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  Antithrombotic Treatment with Low
Molecular Weight Heparin in Unstable
Angina/Non-Q-Wave Myocardial Infarction

Shaun G. Goodman, MD

Division of Cardiology, St. Michael's Hospital and Canadian Heart Research Centre,
Toronto, Ontario, Canada

UNFRACTIONATED HEPARIN: BENEFICIAL BUT THERE'S ROOM FOR IMPROVEMENT
   There is now extensive evidence implicating partial or complete thrombotic occlusion of the coronary artery in the pathogenesis of acute coronary syndromes (ACS), including non-ST segment elevation ACS (i.e., unstable angina or non-Q wave infarction [MI]) (1). The occurrence of complications such as refractory angina, (re)MI, and sudden death after an episode of an ACS has also been attributed to the development of intracoronary thrombosis. The rupture of an atherosclerotic plaque causes platelet activation and aggregation and elicits the coagulation cascade by tissue factor release. The resultant complex of tissue factor and factor VIIa activates factor Xa, which catalyzes the formation of thrombin. In turn, thrombin converts fibrinogen to fibrin, stabilizes the thrombus and further activates platelets and amplifies the coagulation cascade.

   Since both platelet activation are involved in the thrombotic process, there is a rationale for the use of both platelet and coagulation inhibitors in the treatment of ACS (Figure 1). Two meta-analyses have shown that a combination of an intravenous infusion of unfractionated heparin (UFH) and acetylsalicylic acid (ASA) is more effective than ASA alone (2, 3). Despite the advantage of this combination approach, ASA and UFH are associated with a substantial failure rate: recurrent ischemic chest pain, myocardial infarction, or death occur in 15-30%, and 15-25% of patients undergo coronary revascularization within 12 weeks of treatment initiation (4-9). This failure rate is likely due in part to the marked variability in dose response and dose-dependent clearance of UFH (10). In contrast, the reduced binding of low molecular weight heparins (LMWHs) to plasma proteins, endothelial cells, and macrophages is associated with high bioavailability after subcutaneous injection, a longer plasma half-life, dose-independent clearance, and a more predictable anticoagulant response. Further advantages of LMWHs include greater resistance to inhibition by activated platelets, less platelet activation, reduced release of von Willebrand factor, minimal effect on microvascular permeability, a lower incidence of heparin-induced thrombocytopenia, and no need for activated partial thromboplastin time monitoring (10-15). Low molecular weight heparins also have a higher anti-factor Xa to anti-factor IIa ratio and more tissue factor pathway inhibition leading to greater inhibition of thrombin generation and activity (10, 16, 17).


Figure 1

LOW MOLECULAR WEIGHT HEPARINS: CLINICAL TRIALS IN UNSTABLE ANGINA/NON-Q WAVE MYOCARDIAL INFARCTION
Gurfinkel et al
   The superiority of low molecular weight heparins as compared with UFH was first demonstrated by Gurfinkel et al (9) in 219 patients with unstable angina. In a randomized, open-label trial, nadroparin plus aspirin was more effective than either UFH plus aspirin or aspirin alone in the reduction of in-hospital cardiac outcomes (9); however, no longer term data were collected in this pilot study.

FRISC
   The landmark FRISC (Fragmin during Instability in Coronary artery disease) study demonstrated that dalteparin was superior to placebo for the acute-phase management of unstable angina/non-Q-wave MI (18). This double-blind, randomized trial in 1,506 patients evaluated subcutaneous (SC) dalteparin (120 IU/kg twice daily [BID] for 6 days, then 7500 IU once daily for the next 35-45 days) to placebo injections. All patients received an initial 300 mg of ASA followed by 75 mg daily. Patients were eligible for study inclusion if they had been admitted to hospital because of chest pain within the previous 72 hours (newly developed, increased, or rest angina) in the setting of ECG changes.

   During the first 6 days, the rate of death and new MI was significantly lower in the dalteparin group than in the placebo group (1.8% versus 4.8%; Risk Ratio [RR] 0.37, 95% Confidence Intervals [CI] 0.20-0.68) (Figure 2). Similarly, the frequencies of need for intravenous heparin (3.8% vs. 7.7%; RR 0.49, 95% CI 0.32-0.75) and need for revascularization (0.4% vs. 1.2%; RR 0.33, 95% CI 0.10-1.10) were lower among dalteparin-treated patients (Figure 2). The significantly lower death/MI rate represented the first large-scale trial evidence of the benefit of heparin (in this case, a LMWH) in addition to ASA treatment of unstable angina/non-Q-wave MI patients.


Figure 2

   At 40 days, the differences in rates of death and MI and a composite end point (death, MI, or revascularization) persisted, although subgroup analysis showed that the effect was mainly confined to non-smokers (80% of the study population). If interventional procedures done for reasons other than incapacitating symptoms were excluded, there remained a significant reduction in the composite end point. At 4-5 months after the end of treatment, the rates of death, new MI, or revascularization were lower in the dalteparin-treated group but this no longer achieved statistical significance. During the acute phase, there were very few major bleeding episodes, and no differences between the placebo and dalteparin groups. Minor bleeding, mainly SC hematoma at injection sites, was more common in the dalteparin than the placebo group, especially during the acute phase. There were no differences in mean hemoglobin or platelet count between the groups.

FRIC
   The FRIC (Fragmin in Unstable Coronary Artery Disease) study (19) was an open-labeled, randomized comparison in 1,482 patients with unstable angina or non-Q-wave MI. All patients received 75-160 mg of ASA daily. In addition, patients were treated with either dose-adjusted intravenous UFH or SC dalteparin (120 IU/kg BID). In the prolonged treatment phase (days 6-45), patients received SC dalteparin (7500 IU once daily) or placebo in a double-blind fashion.

   During the first 6 days, the rate of death, MI or recurrence of angina was 7.5% in the UFH-treated patients and 9.3% in the dalteparin-treated patients (relative risk 1.18; 95% CI 0.84-1.66). Between days 6 and 45, the composite end point was 12.3% in both the placebo and dalteparin groups. Thus, this direct comparison of UFH and dalteparin showed no difference in efficacy in the hospital phase and in contrast to the FRISC study, there was no benefit to continued use of once daily dalteparin as compared to aspirin alone up to 45 days after treatment initiation.

FRAX.I.S.
    The FRAX.I.S. study was a randomized, double-blind 3,460 patient study in unstable angina/non-Q MI (20). This trial had 3 treatment groups: Group 1 received UFH for 62 days; Group 2 received nadroparin (IV bolus then 86 anti-Xa IU/kg SC BID) for 62 days; and, Group 3 received nadroparin for 14 days. All patients received up to 325 mg daily of ASA. There were no differences between the treatment groups with respect to the composite end point (death, MI, refractory or recurrent angina) at 6 days (14.9% vs. 13.8% vs. 15.8%), 14 days (18.1% vs. 17.8% vs. 20%), or 3 months time (22.2% vs. 22.3% vs. 26.2%). There were more major hemorrhages in Group 3 (14 days of nadroparin: 3.5% vs. 6 days of UFH: 1.5% (Group 1), p=0.0035). Thus, despite the apparent promise seen in an earlier pilot study (9), the results from the FRAX.I.S study failed to demonstrate an advantage of subcutaneous nadroparin over intravenous UFH.

ESSENCE and TIMI 11B
   In contrast, data from the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) (21) and TIMI 11B (22) trials supports the use of low molecular weight heparin (enoxaparin) rather than UFH (in addition to ASA), with evidence of short-, intermediate- (23), and long-term (24-26) reductions in ischemic events.

   The ESSENCE study (21) was a randomized, double-blind, placebo-controlled, parallel group, multicentric trial of 3,171 patients from 176 centres from 10 countries in North and South America and Europe. Patients with unstable angina or non-Q wave myocardial infarction were randomized to receive standard unfractionated, dose-adjusted intravenous heparin or enoxaparin 1mg/kg q12h subcutaneously. All patients received aspirin daily and maximal anti-ischemic therapy (nitrates and/or beta- and/or calcium channel blockers) as per local practice. The treatment phase was a median of 2.6 days.

   The primary composite endpoint of death, MI, and recurrent angina at 14 days was significantly lower in the enoxaparin as compared to the heparin-treated group (16.6% vs. 19.8%; p=0.019) (Figure 3). The beneficial effect of enoxaparin was already evident, although not statistically significant, at 48 hours (relative risk reduction of 16%), and was sustained at 30 days (19.8% vs. 23.3%, p=0.017) and 1 year follow-up (32.0% vs. 35.7%, p=0.022) (Figure 4) (24). In addition, there was a consistent trend towards a lower incidence of the secondary composite end point of death or MI among enoxaparin-treated patients (30 days: 6.2% vs. 7.7%, p=0.081; 1 year: 11.5% vs. 13.5%, p=0.082). This superiority was achieved without an increase in major hemorrhage events and although there was an increase in minor hemorrhage events in enoxaparin treated patients, the majority of these were related to minor ecchymoses at the subcutaneous injection site.


Figure 3


Figure 4

   In addition to greater clinical efficacy, the need for diagnostic cardiac catheterization (30 days: 47.9% vs. 51.9%, p=0.024; 1 year: 55.8% vs. 59.4%, p=0.036) and coronary revascularization (30 days: 27.0% vs. 32.2%, p=0.001; 1 year: 35.9% vs. 41.2%, p=0.002) was significantly less frequent among the patients assigned to enoxaparin than among those assigned to UFH. Decreased resource utilization following enoxaparin treatment led to an impressive potential savings in both a 30-day U.S.-based (27) and a 1-year Canadian-based cost-effectiveness analysis (28).

   The TIMI 11B study (29) was a randomized, double-blind, placebo-controlled trial comparing the strategy of combined short-term (>72 hours) and intermediate-term (43 days) administration of enoxaparin for unstable angina/non-Q wave infarction versus UFH only during the acute phase. Patients were enrolled within 24 hours of their most recent episode of resting ischemic discomfort and were eligible if they had ECG changes or positive serum cardiac markers (or a history of coronary disease among 731 of the first 1,800 patients recruited).

   The results of this 3,910 patient trial confirm the benefit seen with enoxaparin over heparin in the ESSENCE trial: the 14 day composite end-point of death, MI, and urgent revascularization, was significantly lower among the enoxaparin as compared to unfractionated treated patients (14.2% versus 16.7%, relative risk reduction 15%, p=0.03) (Figure 5) (22). While some discussion has arisen regarding the different treatment duration times during the acute phase (median 3 days in the enoxaparin group vs. 4.6 days in the UFH group), the study was a double-dummy, double-blind comparison, the treatment strategy of enoxaparin allowed for therapy up to 8 days (dependent upon the treating physician=s discretion), and by 48 hours, a significant benefit was already evident with enoxaparin (22,30).


Figure 5

   In the chronic phase of the protocol, patients were eligible to remain in the study and receive blinded subcutaneous BID therapy (placebo versus enoxaparin: 40 mg for body weight < 65 kg or 60 mg for > 65 kg) as long as they did not require bypass surgery, experience any bleeding, experience a platelet count of less than 100,000, or require chronic anticoagulation. By day 43, the composite end-point of death, MI, or urgent revascularization remained lower in the enoxaparin-treated patients (17.3% versus 19.7%, relative risk reduction 12%, p=0.048). Thus, there was no further relative decrease in events with enoxaparin over placebo after the acute phase. However, the chronic phase may have been underpowered to detect a difference between treatments, since only 60% of those enrolled in the acute phase continued on to the chronic phase. In addition, lower risk patients entered the chronic phase (e.g., those without a complicated acute course, those not going on to bypass surgery, etc.), making it potentially more difficult to detect an incremental benefit of enoxaparin beyond the acute phase if such a benefit truly existed. Of note, during the outpatient phase, major hemorrhage occurred more frequently in the enoxaparin group (2.9% vs. 1.5%, p=0.021).

   In a meta-analysis combining the ESSENCE and TIMI 11B study results at days 8, 14, and 43, there was evidence of a consistent, approximate 20% relative risk reduction in the occurrence of death, MI, or urgent revascularization and in death or MI alone (Figure 6); (23) this benefit remains at 1 year follow-up (26).


Figure 6

FRISC II
   The FRISC II (Fragmin and Fast Revascularization during InStability in Coronary artery disease) study (31) enrolled 2,267 patients with unstable angina or non-Q wave MI. Patients were randomly assigned to continue double-blind SC dalteparin (120 IU/kg BID) or placebo for 3 months after at least 5 days of initial treatment with open-label dalteparin. Patients were eligible for inclusion if they had crescendo or rest ischemic symptoms in association with ST depression or T wave inversion or serum marker evidence for myocardial necrosis (elevated CK, CK-MB, or troponin).

   During the 3 months of double-blind treatment, there was a non-significant decrease in death or MI in the dalteparin as compared to the placebo group (6.7% vs. 8.0%, p=0.17; RR 0.81, 95% CI 0.60-1.10); however, during the initial 30 days, this decrease was statistically significant (3.1% vs. 5.9%, p=0.002; RR 0.53, 95% CI 0.35-0.80) (Figure 7). For the composite endpoint of death, MI, or revascularization, there was a significant decrease in 3-month rates among dalteparin-treated patients (29.1% vs. 33.4%, p=0.031; RR 0.87, 95% CI 0.77-0.99) (Figure 7). The initial benefits were not sustained at 6-month follow-up. At 1 year follow-up, it was clear that patients who underwent earlier cardiac catheterisation and revascularization (when appropriate) had the best outcome, regardless of whether they had received 3 months of dalteparin therapy or not following their index admission(32). During the open-label dalteparin phase (all patients received this treatment in addition to ASA, nitrates, and beta-blockers), major and minor bleeding occurred in 0.9% and 5.8% of patients, respectively. Major and minor hemorrhagic episodes were more frequently seen in the dalteparin-treated patients during the double-blind, 3 month phase (3.3% vs. 1.5%, and 23.0% vs. 8.4%, respectively).


Figure 7

   Thus, dalteparin lowered the risk of death, MI, and revascularization at least during the first month of treatment beyond the open-label administration, and this could lower the risk of events in patients awaiting invasive procedures.

RISK STRATIFICATION: WHICH PATIENTS SHOULD BE CONSIDERED FOR LMWH THERAPY?
   In a substudy from the FRISC trial, Lindahl et al (33) followed a group of patients (n=971) who underwent troponin T blood sampling at the time of study inclusion. Patients with elevated troponin T levels (indicating myocardial necrosis and those at higher risk for subsequent events) experienced a significant benefit from dalteparin compared with placebo at 40-day follow-up. Dalteparin reduced the incidence of death or MI at 6 days (2.5% vs. 6%, p<0.05) and at 40 days (4.2% vs. 7.4%, p<0.05) in 644 patients with troponin T levels >0.1 µg/L. In contrast, among the 327 patients with troponin T levels <0.1 mg/L there was a modest, non-significant reduction in events among dalteparin-treated patients at 6 days (0% vs. 2.4%, p=0.12); at 40 days there was no difference between the 2 treatment groups (5.7% vs. 4.7%). Thus, elevation of troponin T identified a subgroup of patients in whom twice daily treatment with dalteparin for 6 days was superior to ASA alone.

   In a substudy of TIMI 11B patients, (34) baseline and 12 and 24 hour cardiac troponin I (TnI) samples were collected. Among 359 patients with negative serial creatine kinase, MB fraction (CK-MB) values, 50.1% had a TnI result >0.1 ng/ml within the first 24 hours (£24). Patients with elevated TnI were at higher risk of death or myocardial infarction (MI) at 48 hours (3.9% vs. 0%, p=0.01) and 14 days (13.9% vs. 2.2%, p<0.0001; not shown). Elevated TnI also correlated with higher risk of recurrent ischemia requiring urgent revascularization by 48 hours (10.0% vs. 1.7%, p=0.001) and at 14 days (20.6% vs. 5.6%, p<0.0001). Enoxaparin had a greater benefit among patients with elevated vs. normal TnI (p=0.03), achieving a 47% reduction in the risk of death, MI, or urgent revascularization by 14 days in TnI-positive patients (21% vs. 40%, p=0.007; right bars). Thus, elevation of TnI among patients with non-ST segment elevation ACS and negative levels of CK-MB identifies those at higher risk for very early adverse outcomes and treatment with enoxaparin reduces the risk associated with elevated TnI.

   Antman et al (35) recently published a practical and easy-to-use at the bedside risk stratification scoring system derived and validated from the TIMI 11B and ESSENCE clinical trial databases of over 7,000 patients presenting with non-ST segment elevation ACS. Using multivariate analysis, Antman and colleagues identified 7 common risk features that independently predicted short-term clinical outcome. By simply adding the number of these factors, one can derive a reasonably accurate estimate of the likelihood of the 14-day need for urgent revascularization or risk of MI or death. Based upon the ESSENCE (Figure 8) and TIMI 11B cohorts, the higher the risk level, the greater the magnitude of benefit was demonstrated with enoxaparin as compared to UFH.


Figure 8

   Based upon the clinical trial evidence, the use of LMWH should be strongly considered in patients presenting with ischemic chest discomfort (at rest or with a clear crescendo pattern) within the preceding 12 to 24 hours and one or more of the following features: (1) new or presumably new ECG changes (e.g., ST segment depression >0.1 mV in at least 2 contiguous leads); (2) abnormal cardiac markers (e.g., CK-MB or troponin above the upper limit of normal); or (3) history of coronary artery disease (e.g., documented MI, coronary revascularization) in patients strongly suspected to have an ACS secondary to underlying thrombosis (Figure 9). This suggested approach is consistent with the recently updated American College of Cardiology/American Heart Association Guidelines for the management of patients with unstable angina and non-ST-segment elevation MI, (36) which recommends the use of either intravenous UFH or low molecular weight heparin, but recognizes the potential advantages of LMWH treatment over UFH. I personally believe that evidence-based medicine supports the use of enoxaparin over UFH in this setting with the weight of evidence from the ESSENCE and TIMI 11B trials.


Figure 9

   Others have suggested no advantage of LMWH in ACS; for example, Eikelboom et al (3) performed a meta-analysis comparing UFH and LMWH in death and MI at treatment completion. They concluded that "there is no convincing difference in efficacy or safety between LMWH and UFH" based upon a non-significant 12% relative reduction (RR) in death/MI. Eikelboom et al argue that is most appropriate to combine all of the LMWH trials together in order to evaluate the role of LMWH as compared to UFH; however, the inclusion/exclusion criteria, patient populations, choice of LMWH, and endpoint definition differed from study to study. Further, they suggest that death and MI are "robust and irreversible outcomes, and, therefore, least subject to differences in outcome definitions among the studies". While this is likely to be true, none of the individual studies had even modest power to detect death/MI differences, particularly at the early time point (end of study therapy in each trial, with only 276 events in total from all of the studies) Eikelboom and colleagues chose to evaluate in their meta-analysis. They justify their choice of this extremely short-term outcome cut-point based upon their concern that "unequal duration of active therapy might impact on the results of the TIMI 11B trial and the TIMI11B-ESSENCE meta-analysis"; however, the benefit of enoxaparin over UFH on the TIMI 11B trial primary composite endpoint (death/MI/urgent revascularization) was already evident at 48 hours when their was "equal" duration of active treatment (22).

LMWH USE IN THE CARDIAC CATHETERIZATION LABORATRORY
   While strong data identifying the appropriate use and timing of LMWHs in the cardiac catheterization laboratory are lacking, several trials have employed subcutaneous or intravenous LMWH prior to, during, and following cardiac catheterization and percutaneous coronary intervention. (37-41) Diagnostic catheterization and percutaneous coronary revascularization is not contraindicated during LMWH treatment. Timing of sheath removal and the role of additional UFH in those patients undergoing revascularization is dependent upon when the last dose of LMWH was given. (42) It must be recognized that after SC weight-adjusted LMWH, therapeutic anti-Xa levels are achieved within 30-60 minutes and the maximum anti-Xa and anti-IIa (anti-thrombin) activity occurs at 3-5 hours. Further, the PTT and ACT are not reliable measures of anticoagulation since neither are routinely prolonged with LMWH.

COMBINATION LMWH AND GLYCOPROTEIN IIb/IIIa ANTAGONISTS
   There is a small but growing body of experience with combination glycoprotein (GP) IIb/IIIa inhibition and LMWH therapy in both the initial medical management of non-ST elevation ACS and the setting of percutaneous coronary intervention (Figure 10).


Figure 10

ACUTE AND ACUTE II
   The ACUTE study (43) was a randomized, double-blind pilot comparison of enoxaparin (1 mg/kg Q12H) and UFH in non-ST elevation ACS patients receiving tirofiban. While an increase in cutaneous bleeding was seen in the tirofiban and enoxaparin group (46% vs. 18%), there were no major or minor bleeding events in either treatment group. The ACUTE II study, a double-blind, randomized comparison of enoxaparin versus UFH demonstrated a similar safety profile with enoxaparin and UFH in 525 tirofiban-treated patients (major hemorrhage 0.6% vs. 0.5%).

NICE-3 AND -4
   The NICE-4 registry (44) has determined that the 30-day major bleeding and need for blood transfusion rates among PCI patients receiving enoxaparin (0.75 mg/kg Q12H) and abciximab were 0.4% (0.2% related to coronary artery bypass surgery bleeding) and 1.8%, respectively. (Keriakes et al, unpublished data, March 2000). The NICE-3 registry was an open-label, multicentric pilot evaluation of the safety of enoxaparin and GP IIb/IIIa inhibition (abciximab, eptifibatide, or tirofiban) in non-ST elevation ACS patients. The primary safety endpoint of non-coronary artery bypass graft surgery major bleeding was similar in the enoxaparin plus GP IIb/IIIa inhibition group (1.9%) as compared to a historical control from prior UFH plus GP IIb/IIIa inhibition studies (»2%) (45).

GUSTO-IV ACS
   The GUSTO IV ACS substudy was a randomized, double-blind comparison of dalteparin plus placebo versus 24-hour abciximab versus 48-hour abciximab in non-ST elevation ACS patients. The primary safety endpoint of non-CABG major bleeding was almost double in the dalteparin plus abciximab versus dalteparin plus placebo group (1.3% vs. 0.7%), but this was not statistically significant (Wallentin et al, unpublished data, August 2000).

ONGOING GP IIb/IIIa INHIBITION PLUS LMWH STUDIES
   The largest study to evaluate combination therapy in non-ST elevation ACS patients, A to Z (tirofiban plus enoxaparin vs. UFH), began recruiting patients last year. The Canadian INTegrilin and Enoxaparin Randomized assessment of Acute Coronary syndrome Treatment (INTERACT) study is a randomized, open-label, comparative, multicentric trial in high risk non-ST elevation ACS patients. All patients will receive eptifibatide and either enoxaparin or UFH for 48 hours and will undergo two consecutive 48-hour, 7 lead (3 channel) continuous ECG monitoring; the main endpoints include safety and recurrent ST segment shift (which was found to be less frequent in patients after discontinuing enoxaparin as compared to UFH in the Canadian ESSENCE ECG substudy (46).

   Finally, a large (n»8,000) study (NICE-5) is planned to start in the summer of 2001 with randomisation to enoxaparin or UFH in addition to GP IIb/IIIa inhibition and a strategy of early cardiac catheterisation (and revascularization when appropriate) with the end point of death and MI.
With the recent results from the ACUTE II, NICE-3 registry and GUSTO-IV ACS LMWH substudy, there is growing support for combination therapy with LMWH instead of UFH, in the initial medical management of non-ST elevation ACS patients. However, the combined use of GP IIb/IIIa antagonists with UFH has been examined much more extensively. Therefore, if GP IIb/IIIa inhibition is being considered in patients with unstable angina or non-Q wave MI, UFH is likely the best choice of heparin until further efficacy and safety data regarding LMWH use with GP IIb/IIIa antagonists becomes available.

SUMMARY
I
n patients presenting with non-ST segment elevation ACS (unstable angina and non-Q wave MI), the LMWHs offer a modest but clinically significant advance in antithrombotic therapy: (1) dalteparin is clearly superior to ASA alone; (2) dalteparin and nadroparin appear to be at least as effective and safe as UFH in the acute phase of treatment; and (3) enoxaparin has been superior to UFH in 2 large trials in the acute phase. There is also a potential role for LMWH in the management of unstable angina/non-Q wave MI patients beyond the acute phase while awaiting appropriate coronary intervention. However, the subgroup of patients most likely to benefit from this strategy and the ideal duration of treatment (balancing the modest but increased risk of bleeding against the reduced rate of cardiac events) remains uncertain.
LMWHs do have the advantage of more simple administration by SC injection without PTT monitoring at a very reasonable and similar cost; in fact, if applied to the appropriate patient population, it is likely that an actual cost savings may be achieved due to decreased resource utilization.
In patients presenting with non-ST segment elevation ACS (unstable angina and non-Q wave MI), the LMWHs offer a significant advance in antithrombotic therapy. LMWHs are clearly superior to ASA alone, and are at least as effective and safe as UFH in the acute phase of treatment. There is also a potential role for LMWH in the management of unstable angina/non-Q wave MI patients beyond the acute phase while awaiting appropriate coronary intervention. However, the subgroup of patients most likely to benefit from this strategy and the ideal duration of treatment (balancing the modest but increased risk of bleeding against the reduced rate of cardiac events) remains uncertain. LMWHs do have the advantage of more simple administration by subcutaneous injection without monitoring at a very reasonable and similar cost; in fact, if applied to the appropriate patient population, it is likely that an actual cost savings may be achieved due to decreased resource utilization. It is anticipated that LMWHs will generally replace UFH as the standard of care for the majority of moderate-to-high risk patients with non-ST elevation ACS in the future.

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20. The FRAX.I.S.Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999;20:1553-1562.

21. Cohen M, Demers C, Gurfinkel EP, Turpie AGG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KAA, Premmereur J, Bigonzi F, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-452.

22. Antman EM, McCabe CH, Gurfinkel EP, Turpie AGG, Bernink PJLM, Salein D, Bayes de Luna A, Fox K, LaBlanche J-M, Radley D, Premmereur J, Braunwald E, for the TIMI 11B Investigators. Enoxaparin for the acute and chronic management of unstable angina/non-Q wave myocardial infarction: results of TIMI 11B. Circulation 1999;100:1593-1601.

23. Antman EM, Cohen M, Radley D, McCabe C, Rush J, Premmereur J, Braunwald E, for the TIMI 11B (Thrombolysis in Myocardial Infarction) and ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) Investigators. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999;100:1602-1608.

24. Goodman, S., Langer, A., Demers, C., Turpie, A., Bigonzi, F., Radley, D., Le louer, V., Gosset, F., Fromell, G., Cohen, M., and for the ESSENCE Group. One year follow-up of the ESSENCE trial (enoxaparin vs. heparin in unstable angina/non-Q wave myocardial infarction): sustained clinical benefit. Can.J.Cardiol. 1998;14:122F.(Abstract)

25. Antman, E. M., McCabe, C. H., Gurfinkel, E. P., Turpie, A. G. G., Bernink, P. J. L. M., Salein, D., Bayes de Luna, A., Fox, K., LaBlanche, J-M., Radley, D., Furst, J., and Braunwald, E. Treatment benefit of enoxaparin in unstable angina/non-Q wave myocardial infarction is maintained at one year followup in TIMI 11B. Circulation 1999;100:I-497.(Abstract)

26. Antman, E. M., Cohen, M., McCabe, C. H., Radley, D., and Braunwald, E. Enoxaparin is superior to unfractionated heparin for preventing clinical events at one year followup of TIMI 11B and ESSENCE. Circulation 2000;102:II-429.(Abstract)

27. Mark DB, Cowper PA, Berkowitz SD, Davidson-Ray L, DeLong ER, Turpie AGG, Califf RM, Weatherly B, Cohen M. Economic assessment of low molecular weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients. Results from the ESSENCE randomized trial. Circulation 1998;97:1702-1707.

28. O'Brien BJ, Willan A, Blackhouse G, Goeree R, Cohen M, Goodman S. Is the use of low-molecular-weight heparin (enoxaparin) in acute coronary syndrome patients cost saving in Canada? Am Heart J 2000;139:423-429.

29. Antman EM, and the Thrombolysis in Myocardial Infarction (TIMI) 11B Trial Investigators. TIMI 11B. Enoxaparin versus unfractionated heparin for unstable angina or non-Q-wave myocardial infarction: a double-blind, placebo-controlled, parallel-group, multicenter trial. Rationale, study design, and methods. Am Heart J 1998;135:S353-S360.

30. Lopez-Sendon, J., Antman, E. M., McCabe, C. H., Gurfinkel, E., Turpie, A. G., Fox, K. M., Bernink, P. J. L. M., LaBlanche, J-M., Salein, D., and Braunwald, E. Superiority of enoxaparin over unfractionated heparin in unstable angina occurs early in treatment: results from TIMI 11B. Journal of the American College of Cardiology 1999;33:352A.(Abstract)

31. FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Long-term low molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:701-707.

32. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E, for the FRISC II Investigators. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. Lancet 2000;356:9-16.

33. Lindahl B, Venge P, Wallentin L, for the Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. J Am Coll Cardiol 1997;29:43-48.

34. Morrow DA, Antman EM, Tanasijevic M, Rifai N, de Lemos JA, McCabe CH, Cannon CP, Braunwald E. Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy. J Am Coll Cardiol 2000;36:1812-1817.

35. Antman EM, Cohen M, Bernink PJLM, McCabe CH, Horacek T, Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI Risk Score for unstable angina/non-ST elevation MI. A method for prognostication and therapeutic decision making. JAMA 2000;284:835-842.

36. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Keriakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EEI, Steward DE, Theroux P. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.

37. Karsch KR, Preisack MB, Baildon R, Eschenfelder V, Foley D, Garcia EJ, Kaltenbach M, Meisner C, Selbmann HK, Serruys PW, Shiu MF, Sujatta M, Bonan R, on behalf of the REDUCE Trial Group. Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double blind, unfractionated heparin and placebo controlled, multicenter trial (REDUCE trial). J Am Coll Cardiol 1996;28:1437-1443.

38. Zidar ZP. Low-molecular-weight heparins in coronary stenting (The ENTICES trial). Am J Cardiol 1998;82:29L-32L.

39. Deutsch, E., Cohen, M., Radley, D. R., Tarazona, N., and Fromell, G. J. Safety and efficacy of percutaneous procedures in patients receiving subcutaneous enoxaparin for unstable angina: results of the ESSENCE trial. Circulation 1998;98:I-563.(Abstract)

40. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: Results of TIMI 11A. J Am Coll Cardiol 1997;29:1474-1482.

41. Rabah, M. M., Premmereur, J., Graham, M., Fareed, J., Hoppensteadt, D. A., Khurana, S., Grines, L., and Grines, C. Comparison of an intravenous bolus of enoxaparin versus unfractionated heparin in elective coronary angioplasty. Journal of the American College of Cardiology 1999;33:14A.(Abstract)

42. Montalescot G, Cohen M. Low molecular weight heparins in the cardiac catheterization laboratory. J Thromb Thrombol 1999;7:319-323.

43. Cohen M, Théroux P, Weber S, Laramée P, Huynh T, Borzak S, Diodati JG, Squire IB, Deckelbaum LI, Thornton AR, Harris KE, Sax FL, Lo MW, White HD. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiol 1999;71:273-281.

44. Keriakes DJ, Fry E, Matthai W, Niederman A, Barr L, Brodie B, Zidar J, Casale P, Christy G, Moliterno D, Lengerich R, Broderick T, Shimshak T, Cohen M. Combination enoxaparin and abciximab therapy during percutaneous coronary intervention: "NICE guys finish first". J Invas Cardiol 2000;12:1A-5A.

45. Ferguson, J. J., Antman, E. M., Bates, E. R., Cohen, M., Every, N. R., Harrington, R. A., Pepine, C. J., Theroux, P., and The NICE-3 Investigators. The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI: final results of the NICE-3 study. Journal of the American College of Cardiology 2001;37:365A.(Abstract)

46. Goodman SG, Barr A, Sobtchouk A, Cohen M, Fromell GJ, Laperriere L, Hill C, Langer A, for the Canadian Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) ST Segment Monitoring Substudy Group. Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy. J Am Coll Cardiol 2000;36:1507-1513.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
fgaro@fac.org.ar
fgaro@satlink.com
rbretal@fac.org.ar
rbretal@netverk.com.ar
apacher@fac.org.ar
apacher@satlink.com

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