European Heart Journal Advance Access originally published online on April 24, 2007
European Heart Journal 2007 28(9):1066-1071; doi:10.1093/eurheartj/ehm081
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25
1 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland 1030, New Zealand
2 TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
3 St. John's Hospital, Livingston, West Lothian, UK
4 Cardiology Department, National Heart Center, Sofia, Bulgaria
5 Republic Research-Practical Center ‘Cardiology’, Minsk, Belarus
Received 18 December 2006; revised 22 February 2007; accepted 8 March 2007; online publish-ahead-of-print 24 April 2007.
* Corresponding author. Tel: +64 9 630 9992; fax: +64 9 630 9915. E-mail address: harveyw{at}adhb.govt.nz
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
Aims: To determine the effects of age on outcomes in patients with STEMI treated with a strategy of enoxaparin (ENOX) vs. unfractionated heparin (UFH).
Methods and results: In the ExTRACT-TIMI 25 trial, 20 479 patients with STEMI were randomized in a double-blind fashion to UFH or ENOX. A novel reduced dose of ENOX was administered to patients 
75 years, and a reduced dose in those with an estimated creatinine clearance of < 30 mL/min. Anti-Xa levels were measured in a subset of patients (n = 73). The exposure to anti-Xa over time was lower in the elderly (AUC0–12 h P < 0.0001; AUCsteady-state P = 0.0046). The relative risk reduction (RR) with ENOX on the primary endpoint, i.e. death or non-fatal recurrent myocardial infarction, was greater in patients < 75 years (20%) than > 75 years (6%), but the absolute benefits were similar. When compared with UFH, ENOX was associated with an RR of 1.67 for major bleeding, but the magnitude of the excess risk tended to be lower (RR = 1.15) in patients 75 years assigned to ENOX.
Conclusion: A dose reduction of ENOX in the elderly appears to be helpful in ameliorating bleeding risk. A strategy of ENOX was superior to UFH in both young and elderly patients with STEMI treated with fibrinolysis.
Key Words: ExTRACT-TIMI 25 • Enoxaparin • Unfractionated heparin • Age
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
ST-segment elevation myocardial infarction (STEMI) occurs most frequently in patients ranging from the fourth to the ninth decades, peaking in the seventh and eight decades. Elderly patients are the fastest growing segment of the population, and they make up an increasing proportion of patients who suffer from STEMI.1 It is well established that age is an important determinant of the outcome of STEMI.2 Indeed, patients > 75 years account for over one-half of the mortality from this condition and they are more likely to experience complications of myocardial infarction (MI), such as heart failure, stroke, and re-infarction.3 In addition, the elderly are more likely to have adverse events related to treatments, including bleeding with anti-thrombotic therapies.
Despite progressively impaired renal function with ageing,4 little attention has been paid to dose adjustment of anti-thrombotic therapies. This is of particular importance in the management of drugs such as enoxaparin (ENOX) in which the anti-IIa activity is cleared by non-renal mechanisms and the anti-Xa activity is cleared renally. Earlier studies had shown increased bleeding with ENOX in elderly MI patients.5,6 In the ExTRACT-TIMI 25 trial, a novel modified dosing regimen of ENOX was tested in patients aged 75 years.7,8 The results of the trial focusing on the effects of this dose adjustment in the elderly are reported.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
Patient population and protocol
The study design7 and primary results of ExTRACT-TIMI 25 have been published.8 In brief, 20 479 patients from the intention-to-treat (ITT) cohort of the trial were randomized in 674 sites in 48 countries. Entry criteria included ischaemic symptoms within 6 h of randomization with ST-segment elevation or left bundle branch block. Contraindications included serum creatinine >2.5 mg/dL (>220 µmol/L) for men and >2.0 mg/dL (>175 µmol/L) for women. The fibrinolytic was selected at the discretion of the treating physician and all patients were to receive aspirin. Subjects were randomized either to the standard anti-thrombin strategy with unfractionated heparin (UFH) or to an ENOX strategy. UFH (or matching placebo) was administered to all patients assigned to this strategy with an i.v. bolus of 60 U/kg body weight (4000 U maximum) followed by an infusion of 12 U/kg/h (maximum 1000 U/h) for at least 48 h, with adjustment to an activated partial thromboplastin time of 1.5–2.0x control. ENOX (or matching placebo) was given to patients <75 years as a 30 mg i.v. bolus followed by 1.0 mg/kg subcutaneously every 12 h. For patients
75 years, a modified dosing regimen was tested with omission of the i.v. bolus and reduction of the maintenance dose to 0.75 mg/kg subcutaneously every 12 h until hospital discharge or 8 days. For patients of any age with an estimated creatinine clearance (CrCl) of <30 mL/min, the dose was modified to 1.0 mg/kg every 24 h. CrCl was estimated by the Cockcroft–Gault formula.9 The estimation of CrCl occurred after the serum creatinine measurement from admission was available. This allowed investigators sufficient time to determine if the second subcutaneous injection of ENOX was to be administered either 12 h or 24 h after the initial injection. The primary endpoint was death or non-fatal MI at 30 days. Bleeding was classified according to the TIMI criteria.2,7,9
Pharmacokinetic analyses
The modifications in the ENOX dosing regimen described above for elderly patients and those with severe renal dysfunction (e.g. CrCl <30 mL/min) were based on pharmacokinetic modelling in previous studies.10,11 Body weight and renal function are significantly related to the clearance of anti-Xa activity following ENOX administration. In addition, clearance of anti-Xa activity closely correlates with the risk of bleeding.10 Anticipating that elderly patients have reduced CrCl, the initial i.v. bolus of ENOX was eliminated (to avoid excessive anti-Xa activity when the lytic effect was highest) and the maintenance dose was reduced by 25% to 0.75 mg/kg subcutaneously every 12 h. Since prior studies showed that there was a marked reduction in the clearance of anti-Xa activity in patients with a CrCl <30 mL/min, the dosing interval was widened and the subcutaneous regimen was 1.0 mg/kg every 24 h.10 The goal of the dose modifications in the elderly and severe renal dysfunction patients was to reduce the exposure to anti-Xa activity because of excessive accumulation over time.
On the basis of the pharmacokinetic model developed in the TIMI 11A Study, a sparse sampling strategy was designed as a substudy in the ExTRACT-TIMI 25 trial.10 Two samples were collected per patient, as described previously, after the first subcutaneous dose of ENOX, one between 0.5 and 2.5 h and the other between 4 and 12 h.10,11 Given the plans for a sparse sampling strategy, the pharmacokinetic substudy was conducted in 39 sites from nine countries and was open to all eligible patients for the trial at those sites who consented to the additional blood specimens.
Statistical analysis
All efficacy analyses were based on the ITT principle. The ITT cohort was prespecified to include all patients randomized for whom follow-up information was available. Safety analyses were performed according to the treatment actually received. Continuous variables are presented as median and interquartile range (IQR), and categorical variables as frequencies. In the comparison of baseline characteristics stratified by young (<75 years) and elderly (75 years) age groups, differences in categorical variables were analysed using the 
2 test. Risk ratios (RR) and the corresponding 95% CIs are reported for the comparisons of ENOX:UFH for the given subgroups analysed. The frequency of efficacy and safety outcomes at 30 days in the two age strata were compared with the 2 test. Logistic regression was performed to evaluate the interaction between age group and randomized treatment. All P-values reported are two-sided and performed at 
= 0.05 significance level. Because of the exploratory nature of the analysis, P-values are not adjusted for multiplicity. All statistical analyses were performed using Stata/SE, version 9.1 (StataCorp, College Station, TX, USA).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
Effect of age on baseline characteristics
Baseline characteristics varied substantially in relation to age (Table 1). Compared with the 17 947 patients <75 years, the 2532 patients
75 years (representing 12.4% of the ITT population) had a higher prevalence of hypertension and diabetes, but were less likely to be current smokers. Elderly patients were significantly more likely to have had a prior MI, history of angina pectoris, and be receiving long-term treatment with aspirin. They were also at significantly higher risk of poor outcomes from STEMI as assessed by Killip Class, TIMI Risk Score, and TIMI Risk Index. Of note, the CrCl was markedly lower in elderly patients. Within each age stratum, the patients assigned to the ENOX and UFH strategies were well matched with no significant differences in baseline characteristics (data not shown). Among the patients <75, the median CrCl was 86.7 (69.1, 108.1) mL/min in those assigned to ENOX (n = 9015) and was 86.8 (68.1, 107.6) mL/min assigned to UFH (n = 8932). Among the patients 75, the median CrCl was 51.9 (41.9, 64.7) mL/min in those assigned to ENOX (n = 1241) and 52.1 (41.6, 65.0) mL/min in those assigned to UFH (n = 1291).
|
Effect of age on treatments received
The use of aspirin and beta-blockers (both recommended in the protocol in the absence of contraindications) were significantly lower in elderly when compared with younger patients (Table 1). Other medications, shown to reduce events after STEMI in prior trials, including clopidogrel, inhibitors of the renin–angiotensin system, and statins were also used less frequently in elderly patients. As for the baseline characteristics, no differences were noted between the patients assigned to ENOX or UFH within the two age strata.
Anti-Xa results
A total of 73 patients were included in the pharmacokinetic substudy reported here: 60 were <75 years and 13 were 75 years. The mean clearance of anti-Xa activity in patients <75 years was 0.794 L/h and was reduced by 17.6% to 0.654 L/h in patients 75 years (P = 0.049). The area under the concentration time curve (AUC) from 0 to 12 h was a median of 9839 (8295, 11 579) I·U·h/L in the young patients and 4532 (3816, 6540) (P < 0.001), reflecting the lack of administration of the i.v. bolus in the elderly patients. At steady-state, the AUC was 10 000 (8499, 10926) I·U·h/L in the young patients and 8197 (7395, 8798) in the elderly patients (P = 0.0046), reflecting a significantly lower rate of accumulation of anti-Xa in the elderly patients over time.
Outcome by treatment assignment
The rate of death or non-fatal recurrent MI at 30 days was significantly lower in patients <75 years treated with ENOX (7.9% vs. 9.9%; RR 0.80; 0.72–0.87, P < 0.0001) (Figure 1). This endpoint also tended to occur less frequently with ENOX in patients 75 years (24.8% vs. 26.3%; RR 0.94; 0.82–1.08; Pinteraction = 0.10). The absolute risk difference in favour of ENOX was 2.0% in patients <75 years and 1.5% in those 75 years (Figure 1). These differences translate into a number needed-to-treat (NNT) in order to prevent one event of 50 in patients <75 years treated and 67 in patients 75 years.
|
The rate of the prespecified major secondary endpoint, death, or non-fatal re-infarction or urgent revascularization occurred in 12.4% of UFH patients and 9.7% of ENOX patients <75 years (RR 0.78, CI 0.72–0.85, P < 0.001) and in 28.4% of UFH patients and 26.0% of ENOX patients
75 years (RR 0.92; CI 0.81–1.04, P = 0.18; Pinteraction = 0.12) (Figure 1). The absolute risk difference in favour of ENOX was 2.7% in patients <75 years and 2.5% in those 75 years, corresponding to NNT calculations of 37 and 42, respectively, to prevent one secondary endpoint.
The rate of all-cause mortality was 5.5% in the UFH patients and 5.0% in the ENOX patients <75 years (RR 0.90, CI 0.80–1.02) and was 21.2% in the UFH patients when compared with 21.0% in the ENOX patients 75 years (RR 0.99, CI 0.85–1.15; Pinteraction = 0.45).
Major bleeding occurred in 1.1% of UFH vs. 1.9% of ENOX patients <75 years (RR 1.67, 95% CI 1.31–2.13, P < 0.0001) and 2.9% UFH vs. 3.3% ENOX (RR = 1.15, 95% CI 0.74–1.78, P = 0.53), in patients 75 years (Pinteraction = 0.16) (Figure 2). Although the incidence of intracranial haemorrhage was higher in the elderly, there were no significant differences between the UFH and ENOX groups in each of the two age strata: 0.5% vs. 0.7%, P = 0.06 in patients < 75 years and 1.7% vs. 1.6% P = 0.85 in patients 75 years. Among patients with a major bleed, death with primary cause attributed to haemorrhage or intracranial haemorrhage occurred in 1.3% of both the UFH and ENOX group among patients 75 years and in 0.2% of the UFH and 0.45% of the ENOX group among patients < 75 years.
|
Net clinical benefit
The net clinical benefit endpoint (death or non-fatal re-infarction or non-fatal major bleeding) rate was 10.7% in UFH patients and 9.0% of ENOX patients < 75 years (RR 0.84; 95% CI 0.77–0.92; P < 0.001) and was 27.3% and 25.8%, respectively, in the patients
75 years (RR 0.94; 95% CI 0.83–1.07; P = 0.38; Pinteraction = 0.28). The absolute risk difference in favour of ENOX was 1.7% in patients < 75 years and 1.5% in those 75 years, corresponding to NNT to prevent one event of 59 and 67, respectively (Figure 1). A comparison of the treatment effects of ENOX for every 1000 patients treated, stratified by the age cutpoint of 75 years is shown in Figure 3.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
We tested a novel ENOX dosing regimen in patients
75 years and the findings stratified by age < 75 years vs. 75 years are of interest. Although the relative RR of the primary endpoint with ENOX was greater in the <75 vs. 75 year-old cohorts (20% vs. 6%), because of the higher absolute event rates in the elderly, the absolute risk differences favoured ENOX in both age cohorts (2.0% vs. 1.5%). The NNT to prevent one primary endpoint event were similar in the younger and older cohorts (Figure 1).
The relative increase in major bleeding that was seen with ENOX in the patients 75 years (RR = 1.15) was less than in patients < 75 years (RR = 1.67) (Figure 2) and the rates of intracranial haemorrhage in patients 75 years were similar in the UFH and ENOX groups. We speculate that this trend to a reduced relative rate of excessive bleeding with ENOX in the elderly compared with the young may be a consequence of omission of the i.v. bolus loading dose and reduction in the maintenance dose of ENOX in patients 75 years. In support of this hypothesis are the anti-Xa results that showed significantly lower rates of exposure to anti-Xa activity both between 0 and 12 h and at steady state in the elderly patients. In addition, the protocol mandated modification of the maintenance dose of ENOX to 1.0 mg/kg every 24 h for patients with a CrCl of <30 mL/min and this may also have played a role in limiting the excess bleeding in the elderly patients in whom renal dysfunction occurred more frequently. While advanced age, diminished renal function, and low body weight have all been shown to relate to increased bleeding risk, the relative contribution of each of these inter-related factors is difficult to assess and likely varies from patient to patient.
The rates of major bleeds in young and old patients with STEMI are of considerable clinical interest. Although the absolute rates were lower in the younger patients in ExTRACT-TIMI 25, it is of note that there was a significant relative excess of bleeds in younger patients treated with enoxaparin (Figure 2). This underscores the need for additional studies to define further the optimal ENOX dosing regimen in younger patients, who may benefit from a lower exposure to anti-Xa activity than was achieved in this trial.
With respect to patients 75 years, the findings of ExTRACT-TIMI 25 represent an important advance when compared with prior studies. In the 4078 patients in the ASSENT 3 trial,5 in patients with STEMI treated with tenecteplase, and randomized to receive UFH or ENOX regimens, similar to those used in patients <75 years in ExTRACT-TIMI 25, the rates of major bleeding increased from 1.8% (UFH) vs. 2.4% (ENOX) in patients aged 
75 years to 4.1% (UFH) vs. 13.3% (ENOX), in patients aged >75 years. There also was an increase in the incidence of intracranial haemorrhage in patients treated with ENOX in patients >75 years: 0.74% (UFH) vs. 1.54% (ENOX).12 In the 1639 patients randomized to the ASSENT-3 PLUS trial,6 which compared UFH and ENOX as an adjunct to tenecteplase administered in the prehospital phase, the rate of intracranial haemorrhage was 0.8% (UFH) and 6.7% (ENOX) in patients >75 years (P = 0.01). The investigators hypothesized that this increase in intracranial haemorrhage in older patients may have been due to higher blood pressures in the early stages of STEMI, more frequent use of clopidogrel, IIb/IIIa antagonists, non-therapeutic dosing of UFH and ENOX, more dosing errors with tenecteplase, and more coronary procedures in patients treated during pre-hospitalization. Of note, both the rates of major bleeding and intracranial haemorrhage in patients 75 years in ExTRACT-TIMI 25 treated with the modified doses of ENOX were lower than that reported in the ASSENT-3 and ASSENT-3 PLUS trials.
|
Conclusion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
In patients with STEMI treated with fibrinolytic therapy, the modified (reduced) dosing regimen of ENOX in patients
75 years appears to have been helpful in reducing the magnitude of the relative increase in major bleeding, including the intracranial haemorrhage that has been observed in this age group in previous trials. The similar ARD and NNT in the elderly and young patients suggest that the reduced ENOX dose in the elderly did not compromise its efficacy in preventing death or MI. Thus, the ENOX strategy as implemented in ExTRACT-TIMI 25 is preferred to the standard UFH strategy in both younger and older STEMI patients treated with fibrinolysis.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
Supported by a grant from Sanofi-Aventis.
Conflict of interest: All authors received a research grant from Sanofi Aventis to conduct the ExTRACT-TIMI 25 Trial. H.D.W, E.B. and E.M.A. served on an advisory board of Sanofi Aventis.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionAcknowledgementsReferences |
|---|
- Alexander KP, Newby LK, Armstrong PW, Cannon CP, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman M. Acute coronary care in the elderly (part 2): ST-Segment Elevation Myocardial Infarction. A Statement for Healthcare Professionals from the Acute Cardiac Care Subcommittee, Council of Clinical Cardiology, American Heart Association Endorsed by the Society of Geriatric Cardiology. Circulation. in press.
- Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an Intravenous nPA for Treatment of Infarcting Myocardium Early II Trial substudy. Circulation (2000) 102:2031–2037.
[Abstract/Free Full Text] - White HD, Aylward PE, Huang Z, Dalby AJ, Weaver WD, Barvik S, Marin-Neto JA, Murin J, Nordlander RO, van Gilst WH, Zannad F, McMurray JJ, Califf RM, Pfeffer MA. Mortality and morbidity remain high despite captopril and/or valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation (2005) 112:3391–3399.
[Abstract/Free Full Text] - Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol (2002) 13:745–753.
[Abstract/Free Full Text] - 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) 358:605–613.[CrossRef][ISI][Medline]
- Wallentin L, Goldstein P, Armstrong PW, Granger CB, Adgey AA, Arntz HR, Bogaerts K, Danays T, Lindahl B, Makijarvi M, Verheugt F, Van de Werf F. 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.
[Abstract/Free Full Text] - Antman EM, Morrow DA, McCabe CH, Jiang F, White HD, Fox KA, Sharma D, Chew P, Braunwald E. 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) 149:217–226.[CrossRef][ISI][Medline]
- Antman EM, Morrow DA, McCabe CH, Murphy SA, Ruda M, Sadowski Z, Budaj A, Lopez-Sendon JL, Guneri S, Jiang F, White HD, Fox KA, Braunwald E. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med (2006) 354:1477–1488.
[Abstract/Free Full Text] - Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[ISI][Medline]
- Bruno R, Baille P, Retout S, Vivier N, Veyrat-Follet C, Sanderink GJ, Becker R, Antman EM. Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non-ST-segment elevation myocardial infarction. Br J Clin Pharmacol (2003) 56:407–414.[CrossRef][ISI][Medline]
- TIMI 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. J Am Coll Cardiol (1997) 29:1474–1482.[Abstract]
- Granger CB, Alexander JH, Lesaffre E, Wallentin L, Armstrong PW, Van de Werf F. Differential impact of antithrombotic treatments combined with tenecteplase in the elderly with acute myocardial infarction: results from ASSENT-3. J Am Coll Cardiol (2002) 39:306A.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. G. Goodman, V. Menon, C. P. Cannon, G. Steg, E. M. Ohman, and R. A. Harrington Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 708S - 775S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 American College of Cardiology/American Heart Asso, Developed in Collaboration With the Canadian Cardi, Endorsed by the American Academy of Family Physici, 2007 Writing Group to Review New Evidence and Upda, E. M. Antman, M. Hand, P. W. Armstrong, E. R. Bates, L. A. Green, L. K. Halasyamani, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction J. Am. Coll. Cardiol., January 15, 2008; 51(2): 210 - 247. [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Antman, M. Hand, P. W. Armstrong, E. R. Bates, L. A. Green, L. K. Halasyamani, J. S. Hochman, H. M. Krumholz, G. A. Lamas, C. J. Mullany, et al. 2007 Focused Update of the ACC/AHA 2004 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: Developed in Collaboration With the Canadian Cardiovascular Society Endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee Circulation, January 15, 2008; 117(2): 296 - 329. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||