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ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction

ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease
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J Am Coll Cardiol, 2003; 42:1348-1356, doi:10.1016/S0735-1097(03)01040-4
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CLINICAL TRIAL

The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI)

A randomized trial

Marc Cohen, MD, FACC*,*, Gian Franco Gensini, MD{dagger}, Frans Maritz, MD{ddagger}, Enrique P. Gurfinkel, MD, PhD, FACC§, Kurt Huber, MD, FACC||, Ari Timerman, MD, PhD, Maria Krzeminska-Pakula, MD#, Nicolas Danchin, MD, FACC**, Harvey D. White, DSc{dagger}{dagger}, Jose Santopinto, MD, FACC{ddagger}{ddagger}, Frederique Bigonzi, MD§§, Carole Hecquet, MS§§, Luc Vittori, MS§§ TETAMI Investigators

* Newark Beth Israel Medical Center, Newark, New Jersey, USA
{dagger} University of Florence, Florence, Italy
{ddagger} Karl Bremer Hospital, Bellville, South Africa
§ Favaloro Foundation, Buenos Aires, Argentina
|| University Clinic for Internal Medicine, Vienna, Austria
Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
# Medical University Lodz, Lodz, Poland
** Georges Pompidou Hospital, Paris, France
{dagger}{dagger} Green Lane Hospital, Auckland, New Zealand
{ddagger}{ddagger} Leonidas Lucero Municipal Hospital, Bahia Blanca, Argentina
§§ Aventis Pharmaceuticals, Paris, France

Manuscript received March 12, 2003; revised manuscript received April 28, 2003, accepted May 9, 2003.

* Reprint requests and correspondence: Dr. Marc Cohen, Cardiac Catheterization Laboratory, Newark Beth Israel Medical Center, Newark, New Jersey 07112, USA.
marcohen{at}sbhcs.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 APPENDIX
 References
 
OBJECTIVES: The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban Versus Placebo in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion.

BACKGROUND: An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion.

METHODS: A total of 1,224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups.

RESULTS: The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval {CI} = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]).

CONCLUSIONS: This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non-reperfused STEMI patients. However, enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial.

Abbreviations and Acronyms
  aPTT = activated partial thromboplastin time
  CABG = coronary artery bypass grafting
  CI = confidence interval
  LMWH = low-molecular-weight heparin
  MI = myocardial infarction
  PCI = percutaneous coronary interventions
  PTCA = percutaneous transluminal coronary angioplasty
  STEMI = ST-segment elevation myocardial infarction
  TETAMI = Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous UFH With and Without Tirofiban in the Treatment of Acute Myocardial Infarction in patients ineligible for reperfusion
  UFH = unfractionated heparin

Approximately 750,000 people in the U.S. suffer an acute myocardial infarction (MI) each year (1). For patients presenting within 12 h of symptom onset, the standard of care is prompt coronary reperfusion with either thrombolysis or percutaneous coronary intervention (PCI) (2,3). However, the majority still does not receive reperfusiontherapy (4), owing to presentation later than 12 h after symptom onset or to other clinical or circumstantial factors (5,6). While extending the time window for reperfusion sounds promising (7–10), to date, prospective randomized trials have been unable to substantiate a benefit for such a course of action. There remains, therefore, no consensus on how to treat non-reperfused ST-segment elevation MI (STEMI) patients who normally constitute a high-risk group, with minimum 13% mortality at 30 days (11).

Antithrombotic therapy may be an alternative to late reperfusion therapy, by enhancing endogenous thrombolysis with minimal risk to the patient. The low-molecular-weight heparin (LMWH) enoxaparin has shown greater efficacy than unfractionated heparin (UFH) in non–ST-segment elevation acute coronary syndromes, albeit with an increased risk of minor bleeding (12,13). As an adjunct to thrombolysis in STEMI, greater or equivalent efficacy has been observed with enoxaparin (14–16). Furthermore, compared with standard therapy, adjunctive antiplatelet therapy with glycoprotein IIb/IIIa antagonists in addition to UFH and aspirin reduces the incidence of ischemic events in patients with acute coronary syndromes (17–19). It is possible that the combined use of LMWH and glycoprotein IIb/IIIa antagonists may provide synergistic benefits, and combination therapy with enoxaparin and tirofiban has already been shown to be safe in patients with acute coronary syndromes (20,21).

We therefore established the Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction in patients ineligible for reperfusion (TETAMI) study, a randomized multicenter clinical trial to investigate the risks and benefits of enoxaparin versus UFH, and the addition of tirofiban versus placebo. Our hypothesis was that enoxaparin was superior to UFH in non-reperfused STEMI patients, and that the addition of tirofiban to the anticoagulant regimens was better than that of placebo.


   Methods
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 Abstract
 Methods
Results
 Discussion
 APPENDIX
 References
 
Details of the study design (summarized in the following text) have been published previously (22).

Patients.   Male and non-pregnant female patients at least 18 years of age were enrolled in 91 study centers (listed at the end of this report) in 14 countries between July 1999 and July 2002. Patients were considered for inclusion if they presented with STEMI and were deemed unsuitable for treatment with thrombolytics or primary PCI. All patients gave informed consent. The protocol received ethics committee approval in all countries.

Patients with contraindications to any study drug were excluded, as were those with cardiogenic shock, renal insufficiency, thrombocytopenia, or a current treatment antithrombotic regimen that included more than 24 h of anticoagulation, or any glycoprotein IIb/IIIa antagonist.

Study design.   The trial was a randomized, double-blind, double-dummy, placebo-controlled, parallel group study. Eligible patients were randomized to one of four treatment regimens, according to a two-by-two factorial design (Fig. 1): 1) enoxaparin, 30-mg intravenous bolus, followed by 1mg/kg subcutaneously every 12 h; 2) enoxaparin, 30-mg intravenous bolus, followed by 1mg/kg subcutaneously every 12 h, plus tirofiban, 10 µg/kg intravenous bolus, followed by continuous infusion (0.1 µg/kg per min); 3) UFH, 70 U/kg intravenous bolus followed by continuous infusion (15 U/kg per h initially) adjusted according to activated partial thromboplastin time (aPTT); or 4) UFH, 70 U/kg intravenous bolus followed by continuous infusion (15 U/kg per h) adjusted to aPTT plus tirofiban, 10 µg/kg intravenous bolus, followed by continuous infusion (0.1 µg/kg per min). Treatment with UFH/enoxaparin was given for at least 2 and up to 8 days; tirofiban/placebo was given for between 2 days and 96 h (108 h if percutaneous transluminal coronary angioplasty [PTCA] or stent placement was performed between 84 and 96 h after acute MI). All patients also received oral aspirin, 100 to 325 mg/day, for at least 30 days.



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  		Figure 1 Disposition of patients. UFH = unfractionated heparin.

 
Dose selection.   Dosing regimens for UFH and enoxaparin were based on experience gained from the Thrombolysis In Myocardial Infarction (TIMI) 11B (12) trial, and on a post-hoc meta-analysis of the subgroup of Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) (13) and TIMI 11B patients who were subsequently found to have Q-wave MI (n = 252). This analysis revealed a 28% reduction in the composite incidence of death, MI, and recurrent angina at 30 days (23). Dosing regimens for tirofiban were based on experience gained from the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) (24), and the Platelet Receptor inhibition in Ischemic Syndrome Management in Patients Limited by Unstable signs and Symptoms (PRISM-PLUS) trials (17).

End points.   All efficacy end points were adjudicated by an independent clinical events committee blinded to the treatment allocation. The primary efficacy parameter was the incidence of the composite of all death, reinfarction, or recurrent angina at 30 days. All end points were compared for the pooled UFH and enoxaparin groups, as well as for the pooled tirofiban and placebo groups. Secondary end points were: 1) incidence of the composite triple end point at 48 h and 8 days; 2) incidence of the composite double end point of death and reinfarction at 48 h, 8 and 30 days; 3) rates of cardiac catheterization, PTCA, or coronary artery bypass grafting (CABG) at 30 days; and 4) all outcomes at 6-month follow-up.

Reinfarction was diagnosed on the basis of symptoms, electrocardiogram, and cardiac enzymes. Reinfarction after PCI was defined as creatine kinase of >3 x the upper limit of normal and >50% greater than the previous value or new Q-waves in two or more contiguous leads. Recurrent angina was defined as a single episode of angina at rest lasting at least 20 min or at least two episodes lasting 10 min or more within 24 h associated with new ST-segment changes, invasive cardiac procedures, or rehospitalization for unstable angina.

Safety parameters included the incidence of major hemorrhage, which was categorized according to the TIMI criteria. Thrombolysis in Myocardial Infarction major bleeding was defined as: 1) hemoglobin drop >5 g/dl (with or without an identified site, not associated with CABG); 2) intracranial hemorrhage; 3) cardiac tamponade. Thrombolysis in Myocardial Infarction minor hemorrhage was defined as: hemoglobin drop >3 g/dl but ≤5 g/dl, with an identified bleeding site. Thrombolysis in Myocardial Infarction "loss no site" was hemoglobin drop >3 g/dl but ≤5 g/dl without an identified bleeding site. As well as hemorrhage and stroke, non-hemorrhagic adverse events and thrombocytopenia were also recorded. Efficacy and safety end points were assessed daily between randomization and day 8 or until hospital discharge, and at follow-up visits or by telephone contact at 30 days and 6 months.

Sample size and statistical analysis.   The sample size was calculated assuming a 25.5% overall event rate in UFH-treated patients, and a 30% relative reduction in event rate with enoxaparin versus UFH. Assuming a type I error rate of 5%, a sample size of 450 patients in each treatment arm would provide 80% power to demonstrate superiority of enoxaparin over UFH. The planned, unblinded, sample size reassessment, which was performed after recruitment of 439 patients, revealed a lower UFH event rate than expected. As a result, the sample size was increased to a total of 1,224 to maintain sufficient power to achieve the primary aim.

Primary efficacy analyses were performed on the intention-to-treat population, which included all patients randomized to treatment, irrespective of whether they received study medication. In this population, patients were analyzed in the treatment group they were randomized into. The incidence of the composite triple end point at 30 days was compared between treatment groups (enoxaparin versus UFH; tirofiban vs. placebo) using a chi-square test after checking that there was no interaction between enoxaparin/UFH and tirofiban/placebo. Kaplan-Meier plots were made of the "time-to-first-event," and the log-rank test was used to compare treatment groups. Other analyses of robustness of the primary efficacy parameter and all safety analyses were performed on the all-treated population, which included all patients who received at least one dose of study medication (patients analyzed in the treatment group they actually received); chi-square test or only descriptive statistics were used. Odds ratios and 95% confidence intervals (CI) were also calculated for the main comparisons of enoxaparin versus UFH and tirofiban versus placebo. All tests were performed at a 5% alpha level. Statistical analyses were performed using the Statistical Analysis System (SAS) software package.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 APPENDIX
 References
 
A total of 1,224 patients were enrolled into this study. Of these, 1,216 received treatment (Fig. 1).

Baseline characteristics were similar across the four individual groups (Table 1). The mean age was 63 years, the majority of patients were males (72.4%), and most patients were Caucasian (89.7%). None of the baseline characteristics recorded was found to be significantly different between treatment groups.


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  		Table 1 Summary of Baseline Characteristics (Intention-to-Treat Population, N = 1,224)

 
All 1,224 patients underwent an electrocardiogram, and results indicated ST-segment elevation in 86.8% of patients. Q-wave MI was identified in 68.1% of patients, and conduction abnormalities were present in 12.7% of patients (Table 1). The reasons identified for not reperfusing these patients with thrombolytic therapy were late arrival (79.4%), no ST-segment elevation on admission (8.7%), major contraindication (1.4%), minor contraindication (2.6%), and "other" (12.3%). Percutaneous coronary intervention was not employed as a result of late arrival (65.8%), unavailability of a cath lab (33.8%), PCI not done routinely (27.2%), and "other" (7.1%). In patients arriving within the 12-h window, the predominant reason for not giving a thrombolytic or performing PCI was still late arrival (59.8% and 42.8%, respectively).

A summary of exposure to the study drugs is shown in Table 2. It should be noted that 28.0% of all patients had been given UFH just before the study, and, in total, 32.5% were not administered the bolus dose of the study drugs. The majority of patients received their first dose of study medication more than 12 h after onset of symptoms (80.4%), with 18.6% of patients receiving their first dose between 4 to 12 h from symptom onset, and 1.0% of patients receiving their first treatment dose ≤4 h after onset of symptoms. The mean time to first dose from onset of symptoms was 16.9 h for the enoxaparin groups and 17.5 h for the UFH groups. Median duration of all treatments was similar (range, 2.3 to 2.5 days).


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  		Table 2 Summary of Exposure to Study Drugs (All Treated Population, N = 1,216)

 
A total of 126 patients (10.3%) prematurely discontinued treatment, with the primary reasons being adverse events in 52 patients, death in 15 patients, and study end point in 21 patients. On completion of the study at 30 days, a total of 1,134 patients (92.6%) remained alive, 85 patients died (6.9%), and five patients (0.4%) were lost to follow-up.

Efficacy.   The incidence of the primary efficacy end point (death, reinfarction, or recurrent angina at 30 days) was not significantly different between the pooled enoxaparin and UFH groups (15.7% and 17.3%, Table 3), and similar results were also observed for pooled placebo group versus tirofiban group (Table 4). No statistically significant treatment interactions were seen across the four individual treatment groups (p = 0.846, Table 5). No notable differences were seen in any of the other parameters recorded (Tables 3 and 5), except for the rate of PCI on treatment, which is highest in tirofiban-treated patients (Table 5). Survival rates were similar across all four treatment groups and between the pooled groups.


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  		Table 3 Summary of Efficacy Results: Adjudicated Clinical End Points at 30 Days for Pooled Enoxaparin and UFH Groups (Intention-to-Treat Population, N = 1,224)

 

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  		Table 4 Summary of Efficacy Results: Adjudicated Clinical End Points at 30 Days for Pooled Tirofiban and Placebo Groups (Intention-to-Treat Population, N = 1,224)

 

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  		Table 5 Summary of Efficacy Results: Adjudicated Clinical End Points at 30 Days (Intention-to-Treat Population, N = 1,224)

 
The total percentage of patients requiring at least one revascularization at 30 days was 28.1%; 21.6% required at least one PCI, and 6.6% required at least one CABG (Tables 3 and 4), with only 2.2% of patients undergoing PCI while on treatment with enoxaparin or UFH. There were no differences between the groups with respect to these procedures, and only three patients had an MI after a PCI procedure (one on enoxaparin, two with UFH).

Time to first event for the composite triple end point in the pooled enoxaparin and UFH groups is shown in Figure 2. Although the Kaplan-Meier curves separate by day 5, the differences between the groups did not reach statistical significance.



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  		Figure 2 Time to first event (death or adjudicated MI or adjudicated recurrent angina) at 30 days (enoxaparin vs. unfractionated heparin [UFH]) (intention-to-treat population, N = 1,224). Censor: marks point at which patients were withdrawn from study without further 30-day follow-up data.

 
Safety.   By 30 days, 17 patients suffered a TIMI major hemorrhage 1.5% (9 patients) for enoxaparin versus 1.3% (8 patients) for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% (11 patients) versus 1.0% (6 patients) for tirofiban versus for placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]). A total of 4.2% (51) patients suffered a TIMI minor hemorrhage (enoxaparin groups: 4.0% [24 patients], UFH groups: 4.4% [27 patients]). Results for the four individual groups are given in Table 6. A total of 194 patients (16.0%) suffered any hemorrhage (enoxaparin groups: 17.8% [107 patients], UFH groups: 14.1% [87 patients]). The incidence of any hemorrhage was significantly higher in the pooled tirofiban versus placebo groups (18.9% [116 patients] in tirofiban group versus 12.9% [78 patients] in placebo group, p value = 0.005), with the highest incidence seen in the enoxaparin/tirofiban group (20.1%), Table 6. Eight patients suffered a stroke by the 30-day assessment (four in the enoxaparin groups and four in the UFH groups). The safety profiles were similar across the treatment groups with no notable differences detected. The most common "non-bleeding" adverse event was heart failure (7.0%), followed by chest pain (5.4%) and hypotension (4.8%). A total of 14.7% of patients had a serious adverse event, with rates again being similar between groups (15.7% in pooled enoxaparin groups and 13.8% in pooled UFH groups).


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  		Table 6 Hemorrhage Rates at 30 Days (All Treated Population, N = 1,216)

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
APPENDIX
 References
 
The TETAMI study is the first large, randomized, non-lytic, antithrombotic trial to focus on the significant fraction of patients with STEMI who do not receive reperfusion therapies. The benefits of early coronary artery reperfusion using fibrinolytics or PCI for patients with STEMI have been well established, but typically the majority of large clinical trials investigating STEMI treatments only include patients who present within 12 h of symptom onset. However, around 30% of eligible patients do not receive appropriate reperfusion therapy, and there are no current standard treatment guidelines for this patient group (2,3). The reasons for not receiving reperfusion include presentation later than 12 h from symptom onset; geographic variations in practice patterns (25); and patient race (6), gender (26,27), and age (5). Elderly patients (>65 years) constitute half of hospital admissions for STEMI and as many as 80% of STEMI deaths (28). An analysis of 163,140 elderly Medicare patients revealed that, although mortality after STEMI increased rapidly with age, use of evidence-based therapies (beta-blockers, aspirin, reperfusion) decreased with increasing age (28). Ironically, other high-risk subgroups, such as patients presenting with STEMI and congestive heart failure (29) or previous CABG, are also particularly unlikely to receive reperfusion therapy.

Although the benefits of early reperfusion have been established, the role of late reperfusion remains controversial; significantly reduced rates of clinical events and beneficial effects on left ventricular function have been shown after late PCI (9). Zahn et al. (30) found that, while a pre-hospital delay of more than 12 h prevented any beneficial effect of thrombolysis, primary angioplasty did show beneficial effects in such cases. Multiple logistic regression showed only trends for both end points. A retrospective analysis demonstrated that an initial invasive approach may be more beneficial than medical therapy alone in patients presenting with chest pain after 12 h and STEMI (31). However, physician bias appears to divert the sicker patients preferentially to medical therapy rather than to initial invasive therapy. In contrast, lower risk patients were more commonly given invasive therapy rather than medical therapy. Another retrospective analysis by Srinivas et al. (32) demonstrated no difference between outcomes with early (within 6 h) and delayed (6 to 23 h) angioplasty. The most recent prospective, randomized trial, the Open Artery Trial (TOAT), demonstrated that late PCI after transmural anterior MI is feasible and leads to improved quality of life and exercise tolerance, but is associated with significantly greater left ventricular dilation than a non-invasive strategy (10).

The TETAMI study was designed to compare the efficacy and safety of non-lytic antithrombotic therapy using enoxaparin versus UFH, in combination with tirofiban or placebo, in an attempt to enhance late reperfusion of the infarct-related artery and/or prevent thrombotic re-occlusion of the infarct-related artery in patients with STEMI presenting too late for traditional reperfusion. However, the results of this study did not show that enoxaparin given for 2 to 8 days to STEMI patients significantly reduced the 30-day composite end point of death, reinfarction, and recurrent angina when compared with UFH. Enoxaparin was observed to have a similar safety and efficacy profile to UFH and may be an alternative to UFH in non-reperfused STEMI patients. The addition of tirofiban in combination with enoxaparin or UFH did not show a benefit in this patient population.

A closer look at the treatment effects suggests that none of the antithrombotic regimens tested appear to have a differential effect on mortality. This would be in keeping with the previously described lackluster effects of late PCI (10,30,31). However, the TETAMI data suggest a wider, although not significant, benefit of enoxaparin on the individual outcomes of MI and recurrent angina. Unlike death, which is overwhelmingly determined by left ventricular function at admission, both MI and recurrent angina are predominantly due to recurrent thrombotic events. Reinfarction, in which there is a small trend for reduction with enoxaparin in this study, is sometimes described as a "soft" end point, with "harder" end points such as death being considered more reliable indicators of clinical efficacy. However, studies investigating the incidence of reinfarction after fibrinolysis indicate that patients with reinfarction have significantly higher rates of long-term mortality and heart failure than patients without recurrent ischemic events (33,34). Hudson et al. (34) found that the unadjusted mortality rate was 3 x higher at 30 days and 1.5 higher from 30 days to 1 year in patients with early reinfarction versus those without reinfarction, with most patients dying soon after the event, and 40% of all deaths occurring within 24 h. With reinfarction being a predictor of long-term mortality, early revascularization and prevention of reinfarction should, therefore, be a key goal of STEMI management.

Study limitations.   Several aspects of this study may have confounded the results. First, in retrospect, it appears that the study was underpowered to detect a significant difference given the event rates observed, and a 30% relative reduction in events was perhaps too optimistic. It took 3 years to recruit 1,224 patients into this study, and overall mortality from MI appears to be steadily decreasing over time (35). Even so, the overall mortality rate observed of 7% is much lower than expected, and the low event rate contributes to the reduced power of the study. Second, 28% of all randomized patients had already received an antithrombotic therapy, namely intravenous UFH, before randomization (therefore, polluting the treatment group for enoxaparin patients having received UFH bolus rather than enoxaparin bolus). Third, the study was not designed to assess the effect of treatment in patients presenting earlier in their post-infarction course. Both enoxaparin and tirofiban have been shown to provide benefit in acute coronary syndromes when administered early. It is possible that a benefit of treatment might have been achieved in patients presenting within 12 h but in whom reperfusion was contraindicated for other reasons. In addition, a relatively small number of patients went on to undergo PCI in this study, and it has been observed that glycoprotein IIb/IIIa inhibitors have a greater effect in patients undergoing PCI. Furthermore, the bolus dose of tirofiban utilized in this study could have been too low to give a meaningful level of platelet inhibition (36). Future trials with more statistical power and including much larger numbers of patients may provide the possibility of detecting treatment benefits in this important group of patients, which urgently need optimal treatment regimens to be defined.

Conclusions.   The TETAMI study did not achieve its primary aim, and the newer antithrombotic regimens were not significantly different from the traditional regimen of UFH with regard to the composite triple end point of death, reinfarction, and recurrent angina, and especially death, following STEMI (Appendix).


   APPENDIX
Top
 Abstract
 Methods
 Results
 Discussion
 APPENDIX
References
 
Steering Committee: M. Cohen, U.S. (Study Chairman); G. Gensini, Italy; E. Gurfinkel, Argentina; F. Maritz, South Africa; K. Huber, Austria; M. Krzeminska-Pakula, Poland; A. Timerman, Brazil; N. Danchin, France; H. White, New Zealand; K. A. Fox, UK.

Data Safety Monitoring Board: A. Leizorovicz (Chair); J. Chesebro; M. Flather; M. Kern.

Clinical Events Committee: J. Ambrose; N. Kleiman; J. Zidar.


   Acknowledgments
 
The authors thank Susan Slatylak and Peter M. DiBattiste for their support in developing and conducting this trial in its early phase. The authors would also like to thank Dr. Jacqueline Mason for her assistance in the preparation of this manuscript.


   Footnotes
 
Supported by an educational grant from Aventis Pharma. Aventis Pharma supported the design, conduct and reporting of this study, in consultation with the Steering Committee.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 APPENDIX
 References
 

  1. The American Heart Association. Heart and Stroke Facts: Statistical Supplement. Dallas, TX: The American Heart Association; 2003.
  2. Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2003;24:28–66
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  10. Yousef ZR, Redwood SR, Bucknall CA, Sulke AN, Marber MS. Late intervention after anterior myocardial infarction: effects on left ventricular size, function, quality of life, and exercise tolerance: results of The Open Artery Trial (TOAT study). J Am Coll Cardiol. 2002;40:869–876[Abstract/Free Full Text]
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