific lytics (2.7 vs. 2.1%, ORadj 0.76; 95% CI 0.61–0.93; P = 0.009) as well as SK (3.2 vs. 2.2%, ORadj 0.62; 95% CI 0.41–0.92; P = 0.02) (Table 2). The benefits of the enoxaparin strategy for these end points were also present when alteplase, tenecteplase, and reteplase cohorts were analysed separately (Table 3).
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Safety outcomes stratified by lytic
The rates of TIMI major bleeding (including intracranial hemorrhage) at 30 days in patients treated with fibrin-specific lytics were significantly elevated from 1.2% in the UFH group to 2.0% in the enoxaparin strategy group (ORadj 1.89; 95% CI 1.43–2.51; P < 0.001) (Table 4). Similarly elevated rates of major bleeding without intracranial haemorrhage were seen in patients treated with a strategy of enoxaparin (0.6 vs. 1.1%; ORadj 2.23; 95% CI 1.51–3.30; P < 0.001). Within fibrin-specific-treated patients, intracranial haemorrhage occurred in 0.6% in the UFH group and 0.9% in the enoxaparin group (ORadj 1.55; 95% CI 1.03–2.33; P = 0.04) (Table 4).
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In the SK cohort, major bleeding including intracranial haemorrhage occurred in 2.0% of the patients receiving UFH and 2.4% of those treated with enoxaparin (ORadj 1.38 95% CI 0.88–2.17; P = 0.16) (Table 4). The rates of major bleeding without intracranial haemorrhage were 1.3% in the UFH group and 1.9% in the enoxaparin group (ORadj 1.74; 95% CI 1.02–2.97; P = 0.04). The incidence of intracranial haemorrhage in the SK cohort was 0.7% for patients treated with UFH and 0.5% for those who received the enoxaparin strategy (ORadj 0.75; 95% CI 0.31–1.80; P = 0.52) (Table 4). Interaction tests for major bleeding risk and intracranial haemorrhage were non-significant between fibrin-specific vs. SK cohorts and anticoagulant assigned in the trial (P = 0.20 and 0.12, respectively).
Net clinical benefit
The rates of the pre-specified net clinical benefit end point (all-cause mortality, nonfatal reinfarction, and major bleeding) in the fibrin-specific cohort were 12.7 and 10.8% for patients treated with UFH and enoxaparin, respectively (ORadj 0.82; 95% CI 0.74–0.91; P < 0.001). Although not statistically significant, net clinical benefit in the SK cohort was directionally in favour of enoxaparin (11.8%) vs. UFH (13.0%) (ORadj 0.89; 95% CI 0.72–1.10; P = 0.29). Interaction test between antithrombin groups and fibrin-specific vs. SK cohorts was non-significant for the net clinical benefit comparison (P = 0.53).
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Discussion |
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Our findings demonstrate the superiority of anticoagulant therapy with a strategy of enoxaparin throughout the index hospitalization over the standard strategy of 2 days of UFH in STEMI patients undergoing pharmacological re-perfusion across the spectrum of four lytics available around the world that were used in ExTRACT-TIMI 25. A significant reduction in the primary end point of all-cause mortality, or nonfatal recurrent MI as well as the secondary end point of death, nonfatal reinfarction, or urgent revascularization were observed in patients randomized to enoxaparin in both the fibrin-specific lytic cohort and each of the fibrin-specific lytics analysed independently. Reductions in the primary and secondary efficacy end points were also seen with enoxaparin in the SK cohort, although the magnitude of the benefit was somewhat smaller than in the fibrin-specific cohort. The benefits of the enoxaparin strategy over UFH for the prevention of death or nonfatal MI translate into a number of patients who need to be treated (NNT) to prevent one event of 48 and 67 for the fibrin-specific and SK cohorts, respectively. To prevent the secondary end point of death, nonfatal recurrent MI, or urgent revascularization, the NNTs are 34 for patients receiving fibrin-specific lytics and 43 for those treated with SK. The advantage of enoxaparin over UFH may be related to both a direct anticoagulant benefit as suggested by a significant decrease in the primary end point after 24 h of treatment and to the longer duration of therapy as seen by the incremental advantage after UFH is stopped.
Importantly, the use of enoxaparin was associated with a 32 and 31% reduction in the OR of nonfatal recurrent infarction in the fibrin-specific and SK cohorts, respectively. The rates of myocardial ischemia leading to urgent revascularization were reduced by 24% in the fibrin-specific cohort and 38% in the SK cohort. The observation of reduced reinfarction and recurrent ischemia associated with enoxaparin strategy assumes great relevance, as these complications are associated with increased mortality rates in patients treated with fibrinolysis.1
Major bleeding rates were significantly higher in the enoxaparin group of both fibrin-specific and SK cohorts. While the concomitant use of enoxaparin with fibrin-specific agents increased ICH, the opposite effect was seen in patients treated with SK. Caution should be used during the interpretation of subgroup analysis especially when interaction tests are negative. Despite the increase in bleeding, adjustments of the enoxaparin dose in the elderly and patients with renal failure might have contributed to prevent the highly elevated haemorrhagic rates observed in previous trials in which antiplatelet11 and antithrombin12,13 agents were combined with fibrinolytic agents, particularly SK.
The evaluation of net clinical benefit end points is of particular importance as it integrates efficacy and safety outcomes. Despite the significant increase observed in major bleeding, net clinical benefit analyses favoured the enoxaparin strategy in both fibrin-specific and SK cohorts. These findings highlight the importance of concomitant antithrombin therapy in fibrinolysis with both fibrin-specific agents and SK, as previously demonstrated.14
The results presented are anticipated to impact the treatment of STEMI. From our data, we expect that for every 1000 patients treated with fibrin-specific lytics and enoxaparin, a total of 29 fewer deaths, recurrent MIs, or urgent revascularization will occur. When SK is the lytic chosen, 23 secondary end points will be prevented. Many physicians perceive that fibrin-specific lytics are more efficient than SK. In this case, adjunctive antithrombotic therapy with enoxaparin becomes an attractive therapy as it clearly reduces nonfatal recurrent MI and urgent revascularization in fibrin-specific-treated patients. On the other hand, SK is the most frequently prescribed fibrinolytic agent around the world,15 particularly in developing countries as physicians have accumulated vast experience with this compound that is the least expensive among the available lytics.16 A reduction in the composite secondary end point of death, recurrent MI, and urgent revascularization in patients undergoing fibrinolysis with SK favourably impacts the outcomes of SK-treated patients. Because more patients are treated with SK around the world, it is anticipated that the global impact of the combination with enoxaparin may actually be greater for SK than fibrin-specific lytics.
Limitations
Potential limitations of this ExTRACT-TIMI 25 subanalysis deserve consideration. One important confounding factor is the non-randomized nature of the fibrinolytic therapy administered to the patient. An analysis including prognostic and country variables was performed to adjust for such potential confounders. Another limitation of this study is that it was not powered to detect differences between subgroups. Therefore, a direct comparison of treatment effect between different fibrinolytics cohorts was not possible. Interaction tests, however, suggested similar benefits from all lytic subgroups.
Clinical implications
In patients with STEMI undergoing pharmacological re-perfusion, recurrent MI, and ischaemic events leading to urgent revascularization were significantly reduced with the enoxaparin strategy compared with UFH as adjunctive anticoagulant therapy with both fibrin-specific lytics and SK. Although major bleeding was higher in both lytic cohorts, all composite net clinical benefit end points favoured enoxaparin regardless of the lytic prescribed. These findings strongly suggest that a strategy of enoxaparin is preferred over UFH to support fibrinolysis for STEMI across the range of lytics in common clinical use.
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This work was supported by a grant from sanofi-aventis.
Conflict of interest: All authors received research grants from sanofi-aventis to conduct ExTRACT-TIMI 25.
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