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Anticoagulant therapy in unstable angina and acute non-ST elevation myocardial infarction

Last literature review version 17.3: September 2009  |  This topic last updated: August 11, 2009   (More)

INTRODUCTION — Unstable angina (UA) and non-ST elevation (non-Q wave) myocardial infarction (NSTEMI) are part of the continuum of acute coronary syndrome (ACS), which also includes ST elevation (Q wave) myocardial infarction (STEMI). (See "Criteria for the diagnosis of acute myocardial infarction", section on 'Definitions' and "Classification of unstable angina and non-ST elevation myocardial infarction".)

The frequency of adverse outcomes such as myocardial infarction (MI), death, and heart failure in patients with UA and NSTEMI can be reduced with interventions such as antiischemic, antiplatelet, and anticoagulant (antithrombotic) medications, particularly if instituted early, as well as the use of an early invasive approach in selected patients. (See "Overview of the management of unstable angina and acute non-ST elevation myocardial infarction".)

ACS usually results from plaque disruption (fissure, erosion, or rupture) and the subsequent activation of circulating clotting elements and platelets by exposure to components of the arterial wall such as tissue factor. (See "The role of plaque rupture in acute coronary syndromes".)

The heparins and the direct antithrombin agents limit the conversion of fibrinogen to fibrin and therefore interfere with the formation of the scaffolding necessary for clot formation. (See "Overview of hemostasis" and "Therapeutic use of heparin and low molecular weight heparin".)

The heparins include unfractionated heparin, low molecular weight heparin, and fondaparinux, which is a synthetic heparin pentasaccharide that primarily acts by neutralizing factor Xa (algorithm 1). The direct thrombin inhibitors include hirudin, inogatran, and bivalirudin.

The use of these agents early in the treatment of patients with non-ST elevation ACS, including the supporting evidence, will be reviewed here. An overview of the total therapeutic approach to non-ST elevation ACS and the role of antiplatelet agents and chronic oral anticoagulation in this setting are discussed separately. (See "Overview of the management of unstable angina and acute non-ST elevation myocardial infarction" and "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction" and "Chronic anticoagulation after myocardial infarction".)

MECHANISMS OF ACTION — There are three classes of anticoagulants that have been evaluated in the management of acute coronary syndromes: the heparins (unfractionated and low molecular weight); the direct thrombin inhibitors; and fondaparinux, which is a synthetic heparin pentasaccharide.

The heparins — The heparins, including unfractionated heparin (UFH) and the low molecular weight heparins (LMWH), are indirect thrombin inhibitors that complex with antithrombin (AT, formerly known as AT III) and convert AT from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa. (See "Overview of hemostasis" and "Therapeutic use of heparin and low molecular weight heparin".)

Limitations to use — As described in the following sections, enoxaparin, bivalirudin, and fondaparinux may be associated with better outcomes than unfractionated heparin (UFH) in selected patients with non-ST elevation ACS. This difference may be due at least in part to UFH having a number of intrinsic limitations.

  • The most important is that the heparin-antithrombin (AT, formerly called antithrombin III) complex cannot bind or inactivate thrombin bound within a clot [1]. One possible mechanism is inability of the bulky heparin-AT complex to penetrate clot. In addition, the binding site for heparin-AT on the thrombin molecule is masked following the attachment of thrombin to fibrin or arterial wall matrix [1,2]. Such clot-bound thrombin acts as an important thrombogenic stimulus at a site of coronary thrombosis [2].
  • Heparin is susceptible to inactivation by circulating inhibitors released from activated platelets, including platelet factor 4 and heparinase [3].
  • The anticoagulant effect of heparin is diminished in states of acquired or inherited antithrombin deficiency.
  • Heparin binds to a number of tissue and plasma proteins, which alters the bioavailability and clearance of heparin; this binding makes dosing of this agent both complex and highly variable from patient to patient [4].
  • Heparin appears to have a platelet activating effect [5,6].

The direct thrombin inhibitors — The direct thrombin inhibitors (eg, hirudin, bivalirudin, lepirudin, inogatran, and ximelagatran) bind to and inactivate one or more of the active sites on the thrombin molecule [4]. These drugs share a number of the following properties which make them attractive as potential therapeutic agents compared to UFH:

  • Antithrombin is not required as a cofactor
  • Clot-bound thrombin can be inhibited
  • Circulating inhibitors do not inhibit their function
  • There is no appreciable binding to plasma proteins
  • There is no activation of platelets and, in contrast, these drugs inhibit thrombin-mediated platelet activation.

Thrombin bound to clot or fibrin derivatives is susceptible to inactivation by direct thrombin inhibitors, but is protected from inhibition by heparin [2].

Fondaparinux — The synthetic heparin pentasaccharide fondaparinux, acts through antithrombin to exclusively neutralize factor Xa.

UNFRACTIONATED HEPARIN

Efficacy — The following discussion will briefly review the evidence supporting benefit from heparin compared to no heparin and of heparin and aspirin compared to aspirin alone in non-ST elevation ACS. A major limitation to all of these trials is that they were performed prior to the use of current therapies that have substantially improved outcomes, including the addition of clopidogrel to aspirin, the use of glycoprotein IIb/IIIa inhibitors, and the performance of early revascularization in many patients. (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction" and "Coronary arteriography and revascularization for unstable angina or non-ST elevation acute myocardial infarction".)

Early randomized trials demonstrated that, in patients with non-ST elevation ACS, unfractionated heparin (UFH) was more effective than no therapy who were not treated with aspirin [7] and that heparin might be more effective than aspirin alone [7,8]. Later trials compared UFH to placebo or no therapy in aspirin-treated patients and demonstrated clear benefit from combined therapy [9,10]. A pooled analysis of six small trials demonstrated a significant short-term (seven days) reduction in death or MI with combined therapy compared to aspirin alone (summary odds ratio 0.53, 95% CI 0.38-0.73) [9]. The absolute benefit was approximately 3 events prevented per 100 patients treated.

More limited data suggests that UFH is more more effective when given by continuous intravenous infusion compared to intermittent boluses [11]. The relationship between improved clinical outcome and the degree of anticoagulation is unclear [12].

Complications — Despite its clinical benefit, continuous UFH infusion is associated with a small but significant incidence of complications. In addition, UFH requires frequent monitoring, the activated partial thromboplastin time can be difficult to control, and the UFH has a narrow therapeutic window. (See "Therapeutic use of heparin and low molecular weight heparin".)

There are three important complications of heparin therapy: major bleeding; thrombocytopenia; and reactivation of ischemia after heparin is discontinued [7,9,10,13].

Major bleeding — The main acute danger of heparin treatment is bleeding. Short-term UFH therapy compared to placebo in aspirin-treated patients was associated with an increase in the rate of major bleeding of approximately 0.7 to 1.5 percent in trials prior to percutaneous coronary intervention (PCI) and prior to the use of clopidogrel and glycoprotein (GP) IIb/IIIa inhibitors [9,10]. The rate of major bleeding appears to be similar with UFH and the low molecular weight heparin enoxaparin [14,15].

Among patients treated with UFH and aspirin, the incidence of major or severe bleeding, which is variably defined, is somewhat higher with the addition of a GP IIb/IIIa inhibitor compared to placebo in patients not undergoing PCI (eg, 1.5 versus 0.9 percent in the PURSUIT trial, and 4.0 versus 3.0 percent in PRISM-PLUS) [16,17]. The rates of major bleeding are higher when, in patients undergoing PCI, clopidogrel is given in addition to aspirin, heparin, and a GP IIb/IIIa inhibitor. (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction", section on 'Bleeding risk'.)

Thrombocytopenia — Issues related to heparin-induced thrombocytopenia are discussed below. (See 'Heparin-induced thrombocytopenia' below.)

Discontinuation of therapy and reactivation of ischemia — Although there is a trend toward benefit of continuous infusion of heparin or other antithrombin drugs alone compared to aspirin alone in the acute phase of management of non-ST elevation ACS, there may be a rebound in coronary ischemia within 12 hours of discontinuing UFH or LMWH therapy or the reactivation of unstable angina after hospital discharge [18-21].

Reactivation of ischemia after discontinuation of anticoagulant therapy has been evaluated ONLY in patients who underwent a conservative strategy (ie, no intended percutaneous intervention). For patients who undergo an early invasive approach with PCI, this problem is less likely to exist due to administration of a glycoprotein IIb/IIIa inhibitor and long term aspirin and clopidogrel use in most patients.

Reactivation of ischemia was seen in the PURSUIT, GUSTO-IIb, TIMI 11B, and ESSENCE trials [18,20-22]. Excess events in the form of death, MI, or urgent revascularization were detected as early as 4 to 12 hours after discontinuing heparin. Most events occurred in the first two days after withdrawal of heparin therapy. This general pattern was illustrated in pooled analysis from the TIMI 11B and ESSENCE trials in which cessation of short-term UFH or enoxaparin was associated with a 2.8 percent incidence of recurrent events on the first day, which accounted for 40 percent of recurrent events in the first week [18].

A rebound in thrombin generation appears to be responsible for the reactivation of coronary ischemia [23]. Thrombin generation and levels of D-dimer and antithrombin III complexes, both markers of coagulation, increase within one hour after heparin discontinuation and then rise steadily over the next 24 to 48 hours [24,25].

Recurrent ischemia can be prevented by coadministration of aspirin, prolonged antithrombin therapy, and perhaps other strategies:

  • The efficacy of aspirin was illustrated in a randomized trial in which patients with unstable angina were assigned to UFH, aspirin, both, or neither [19]. The rate of recurrent events (eg, reactivation of unstable angina or myocardial infarction) within 96 hours after hospitalization was 13.1 percent with UFH alone compared to 5.1 percent in the other three groups.
  • Similar efficacy of continued therapy with the GP IIb/IIIa inhibitor eptifibatide was seen in the PURSUIT trial [20]. In the 12 hours after cessation of UFH, patients who were on eptifibatide at the time of heparin cessation had, compared to placebo, a significantly lower mortality rate in the following two days (0.06 versus 0.68 percent). (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction".)
  • The potential efficacy of prolonged antithrombin therapy was illustrated in the pooled analysis from TIMI 11B and ESSENCE [18]. In this analysis, 1179 patients received continued outpatient treatment with enoxaparin at a fixed dose through day 43. During the first and second 24 hours after cessation of therapy with this prolonged regimen, there was no significant increase in cardiac events compared with the 24 hours prior to cessation (0.4 and 0.7 versus 0.2 percent). In contrast, as noted above, 2.8 percent of patients had recurrent events on the first day after cessation of short-term UFH or enoxaparin therapy. In addition, rebound ischemia after short-term therapy in ESSENCE was significantly lower with enoxaparin compared to UFH [22]. (See 'ESSENCE trial' below.)

LOW MOLECULAR WEIGHT HEPARIN — Low molecular weight heparin (LMWH) inactivates factor Xa, like UFH, but has a lesser effect on thrombin (algorithm 1). As a result, LMW heparins do not prolong the aPTT in a predictable fashion. They have a number of advantages over UFH, including a more predictable anticoagulant effect and a reduced likelihood of inducing immune-mediated thrombocytopenia. (See "Therapeutic use of heparin and low molecular weight heparin" and 'Heparin-induced thrombocytopenia' below.)

A number of trials have evaluated the effects of LMWH in patients with unstable angina or NSTEMI. The main conclusion from these trials is that enoxaparin provides comparable or superior benefit to UFH. The other LMWHs are effective compared to placebo, may be less effective than enoxaparin, are not more effective than UFH, and may be associated with an increased bleeding risk. The data supporting these conclusions are presented in the following sections.

Enoxaparin — The efficacy of enoxaparin was demonstrated in the ESSENCE, TIMI 11B, and SYNERGY trials.

ESSENCE trial — The ESSENCE trial compared the effectiveness of aspirin plus LMWH (enoxaparin, 1 mg/kg every 12 hours) to aspirin plus continuous intravenous UFH in 3171 patients with unstable angina (angina at rest) or acute NSTEMI; therapy was given for a minimum of 48 hours to a maximum of eight days [26]. At 30 days, enoxaparin therapy was associated with significant reductions in the incidence of a combined end point or death, MI, and recurrent angina (19.8 versus 23.3 percent with UFH) or a revascularization procedure (27.0 versus 32.2 percent). There was no difference between the two groups in the rates of major bleeding (6.5 versus 7.0 percent) or severe thrombocytopenia (0.4 versus 0.6 percent) [15]. These benefits were maintained at one year for both the combined end point (32 versus 36 percent) and the need for repeat revascularization (36 versus 41 percent) [27].

Enoxaparin therapy was also associated with a significantly lower rate of recurrent ischemic events on 48 hour ST segment monitoring after drug discontinuation (26 versus 45 percent with UFH) [22]. In addition, the duration of ischemic episodes was shorter with enoxaparin (4.6 versus 18.0 minutes per 24 hours). (See 'Discontinuation of therapy and reactivation of ischemia' above.)

TIMI 11B trial — The benefits of enoxaparin (1 mg/kg every 12 hours for eight days, then 40 to 60 mg every 12 hours through day 43) compared to UFH (continuous intravenous infusion for at least three days) in UA or NSTEMI were confirmed in the TIMI 11B trial of 3910 patients [14,28]. The incidence of the primary end point (death, MI, or urgent revascularization) was significantly lower with enoxaparin at eight days (12.4 versus 14.5 for heparin). There was no further incremental benefit with continued outpatient therapy through day 43 with enoxaparin (17.3 versus 19.7 percent), but major bleeding events were more frequent (2.9 versus 1.5 percent for placebo). The benefit of enoxaparin was limited to patients with elevated levels of troponin I [29], as was true with dalteparin and elevated troponin T in the FRISC trial discussed below [30].

Use with GP IIb/IIIa inhibitor — Intravenous GP IIb/IIIa inhibitors are beneficial in patients with a non-ST elevation ACS undergoing PCI and in those at high risk of further cardiac events. (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction".)

UFH has been compared to enoxaparin in patients receiving a GP IIb/IIIa inhibitor [31-34]. This issue was best addressed in Phase A of the A to Z trial, in which 3987 patients with a non-ST elevation ACS (74 percent NSTEMI) were treated with tirofiban and aspirin and then randomly assigned to enoxaparin or UFH [31]. An early invasive strategy was declared in 55 percent of the study subjects, at the discretion of the physician.

The following findings were noted:

  • At seven days, there was no significant difference in the incidence of the primary end point (death, MI, or refractory ischemia) between the enoxaparin and UFH arms (8.4 versus 9.4 percent; hazard ratio 0.88; 95% CI 0.71-1.08). These findings met the prespecified criteria for noninferiority and, although not significant, the 1 percent absolute reduction in the primary end point was consistent with the findings in the above trials performed without GP IIb/IIIa inhibitors.
  • An analysis of prespecified subgroups found no difference in outcome in the 55 percent of patients treated with an intended early invasive strategy (8.8 versus 8.5 percent). In contrast, there was a significant reduction in the primary end point with enoxaparin (7.7 versus 10.6 percent) in the remaining patients who were treated with an intended early conservative strategy.
  • The incidence of major bleeding was greater with enoxaparin (0.9 versus 0.4 percent with UFH) but there was no increase in transfusion rates.

The authors concluded that enoxaparin compares favorably to heparin in patients with non-ST elevation ACS treated with aspirin and tirofiban, although this benefit appeared limited to those treated with an intended early conservative strategy.

SYNERGY trial of use in PCI — There has been concern about the use of enoxaparin in patients with UA or NSTEMI scheduled for an early invasive strategy due to:

  • The inability to easily monitor or fully reverse the anticoagulant effects of LMWH.
  • The higher rate of bleeding with equivalent efficacy end points using enoxaparin compared to UFH in patients with an intended early invasive strategy in Phase A of the A to Z trial discussed in the preceding section [31].

This issue was formally evaluated in the SYNERGY trial of 10,027 patients with a non-ST elevation ACS for whom an early invasive management strategy was planned [35,36]. Patients were randomly assigned to receive open label enoxaparin (1 mg/kg subcutaneously every 12 hours) or UFH (60 U/kg initial bolus followed by an infusion of 12 U/kg per hour, adjusted to a goal activated partial thromboplastin time [aPTT] of 1.5 to 2.0 times the upper limit of normal or 50 to 70 seconds).

Concomitant medications in SYNERGY included aspirin (95 percent), clopidogrel or ticlopidine (66 percent), and a GP IIb/IIIa inhibitor (57 percent). Coronary angiography was performed in 92 percent of the SYNERGY patients; 47 percent underwent PCI and 19 percent underwent surgical revascularization.

The following findings were noted:

  • There was no significant reduction in the primary end point of death or nonfatal MI at 30 days or at six months with enoxaparin (14.0 versus 14.5 percent and 17.6 versus 17.8 percent, respectively, with UFH). There was also no difference in death or nonfatal MI or in all-cause mortality at one year (7.4 versus 7.8 percent).
  • There was a significant increase in in-hospital major bleeding by TIMI criteria (at least a 5 g/dL decrease in hemoglobin, at least a 15 percent decrease in hematocrit, or intracranial bleeding) with enoxaparin (9.1 versus 7.6 percent for UFH). There was no significant difference in the need for transfusion (17 versus 16 percent). These findings are consistent with those found in Phase A of the A to Z trial discussed above.
  • Both cardiovascular and bleeding outcomes were worse in patients initially treated with either enoxaparin or UFH and then switched over compared to patients who did not switch. (See 'Switching therapy' below.)

The results from SYNERGY suggest that, in patients with a non-ST elevation ACS who receive a GP IIb/IIIa inhibitor and undergo PCI, enoxaparin is as effective as UFH, but is associated with a small but statistically significant increase in major bleeding.

Dalteparin, nadroparin, and tinzaparin — Other LMWHs, including dalteparin, nadroparin, and tinzaparin, have been compared to placebo, UFH, or enoxaparin. These drugs have equivalent efficacy to UFH, may be less effective than enoxaparin, and may be associated with higher rates of major bleeding.

FRISC trial — The FRISC trial evaluated 1506 patients with non-ST elevation ACS who were randomly assigned to either placebo or LMWH (dalteparin) [37]. Dalteparin was given twice daily for five to seven days, followed by 7500 international units/day for five weeks in the long-term phase. The rate of death or new MI was significantly lower in patients treated with dalteparin (1.8 versus 4.8 percent) and there was a reduced frequency of the need for revascularization. The benefit associated with dalteparin was limited to patients with serum troponin T levels ≥0.1 µg/L [30]. The incidence of major and minor bleeding was the same as placebo.

FRAXIS trial — In the FRAXIS trial of over 2300 patients with a non-ST elevation ACS, intravenous UFH given for six days was compared with nadroparin given for either six or fourteen days [38]. There was no advantage to nadroparin compared to UFH in the incidence of the primary end point (cardiac death, MI, refractory angina, or recurrence of unstable angina at day 14). Furthermore, there was a significantly increased risk of major hemorrhage among those receiving nadroparin for fourteen days (3.5 versus 1.6 percent for UFH).

Comparison to enoxaparin in EVET trial — Enoxaparin and tinzaparin given for seven days were directly compared in the EVET trial of 438 patients with a non-ST elevation ACS [39]. Enoxaparin therapy was associated with a significantly greater reduction in the recurrence of unstable angina at seven days (11.8 versus 19.3 percent) and the incidence at 30 days of recurrent angina (17.3 versus 26.1 percent) or MI (0.5 versus 2.8 percent). The benefit persisted at six months, as the enoxaparin group had significantly lower rates of death, MI, or recurrent angina (26 versus 44 percent) and death or MI (2.7 versus 6.9 percent) [40].

Long-term therapy in FRIC and FRISC II — The efficacy of longer-term therapy with dalteparin was evaluated in two trials: in FRIC, in which patients received either dalteparin or placebo for 45 days after six days of dalteparin or UFH; and in FRISC II in which patients received dalteparin acutely and then dalteparin or placebo for three months [41,42]. There was no benefit of prolonged therapy in FRIC, which also failed to demonstrate better outcomes with dalteparin than with heparin. FRISC II found no difference in death or MI at three or six months. There was a reduction in the combined end point of death, MI, or revascularization at three months, but not at six months. However, there was an increased incidence of intracranial hemorrhage with dalteparin (5 versus 0 with placebo).

Anticoagulation monitoring with LMWH — A principal advantage of LMWH compared to UFH is the use of a weight-adjusted dose regimen that does not require monitoring of the anticoagulant effect [43]. Monitoring of anti-factor Xa activity was not performed in most trials nor is it routinely performed clinically. However, there is some evidence that patients who do not achieve anti-Xa activity >0.5 IU/mL have a higher rate of death or nonfatal MI [44].

Meta-analyses of enoxaparin versus UFH — A 2004 meta-analysis included data on 21,946 patients from six randomized trials including ESSENCE, TIMI 11B, Phase A of the A to Z, and SYNERGY trials [45]. Enoxaparin was associated with a significant reduction in the incidence of death or nonfatal MI at 30 days (10.1 versus 11.0 percent with UFH, odds ratio 0.91, 95% CI 0.83-0.99) [45]. A similar significant reduction in the rate of death or nonfatal MI at 30 days was noted in a 2007 meta-analysis (9.8 versus 11.4 percent with UFH, odds ratio 0.84) [46]. The two meta-analyses differed as to whether enoxaparin was [46] or was not [45] associated with a small but significant increase in major bleeding.

In analyses from TIMI 11B and ESSENCE, the benefit of enoxaparin was primarily seen in high-risk patients with TIMI risk scores ≥4 (TIMI 11B) or ≥5 (ESSENCE) (calculator 1) [47,48]. Such a subset analysis was not included in the meta-analyses.

The utility of the meta-analyses is limited by the heterogeneity of the studies evaluated. GP IIb/IIIa inhibitors were not used in ESSENCE and TIMI 11B, were given to all patients in Phase A of A to Z, and to approximately one-half of patients in SYNERGY. In addition, diagnostic catheterization was performed in 92 percent of patients in SYNERGY but in only 45 to 65 percent of patients in the other trials. Thus, the specific role of enoxaparin in patients treated with GP IIb/IIIa inhibitors and in patients undergoing invasive management cannot be determined from the meta-analyses.

Guidelines on heparin use — To summarize the above observations, enoxaparin and UFH appear to be of equal efficacy when patients with UA and NSTEMI are evaluated in the aggregate. However, patients who are managed by a conservative strategy appear to have fewer adverse cardiovascular events when treated with enoxaparin compared to UFH. On the other hand, for patients undergoing an early invasive strategy, UFH may be preferable due to the increased risk of bleeding with enoxaparin seen in the SYNERGY trial. (See 'SYNERGY trial of use in PCI' above.)

The 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on non-ST elevation ACS reached the following conclusions concerning the role of enoxaparin and UFH in such patients [49]:

  • Among patients in whom a conservative strategy is selected, either enoxaparin or UFH was recommended, but it was considered reasonable (a weaker recommendation) to prefer enoxaparin (or fondaparinux). The recommended duration of therapy was enoxaparin for the duration of hospitalization (maximum eight days) or UFH for 48 hours.
  • Among patients at increased risk for bleeding, fondaparinux was preferred. (See 'Fondaparinux' above.)

  • Among patients in whom coronary artery bypass graft surgery (CABG) is planned within the next 24 hours. UFH was preferred because its anticoagulant effect can be more rapidly reversed than that of enoxaparin. In patients already being treated with enoxaparin, enoxaparin should be discontinued and the patient should be switched to UFH at a dose consistent with institutional practice.
  • Among patients who undergo PCI, it was recommended that anticoagulant therapy be discontinued after the procedure in uncomplicated cases.
  • Among patients in whom medical therapy is selected after coronary angiography and a heparin has been given prior to angiography, enoxaparin should be continued for the duration of hospitalization (maximum eight days) and UFH should be continued for at least 48 hours or until discharge.

The other LMWHs - dalteparin, nadroparin, and tinzaparin - are not recommended in patients with a non-ST elevation ACS. Although these drugs are effective compared to placebo, they may be less effective than enoxaparin, are not more effective than UFH, and may be associated with an increased bleeding risk. (See 'Dalteparin, nadroparin, and tinzaparin' above.)

DIRECT THROMBIN INHIBITORS — Hirudin, a naturally occurring anticoagulant, and its synthetic analog bivalirudin, bind directly to the catalytic site of thrombin rather than to antithrombin. These drugs are therefore able to inactivate thrombin in blood clots in contrast to heparin, which acts only on soluble thrombin.

A number of trials have examined the use of hirudin and one the use of bivalirudin in unstable angina [50-53].

Hirudin — Two large trials, GUSTO IIb and OASIS-2, found a modest benefit from recombinant hirudin at the price of an increased risk of major bleeding.

GUSTO-IIb — GUSTO IIb compared recombinant hirudin (0.6 mg/kg bolus and 0.20 mg/kg per h) with unfractionated heparin (UFH) in 8011 patients who were considered to have a non-ST elevation acute coronary syndrome (ACS) [52]. At 30 days, hirudin therapy was associated was associated with a reduction in the incidence of the primary end point of death, nonfatal MI, or reinfarction (8.9 versus 9.8 percent, odds ratio 0.89, 95% CI 0.79-1.00). Hirudin was also associated with a significant increase in moderate (8.8 versus 7.7 percent) but not severe bleeding.

OASIS 2 — OASIS-2 randomly assigned 10,141 patients with non-ST elevation ACS to medium dose recombinant hirudin or UFH for 72 hours [53]. At seven days, hirudin therapy was associated with a significant reduction in the primary end point of cardiac death, new myocardial infarction, or refractory angina (5.6 versus 6.7 percent with UFH) and a lower frequency of revascularization (6 versus 7 percent). The benefit of hirudin persisted for 35 days (graph 1). The risk for major bleeding requiring transfusion was significantly greater with hirudin (1.2 versus 0.7 percent), but there was no difference in life-threatening bleeding or stroke.

The incidence of thrombocytopenia with hirudin was similar to that with UFH (1 percent) [54]. The development of thrombocytopenia was associated with significant increases in death (odds ratio 6.7), the need for revascularization, and major bleeding (with hirudin but not UFH). (See 'Heparin-induced thrombocytopenia' below.)

Role during PCI — The benefit of hirudin over heparin is particularly evident in patients with unstable angina who undergo a percutaneous coronary intervention (PCI). Short term (7 to 30 days) benefits, particularly a reduction in MI, were demonstrated in the HELVETICA trial, and in subset analyses in GUSTO IIb and OASIS-2 [55-57]. Longer term benefits were less clear.

Bivalirudin — An interest in bivalirudin (previously called hirulog) increased after the demonstration of increased bleeding with hirudin. The efficacy of bivalirudin in unstable angina was initially evaluated in the TIMI 7 trial and the Bivalirudin Angioplasty Study [58,59]. Results from these two trials suggested that, in patients undergoing PCI, bivalirudin was more effective than UFH and associated with a lower risk of major hemorrhage.

The efficacy of bivalirudin in the era of GP IIb/IIIa inhibitor therapy was subsequently evaluated in the much larger ACUITY trial. (See 'ACUITY trial' below.)

Inogatran — The TRIM trial compared inogatran, a low molecular weight selective thrombin inhibitor, to heparin in 1209 patients with unstable angina or non-Q wave myocardial infarction [60]. There was no evidence of benefit with inogatran.

Meta-analysis of early studies — In order to obtain more reliable estimates of the effect of direct thrombin inhibitors in patients with a non-ST elevation ACS, including those undergoing PCI, a meta-analysis performed by the Direct Thrombin Inhibitor Trialists' Collaborative Group included individual data from 35,970 patients enrolled in 11 randomized trials of four direct thrombin inhibitors who were followed for at least 30 days [61].

The following results were noted:

  • Direct thrombin inhibitors were associated with a significantly lower risk of death or MI at 30 days (7.4 versus 8.2 percent with UFH, odds ratio 0.91, 95% CI 0.84-0.99), which was primarily due to a reduction in MI. The treatment benefit was seen with hirudin and bivalirudin, but not with inogatran or argatroban. The better outcome was significant only in patients who underwent early PCI [62].
  • Compared to UFH, the risk of major bleeding was increased with hirudin and reduced with bivalirudin; there was no difference in intracranial hemorrhage.

ACUITY trial — Patients enrolled in the early trials included in the meta-analysis did not receive either glycoprotein (GP) IIb/IIIa inhibitors or clopidogrel on a regular basis. The efficacy and safety of bivalirudin alone or with GP IIb/IIIa inhibitors compared to UFH or enoxaparin with GP IIb/IIIa inhibitors was evaluated in the ACUITY trial of almost 14,000 patients with moderate to high risk acute coronary syndromes undergoing PCI [63,64]. The primary end point was a composite of death, MI, or unplanned revascularization for ischemia at 30 days.

Bivalirudin alone was noninferior to UFH or enoxaparin plus a GP IIb/IIIa inhibitor for the rate of ischemic complications at 30 days (7.8 versus 7.3 percent, relative risk 1.08, 95% CI 0.93-1.24), while the rate of major bleeding was significantly lower with bivalirudin (3.0 versus 5.7 percent, relative risk 0.53, 95% CI 0.43-0.65). A pre-specified analysis of 30-day and 1 year major bleeding rates revealed a progressive increase in the frequency of bleeding with age irrespective of therapy [65]. However, bivalirudin was associated with a significantly lower rate of non-CABG major bleeding in all ages group, with the magnitude of the absolute difference greatest inpatients ≥75 years (5.8 versus 10.1 percent).

Similar findings with bivalirudin alone were noted in the HORIZONS AMI trial of patients with ST elevation MI undergoing primary PCI. (See "Anticoagulant therapy in acute ST elevation myocardial infarction", section on 'Bivalirudin'.)

ACUITY also emphasized the importance of clopidogrel pretreatment in patients given bivalirudin who are not treated with a GP IIb/IIIa inhibitor. On subset analysis, ischemic outcomes tended to be worse if clopidogrel was not given before angiography or PCI. (See "Antithrombotic therapy for intracoronary stent implantation: Clinical trials", section on 'Bivalirudin'.)

Guidelines on direct thrombin inhibitor use — Hirudin has a small, but significant, benefit in non-ST elevation ACS (particularly in patients undergoing PCI) compared to UFH. However, it is associated with an increase in major bleeding episodes and the need for transfusion. Bivalirudin alone is as effective as UFH or enoxaparin plus a GP IIb/IIIa inhibitor in patients with moderate to high risk acute coronary syndromes undergoing PCI and is associated with a lower risk of bleeding.

The 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on non-ST elevation ACS reached the following conclusions concerning the direct thrombin inhibitors in such patients [49]:

  • Among patients in whom an invasive strategy is selected, bivalirudin was recommended, with enoxaparin, UFH, and fondaparinux being alternatives. When bivalirudin is selected as the anticoagulant, it is reasonable to omit a GP IIb/IIIa inhibitor before diagnostic angiography and PCI as long as clopidogrel (at least 300 mg) was given at least six hours earlier.
  • Among patients in whom CABG is selected as a treatment strategy after coronary angiography, discontinue bivalirudin three hours before CABG and switch to UFH at a dose consistent with institutional practice.
  • Among patients in whom medical therapy is selected after coronary angiography and bivalirudin has been given prior to angiography, either discontinue bivalirudin or continue at a dose of 0.25 mg/kg per h for up to 72 hours at the discretion of the physician.

SWITCHING THERAPY — A separate issue from the relative efficacy of the heparins and direct thrombin inhibitors is the effect of switching therapy. In the SYNERGY trial, patients with an ACS selected for an early invasive strategy, who are switched from either enoxaparin or heparin to the other prior to the procedure, had significantly worse outcomes [35]. In contrast, the trial as a whole found similar rates of cardiovascular events with enoxaparin and UFH with a modest increase in bleeding with enoxaparin. (See 'SYNERGY trial of use in PCI' above.)

The magnitude of this effect is illustrated by the following observations:

  • The 12 percent of patients who crossed over from UFH to enoxaparin had, compared to those who did not crossover, significantly higher rates of death or MI at 30 days (17.4 versus 13.5 percent) and any transfusion (30.2 versus 15.3 percent).
  • The 4 percent of patients who crossed over from enoxaparin to UFH had, compared to those who did not crossover, significantly higher rates of death or MI at 30 days (22.0 versus 14.2 percent) and any transfusion (35.1 versus 15.1 percent).

A similar issue with respect to bivalirudin was evaluated in a substudy in the ACUITY trial [66]. Patients who were already on either enoxaparin or heparin and then switched to bivalirudin had similar rates of ischemia and less major bleeding compared to those not switched. These findings were similar to those seen in patients who were not switched. (See 'ACUITY trial' above.)

FONDAPARINUX — The suggestion in the dose finding PENTUA study that fondaparinux and enoxaparin have similar efficacy in non-ST elevation ACS was directly evaluated in the OASIS-5 trial in which 20,078 patients were randomly assigned to fondaparinux (2.5 mg/day) or enoxaparin (1 mg/kg twice daily) for a mean of six days [67-70]. Over 60 percent of patients underwent catheterization and over 30 percent had PCI; these patients received weight-adjusted UFH if the last dose of enoxaparin was greater than six hours before the procedure.

For patients who received an initial dose of subcutaneous dose of fondaparinux and then underwent PCI, an additional dose was given intravenously (table 1).

The following findings were noted:

  • The two groups had similar rates of the primary end point, defined as death, MI, or refractory ischemia at nine days (5.8 versus 5.7 percent with enoxaparin), and the secondary end point of death or MI (4.1 percent in both groups).
  • At longer term follow-up, there was a reduction in the primary end point with fondaparinux at 30 days (2.9 versus 3.5 percent, hazard ratio 0.83, 95% CI 0.71-0.97) and six months (5.8 versus 6.5 percent, hazard ratio 0.89, 95% CI 0.81-1.00). These differences were entirely due to a significantly lower rate of death.
  • The rate of major bleeding was significantly reduced with fondaparinux (2.2 versus 4.1 percent, HR 0.52, 95% CI 0.44-0.61). However, it is unclear what role the addition of unfractionated heparin (UFH) in the catheterization laboratory played in the excess bleeding noted in patients treated with enoxaparin.
  • The benefits and risks were consistent among various subgroups, including age and sex, the spectrum of renal function, and whether or not revascularization was performed within nine days [67,68].

The safety of fondaparinux relative to enoxaparin was confirmed in two important prespecified subgroups:

  • In the 6238 patients who underwent PCI, fondaparinux significantly reduced major bleeding at day nine (2.4 versus 5.1 percent, hazard ratio 0.46, 95% CI 0.35-0.61), with comparable rates of the combined end point of death, MI or stroke [69]. Fondaparinux was associated with a small but significant increase in catheter-related thrombi (0.9 versus 0.4 percent). The frequency of catheter related thrombi was significantly reduced in both groups in those patients who received open-label UFH before the procedure.
  • Fondaparinux significantly reduced major bleeding in the 3630 patients who received GP IIb/IIIa inhibitors and the 13,531 patients who received thienopyridines (5.2 versus 8.2 percent, hazard ratio 0.46, 95% CI 0.35-0.61 and 3.4 versus 5.4 percent, hazard ratio 0.62, 95% CI 0.52-0.73 respectively) [70]. Ischemic events were similar between the two treatment arms in these two subsets, as in the entire OASIS-5 population. In addition these findings regarding safety and efficacy were similar in the 3246 patients who received both antiplatelet therapies.

Guidelines on fondaparinux use — The 2007 ACC/AHA guidelines on non-ST elevation ACS reached the following conclusions on the use of fondaparinux [49]:

  • Among patients undergoing an early invasive strategy, fondaparinux had established efficacy along with enoxaparin, UFH, and bivalirudin. In fondaparinux if given, supplemental UFH should be administered during PCI.

However, our experts do not recommend the use of fondaparinux in patients undergoing an invasive strategy, as a second anticoagulant (either heparin or bivalirudin) must be given to prevent catheter related thrombosis.

  • When CABG is planned with 24 hours, UFH was preferred to fondaparinux or enoxaparin, since its anticoagulant effect can be more rapidly reversed.

The 2007 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of non-ST segment elevation ACS recommended fondaparinux in preference to LMWH for patients in whom a decision between an early invasive or conservative strategy had not been made [71]. This recommendation was made based upon the favorable efficacy/safety profile of fondaparinux seen in the OASIS-5 trial. In patients not at increased risk for bleeding, LMWH was thought to represent a reasonable alternative.

The 2008 American College of Chest Physicians guidelines on Antithrombotic and thrombolytic therapy recommended fondaparinux over enoxaparin for patients in whom a conservative or delayed invasive strategy of management was to be used [72].

The ESC guidelines also made the following points regarding the use of fondaparinux:

  • UFH in standard dose (30-100 units/kg bolus) should be added in the catheterization laboratory for patients undergoing PCI because of the associated increase in guiding catheter thrombosis seen in other trials.
  • Fondaparinux can be stopped within 24 hours of an invasive procedure.
  • Fondaparinux may be continued until the time of discharge in patients undergoing a conservative strategy.

The guidelines did not recommend fondaparinux in patients who required an urgent/emergent procedure, presumably because there was insufficient evidence for its use in this setting.

Based upon available evidence, we suggest that fondaparinux be used as the anticoagulant agent in patients with UA/NSTEMI at increased risk for bleeding, who are managed with a conservative strategy. Bivalirudin is preferred to enoxaparin and UFH in patients undergoing an invasive approach who are at increased risk of bleeding.

HEPARIN-INDUCED THROMBOCYTOPENIA — The incidence of immune-mediated heparin-induced thrombocytopenia (HIT) is approximately 2.5 to 3.0 percent in patients exposed to UFH for more than four days [73]. The incidence is much lower in patients treated with UFH for less than four days (0.2 percent) and in those treated with LMW heparin (0.2 versus 2.6 percent with UFH in a meta-analysis of studies that mostly consisted of patients who had undergone orthopedic surgery) [73]. The development of immune-mediated HIT is particularly important because it is associated with a high risk of venous and arterial thrombotic events. (See "Heparin-induced thrombocytopenia".)

Based upon these observations, the ACC/AHA guidelines on non-ST elevation acute coronary syndromes recommended that the platelet count should be measured serially in patients treated with UFH [57]. Routine monitoring of the platelet count is not recommended in patients treated with LMW heparin or fondaparinux.

In patients with a history of HIT, or in whom HIT develops or is suspected while on UFH therapy, the preferred anticoagulant is bivalirudin rather than argatroban or lepirudin because its efficacy has been established in patients with non-ST elevation acute coronary syndromes. LMW heparin should also be avoided since it may crossreact with the heparin-induced antibodies. (See "Heparin-induced thrombocytopenia" and 'ACUITY trial' above.)

SUMMARY AND RECOMMENDATIONS — Anticoagulant therapy is used to prevent thrombus related events in patients with UA/NSTEMI . Combination therapy with anticoagulants and antiplatelet agents has been show to reduce the incidence of MI, death, and need for revascularization (in patients managed with a conservative strategy). An increased risk of patient bleeding exists with these agents and decisions surrounding their use must weigh benefits and risks.

The 2007 ACC/AHA guidelines on non-ST elevation ACS reached the following general conclusions regarding anticoagulant therapy [49]:

  • Among patients in whom an invasive strategy is selected, drugs with established efficacy include enoxaparin, UFH, bivalirudin, and fondaparinux.
  • Among patients in whom a conservative strategy is selected, drugs with established efficacy include enoxaparin, UFH, and fondaparinux. Enoxaparin and fondaparinux were considered preferable to UFH. Fondaparinux was also recommended in such patients who are at increased risk for bleeding.
  • Among patients in whom CABG is planned with 24 hours, UFH was preferred to fondaparinux or enoxaparin, since its anticoagulant effect can be more rapidly reversed.

The recommendations for the use of specific drugs are presented in the appropriate sections above. The following will provide general recommendations for the use of anticoagulant therapy in non-ST elevation ACS. (See 'Guidelines on heparin use' above and 'Guidelines on direct thrombin inhibitor use' above and 'Guidelines on fondaparinux use' above.)

Since strong evidence supporting the use of one anticoagulant over another is not present for many patient situations, clinicians may choose one agent over another based upon issues such as cost, availability, and local practice patterns. Enoxaparin has been chosen in preference to UFH by some experts in many situations for the following reasons:

  • Ease of administration without the need for monitoring [43]

  • Possible improvement in outcomes, particularly in patients with high-risk features or those managed with a conservative strategy. (See 'Enoxaparin' above.)

For all patients with UA/NSTEMI we recommend initiation of anticoagulant therapy, in addition to antiplatelet therapy, as soon as possible after presentation (Grade 1A).

The potentially useful anticoagulant agents and their dosing schedules include:

  • UFH — Intravenous bolus of 50-60 units/kg followed by 12 units/kg per h intravenously to achieve an activated partial thromboplastin time of 50 to 75 seconds.

Effective in early October 2009, heparin will be manufactured in the United States according to a new standard and concerns about potency have arisen. For patients who are managed early in their course with activated clotting times (ACT), this change in formulation will not likely affect practice. For those patients who are managed with only activated PTTs (aPTT), the management strategy should be determined at the local institution. This issue is discussed in detail separately. (See "Therapeutic use of heparin and low molecular weight heparin", section on Effect of the change in heparin potency.)

  • Enoxaparin — Loading dose of 30 mg intravenous bolus followed by 1 mg/kg subcutaneously twice daily (or once daily in patients with an estimated creatinine clearance less than 30 mL/min).
  • Fondaparinux — 2.5 mg subcutaneously once daily. UFH or bivalirudin should be added in the catheterization laboratory if PCI is performed. (See 'Fondaparinux' above.)

  • Bivalirudin — Intravenous bolus of 0.1 mg/kg and an infusion of 0.25 mg/kg per h before angiography; if PCI is performed, an additional 0.5 mg/kg bolus is given and the infusion rate is increased to 1.75 mg/kg per h.

The choice of anticoagulant agent depends on the particular clinical scenario:

For patients in whom an urgent/emergent invasive strategy (immediate transfer to the catheterization laboratory) is planned, we recommend UFH (Grade 1B).

For patients in whom an early invasive strategy is planned, we suggest bivalirudin  (Grade 2B). Enoxaparin, and UFH are other acceptable alternatives. (See 'Bivalirudin' above and 'Fondaparinux' above.)

For patients at high risk of bleeding in whom an early invasive strategy is planned, we recommend either bivalirudin in preference to either enoxaparin or UFH (Grade 1B). (See 'Bivalirudin' above.)

For patients in whom a conservative strategy is planned, we suggest fondaparinux (Grade 2A). Enoxaparin and UFH are acceptable alternatives. (See 'Meta-analyses of enoxaparin versus UFH' above and "Periprocedural complications of percutaneous coronary intervention", section on 'Access site bleeding'.)

If catheterization is performed after initial medical therapy has been initiated, the subsequent anticoagulant approach depends upon which anticoagulant was given initially.

  • If UFH was given, we continue with an additional bolus of UFH after sheath insertion with an activated clotting time (ACT) of 200 to 250 seconds if the patient is treated with a GP IIb/IIIa inhibitor and 250 to 300 seconds if a GP IIb/IIIa inhibitor has not been given and is not planned during PCI.
  • If enoxaparin was initiated and two or more doses were given and the last dose was given less than eight hours earlier, we proceed without additional enoxaparin or UFH.
  • If enoxaparin was initiated and the patient was given only one dose or the last dose was more than eight hours earlier, we give an additional bolus of enoxaparin (0.3 mg) or give UFH according to the above protocol. It may be better to continue with enoxaparin, especially if anticoagulation may be continued after the procedure, since extrapolation from SYNERGY suggests that switching to UFH may be associated with an increased risk of death or MI at 30 days. (See 'SYNERGY trial of use in PCI' above.)

  • If fondaparinux was initiated, UFH in standard dose (30-100 units/kg bolus) should be added in the catheterization laboratory for patients undergoing PCI because of the associated increase in guiding catheter thrombosis. An additional intravenous dose of either 2.5 or 5 mg may be required also. (See 'Fondaparinux' above.)

The duration of anticoagulant therapy depends on the initial management strategy, although the optimal treatment length has not been determined:

  • For patients receiving a conservative approach, UFH has been continued two to five days in most trials. Fondaparinux and enoxaparin have been continued for the duration of hospitalization (up to eight days).
  • For patients undergoing an invasive approach, anticoagulant therapy is stopped at the end of the procedure in uncomplicated cases.

Our recommendations are generally in accord with the 2004 Seventh ACCP Consensus Conference on Antithrombotic Therapy, the 2007 ACC/AHA guidelines and the 2007 European Society of Cardiology (ESC) guidelines, but differ in the following two ways [49,71,72]:

  • The ACC/AHA guidelines give no preference for the use of UFH, enoxaparin, fondaparinux, or bivalirudin in patients in when an invasive strategy is selected, but state that the evidence for the use of the first two is stronger. The ESC guidelines prefer bivalirudin or heparin to enoxaparin in this setting, and state the evidence for the use of bivalirudin is stronger than that for heparin.
  • The ESC guidelines prefer fondaparinux to either enoxaparin, bivalirudin or UFH for patients in whom an urgent/emergent procedure is not necessary. Enoxaparin is an acceptable alternative for patients with a low bleeding risk.

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REFERENCES

  1. Weitz, JI, Hudoba, M, Massel, D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III independent inhibitors. J Clin Invest 1990; 86:385.
  2. Weitz, JI, Leslie, B, Hudoba, M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97:544.
  3. Eitzman, DT, Chi, L, Saggin, L, et al. Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4. Circulation 1994; 89:1523.
  4. Lefkovits, J, Topol, EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90:1522.
  5. Xiao, X, Theroux, P. Platelet activation with unfractioned heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97:251.
  6. Sobel, M, Fish, WR, Toma, N, et al. Heparin modulates integrin function in human platelets. J Vasc Surg 2001; 33:587.
  7. Theroux, P, Ouimet, H, McCans, J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319:1105.
  8. Theroux, P, Waters, D, Qiu, S, et al. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88:2045.
  9. Eikelboom, JW, Anand, SS, Malmberg, K, et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355:1936.
  10. Collins, R, MacMahon, S, Flather, M, et al. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials. BMJ 1996; 313:652.
  11. Neri Serneri, GG, Gensini, GF, Poggesi, L, et al. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet 1990; 335:615.
  12. Becker, RC, Cannon, CP, Tracey, RP, et al. Relation between systemic anticoagulation as determined by activated partial thromboplastin time and heparin measurements and in-hospital clinical events in unstable angina and non-Q wave myocardial infarction. Thrombolysis in Myocardial Ischemia III B Investigators. Am Heart J 1996; 131:421.
  13. Oler, A, Whooley, MA, Oler, J, Grady, D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. JAMA 1996; 276:811.
  14. Antman, EM, McCabe, CH, Gurfinkel, EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999; 100:1593.
  15. Berkowitz, SD, Stinnett, S, Cohen, M, et al. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2001; 88:1230.
  16. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998; 339:436.
  17. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998; 338:1488.
  18. Bijsterveld, NR, Peters, RJ, Murphy, SA, et al. Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: results from the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) studies. J Am Coll Cardiol 2003; 42:2083.
  19. Theroux, P, Waters, D, Lam, J, et al. Reactivation of unstable angina after discontinuation of heparin. N Engl J Med 1992; 327:141.
  20. Lauer, MA, Houghtaling, PL, Peterson, JG, et al. Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation 2001; 104:2772.
  21. Bahit, MC, Topol, EJ, Califf, RM, et al. Reactivation of ischemic events in acute coronary syndromes: results from GUSTO-IIb. Global Use of Strategies To Open occluded arteries in acute coronary syndromes. J Am Coll Cardiol 2001; 37:1001.
  22. Goodman, SG, Barr, A, Sobtchouk, A, et al. 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.
  23. Bijsterveld, NR, Moons, AH, Meijers, JC, et al. Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin. J Am Coll Cardiol 2002; 39:811.
  24. Flather, MD, Weitz, JI, Yusuf, S, et al. Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial. OASIS Pilot Study Investigators. Organization to Assess Strategies for Ischemic Syndromes. Eur Heart J 2000; 21:1473.
  25. Becker, RC, Spencer, FA, Li, Y, et al. Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: potential mechanisms for heightened prothrombotic potential. J Am Coll Cardiol 1999; 34:1020.
  26. Cohen, M, Demers, C, Gurfinkel, EP, et al, 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.
  27. Goodman, SG, Cohen, M, Bigonzi, F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol 2000; 36:693.
  28. Bozovich, GE, Gurfinkel, EP, Antman, EM, et al. Superiority of enoxaparin versus unfractionated heparin for unstable angina/non-Q-wave myocardial infarction regardless of activated partial thromboplastin time. Am Heart J 2000; 140:637.
  29. Morrow, DA, Antman, EM, Tanasijevic, M, et al. 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.
  30. 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.
  31. Blazing, MA, de Lemos, JA, White, HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004; 292:55.
  32. Goodman, SG, Fitchett, D, Armstrong, PW, et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 2003; 107:238.
  33. Cohen, M, Theroux, P, Borzak, S, et al. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin. Am Heart J 2002; 144:470.
  34. Mukherjee, D, Mahaffey, KW, Moliterno, DJ, et al. Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network B (PARAGON B). Am Heart J 2002; 144:995.
  35. Ferguson, JJ, Califf, RM, Antman, EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004; 292:45.
  36. Mahaffey, KW, Cohen, M, Garg, J, et al. High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. JAMA 2005; 294:2594.
  37. Low-molecular-weight heparin during instability in coronary artery disease. Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet 1996; 347:561.
  38. 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.
  39. Michalis, LK, Katsouras, CS, Papamichael, N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am Heart J 2003; 146:304.
  40. Katsouras, C, Michalis, LK, Papamichael, N, et al. Enoxaparin versus tinzaparin in non-ST elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months. Am Heart J 2005; 150:385.
  41. Klein, W, Buchwald, A, Hillis, SE, et al, for the FRIC Investigators. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation 1997; 96:61.
  42. Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Investigators. Lancet 1999; 354:701.
  43. Kaul, S, Shah, PK. Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol 2000; 35:1699.
  44. Montalescot, G, Collet, JP, Tanguy, ML, et al. Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004; 110:392.
  45. Petersen, JL, Mahaffey, KW, Hasselblad, V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA 2004; 292:89.
  46. Murphy, SA, Gibson, CM, Morrow, DA, et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007; 28:2077.
  47. Antman, EM, Cohen, M, Bernink, PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000; 284:835.
  48. Sabatine, MS, McCabe, CH, Morrow, DA, et al. Identification of patients at high risk for death and cardiac ischemic events after hospital discharge. Am Heart J 2002; 143:966.
  49. Anderson, J, Adams, C, Antman, E, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College or Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007; 50:e1. Available at: www.acc.org/qualityandscience/clinical/statements.htm (accessed September 18, 2007).
  50. Topol, EJ, Fuster, V, Harrington, RA, et al. Recombinant hirudin for unstable angina pectoris. Circulation 1994; 89:1557.
  51. Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation 1997; 96:769.
  52. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med 1996; 335:775.
  53. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet 1999; 353:429.
  54. Eikelboom, JW, Anand, SS, Mehta, SR, et al. Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation: Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) study. Circulation 2001; 103:643.
  55. Serruys, PW, Herrman, JP, Simon, R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. N Engl J Med 1995; 333:757.
  56. Roe, MT, Granger, CB, Puma, JA, et al. Comparison of benefits and complications of hirudin versus heparin for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. Am J Cardiol 2001; 88:1403.
  57. Mehta, SR, Eikelboom, JW, Rupprecht, HJ, et al. Efficacy of hirudin in reducing cardiovascular events in patients with acute coronary syndrome undergoing early percutaneous coronary intervention. Eur Heart J 2002; 23:117.
  58. Fuchs, J, Cannon, CP, and TIMI 7 Investigators. Hirulog in the treatment of unstable angina. Circulation 1995; 92:727.
  59. Bittl, JA, Chaitman, BR, Feit, F, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952.
  60. A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients. A double-blind, randomized, dose-finding study. Thrombin inhibition in Myocardial Ischaemia (TRIM) study group. Eur Heart J 1997; 18:1416.
  61. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Lancet 2002; 359:294.
  62. Sinnaeve, PR, Simes, J, Yusuf, S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 2005; 26:2396.
  63. Stone, GW, McLaurin, BT, Cox, DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355:2203.
  64. Stone, GW, White, HD, Ohman, EM, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369:907.
  65. Lopes, RD, Alexander, KP, Manoukian, SV, et al. Advanced age, antithrombotic strategy, and bleeding in non-ST-segment elevation acute coronary syndromes: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009; 53:1021.
  66. White, HD, Chew, DP, Hoekstra, JW, et al. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008; 51:1734.
  67. Yusuf, S, Mehta, SR, Chrolavicius, S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464.
  68. Fox, KA, Bassand, JP, Mehta, SR, et al. Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007; 147:304.
  69. Mehta, SR, Granger, CB, Eikelboom, JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007; 50:1742.
  70. Jolly, SS, Faxon, DP, Fox, KA, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol 2009; 54:468.
  71. Bassand, JP, Hamm, CW, Ardissino, D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007; 28:1598.
  72. Harrington, RA, Becker, RC, Cannon, CP, et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:670S.
  73. Martel, N, Lee, J, Wells, PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710.
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