Non-ST-Segment Elevation MI and Unstable Angina: What Role for Anticoagulants and Antiplatelet Agents?

Varying degrees of coronary atherothrombosis are seen in patients with acute coronary syndromes (ACS), from significant coronary stenosis in unstable angina to overt occlusion of coronary blood flow in ST-segment elevation myocardial infarction (STEMI). The goal of treatment in all cases is the restoration and maintenance of myocardial perfusion. To this end, numerous pharmacological agents are available, as well as percutaneous coronary intervention (PCI). The agents used target multiple sites in the coagulation cascade (Figure 1).

In this article, we review the recommended uses of the various antiplatelet and anticoagulant agents in the treatment of non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina, and we summarize the evidence for these recommendations. There is currently no role for fibrinolytic agents in the management of either unstable angina or NSTEMI. In a coming issue, we will review the treatment of STEMI.

PATHOPHYSIOLOGY OF NSTEMI AND UNSTABLE ANGINA
NSTEMI and unstable angina are clinical syndromes of chest pain accompanied by ST-segment depression or ischemic T-wave inversion on a 12-lead ECG. In NSTEMI, levels of serum biochemical markers of myocardial ischemia are elevated, indicating myocardial injury. In unstable angina, the levels of biochemical markers are normal.

Unstable angina is defined as a progression in the quality, duration, or frequency of angina, or the presence of angina at rest. NSTEMI results from rupture of an unstable coronary plaque with subsequent thrombus formation and incomplete occlusion of blood flow and/or microembolization down the affected artery. Both entities represent a mismatch between myocardial oxygen supply and demand. Moreover, both NSTEMI and unstable angina can progress rapidly and cause significant loss of ischemic myocardial tissue if not recognized and promptly treated.

ANTIPLATELET THERAPY
The antiplatelet agents used in NSTEMI and unstable angina include aspirin, clopidogrel, and glycoprotein (GP) IIb/IIIa inhibitors.

Aspirin.This agent irreversibly inhibits cyclooxygenase-1 in platelets, thereby preventing the formulation of thromboxane A₂, which is a powerful mediator in platelet aggregation. When given orally as a chewable tablet, aspirin is rapidly absorbed through the buccal mucosa. In accord with the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, we recommend immediate administration of 4 chewable 81-mg non-enteric-coated aspirin, followed by daily maintenance with 75 to 162 mg (325 mg if a coronary stent is placed).¹ Aspirin therapy alone has been shown to significantly decrease mortality in patients with ACS when compared with placebo.²

Clopidogrel. Clopidogrel belongs to the thienopyridine class of drugs, which inhibit platelet aggregation by antagonizing adenosine 5'-diphosphate (ADP) receptors. In the CURE trial (acronyms for all trials mentioned in this article are expanded in the Box), 12,562 patients were randomized to receive either clopidogrel/aspirin (loading dose of clopidogrel, 300 mg, followed by 75 mg/d) or placebo/aspirin. The initial dose was given within 12 hours of presentation for NSTEMI, and treatment was continued for a minimum of 3 months (mean duration of treatment, 9 months). Treatment with clopidogrel and aspirin was associated with a 20% reduction in the relative risk of the primary composite end point of cardiovascular death, myocardial infarction (MI), or stroke. Benefit was seen as early as 2 hours after initiation of treatment, and patients continued to derive benefit from the treatment throughout the 12-month follow-up period (Figure 2). There was a statistically significant increase in major bleeding in the clopidogrel treatment group, but the overall rate was low (3.7% vs 2.7% in the placebo group; P = .001).³

One caveat regarding early treatment with clopidogrel is that as many as 15% of patients with NSTEMI or unstable angina subsequently need coronary artery bypass grafting (CABG).⁴ In these patients, administration of clopidogrel increases rates of major bleeding complications if CABG is performed less than 5 days after the last dose. Early treatment with clopidogrel thus increases the perioperative complication rate in a population already at high risk—or necessitates a 5- to 7-day waiting period for CABG.⁵ Current ACC/ AHA guidelines recommend waiting at least 5 days after administration of clopidogrel before performing CABG.

For these reasons, many institutions, including our own, have initiated policies for NSTEMI patients that delay treatment with clopidogrel in favor of dual antiplatelet therapy with aspirin and a short-acting GP IIb/IIIa inhibitor coupled with an early invasive strategy; clopidogrel use is postponed until the coronary anatomy has been defined.

If clopidogrel is used before angiography, current guidelines recommend a loading dose of 300 mg followed by continued treatment (75 mg/d) for 12 months, although longer durations may be indicated in patients who receive drug-eluting stents. The recommendation to extend clopidogrel therapy in the latter group of patients is based on recent studies that show increased rates of in-stent thrombosis after termination of clopidogrel therapy as late as 18 months after placement of a drug-eluting stent.⁶

GP IIb/IIIa inhibitors. Abciximab, eptifibatide, and tirofiban are currently available in the United States. All these agents inhibit platelet aggregation by binding to the GP IIb/IIIa receptor on the platelet surface, thereby preventing platelet adhesion and cross-linking with fibrinogen. When they are used in combination with unfractionated heparin or enoxaparin, a synergistic effect is seen. All 3 GP IIb/IIIa inhibitors are administered intravenously, starting with a bolus and followed by continuous drip.

In NSTEMI and unstable angina, numerous trials have shown a reduction in the combined end point of mortality, MI, and urgent revascularization as well as a reduction in the rate of rehospitalization with the use of a GP IIb/IIIa inhibitor.^7,8 The FRISC II and TACTICS TIMI-18 trials demonstrated an additional benefit when a GP IIb/IIIa inhibitor was combined with an early invasive strategy (Figure 3).^9,10 Thus, we recommend early (within 48 hours of pre-sentation) initiation of GP IIb/IIIa inhibitors in combination with cardiac catheterization. The largest benefit from early use of GP IIb/IIIa inhibitors is seen in patients at high risk, particularly those with significant elevations in troponin levels.

Early administration of tirofiban or eptifibatide is indicated in patients with NSTEMI who are at moderate to high risk. Abciximab is indicated only in patients who undergo percutaneous transluminal coronary angioplasty/stent placement in the cardiac catheterization laboratory; this agent should not be administered during the early treatment of ACS.^11,12

Significant antibody-mediated reactions to platelets, resulting in severe thrombocytopenia, have been reported with all GP IIb/IIIa inhibitors. Daily monitoring of the complete blood cell count—specifically the platelet count—is required when these agents are used. Both eptifibatide and tirofiban can be given for up to 72 hours; the recommended duration of therapy with abciximab is 24 hours.

ANTICOAGULANT THERAPY
The agents used for anticoagulation in patients with NSTEMI or unstable angina include unfractionated heparin, various low molecular weight heparins (LMWHs), and the direct thrombin inhibitor, bivalirudin.

Unfractionated heparin. This is a heterogeneous mixture of glycoaminoglycans of varying molecular sizes and weights. Unfractionated heparin combines with antithrombin, inactivating factor IIa (thrombin) and factors IXa, Xa, XIa, and XIIa. Treatment doses of unfractionated heparin are directed at maintaining an activated partial thromboplastin time of 1.5 to 2.0 times control (about 50 to 70 seconds). One drawback to therapy with unfractionated heparin is that its molecules react to multiple plasma proteins and interact with endothelial receptors; as a result, there is significant individual variation in this agent's effect. The benefits of unfractionated heparin are that it is relatively inexpensive, that measurement of its activity is quickly and easily performed, and that its effects can be rapidly and fully reversed with protamine.

LMWHs. These agents are created by chemical or enzymatic depolymerization of unfractionated heparin. Depolymerization yields fragments that are roughly one third the size of a standard heparin molecule. Unlike the larger unfractionated heparin molecule, these smaller fragments are not large enough to bind to both thrombin and antithrombin. However, these compounds all contain the sequence needed to bind to and inactivate factor Xa. Thus, although each of the LMWHs (eg, dalteparin, enoxaparin) exhibits a different ratio of IIa/Xa inhibition, they all have a greater effect on factor Xa than they do on factor IIa.

Enoxaparin. This agent has been extensively studied in patients with NSTEMI and is the only LMWH currently indicated for treatment of these patients. Enoxaparin inhibits factor Xa more selectively than does unfractionated heparin; it thus has a more predictable and stable anticoagulant effect than unfractionated heparin. Its predictable action makes monitoring unnecessary, and in addition, its longer half-life permits twice-daily dosing instead of continuous infusion.

The role of enoxaparin in the treatment of NSTEMI has been established in several trials. In the ESSENCE trial, use of enoxaparin in place of unfractionated heparin reduced the combined end point of death, MI, and recurrent angina and the need for urgent revascularization at 30 days.¹³ The TIMI IIb study demonstrated similar benefits for enoxaparin when compared with unfractionated heparin.¹⁴

Although these data support the use of enoxaparin in patients with NSTEMI, interventional cardiologists have been slow to adopt the practice. One reason for their reluctance is that no laboratory test is currently available to monitor the use of enoxaparin during PCI. Another is the inability to fully reverse this agent's anticoagulant effects.

The National Institute for Clinical Excellence (NICE) registries, the CRUISE trial, the SYNERGY trial, and the recentlypublished STEEPLE trial have established the safety of enoxaparin in PCI. In the STEEPLE trial, 2298 patients undergoing nonemergent PCI were randomized to receive either intravenous enoxaparin, 0.5 mg/kg; enoxaparin, 0.75 mg/kg; or an activated clotting time-adjusted unfractionated heparin regimen. Patients were given a GP IIb/IIIa inhibitor at the discretion of the operator. There was no difference in minor bleeding or in the composite end point of non-CABG-related major bleeding during the first 48 hours, all-cause mortality, MI, or urgent target vessel revascularization during the first 30 days after PCI.^15-17

Based on the current data, enoxaparin can be considered as an alternative to unfractionated heparin in patients with NSTEMI, particularly in those who do not require immediate or urgent evaluation in the cardiac catheterization laboratory. If a patient requires urgent catheterization, either unfractionated heparin, 50 U/kg (maximum, 5000 U), or enoxaparin, 0.75 mg/kg IV, can be given. In this setting, enoxaparin must be administered intravenously; if the subcutaneous route is used, an adequate level of anticoagulation will not be attained for at least 8 hours.

Two other important caveats regarding enoxaparin deserve mention:

• The need for dosage adjustments in patients with renal failure.
• The risks involved in switching anticoagulants.

Because enoxaparin is primarily excreted by the kidneys, the dosage must be adjusted in patients with decreased creatinine clearance. For this reason, the risk of adverse events in patients with renal failure may outweigh its benefits over unfractionated heparin.

In addition, the results of the SYNERGY trial demonstrated that converting from enoxaparin to unfractionated heparin or vice versa is associated with a greater number of adverse events, particularly bleeding.¹⁶ Once an anticoagulation regimen has been initiated, continue unless there is a compelling clinical reason to change medications.

Fondaparinux. This synthetic pentasaccharide that selectively inhibits factor Xa was studied in patients with NSTEMI in the OASIS-5 trial.¹⁸ In this trial, 20,078 patients with NSTEMI were randomly assigned to receive fondaparinux or enoxaparin in addition to standard therapy with aspirin, clopidogrel, and GP IIb/IIIa inhibitors (the last at the discretion of the investigators). The study demonstrated that fondaparinux was noninferior to enoxaparin with respect to reducing the composite end point of death, MI, refractory ischemia, or major bleeding.

There was an observed benefit in those patients who were older than 65 years and received fondaparinux, and mortality was lower among patients who received fondaparinux and underwent PCI. However, the observed benefits in these 2 groups may have resulted from the following circumstances:

• More than half the patients who underwent PCI in the enoxaparin group also received unfractionated heparin.
• Older patients are more likely to have impaired renal function, which would have necessitated a dosage adjustment in those who received enoxaparin.¹⁶

In addition, as with enoxaparin, there is no laboratory test to measure the activity of fondaparinux. Thus, more data are needed before fon- daparinux can be routinely recommended as an alternative to enoxaparin or unfractionated heparin.

Direct thrombin inhibitors. These agents directly inhibit thrombin without the need for a cofactor such as antithrombin (as is the case with the heparins). Although many direct thrombin inhibitors are available (eg, argatroban, lepirudin), only bivalirudin has been studied extensively in ACS. The recently published ACUITY trial found that in patients with NSTEMI who were to undergo PCI, treatment with bivalirudin after pretreatment with clopidogrel was noninferior to treatment with either unfractionated heparin or enoxaparin (with or without a GP IIb/IIIa inhibitor).¹⁹ As demonstrated in earlier studies in elective PCI, bivalirudin significantly reduced rates of both major and minor bleeding.^19,20 However, several key points regarding the results of the ACUITY study must be kept in mind:

• The incidence of ischemic events was greater in patients who received bivalirudin without clopidogrel or GP IIb/IIIa inhibitors than in those who received antiplatelet therapy.
• The majority of patients treated with bivalirudin received either unfractionated heparin or enoxaparin before randomization—some for as long as 6 hours. This crossover of medications confounds the results in the bivalirudin treatment groups.

Thus, bivalirudin should be considered in patients with unstable angina or NSTEMI only if adequate antithrombin and antiplatelet therapy have been given before PCI.