Aspirin blocks the synthesis of thromboxane A2 by irreversibly inhibiting cyclooxygenase 1, thereby diminishing platelet aggregation. Four randomized trials have each demonstrated that, compared with placebo, aspirin reduces the risk of death or MI by more than 50% for patients presenting with UA/NSTEMI.35,36,119,120
The ACC/AHA guidelines recommend an initial daily dose of 162 to 325 mg, followed by a daily dose of 75 to 162 mg for long-term secondary prevention.42
Absolute contraindications to aspirin therapy include documented aspirin allergy (eg, asthma or anaphylaxis), active bleeding, or a known platelet disorder. Clopidogrel is a recommended alternative for patients who cannot tolerate aspirin.42
Clopidogrel. Clopidogrel is a thienopyridine derivative that blocks the P2Y12 adenosine diphosphate (ADP) receptor on platelets. This action decreases platelet activation and aggregation, increases bleeding time, and reduces blood viscosity. Therapy with clopidogrel and aspirin is recommended for essentially all patients with UA/NSTEMI.
The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial randomly assigned 12,562 patients to receive either aspirin alone (75-325 mg/d) or aspirin plus clopidogrel (300-mg loading dose, then 75 mg/d).121
The incidence of the primary end point of cardiovascular death, MI, or stroke was 20% lower for both low-risk and high-risk patients with UA/NSTEMI who received aspirin plus clopidogrel (11.4%) than for those who received aspirin alone (9.3%; P
Benefit was seen as early as 24 hours after the initiation of treatment (the Kaplan-Meier curves began diverging after just 2 hours) and continued throughout the trial's 1-year treatment period. Clopidogrel was associated with substantially more instances of major bleeding but not with more instances of life-threatening bleeding. The prespecified subgroup analysis, PCI-CURE, found that treatment with clopidogrel before PCI was also associated with a substantial benefit: the reduction in cardiac events was 31% at 30 days and at 1 year.122
On the basis of the results of the PCI-CURE trial, the CREDO (Clopidogrel for the Reduction of Events During Observation) trial and the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28) trial, together with the results of a meta-analysis (which found that, in comparison with no pretreatment, clopidogrel pretreatment reduced the incidence of cardiovascular death, MI, or stroke from randomization through 30 days by 41%; P
), the 2005 guidelines from the ACC, the AHA, and the Society for Coronary Angiography and Interventions contain a class I, level of evidence A recommendation for clopidogrel pretreatment before PCI.124,125
The risk of major bleeding was increased when patients had received clopidogrel within 5 days before undergoing CABG.38
Therefore, the ACC/AHA guidelines recommend discontinuing the administration of clopidogrel at least 5 days before surgery, if possible.42,126
The current practice in most hospitals is either to initiate clopidogrel administration at the time of admission (this action affords the benefits of reducing the incidence of early ischemic events and of pretreatment before PCI) or to delay treatment until after
coronary angiography has been performed, in which case the drug can be either administered while PCI is carried out or withheld until after CABG has been performed.
Newer P2Y12 ADP Inhibitors. A high rate of recurrent atherothrombotic events despite the administration of dual-antiplatelet therapy with aspirin and clopidogrel has sparked great interest in finding more potent inhibitors of the P2Y12 ADP receptor.
Prasugrel is an irreversible P2Y12 ADP receptor antagonist that was recently approved by the US Food and Drug Administration. Several studies have shown that prasugrel achieves much higher (nearly double) levels of platelet inhibition
than does daily clopidogrel dosing of 75 mg or even 150 mg.127
The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38) trial administered prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel to 13,608 high-risk patients with ACS who were scheduled for PCI.128
The incidence of the primary end point of cardiovascular death, MI, or stroke at 6 to 15 months was significantly lower in the prasugrel group (9.9%) than in the clopidogrel group (12.1%; P
<.001). The incidence of stent thrombosis was 52% lower with prasugrel (1.1%) than with clopidogrel (2.4%; P
<.001). The risk of TIMI major bleeding, including the risk of fatal bleeding, was higher for the patients receiving prasugrel (2.4%) than for those receiving clopidogrel (1.8%; P
Ticagrelor (AZD6140) is a reversible oral P2Y12 receptor antagonist with a half-life of approximately 12 hours. The recently completed PLATO (Study of Platelet Inhibition and Patient Outcomes) randomized 18,624 patients with ACS to either ticagrelor (loading dose of 180 mg followed by 90 mg twice daily) or clopidogrel for up to 12 months.129
The primary end point of death from vascular causes, MI, or stroke occurred in 9.8% of patients receiving ticagrelor vs 11.7% of those receiving clopidogrel (HR, 0.84; 95% CI, 0.77-0.92; P
<.001). The rate of death from any cause was also reduced with ticagrelor vs clopidogrel (4.5% vs 5.9%; P
<.001). The rates of major bleeding overall were similar between the ticagrelor and clopidogrel groups (11.6% vs 11.2%; P
GP IIb/IIIa Inhibitors.
The platelet GP IIb/IIIa inhibitors are potent and specific inhibitors of platelet aggregation. They act by interrupting the final common pathway of fibrinogen-mediated cross-linkage of platelets. Several large trials involving patients with UA/NSTEMI have shown that the GP IIb/IIIa inhibitors are of substantial benefit for patients at high risk, those undergoing PCI, or both.39,130
Three agents are currently available for use: abciximab, eptifibatide, and tirofiban. Abciximab is indicated only if angiography will not be appreciably delayed and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice. The main risk associated with GP IIb/IIIa inhibitors is an increased rate of hemorrhage, usually at the site of vascular intervention. Therefore, patients should be monitored closely for bleeding, and complete blood cell counts should be determined regularly.
The benefit of GP IIb/IIIa inhibition appears to be greatest for patients at higher risk of complications, eg, those with elevated troponin concentrations,62,63
previous aspirin use,132
or a TIMI risk score of 4 or higher.83
The benefit of GP IIb/IIIa inhibition has been confirmed even for patients who have been pretreated with clopidogrel.133
The optimal timing for the initiation of GP IIb/IIIa inhibitors has been debated. The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial involved 9492 patients who were randomly assigned either to early GP IIb/IIIa inhibition or to the provisional use of GP IIb/IIIa inhibitors after angiography. The results showed that early eptifibatide exerted no statistically significant benefit in reducing the composite end point of adverse cardiovascular events but was associated with a statistically significant increase in bleeding rates.134
The 2007 ACC/AHA guidelines recommend that, for patients with UA/NSTEMI who will be treated initially according to an invasive strategy, either an intravenous GP IIb/IIIa inhibitor or clopidogrel should be added to aspirin and anticoagulant therapy (upstream) before diagnostic angiography is performed (class I recommendation). They also state that adding both agents is reasonable (class IIa recommendation).42
The 2007 ACC/AHA UA/NSTEMI guidelines recommend the initiation of anticoagulant therapy for all patients (without contraindications) as soon as possible after presentation (class I recommendation). The guidelines recommend 4 agents as options: unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin (approved only for patients managed according to an invasive strategy).
The results of several randomized trials suggest that UFH is associated with lower rates of death or MI than is aspirin alone.36,120,135
The anticoagulant effects of UFH are variable.136
The ACC/AHA guidelines recommend weight-adjusted dosing of UFH (60 U/kg bolus and 12 U/kg/hr infusion), frequent monitoring of activated partial thromboplastin time (every 6 hours until 2 consecutive values are within the target range, and every 24 hours thereafter), and titration of UFH according to a standardized nomogram with a target range of activated partial thromboplastin time between 1.5 and 2.0 times that of control, or approximately 50 to 70 seconds.42
Administration of UFH should continue for at least 48 hours after presentation with UA/NSTEMI.42
Complete blood cell counts should be determined at least daily during therapy with UFH. Autoimmune heparin-induced thrombocytopenia in association with thrombosis is a rare but dangerous complication of UFH administration (incidence is <0.2%).137
When clinical findings suggest that this complication has occurred, all heparin therapy should be immediately discontinued.
Because the rates of recurrence of ischemic events remain high even when UFH is administered, low—molecular-weight heparins (LMWHs) were developed with the goal of providing improved anticoagulation. They are active against both factor Xa and factor IIa; therefore, they inhibit both the action and the generation of thrombin. Their other advantages over UFH include a lower rate of thrombocytopenia,138
more bioavailability, and less binding to plasma proteins, a factor that renders monitoring the level of anticoagulation unnecessary.
Various LMWHs (dalteparin, enoxaparin, and nadroparin) have been compared with UFH for the treatment of UA/NSTEMI, but only enoxaparin has been found to have a clear benefit. Early trials, such as ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) and the TIMI 11B, showed that, compared with UFH, enoxaparin achieved a 20% reduction in the incidence of death, MI, recurrent ischemia, or some combination of these factors.139
The SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial found that enoxaparin was not inferior to UFH in the setting of an early invasive strategy.140
However, enoxaparin achieved a clear benefit over UFH in the setting of a conservative strategy, as shown by the older trials and the more recent A-to-Z (Aggrastat to Zocor) trial.141
The 2007 ACC/AHA guidelines contain a class IIa recommendation stating that enoxaparin or fondaparinux (see Factor Xa Inhibitors) is preferable to UFH as anticoagulant therapy for UA/NSTEMI patients who will be treated conservatively, unless CABG is planned within 24 hours.42
The benefit of enoxaparin is greater for patients at higher risk, such as those with ST-segment deviation,142
elevated troponin concentrations,143
and high TIMI risk scores.82
The rates of major bleeding associated with LMWHs have been found to be similar to those associated with UFH, with 1 exception: the SYNERGY trial found a statistically significant increase in the incidence of major bleeding in association with enoxaparin administration.140
Direct Thrombin Inhibitors. Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors (such as UFH or LMWH): they do not require a cofactor such as antithrombin for their action and can thus directly inhibit clot-bound thrombin; they do not interact with plasma proteins; and they do not cause thrombocytopenia.
The administration of bivalirudin to patients with UA/NSTEMI was recently studied in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, which randomly assigned 13,819 patients with ACS managed with an early invasive strategy to one of 3 antithrombotic regimens: UFH (or enoxaparin) plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone.144
No differences in the rates of the primary end point (composite of death, MI, unplanned revascularization for ischemia, and major bleeding at 30 days) were observed between the group receiving UFH plus a GP IIb/IIIa inhibitor and the group receiving bivalirudin plus a GP IIb/IIIa inhibitor. However, the 30-day net clinical outcomes were significantly better for the group receiving bivalirudin alone than for the group receiving UFH plus a GP IIb/IIIa inhibitor (rates of primary end point, 10.1% vs 11.7%; P
=.015); this difference was due primarily to a substantially reduced rate of major bleeding. The ACC/AHA guidelines have given bivalirudin a class I recommendation for the treatment of patients with UA/NSTEMI selected for an early invasive strategy. The guidelines further state that it is reasonable to omit the administration of an intravenous GP IIb/IIIa antagonist if a thienopyridine is administered simultaneously with bivalirudin (class IIa recommendation).42
The 2007 ACC/AHA guidelines recommend the use of other direct thrombin inhibitors, such as lepirudin (recombinant hirudin) and argatroban, only for patients with heparin-induced thrombocytopenia.42
Factor Xa Inhibitors.
Fondaparinux is a synthetic pentasaccharide that is an indirect factor Xa inhibitor and requires antithrombin for its action. The OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial, which involved 20,078 patients with high-risk UA/NSTEMI, compared subcutaneous fondaparinux at a once-daily dose of 2.5 mg with standard-dose enoxaparin.145
Fondaparinux was found to be not inferior to enoxaparin in reducing the incidence of the primary outcomes of death, MI, or refractory ischemia at 9 days. The rate of major bleeding, however, was almost 50% lower in the fondaparinux arm than in the enoxaparin arm, and analyses using the composite variable of the primary outcome and major bleeding at 9 days demonstrated an advantage of fondaparinux over enoxaparin (incidence, 7.3% vs 9.0%; HR, 0.81; P
<.001). Fondaparinux was also associated with a statistically significant reduction in 30-day and 6-month mortality rates. In the subset of patients undergoing PCI, the risk of catheter-related thrombi was more than 3 times higher in the fondaparinux arm than in the enoxaparin arm; supplemental UFH at the time of catheterization appeared to minimize the risk of this complication.
The 2007 ACC/AHA guidelines contain a class I recommendation for fondaparinux as treatment for patients with UA/NSTEMI who will be managed by either a conservative strategy or an early invasive strategy, unless CABG is planned within 24 hours.42
They further state that fondaparinux is preferred over other anticoagulants for patients who are selected for a conservative treatment strategy and who are at an increased risk of bleeding (class I recommendation).
Trials of oral anticoagulation with warfarin after ACS have demonstrated the benefit of the combination of warfarin plus aspirin over aspirin alone, provided a sufficient degree of anticoagulation was achieved.146-148
However, a similar degree of benefit is seen
with clopidogrel plus aspirin rather than with aspirin alone, without the drawback of monitoring the international normalized ratio, as is necessary with warfarin therapy. In addition, the use of clopidogrel is well established for patients with ACS who undergo PCI and stenting. Thus, the clinical use of aspirin plus warfarin is limited. Occasionally, an indication for warfarin, in addition to aspirin and clopidogrel, arises after UA/NSTEMI (eg, for patients with atrial fibrillation, a mechanical prosthetic valve, or LV thrombus).
Discharge Antithrombotic Therapy.
The 2007 ACC/AHA guidelines provide clear recommendations for antithrombotic therapy at the time of discharge; these recommendations are based on the management strategy (). The benefits and risks of triple antithrombotic therapy with aspirin, clopidogrel, and warfarin have not been clearly established. Such therapy should be selected only when clear indications are present and should be administered for the shortest possible time and at the lowest effective doses: aspirin, 81 mg; warfarin, titrated to the dosage necessary to sustain an international normalized ratio of 2.0 to 2.5 (class IIb recommendation).42
Long-term antithrombotic therapy at hospital discharge after unstable angina (UA)/non—ST-segment elevation myocardial infarction (NSTEMI). LOE = level of evidence.