The Impact of Renal Dysfunction on Outcomes in the ExTRACT-TIMI 25 Trial

Transcription

1 Journal of the American College of Cardiology Vol. 49, No. 23, by the American College of Cardiology Foundation ISSN /07/$32.00 Published by Elsevier Inc. doi: /j.jacc The Impact of Renal Dysfunction on Outcomes in the ExTRACT-TIMI 25 Trial Keith A. A. Fox, FRCP,* Elliott M. Antman, MD, FACC, Gilles Montalescot, MD, Stefan Agewall, MD, Bhupathi SomaRaju, MD, Freek W. A. Verheugt, MD, FACC, Jose Lopez-Sendon, MD, FACC,# Hanoch Hod, MD, FACC,** Sabina A. Murphy, MPH, Eugene Braunwald, MD, MACC Edinburgh, United Kingdom; Boston, Massachusetts; Paris, France; Stockholm, Sweden; Hyderabad, India; Nijmegen, the Netherlands; Madrid, Spain; and Tel Hashomer, Israel Objectives Background Methods Results Conclusions The ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis In Myocardial Infarction 25) trial provided the opportunity to evaluate the impact of renal dysfunction on outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and compare enoxaparin () and unfractionated heparin (). It is unclear how renal dysfunction influences the balance between benefit and risk of antithrombotic therapy. In the ExTRACT-TIMI 25 trial, 20,479 patients were randomized to or. A reduced dose was administered to patients age 75 years and those with an estimated creatinine clearance (CrCl) 30 ml/min. A powerful relationship was observed between the severity of renal dysfunction (per 10 ml/min decrement in CrCl) and death, stroke, intracranial hemorrhage, and major and minor bleeding (p for each). There was a progressive increase in the treatment benefit with on death or nonfatal myocardial infarction (p 0.01) with better renal function. Net clinical benefit (death, nonfatal MI, or nonfatal major bleeding) was significantly superior with (p 0.001) for patients with a CrCl 60 ml/min (79.1% of the study population). Major bleeding and intracranial hemorrhage did not differ for patients with preserved renal function (CrCl 90 ml/ min), but in those with renal dysfunction there was a progressively greater increase in the risk of major and minor bleeding with. Enoxaparin was superior to for the majority of subjects. With more severe renal dysfunction, the net clinical benefit between and did not differ, despite the rise in adverse events in both treatment groups. Future studies should take renal dysfunction into account when assessing antithrombotic regimens. (J Am Coll Cardiol 2007;49: ) 2007 by the American College of Cardiology Foundation Patients with acute coronary syndromes and renal dysfunction have been observed to have increased risks of adverse events in epidemiological studies (1 5), observational studies, and clinical trials (6 13). These events include death, stroke, and bleeding. However, it is unclear whether renal From the *University of Edinburgh, Edinburgh, United Kingdom; TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts; Institut de Cardiologie, Pitie-Salpetriere University Hospital, Paris, France; Coronary Care Unit, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; CARE Hospital, Hyderabad, India; University Hospital Nijmegen, Nijmegen, the Netherlands; #Hospital Universitario La Paz Madrid, Madrid, Spain; and the **Heart Institute, Sheba Medical Center, Tel Hashomer, Israel. This work was supported by a grant from Sanofi-Aventis. All authors received research grants from Sanofi-Aventis to conduct the ExTRACT-TIMI 25 trial. Drs. Fox, Antman, Montalescot, and Braunwald received honoraria for speaking activities from Sanofi-Aventis. Manuscript received September 7, 2006; revised manuscript received December 5, 2006, accepted December 10, dysfunction influences the balance between benefit and risk in the context of antithrombotic therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing fibrinolysis. The issue is important, because worldwide the majority of patients with STEMI undergoing reperfusion continue to receive fibrinolytic therapy. The ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis In Myocardial Infarction 25) trial compared a strategy of enoxaparin () with a strategy of unfractionated heparin () as an adjunct to fibrinolytic therapy for STEMI (14). The strategy was significantly superior to the strategy in reducing death or nonfatal reinfarction through 30 days. Major bleeding was increased with, but net clinical benefit favored (14). The ExTRACT-TIMI 25 trial provides the opportunity to

2 2250 Fox et al. JACC Vol. 49, No. 23, 2007 Renal Dysfunction and the ExTRACT-TIMI 25 Trial June 12, 2007: Abbreviations and Acronyms CI confidence interval CrCl creatinine clearance enoxaparin LMWH low-molecularweight heparin MI myocardial infarction OR adj adjusted odds ratio STEMI ST-segment elevation myocardial infarction unfractionated heparin evaluate the risk of varying degrees of renal dysfunction on outcomes in STEMI patients and to test whether the balance of risk versus benefit of compared with was influenced by the extent of renal dysfunction. Methods The design, patient population, and study protocol have been reported in detail (15). In brief, 20,479 patients with STEMI formed the intention-to-treat cohort and were randomized within 6 h of onset of symptoms. They had ST-segment elevation or left bundle-branch block and were scheduled to undergo fibrinolysis. Patients were excluded if they had cardiogenic shock, contraindications to fibrinolysis, or known renal insufficiency with serum creatinine 200 mol/l (2.5 mg/dl) for men and 175 mol/l (2.0 mg/dl) for women (13). In addition to the fibrinolytic regimen all patients received 150 to 325 mg of aspirin and maintenance therapy of 75 to 325 mg of aspirin once daily. The evidence in favor of clopidogrel treatment for STEMI emerged while the ExTRACT-TIMI 25 trial was underway (16,17), and clinicians were allowed to administer clopidogrel at their discretion. The study medication was administered in a double-blind fashion with a double-dummy design. In patients age 75 years, was administered as an initial 30-mg intravenous bolus followed by subcutaneous injections of 1.0 mg/kg every 12 h (15). For patients age 75 years, the intravenous bolus was omitted and the maintenance dose was reduced to 0.75 mg/kg every 12 h. For patients of any age with an estimated creatinine clearance (CrCl) 30 ml/min, the dose was reduced to 1 mg/kg every 24 h. The dosing strategy described in the preceding text was designed so as not to interfere with the goal of prompt administration of pharmacologic reperfusion (lytic and initial dosing of adjunctive therapy), because the adjustment of dosing for CrCl 30 ml/min does not need to occur until 12 h after the initial dose, by which time the serum creatinine has returned from the chemistry laboratory and CrCl can be estimated. The double-blind subcutaneous injections of or matching placebo were continued until hospital discharge or a maximum of 8 days. The was administered as an intravenous bolus of 60 U/kg (maximum 4,000 U); this bolus was omitted in patients who had received open-label within the 3 h prior to randomization. The was administered according to the guideline recommended strategy for at least 48 h but could be continued longer at the treating physician s discretion (18,19). The monitoring of was performed in a blinded fashion. The CrCl was estimated with the Cockcroft-Gault formula (20,21), and the population was divided according to strata of CrCl ( 30 ml/min, 30 to 60 ml/min, 60 to 90 ml/min, and 90 ml/min). The primary end point of the trial was the composite of death from any cause or nonfatal recurrent myocardial infarction (MI) within the first 30 days of randomization (12,13). Bleeding was classified according to the TIMI criteria (15). All ischemic and clinically significant bleeding events were adjudicated in a blinded fashion by an independent clinical-events committee with prespecified definitions (15). Statistical analyses. All efficacy analyses were based on the intention-to-treat principle. Safety analyses were performed according to the treatment actually received. Continuous variables are presented as median and interquartile range, and categorical variables are presented as frequencies. In the comparison of baseline characteristics stratified by CrCl strata (see preceding text), differences in continuous variables were analyzed with the Kruskal-Wallis rank test, and differences in categorical variables were analyzed with the chi-square test. Frequency of efficacy and safety outcomes at 30 days were compared with the categorical CrCl variable and analyzed with the chi-square test as well as the test for trend. Logistic regression models for efficacy and safety outcomes were performed with a 10 ml/min decrease in CrCl, adjusting for components of the TIMI risk score (22) with the exception of age (which is included in the estimation of the CrCl by the Cockroft-Gault formula), and the results are presented as adjusted odds ratio (OR adj ). The elements of the TIMI risk score for STEMI include: systolic blood pressure 100 mm Hg (3 points); heart rate 100 beats/min (2 points); Killip class II to IV (2 points); anterior STsegment elevation or left bundle branch block (1 point); diabetes, history of hypertension, or history of angina (1 point); weight 67 kg (1 point); and time to treatment 4 h (1 point). The treatment effect of the randomization strategies ( vs. ) was evaluated for efficacy and safety outcomes, stratified by CrCl group (see Table 1 for definitions of CrCl groups) with a chi-square test. All statistical analyses were performed with Stata/SE version 9.1 (Stata Corp., College Station, Texas). Results Assessment of baseline characteristics showed that for each of the major risk characteristics there was an inverse relationship between the stratum of CrCl and the severity of the risk characteristics (Table 1). For example, patients in each lower stratum of CrCl were older and more frequently had hypertension, diabetes, previous MI, and a higher TIMI risk score. Thus, the median age was 52 years in patients with CrCl 90 ml/min and 78 years in those with

3 JACC Vol. 49, No. 23, 2007 June 12, 2007: Fox et al. Renal Dysfunction and the ExTRACT-TIMI 25 Trial 2251 Baseline Characteristics of Patients Stratified by CrCl Table 1 Baseline Characteristics of Patients Stratified by CrCl < >60 90 >90 Characteristic (n 212) (n 3,671) (n 7,203) (n 7,462) p Value Age (yrs) Median Interquartile range Male (%) Weight, kg (median) Hypertension (%) Hyperlipidemia (%) Current smoker (%) Diabetes mellitus (%) Prior MI (%) Prior angina pectoris (%) Anterior MI (%) Killip class II (%) TIMI risk score 3 (%)* Fibrin-specific lytic (%) Lytic type (%) Fibrin-specific Streptokinase Cardiac medications during index hospital stay (%) Aspirin Clopidogrel Beta-blockers ACE inhibitors or ARBs Statins *Excluding age, because it is included in estimation of creatinine clearance. Fibrinolytic group (fibrin specific) tenecteplase or alteplase or reteplase. ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker; CrCl creatinine clearance; MI myocardial infarction; TIMI Thrombolysis In Myocardial Infarction. CrCl 30 ml/min. The percentage of low-risk patients (TIMI risk score 3) in these 2 groups was 85.3% and 8.5%, respectively. In addition, concomitant medications were used less frequently in patients with lower CrCl (Table 1). Effect of CrCl on outcomes (full trial population). For all patients, a powerful and direct relationship was noted between the severity of renal dysfunction and death, stroke, major bleeding, intracranial hemorrhage, and minor bleeding (Table 2). A continuous inverse relationship was evident Outcomes at 30 Days by CrCl (Full Trial Population) Table 2 Outcomes at 30 Days by CrCl (Full Trial Population) < >60 90 >90 p Value Outcome (%) (n 212) (n 3,671) (n 7,203) (n 7,462) for Trend Death or nonfatal re-mi Death Nonfatal re-mi Urgent revascularization Stroke Death, nonfatal re-mi, or urgent revascularization Major bleeding (including ICH) ICH Minor bleeding Death, nonfatal re-mi, or nonfatal major bleeding* Values shown in CrCl strata represent percentages. *Net clinical benefit. ICH intracranial hemorrhage; other abbreviations as in Table 1.

4 2252 Fox et al. JACC Vol. 49, No. 23, 2007 Renal Dysfunction and the ExTRACT-TIMI 25 Trial June 12, 2007: Figure 1 Relationship Between Creatinine Clearance and Outcomes Panels A to D plot the outcomes shown as estimated from a univariate regression model treating creatinine clearance (CrCl) as a continuous variable. MI myocardial infarction. between CrCl and mortality (Fig. 1A), the primary end point (death or nonfatal recurrent MI) (Fig. 1B), major bleeding (Fig. 1C), and net clinical benefit (death or nonfatal recurrent MI or nonfatal major bleeding) (Fig. 1D). In a univariate regression model, a 10-ml/min decrease in CrCl conferred an increased risk of death (OR 1.34, p 0.001) and of stroke at 30 days (OR 1.22, p 0.001). Similarly, a 10-ml/min decrease in CrCl increased the risk of both major (OR 1.15, p 0.001) and minor bleeding (OR 1.19, p 0.001). In a multivariable regression model, adjusting for components of the TIMI risk score (excluding age), CrCl remained an independent predictor of death (OR adj 1.27, 95% confidence interval [CI] 1.24 to 1.31, p 0.001). Multivariate analysis confirmed the effect of a 10-ml/min decrement in CrCl in predicting an increased risk of the following additional events at 30 days: death or nonfatal recurrent MI (OR adj 1.14, 95% CI 1.13 to 1.17), stroke (OR adj 1.26, 95% CI 1.19 to 1.35), intracranial hemorrhage (OR adj 1.24, 95% CI 1.15 to 1.35), major bleed (OR adj 1.16, 95% CI 1.10 to 1.22), minor bleed (OR adj 1.16, 95% CI 1.11 to 1.21) (p value for each 0.001). However, changes in CrCl were not predictive of nonfatal recurrent MI alone (OR adj 1.01, 95% CI 0.99 to 1.04). Comparison between and at varying levels of renal function. The rates of death were similar for and, irrespective of CrCl (Table 3). However, for the composite of death or nonfatal recurrent MI at 30 days (the primary end point of the ExTRACT-TIMI 25 trial), there were significant differences in favor of (p interaction 0.005) (Table 3) that persisted after adjustment for baseline risk (Table 4, Fig. 2). Major bleeding was similar in the 2 treatment groups for patients with CrCl 90 ml/min, but with increasing renal dysfunction a progressive excess in bleeding was seen with (Tables 3 and 4). The rates of intracranial hemorrhage in the 2 treatment groups were low and did not differ across the range of renal dysfunction. The primary end point, composite of death or nonfatal recurrent MI, and the net clinical benefit end point, a composite of the primary end point plus nonfatal major

5 JACC Vol. 49, No. 23, 2007 June 12, 2007: Outcomes at 30 Days by Treatment Assignment Table 3 Outcomes at 30 Days by Treatment Assignment Fox et al. Renal Dysfunction and the ExTRACT-TIMI 25 Trial 2253 (n 106) < >60 90 >90 (n 106) (n 1,813) (n 1,858) (n 3,583) (n 3,620) (n 3,739) (n 3,723) Death or nonfatal re-mi* Death Nonfatal re-mi Stroke Major bleed (including ICH) ICH Minor bleed Death/nonfatal re-mi, nonfatal major bleed* Values shown in CrCl strata represent percentages. *p 0.05 for interaction between randomization group and renal function group. p 0.01 for comparison of versus. p for comparison of versus. p 0.05 for comparison of versus. Net clinical benefit. Abbreviations as in Tables 1 and 2. bleeding, favored and achieved statistical significance in patients with preserved or only minor impairment of renal function (CrCl 60 ml/min) (Table 3). This constituted the majority (79.1%) of the study population. Discussion In this large, multinational, and well characterized clinical trial population, estimated CrCl varied substantially and impairment of renal function was a powerful determinant of adverse outcome. These observations are consistent with data from both epidemiological (1 5) and observational studies (6 10) as well as clinical trials in various population groups (11 13,23,24). Our findings illustrate the value of a large heterogeneous clinical trial population (as in the ExTRACT-TIMI 25 trial) to reflect clinical practice. Renal dysfunction does not exist in isolation. The severity of renal dysfunction was strongly associated with a series of risk characteristics, evident at the time of presentation with STEMI. These include older age, male gender, hypertension, diabetes mellitus, previous MI, previous angina pectoris, heart failure, and a higher TIMI risk score (22). Nevertheless, previous studies have demonstrated the independence of renal dysfunction as a predictor of in-hospital and subsequent death (6,25). These findings are consistent with those seen from a broader range of patients with acute coronary syndromes. In the ExTRACT-TIMI 25 trial, CrCl remained an independent predictor of death, stroke, intracranial hemorrhage, and both major and minor bleeding, after adjustment for the components of the TIMI risk score (p for each comparison). Interestingly, no significant association was demonstrated with nonfatal recurrent MI. Major bleeding and intracranial hemorrhage were systematically and prospectively captured, and the rates of these bleeding complications of fibrinolytic therapy were lower than those reported in recent similarly designed trials (26). Nevertheless, the longer-term adverse outcomes associated with bleeding have been increasingly recognized, and full assessment of adjunctive antithrombotic therapy requires evaluation of benefits against bleeding risks. With each successive 30-ml/min stratum of declining CrCl, the risk of major or minor bleeding increased by approximately 50% (ranging from 2.3% in patients with a CrCl 90 ml/min to 9.4% in those with a CrCl 30 ml/min). Even modest degrees of renal dysfunction (CrCl 60 ml/min) were associated with increased risks of major, minor, and Outcomes at 30 Days by Randomized Treatment (Odds Ratio [95% CI] vs. ), Adjusted for Baseline Risk Table 4 Outcomes at 30 Days by Randomized Treatment (Odds Ratio [95% CI] vs. ), Adjusted for Baseline Risk < >60 90 >90 Death or nonfatal re-mi 0.74 ( ) 0.94 ( ) 0.78 ( ) 0.69 ( ) Death 0.75 ( ) 0.97 ( ) 0.87 ( ) 0.92 ( ) Nonfatal re-mi 0.93 ( ) 0.88 ( ) 0.68 ( ) 0.58 ( ) Stroke 0.94 ( ) 0.68 ( ) 1.43 ( ) 0.77 ( ) Major bleed (including ICH) 3.60 ( ) 1.73 ( ) 1.91 ( ) 1.49 ( ) ICH 0.73 ( ) 1.66 ( ) 3.33 ( ) Minor bleed 1.68 ( ) 1.46 ( ) 1.51 ( ) 1.37 ( ) Death/nonfatal re-mi nonfatal major bleed* 0.83 ( ) 0.98 ( ) 0.83 ( ) 0.71 ( ) Adjusted for components of TIMI risk score, with the exception of age (age included in the Cockcroft-Gault calculation of CrCl). *Net clinical benefit. CI confidence interval; other abbreviations as in Tables 1 and 2.

6 2254 Fox et al. JACC Vol. 49, No. 23, 2007 Renal Dysfunction and the ExTRACT-TIMI 25 Trial June 12, 2007: Reprint requests and correspondence: Dr. Elliott M. Antman, TIMI Study Group, 350 Longwood Avenue, First Floor, Boston, Massachusetts REFERENCES Figure 2 intracranial bleeding, irrespective of assigned antithrombotic strategy. Although, by trial design, the dose of was halved in those with CrCl 30 ml/min (1.0 mg/kg every 24 h), excess bleeding was still observed with in this group. This observation, albeit limited by the small number of subjects, suggests that until alternative dosing regimens are developed, should not be administered to patients with a known CrCl 30 ml/min. For patients with well preserved renal function (CrCl 90 ml/min) major bleeding did not differ significantly between and, although a numerically higher bleeding rate was seen with. However, with renal dysfunction, bleeding with was significantly higher than with. This raises the possibility that dose adjustment of might be required in patients with even moderate renal dysfunction (e.g., CrCl 30 to 90 ml/min) (23,27) to achieve the benefits of administration of throughout the index hospital stay while minimizing the risk of bleeding. This is beyond the steps taken in this trial to reduce the dose of in those with estimated CrCl 30 ml/min as well as in patients 75 years of age. Conclusions Death or Nonfatal Recurrent MI at 30 Days in Strata of CrCl According to Treatment Assignment CrCl creatinine clearance; enoxaparin; MI myocardial infarction; OR adj odds ratio adjusted for baseline risk; unfractionated heparin. Renal dysfunction is an important independent predictor of adverse outcome death, stroke, and bleeding in STEMI patients receiving fibrinolytic therapy. The net clinical benefit (the composite of death, nonfatal MI, or nonfatal major bleeding) was significantly superior for for a large majority of the study population (the 79% of the trial population with CrCl 60 ml/min). With more severe degrees of renal dysfunction, net clinical benefit did not differ between patients treated with and. 1. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels: the Framingham heart study. Arch Intern Med 1999;159: Landray MJ, Thambyrajah J, McGlynn FJ, et al. Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment. Am J Kidney Dis 2001;38: Culleton BF, Larson MG, Wilson PW, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999;56: Cerne D, Kaplan-Pavlovcic S, Kranjec I, et al. Mildly elevated serum creatinine concentration correlates with the extent of coronary atherosclerosis. Ren Fail 2000;22: Fried LF, Shlipak MG, Crump C, et al. Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 2003;41: Santopinto JJ, Fox KA, Goldberg RJ, et al. Creatinine clearance and adverse hospital outcomes in patients with acute coronary syndromes: findings from the global registry of acute coronary events (GRACE). Heart 2003;89: Shlipak MG, Heidenreich PA, Noguchi H, et al. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 2002;137: Pahor M, Shorr RI, Somes GW, et al. Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the systolic hypertension in the elderly program. Arch Intern Med 1998;158: Wright RS, Reeder GS, Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 2002;137: Collet JP, Montalescot G, Agnelli G, et al. Non ST-segment elevation acute coronary syndrome in patients with renal dysfunction: benefit of low-molecular-weight heparin alone or with glycoprotein IIb/IIIa inhibitors on outcomes. The Global Registry of Acute Coronary Events. Eur Heart J 2005;26: Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351: Gibson CM, Dumain RL, Gelfand EV, et al. Association of glomerular filtration rate on presentation with subsequent mortality in non ST-segment elevation acute coronary syndrome: observations in 13,307 patients in five TIMI trials. Eur Heart J 2004;25: Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol 2003;42: 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: Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for ST-elevation myocardial infarction. Design and rationale for the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25). Am Heart J 2005;149: Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005:352; Chen ZM, Jiang LX, Chen YP, et al., COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005:366; Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise

7 JACC Vol. 49, No. 23, 2007 June 12, 2007: Fox et al. Renal Dysfunction and the ExTRACT-TIMI 25 Trial 2255 the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:e Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999;130: Morrrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, beside, clinical score for risk assessment at presentation. An Intravenous NPA for Treatment of Infarcting Myocardium Early II trial substudy. Circulation 2000;102: Collet JP, Montalescot G, Choussat R, et al. Enoxaparin in unstable angina patients with renal failure. Int J Cardiol 2001;80: Eikelboom JW, Quinlan DJ, Mehta SR, et al. Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirintreated patients with ST-elevation acute myocardial infarction: a metaanalysis of the randomized trials. Circulation 2005;112: Eagle KA, Lim MJ, Dabbous OH, et al.; GRACE Investigators. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month post-discharge death in an international registry. JAMA 2004;291: The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358: