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Antithrombotic Therapy for Coronary Artery Disease

The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Correspondence to: Robert A. Harrington, MD, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705; e-mail: Harri019{at}dcri.duke.edu

	Abstract

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
This chapter about antithrombotic therapy for coronary artery disease (CAD) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: For patients presenting with non–ST-segment elevation (NSTE) acute coronary syndrome (ACS), we recommend immediate and then daily oral aspirin (Grade 1A). For patients with an aspirin allergy, we recommend immediate treatment with clopidogrel, 300-mg bolus po, followed by 75 mg/d indefinitely (Grade 1A). In all NSTE ACS patients in whom diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > 5 days, we recommend clopidogrel as bolus therapy (300 mg), followed by 75 mg/d for 9 to 12 months in addition to aspirin (Grade 1A). In NSTE ACS patients in whom angiography will take place within 24 h, we suggest beginning clopidogrel after the coronary anatomy has been determined (Grade 2A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). In moderate- to high-risk patients presenting with NSTE ACS, we recommend either eptifibatide or tirofiban for initial (early) treatment in addition to treatment with aspirin and heparin (Grade 1A). For the acute treatment of NSTE ACS, we recommend low molecular weight heparins over unfractionated heparin (UFH) [Grade 1B] and UFH over no heparin therapy use with antiplatelet therapies (Grade 1A). We recommend against the direct thrombin inhibitors as routine initial antithrombin therapy (Grade 1B). For patients after myocardial infarction, after ACS, and with stable CAD, we recommend aspirin in doses from 75 to 325 mg as initial therapy and in doses of 75 to 162 mg as indefinite therapy (Grade 1A). For patients with contraindications to aspirin, we recommend long-term clopidogrel (Grade 1A). For primary prevention in patients with at least moderate risk for a coronary event, we recommend aspirin, 75 to 162 mg/d, over either no antithrombotic therapy or vitamin K antagonist (VKA) [Grade 2A]; for patients at particularly high risk of events in whom the international normalized ratio (INR) can be monitored without difficulty, we suggest low-dose VKA (target INR, 1.5) [Grade 2A].

Key Words: acute coronary syndrome • antithrombotic • aspirin • clopidogrel • coronary artery disease • prophylaxis

	Introduction

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
Antithrombotic therapies, both antiplatelet as well as anticoagulant, have become the mainstays of treatment for coronary artery diseases (CADs). Based on the important role of thrombosis in the pathogenesis and complications of the atherosclerotic process, antithrombotic therapy has become essential treatment for both acute and chronic CAD. This section will cover the broad topic of CAD with the exception of reperfusion therapies for ST-segment elevation acute myocardial infarction (AMI) and antithrombotic therapy for patients undergoing percutaneous coronary intervention (PCI).

Interpretation of the results of the trials of antithrombotic therapies in CAD requires familiarity with the changing nomenclature for categorizing patients with acute coronary disease. Following the observation by DeWood et al¹ in the late 1970s that intracoronary thrombosis was a key mechanism in the pathophysiology of AMI, the focus in acute cardiovascular research throughout the 1980s and into the early 1990s centered on reperfusion therapy. Data from the large trials demonstrated the importance of rapid and accurate diagnosis coupled with rapid administration of fibrinolytic therapy. Such an approach reduced premature deaths and therefore became incorporated into the quality assessment of the care given to these patients.

During this period of intense investigation of AMI, investigators became increasingly aware of a much larger group of patients presenting to hospitals for evaluation of acute chest pain who did not have the dramatic findings of ST-segment elevation on the initial ECG. Overview analyses² from the Fibrinolytic Trialists’ Collaboration showed that among patients with suspected AMI, virtually all ECG subgroups benefited from treatment with fibrinolysis with the notable exception of patients presenting initially with ST-segment depression.

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial³ was one of the first large-scale attempts to study the spectrum of patients presenting with acute chest pain, stratifying the randomization on the basis of their initial ECG findings (ST-segment elevation or not). GUSTO IIb results showed that patients without ST-segment elevation represent a different population from those with ST-segment elevation. They were older, more likely to be female, and have more comorbidity than the group with ST-segment elevation. For descriptive purposes, these patients were being categorized not on the basis of their admitting diagnosis, but rather on the diagnosis that became clear 12 to 24 h later, namely unstable angina (UA) or myocardial infarction (MI), typically non–Q-wave infarction.

Investigators were performing fewer studies in the UA and non–Q-wave MI patients, due in part to the heterogeneity of the presenting symptoms and signs and in part to a lack of knowledge of the seriousness of the condition. Unlike patients presenting with ST-segment elevation, these patients had much more diverse and much less dramatic initial clinical presentations. Consequently, their initial medical evaluation was less urgent and less focused, and they were typically admitted to the hospital for observation (ie, to rule out MI) rather than treated aggressively. Recognition of the size and clinical importance of this neglected group of patients shifted the focus of acute cardiovascular clinical research from fibrinolytic therapy in ST-segment elevation infarction patients to those with non–ST-segment elevation (NSTE).

The diagnoses of UA and non–Q-wave infarction are made retrospectively, after a period of observation and a review of serial ECGs and cardiac enzymes. The results of these trials showed that these patients have a moderate-to-high risk of early adverse outcomes, and therefore may benefit from more rapid assessment, triage, and treatment.⁴

A change in the terminology describing these patients reflects this evolution in thinking. Patients presenting with symptoms consistent with acute ischemic chest pain can be quickly differentiated by their ECG as having an acute coronary syndrome (ACS) with or without persistent ST-segment elevation. Those with ST-segment elevation can be rapidly evaluated for treatment with reperfusion therapy, and those without ST-segment elevation can be further risk stratified (including with troponin testing) and treated with appropriate antiplatelet and antithrombin therapies.

The recently revised American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of patients with UA and NSTE MI reflect this changing nomenclature.⁵ The initial focus of the guidelines is to consider the patients with acute ischemic symptoms as having an ACS, and then to further differentiate them into ACS with or without ST-segment elevation. The immediate treatment decisions then flow from this differentiation and categorization.

This chapter is organized around the various disease states, with a focus on the antithrombotic recommendations for each patient group: (1) those presenting with NSTE ACSs; (2) ACS patients post-MI; (3) patients with chronic, stable CAD; (4) patients with congestive heart failure (CHF); and (5) patients without a clinical diagnosis of CAD. Table 1 describes the question definition and eligibility criteria for the studies considered in each section of the recommendations that follow.

	1.0 Acute Management of NSTE ACSs

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

An estimated 5.2 to 40% of aspirin-treated patients have some level of GI intolerance.⁶ An analysis⁷ from the Duke Databank for Cardiovascular Diseases reported that among a sample of 2,694 patients with CAD, > 13% did not report aspirin use at the 1-year follow-up; more detailed surveying revealed that 1.9% had symptoms or signs consistent with a true allergic reaction.

Various drugs inhibiting thromboxane A₂ synthase or blocking the thromboxane A₂ receptor, or both, have been investigated in clinical trials. Although they do not decrease prostacyclin production, they have shown no advantage over aspirin.

Evidence from clinical trials. Oral antiplatelet therapy, mainly aspirin, has been the cornerstone of short-term treatment for > 10 years.⁶ Despite its biochemical limitations, aspirin profoundly reduces adverse clinical events among a broad group of patients treated for acute and chronic vascular diseases.^89101112

In the systematic review by the Antithrombotic Trialists’ Collaboration,⁸ there were 5,031 patients with UA in 12 trials comparing aspirin to either placebo or no treatment. Treatment with aspirin was associated with an odds reduction in vascular events of 46%.

Most of the excess bleeding related to aspirin is GI. In the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study¹³ comparing clopidogrel vs aspirin among patients with chronic vascular disease, the risk of GI bleeding that led to aspirin discontinuation was 0.93%.

While the risk of side effects, particularly GI bleeding, appears to increase with increasing dose, the relationship between efficacy and aspirin dose is less certain. Analyses⁸ from the Antithrombotic Trialists’ Collaboration suggested that the benefits of aspirin were consistent on a relative basis across a wide range of doses (< 160 mg/d to approximately 1,500 mg/d), while other analyses by Kong et al¹⁴ suggested that the effect of aspirin is weaker at higher doses. Although a head-to-head comparison is necessary to completely resolve the issue, given that the bulk of the available evidence suggests equivalent or even superior effectiveness at lower doses, clinicians can be confident in administering relatively low aspirin doses.

	Recommendations

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
1.1.1. For all patients presenting with NSTE ACS, without a clear allergy to aspirin, we recommend immediate aspirin, 75 to 325 mg po, and then daily, 75 to 162 mg po (Grade 1A).

1.1.2 Thienopyridines
Ticlopidine and clopidogrel are adenosine diphosphate (ADP) receptor antagonists that inhibit ADP-induced platelet aggregation and prolong bleeding time (see chapter by Patrono et al).¹⁵ Combining platelet antagonists that have different mechanisms of actions is attractive. Aspirin inhibits the thromboxane A₂-mediated activation and clopidogrel inhibits ADP-mediated activation.

Evidence from clinical trials. The safety profile of ticlopidine is unfavorable, with frequent GI side effects, rash, neutropenia (rarely fatal), thrombocytopenia, and liver function abnormalities (rare). Clopidogrel has a much more favorable safety profile and is well tolerated, as demonstrated in the CAPRIE study¹³ of > 19,000 patients. The benefit derived from antiplatelet therapy in patients with coronary heart disease, UA, AMI, and previous MI is well established; however, the question of added benefit from multitargeted antiplatelet regimens, particularly among high-risk patients with NSTE ACS, until recently remained unanswered.

In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁶ 12,562 patients with NSTE ACS were randomly assigned to receive clopidogrel (300 mg immediately followed by 75 mg qd) or placebo in addition to aspirin, 75 to 325 mg/d, for 3 to 12 months. The first primary outcome—a composite of death from cardiovascular causes, nonfatal MI, or stroke—occurred in 9.3% and 11.4% of patients receiving clopidogrel and placebo, respectively (relative risk [RR], 0.80; 95% confidence interval [CI], 0.72 to 0.90; p < 0.001). Considered individually, CURE¹⁶ showed significant reductions in nonfatal MI (5.2% vs 6.7%; RR, 0.77; 95% CI, 0.67 to 0.89) and trends toward reduction in death (5.1% vs 5.5%; RR, 0.93; 95% CI, 0.79 to 1.08), and stroke (1.2% vs 1.4%; RR, 0.86; 95% CI, 0.63 to 1.18) with clopidogrel. The rate of the second primary outcome—death from cardiovascular causes, nonfatal MI, stroke, or refractory ischemia—was also lower in the clopidogrel group (16.5% vs 18.8%; RR, 0.86; 95% CI, 0.79 to 0.94; p = 0.001). Significantly fewer patients in the clopidogrel group had severe ischemia (2.8% vs 3.8%; RR, 0.74; 95% CI, 0.61 to 0.90; p = 0.003) or recurrent angina (20.9% vs 22.9%; RR, 0.91; 95% CI, 0.85 to 0.98; p = 0.01). The benefits of clopidogrel were consistent across a broad range of patient subsets, including those with MI, ST-segment deviation, elevated cardiac biomarkers, diabetes mellitus, age > 65 years, and high-risk features. Although the absolute use of concomitant glycoprotein (GP) IIb/IIIa inhibitors was low in CURE,¹⁶ the treatment effect of clopidogrel was consistent among those receiving and not receiving the IV platelet inhibitors.

There was a 34% RR reduction (RRR) [95% CI, 0.51 to 0.86] in the occurrence of cardiovascular death, MI, stroke, or severe ischemia at 24 h among patients receiving clopidogrel (p < 0.01). A significant benefit was reported at 7 days (RR, 0.77; 95% CI, 0.67 to 0.89), and an appreciable trend at 30 days (RR, 0.86; 95% CI, 0.73 to 1.01).

Major bleeding (defined as disabling hemorrhage, intraocular hemorrhage leading to visual loss, or bleeding requiring transfusion of at least 2 U of blood) was significantly more common in clopidogrel-treated patients (3.7% vs 2.7%; RR, 1.38; 95% CI, 1.13 to 1.67; p = 0.001). Life-threatening bleeding (fatal hemorrhage or causing a reduction in hemoglobin of 5 g/dL or to substantial hypotension requiring inotropic support, or surgical intervention; symptomatic intracranial hemorrhage or transfusing of 4 U of blood) was also more common, although the difference did not reach conventional levels of statistical significance (2.2% vs 1.8%; RR, 1.21; 95% CI, 0.95 to 1.56). There was not an excess rate of fatal bleeding, bleeding that required surgical intervention, or hemorrhagic stroke. The number of patients requiring transfusion of 2 U of blood was higher in the clopidogrel group (2.8% vs 2.2%, p = 0.02).

The rate of major bleeding with clopidogrel was higher early (within 30 days of randomization (2.0% vs 1.5%; RR, 1.31; 95% CI, 1.01 to 1.70) and also late (> 30 days after randomization: 1.7% vs 1.1%; RR, 1.48; 95% CI, 1.10 to 1.99). Bleeding associated with coronary artery bypass grafting (CABG) was particularly high among patients receiving clopidogrel within 5 days of surgery (9.6% vs 6.3%; RR, 1.53; p = 0.06). Overall, the risk of minor bleeding was significantly higher in clopidogrel-treated patients (5.1% vs 2.4%; p = 0.001).

	Recommendations

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
1.1.2.1. For all NSTE ACS patients with an aspirin allergy, we recommend immediate treatment with clopidogrel, 300-mg bolus po, followed by 75 mg/d indefinitely (Grade 1A).

1.1.2.2. In all NSTE ACS patients in whom diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > 5 days following coronary angiography, we recommend clopidogrel be administered immediately as bolus therapy (300 mg), followed by 75 mg/d for 9 to 12 months in addition to aspirin (Grade 1A).

Underlying values and preferences: This recommendation places a relatively high value on avoiding MI and a relatively low value on avoiding major bleeding.

1.1.2.3. In NSTE ACS patients in whom angiography will take place rapidly ( 24 h), we suggest beginning clopidogrel after the coronary anatomy has been determined (Grade 2A).

Underlying values and preferences: This recommendation places a relatively high value on avoiding serious bleeding balanced against a low absolute benefit of clopidogrel in the first 24 h of treatment.

1.1.2.4. For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A).

1.1.3 Dipyridamole
The effects of dipyridamole appear to be related to an increase in platelet cyclic adenosine monophosphate. Its antithrombotic effects are more evident on prosthetic surfaces. In contrast to aspirin, it does not increase the risk of GI bleeding even when combined with warfarin. Currently, there is no evidence to support use of dipyridamole either instead of, or in addition to, aspirin and the thienopyridines in the acute treatment of patients presenting with NSTE ACS.

1.1.4 GP IIb/IIIa inhibitors
GP IIb/IIIa receptor inhibitors have been tested as arterial antithrombotics, and three have gained market approval for clinical use: abciximab, a monoclonal antibody fragment; eptifibatide, a peptide inhibitor; and tirofiban, a peptidomimetic inhibitor. Abciximab and eptifibatide are indicated as adjunctive antithrombotics in patients undergoing PCI, while eptifibatide and tirofiban are approved among patients presenting with NSTE ACSs.

The chapter by Popma et al in this Supplement covers the use of the GP IIb/IIIa inhibitors during PCI, and the chapter by Ohman et al contains information regarding their role in NSTE MI. This chapter will review use of these drugs in patients with NSTE ACS.

Clinical trials. A systematic overview by Boersma and colleagues²⁰ included all 31,402 patients presenting with NSTE ACS enrolled in trials of GP IIb/IIIa inhibitors randomizing 1,000 patients. Overall, there was a significant 1.2% absolute decrease in the 30-day incidence of death or MI (5.7% vs 6.9%). The data were consistent across multiple subgroups with the exception of women, in whom the estimate of the treatment effect favored placebo (interaction p < 0.0001 for the difference in effect between men and women; Fig 1 ). In the overview by Boersma and colleagues,¹⁷ men and women who are troponin positive have a similar beneficial treatment effect, while men and women who are troponin negative do not appear to gain a benefit from the platelet inhibitors. Men were twice as likely in this analysis to be troponin positive as women. This suggests that the observed gender difference is less likely to be a treatment issue and more likely to be an issue with diagnosis. This hypothesis warrants further consideration and evaluation but is consistent with the general observation that these therapies are most beneficial among the groups at highest risk, such as those with diabetes¹⁸¹⁹ or dynamic ST-segment changes.²⁰ Boersma, in an overview analysis of three trials (Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment, Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms [PRISM-PLUS], and Platelet Glycoprotein IIb/IIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy [PURSUIT])²¹²² also demonstrated a convincing effect of the GP IIb/IIIa inhibitors before, after, and independent of coronary procedures.

View larger version (25K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Systematic overview of GP IIb/IIIa inhibitor trials among patients presenting with NSTE ACS. This shows the major subgroups at baseline. PTCA = percutaneous translminal coronary angioplasty; SBP = systolic BP; CK = creatine kinase; ULN = upper limit of normal. Reprinted with permission from Elsevier (The Lancet 2002; 359:189–198).

Eptifibatide. The large, international PURSUIT study²⁴ enrolled 10,948 patients presenting with a NSTE ACS and randomized to one of three drug regimens on a background of aspirin and unfractionated heparin (UFH): eptifibatide, 180 µg/kg bolus, followed by an infusion of either 2.0µg/kg/min or 1.3 µg/kg/min or placebo bolus plus infusion. The primary end point of the PURSUIT study²⁴ was the composite of death or MI at 30 days. Since neither dose of eptifibatide had yet been studied in randomized clinical trials, the study was designed to drop the lower dose if the high dose appeared to have an acceptable bleeding profile after approximately 1,000 patients had been enrolled per treatment group. In the primary analysis of high dose vs placebo, eptifibatide reduced the 30-day composite from 15.7 to 14.2% (p = 0.042). The benefit was maintained at 6 months. Bleeding was increased overall among the treated patients, with GUSTO moderate or severe bleeding occurring at a rate of 12.8% among eptifibatide patients compared with 9.9% among placebo patients. This bleeding difference was confined to patients not undergoing CABG. There was a significant increase in thrombocytopenia among the patients treated with the platelet inhibitor.²⁵ There was no increase in the risk of intracranial hemorrhage among those treated with eptifibatide.

Lamifiban. Lamifiban, while not approved for clinical use, has been studied in two moderate-to-large-scale randomized clinical trials: Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) A and PARAGON B.²⁶ PARAGON A enrolled 2,282 patients in a modified 3 x 2 factorial design to either high- or low-dose lamifiban or placebo, and UFH or placebo.²⁶ No patients were enrolled into a group with double placebo. The primary end point of the trial was the 30-day composite of death or MI. The primary results showed no significant differences among the treatment groups with an increased risk of bleeding among lamifiban patients. Post hoc analyses demonstrated that a mid-range concentration of lamifiban was associated with substantial reductions in the 30-day and 6-month composite end points.²⁷

Based on these post hoc analyses, PARAGON B²⁷ was designed to test the adjusted dosing strategy of lamifiban; consequently, 5,225 patients were randomized to receive lamifiban (adjusted for weight and estimated creatinine clearance [CrCl]) or placebo on a background of aspirin and either UFH or low molecular weight heparin (LMWH).²⁸ The primary end point was the 30-day composite of death, MI, or severe recurrent ischemia. There was no significant benefit of lamifiban over placebo (11.8% vs 12.8%, p = 0.329) while lamifiban was associated with a greater incidence of intermediate bleeding (14.0% vs 11.5%, p = 0.002). Based on the nonsignificant findings of these two trials, product registration was not sought.

Tirofiban. Two moderate-size trials have been completed and reported with tirofiban in an NSTE ACS population: Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM)²⁹ and PRISM-PLUS.³⁰ The PRISM trial²⁹ randomized 3,231 patients presenting with an ACS to either tirofiban (loading dose of 0.6 µg/min for 30 min followed by 0.15 µg/kg/min for 47.5 h) or heparin. The drugs were to be administered for 48 h, and cardiac catheterization was to be deferred until the study drug was discontinued. The 48-h primary composite of death, MI, or refractory ischemia was reduced with tirofiban from 5.6 to 3.8% with heparin (p = 0.01). The absolute benefit of tirofiban was maintained through 30 days although the relative benefit was lessened, as expected when additional events accrued in both treatment arms after discontinuation of the therapy. Both groups had a 0.4% incidence of major bleeding.

In the PRISM-PLUS trial,²⁹ 1,915 patients were randomized to treatment with tirofiban alone, tirofiban with heparin, or heparin alone. The primary end point was the composite of death, MI, or refractory ischemia at 7 days. During an interim review by the Data Safety and Monitoring Board, the tirofiban-alone arm was dropped due to excess mortality at 7 days. The trial continued with the remaining two treatment arms. Tirofiban plus heparin was associated with a significant reduction in the primary composite compared with heparin alone (12.9% vs 17.9%, p = 0.004). This benefit was maintained at 30 days and 6 months. Thrombolysis in Myocardial Infarction (TIMI) trial major bleeding was not significantly increased among the non-CABG patients (1.4% vs 0.8%, p = 0.23).³⁰

Broad drug class issues to consider with GP IIb/IIIa inhibitors. Three trials,²⁸²⁹³¹ PRISM, CAPTURE (Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment), and PARAGON B, have reported a preferential treatment effect of the GP IIb/IIIa inhibitor among patients with elevated troponin levels. Newby et al^31a have shown that there is a strong treatment interaction with this subgroup, suggesting that the quantitative difference in effect seen in this group is greater than in the troponin-negative population. The ACC-AHA Taskforce Guidelines are consistent with this in putting forth GP IIb/IIIa inhibitors as a class IA recommendation for moderate- to high-risk patients.⁵

Part of the reason for the recommendations that this class of drugs should be used in moderate- to high-risk patients is their value in an invasive strategy.⁵³² None of the six large randomized trials specifically addressed the issue of whether the GP IIb/IIIa inhibitors add incremental value to medical therapy without PCI or CABG by randomizing an appropriate group of patients. Inappropriate analysis of postrandomization subgroups (ie, PCI subgroups that accrue after randomization and thus are subject to bias) suggested that the GP IIb/IIIa inhibitors preferentially benefit patients undergoing percutaneous procedures more than those not undergoing such procedures.³³ Two important issues help to understand this controversy. First, at the time of presentation, it is challenging to predict which specific patients will undergo PCI or CABG based on clinical characteristics alone. It is knowledge of the coronary anatomy gained from a diagnostic cardiac catheterization that dictates revascularization strategy. Second, although the evidence suggests that an early invasive strategy (early cardiac catheterization followed by anatomy-driven revascularization) is superior to a conservative management strategy, the optimal timing of the early catheterization strategy is unknown. In US-based practices, where the median time to catheterization is approximately 24 h, there is a substantial period prior to the procedure that corresponds with the period of highest risk.

The use of multiple antithrombotic agents is complicated for this group of patients. It is clear from the trial data that GP IIb/IIIa inhibitors add clinical value on background therapy of aspirin and heparin. But, the major trials of the GP IIb/IIIa inhibitors were performed prior to the completion of the CURE trial, which itself was predominantly conducted in countries where there was a low usage of the IV platelet inhibitors. Thus, while the effect of clopidogrel, administered in addition to aspirin and heparin, was consistent among the groups receiving and not receiving concomitant GP IIb/IIIa inhibitors, the incremental value of adding GP IIb/IIIa inhibitors to aspirin, heparin, and clopidogrel remains all uncertain.

	Recommendations

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
1.1.4.1. In moderate- to high-risk patients presenting with NSTE ACS, we recommend either eptifibatide or tirofiban for initial (early) treatment in addition to treatment with aspirin and heparin (Grade 1A). In these moderate- to high-risk patients who are also receiving clopidogrel, we recommend eptifibatide or tirofiban as additional initial treatment (Grade 2A).

1.1.4.2. For patients presenting with NSTE ACS, we recommend againstabciximab as initial treatment except when coronary anatomy is known and PCI is planned within 24 h (Grade 1A).

	1.2 Antithrombin Therapies

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
Pharmacologic therapies designed to attenuate thrombin generation and activity are clinically attractive because of the critical role of thrombosis in ACSs.

1.2.1. UFH
UFH is a heterogeneous mixture of polysaccharide molecules (average molecular weight, 15,000 to 18,000 d) [see chapter by Hirsh et al in this Supplement]. In addition to a high degree of size/length heterogeneity, there is also a substantial amount of compositional heterogenicity. Typically, one third of the molecules found within a standard pharmaceutical heparin preparation contain the pentasaccharide sequence required for antithrombin binding and anticoagulant activity.

A pooled analysis of the Antithrombotic Therapy in Acute Coronary Syndromes study,³⁴³⁵ Research on Instability in Coronary Artery Disease,³⁶ and Théroux et al¹¹ studies yields an RR of 0.44 (95% CI, 0.21 to 0.93) for death/MI with combination aspirin and UFH therapy compared with aspirin alone.^35363738

The first trial, conducted by Théroux and colleagues,¹¹ compared aspirin (325 mg bid), UFH (5,000-U bolus, 1,000 U/h IV), their combination, and placebo in 479 patients. It is the only study that compared UFH (alone) and aspirin (alone) as well as combination therapy. Refractory angina occurred in 8.5%, 16.5%, and 10.7% of patients, respectively (0.47 RR for UFH compared with aspirin; 95% CI, 0.21 to 1.05; p = 0.06). MI occurred in 0.9%, 3.3%, and 1.6% of patients, respectively (RR, 0.25; 95% CI, 0.03 to 2.27; p = 0.18) while any event was observed in 9.3%, 16.5%, and 11.5% of patients, respectively (RR, 0.52; 95% CI, 0.24 to 1.14; p = 0.10). Serious bleeding, defined as a fall in hemoglobin of 2 g or the need for a transfusion, occurred in 1.7%, 1.7%, and 3.3% of patients, respectively. A majority of events were associated with cardiac catheterization.

The remaining trials investigated potential advantages of combination therapy (UFH plus aspirin) over aspirin monotherapy. Although not statistically different, consistent trends across each study favored combined pharmacotherapy and its ability to reduce death or MI (combined end point).

Therapeutic levels of anticoagulation. The optimal level of anticoagulation in ACS is not well defined. The reason likely relates to inherent complexities in the pharmacokinetics and pharmacodynamics of UFH, the dynamic nature of coronary arterial thrombosis, and the use of coagulation tests designed primarily to assess hemostatic potential. In essence, current laboratory-based tests are oriented more toward the potential of the drug than to treat the thrombus.

The activated partial thromboplastin time (aPTT), used widely to monitor UFH, provides a general assessment of coagulation potential; however, it is most sensitive to factor IIa activity. The "therapeutic" level of anticoagulation with UFH may vary with disease state. In venous thromboembolism, heparin levels > 0.2 U/mL (protamine titration method) accompanied by aPTT values > 1.5 times the upper limit of control appear to reduce the recurrence of thromboembolism.³⁹⁴⁰ A similar aPTT range may be sufficient in the context of left ventricular mural thrombus prophylaxis,⁴¹ and the maintenance of coronary arterial patency following tissue-type plasminogen activator administration.⁴²

The TIMI IIIB investigators⁴³ evaluated the relationship between levels of systemic anticoagulation and clinical events among 1,473 patients with NSTE ACS. Although heparin levels (chromogenic anti-IIa activity) and aPTT values (measured serially over a 72- to 96-h UFH infusion period) did not differ significantly between patients experiencing vs those free of clinical events (spontaneous ischemia, MI, death), a trend favored heparin levels > 0.2 U/mL and aPTTs in the 45- to 60-s range as being protective. In addition, high levels of anticoagulation (aPTT > 80 s) were not beneficial.

The GUSTO-IIB study⁴⁴ included 5,861 patients with NSTE ACS who received UFH for 72 h. A dose of 60 U/kg bolus and 12 U/kg/h infusion resulted in the highest proportion of aPTT values within the prespecified target range of 50 to 70 s. After adjustment for baseline variables, a higher 12-h aPTT was associated with death or reinfarction at 30 days. A prolonged aPTT at 6 h increased the risk of moderate or severe bleeding. An aPTT of 50 to 60 s at 12 h was associated with the lowest risk of hemorrhagic complications.

The available evidence supports a weight-adjusted dosing regimen with UFH as a means to provide a more predictable and constant level of systemic anticoagulation.⁴⁵⁴⁶⁴⁷ An initial bolus of 60 to 70 U/kg (maximum, 5,000 U) and initial infusion of 12 to 15 U/kg/h (maximum, 1,000 U/h) titrated to a target aPTT of 50 to 75 s is recommended.⁵ A "weaning" schedule at the time of treatment completion may reduce rebound thrombin generation and ischemic/thrombotic events,⁴⁶ although the proven clinical benefit of this approach requires an adequately powered randomized clinical trial.

	Recommendation

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
1.2.1. For patients presenting with NSTE ACS, we recommend UFH over no heparin therapy for short-term use with antiplatelet therapies (Grade 1A). We recommend weight-based dosing of UFH and maintenance of the aPTT between 50 s and 75 s (Grade 1C+).

1.2.2 LMWH
LMWH preparations represent a class of heparin-derived compounds with varying molecular weights (2,000 to 10,000 d). LMWH has pharmacokinetic and pharmacodynamic biophysical advantages over UFH (see chapter by Hirsh et al for details).

Clinical trials with LMWHs. Clinical trials comparing the benefits of UFH and aspirin among patients with UA and NSTE MI are summarized in Tables 234 . The original experience with LMWH⁴⁸ included 205 patients with UA who were randomized to either aspirin (200 mg/d), aspirin (200 mg/d) plus UFH (5,000-U bolus, 400 U/kg/d infusion), or aspirin (200 mg/d) plus high-dose nadroparin (214 IU/kg bid by subcutaneous [SQ] injection). Patients underwent continuous ST-segment monitoring during the first 48 h of treatment. Overall, 73% of patients receiving LMWH were free from ischemic events, compared with 39% of those receiving UFH and 40% of patients receiving aspirin alone. There were fewer silent ischemic events in the LMWH group (18%), compared with those receiving UFH (29%) or aspirin alone (34%). Recurrent angina occurred in 9%, 26%, and 19% of patients, respectively, and MIs were not observed in LMWH-treated patients (compared with 1% in the UFH group and 6% in the aspirin-alone group). Major bleeding occurred infrequently in all treatment groups.

In the Fragmin in Unstable Coronary Artery Disease (FRIC) study,⁵⁰ 1,482 patients with UA and NSTE MI were assigned either twice-daily weight-adjusted SC injections of LMWH (dalteparin, 120 IU/kg) or dose-adjusted (target aPTT 1.5 times the control) IV UFH for 6 days (acute treatment phase) [Table 2]. Patients randomized to UFH received a continuous infusion for at least 48 h, and were given the option of either continuing the infusion or changing to an SC regimen (12,500 U q12h). In the blinded comparison that took place from days 6 to 45 (prolonged treatment phase), patients received either LMWH (dalteparin, 7,500 IU SC qd) or placebo. Aspirin, 75 to 165 mg/d, was started in all patients as early as possible after hospital admission and continued throughout the study. During the first 6 days, the rate of death, recurrent angina, and MI was 7.6% in the UFH-treated patients and 9.3% in the LMWH-treated patients (RR, 1.18; 95% CI, 0.84 to 1.66). Revascularization was required in 5.3% and 4.8%, respectively (CI, 0.57 to 1.35). Between day 6 and day 45, the composite end point was reached in 12.3% of patients in both the LMWH and placebo groups. Revascularization procedures were undertaken in 14.2% and 14.3% of patients, respectively.

The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) trial⁵¹ randomly assigned 3,171 patients with angina at rest or NSTE MI to either LMWH (enoxaparin, 1 mg/kg SC bid) or IV UFH (target aPTT, 55 to 85 s). Therapy was continued for a minimum of 48 h (maximum 8 days). All patients received aspirin (100 to 325 mg/d). The median duration of therapy for both groups was 2.6 days. At 14 days, the risk of death, recurrent angina, or MI was 16.6% among patients receiving LMWH and 19.8% for patients receiving UFH (16% risk reduction). A similar risk reduction (15%) for the composite outcome was observed at 30 days. The need for revascularization procedures within the first 30 days was also lower in LMWH-treated patients (27% vs 32.2%). The benefit of LMWH treatment was maintained at 1 year.⁵²

The TIMI 11B study⁵³ compared enoxaparin and UFH in 3,910 patients with UA and NSTE MI. The trial design had several unique features. First, enoxaparin therapy was initiated with a 30-mg IV bolus, followed by 1 mg/kg SC bid. Second, UFH treatment was administered according to a weight-adjusted dosing strategy (70 U/kg bolus, followed by 15 U/kg/h infusion to a target aPTT of 1.5 to 2.5 times control). Lastly, there was an out-of-hospital treatment phase comparing enoxaparin and placebo for approximately 6 weeks (patients 65 kg received < 60 mg SC bid; those < 65 kg received 40 mg SC bid for a total of 43 days). Treatment with enoxaparin was associated with a significant reduction in the composite outcome of death, MI, or urgent revascularization compared with UFH at day 14 (14.2% vs 16.7%; RRR, 15%; p = 0.03). Continued treatment beyond the initial hospital phase did not provide added benefit (17.3% vs 19.7%; RRR, 12%; p = 0.05).

The Fraxiparine in Ischemic Syndromes study⁵⁴ compared the efficacy of nadroparin vs UFH in 3,468 patients with NSTE ACS. Patients were randomized to either UFH, 6-day treatment with nadroparin (86 IU/kg IV bolus, 86 IU/kg SC bid), or 14-day treatment with nadroparin. The combined outcome of cardiovascular death, MI, and recurrent/refractory angina at 14 days occurred in 18.1%, 17.8%, and 20% of patients, respectively (no significant difference). Hemorrhagic events were more common in patients receiving nadroparin for 14 days.

A pooled analysis of the ESSENCE and TIMI 11B trials, totaling 7,081 patients with NSTE ACS, revealed a 20% reduction in the risk of any ischemic event⁵⁵ favoring enoxaparin over UFH. The differences were statistically significant at 48 h and 43 days. The combined end point of death or MI was reduced by 20% at 48 h (p = 0.02) and 18% at 43 days (p = 0.02). A significant treatment benefit for enoxaparin on the rate of death, nonfatal MI, or urgent revascularization was observed at 1 year (hazard ratio, 0.88; p = 0.008; absolute difference, 2.5%). A progressively greater treatment benefit was observed as the level of patient risk at baseline increased.⁵⁵

The FRISC II⁵⁶ included 2,267 patients with unstable coronary disease who received 5 days of dalteparin (120 IU/kg SC q12h) and were then randomized to either an invasive or conservative treatment strategy. In separate randomization, patients received either dalteparin (5,000 to 7,500 IU SC q12h) or placebo injections for 3 months (Table 3). By 30 days, there was a significant reduction in death or MI favoring dalteparin-treated patients (3.1% vs 5.9%; p = 0.002). The benefit diminished over the next 2 months. An invasive strategy (coronary angiography and revascularization) was associated with a significant reduction in death or MI at 6 months compared with ischemia-driven revascularization (9.4% vs 12.1%, p = 0.03). The mortality rates were 1.9% and 2.9%, respectively.⁵⁷ At 24-month follow-up, there were reductions in mortality (3.7% vs 12.7%; risk ratio, 0.72; p = 0.005) and the composite end point of death or MI (12.1% vs 16.3%; risk ratio, 0.74; p = 0.003) in the invasive group compared with the noninvasive group. The need for repeat hospitalizations and late revascularization procedures was lower with an early invasive strategy as well.⁵⁸

The Randomized Intervention Trial of Unstable Angina⁵⁹ randomized 1,810 patients with NSTE ACS who received enoxaparin (1 mg/kg SC bid for 2 to 8 days) and aspirin to either an early intervention or conservative strategy.⁵⁹ At 4 months, 9.6% of patients randomized to early intervention had died or experienced an MI or refractory angina compared with 14.5% in the conservative group (risk ratio, 0.66; 95% CI, 0.51 to 0.85; p = 0.001). Death or MI was similar in both treatment groups at 1 year (7.6% vs 8.3%, respectively; risk ratio, 0.91; 95% CI, 0.67 to 1.25; p = 0.58). Fewer patients undergoing early intervention experienced symptoms of angina or required antianginal medications.

In a prospective, comparative study⁶⁰ of LMWH preparations, 438 patients with NSTE ACS were randomized to receive either SC injections of 100 mg of enoxaparin bid or 175 IU/kg of tinzaparin qd for 7 days. There were no differences in the primary outcome (death, MI, refractory angina, or recurrence of UA); however, there was a lower incidence of recurrent UA and need for revascularization at 30 days among enoxaparin-treatment patients (p = 0.02). Hemorrhagic events were similar in the two groups.⁶⁰

Duration of treatment with LMWH. The potential benefit of extended therapy with LMWH has been evaluated in several clinical trials. In the FRIC study⁵⁰ dalteparin was continued at a dose of 7,500 IU IV qd for 39 days. A minority of patients experienced NSTE MI; no additional benefit from extended therapy was observed. Similar findings were reported with enoxaparin (40 mg or 60 mg bid for 43 days) in the TIMI 11 trial (Table 4).⁵³

The FRISC I trial⁴⁹ suggested that extended LMWH treatment (dalteparin, 7,500 IU qd) might benefit selected patients. The combined end point of death or MI was reduced by 40% (p = 0.003) at day 40 in nonsmokers, as well as in patients with NSTE MI, diabetes mellitus, prior MI, age > 70 years, and those treated for heart failure. During extended therapy, patients with an initial troponin level > 0.1 µg/L derived the greatest overall benefit (RRR, 0.48 at day 40; p = 0.01).⁴⁹

The FRISC II trial⁵⁶⁵⁷ extended several important observations made in FRISC I. Patients experiencing chest pain associated with either ECG changes or elevated cardiac biomarkers received dalteparin, 120 IU/kg SC q12h, plus aspirin. Those assigned to a noninvasive strategy received dalteparin for 5 to 7 days (until an exercise tolerance test was performed). Patients in the invasive strategy arm of the trial received dalteparin for at least 5 days (until an invasive procedure was performed). Thereafter, either dalteparin (5,000 IU SC bid [women < 80 kg, men < 70 kg]; or 7,500 IU SC bid in heavier patients) or placebo was administered by self-injection for 90 days.

A total of 2,267 patients were included in the noninvasive arm of FRISC II. At 90 days, there was a 1.3% absolute (19% relative) RR in death or MI associated with prolonged dalteparin administration (p = 0.17). The combined end point was 3.1% in dalteparin-treated patients compared with 5.9% in those receiving placebo at 30 days (RR, 0.5; p = 0.002). The triple composite of death, MI, or revascularization was 13% lower (p = 0.031) at 90 days with prolonged LMWH administration. The rates of hemorrhage were 2.2% and 1.2%, respectively.

The available evidence favors an early invasive strategy for patients with NSTE ACS. Although prolonged LMWH administration provides an element of protection for high-risk patients, those individuals should be treated aggressively (and early) whenever possible. If coronary angiography and intervention are planned but delayed, continued therapy as a "bridge" to revascularization should be considered.

Platelet GP IIb/IIIa inhibitors and LMWH, combination therapy. The contribution of platelets and coagulation proteins to coronary arterial thrombosis supports combination pharmacotherapy in NSTE ACS. In the Anti Thrombotic Therapy Combination Using Tirofiban and Enoxaparin II study,⁶¹ 525 patients with NSTE ACS were treated with tirofiban plus aspirin and randomized to received either UFH (5,000-U bolus, 1,000 U/h adjusted to an aPTT of 1.5 to 2.5 times control) or enoxaparin (1.0 mg/kg SC q12h). Therapy was administered for 24 to 96 h. In-hospital death or MI occurred in 9.0% and 9.2% of patients, respectively; however, refractory ischemia requiring urgent revascularization and rehospitalization because of UA occurred more frequently in the UFH group (4.3% vs 0.6%; risk ratio, 0.72 [p = 0.01]; and 7.1% vs 1.6%; risk ratio, 0.44 [p = 0.002], respectively). TIMI major bleeding occurred in 1.0% and 0.3% of patients, respectively.

National Investigators Collaborating on Enoxaparin 3 trial⁶² was an open-label observational study of enoxaparin conducted at 56 sites in North America. All patients (n = 628) had chest pain at rest lasting at least 20 min within the prior 24 h and CAD documented by ECG changes, elevated cardiac biomarkers, or history (MI, PCI, coronary angiogram with 50% luminal narrowing, or abnormal exercise tolerance test result). Patients received aspirin (162.5 to 325 mg) and enoxaparin (1.0 mg/kg SC) q12h. For the primary end point of non-CABG major bleeding, the cumulative incidence was 1.9%. At 30 days, the incidence of death or MI (double end point) and death, MI, or urgent revascularization (triple end point) was 6.2% and 11.6%, respectively.

In a GUSTO IV substudy,⁶³ 646 patients received dalteparin (120 IU/kg SC every 12 h), aspirin, and either 24 h or 48 h of abciximab administered as an initial bolus followed by a continuous infusion. Death or MI at 30 days occurred in 9.6% of dalteparin-treated patients and 8.5% of UFH-treated patients. The rates of major non-CABG bleeding were 1.2% and 0.7%, respectively.

The Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment study⁶⁴ randomized 746 patients with NSTE ACS to open-label enoxaparin (1 mg/kg SC bid) or UFH (70 U/kg bolus, 15 U/kg/h to a target aPTT of 1.5 to 2.0 times control) for 48 h. All patients received aspirin and eptifibatide (180 µg/kg bolus, 2 µg/kg/min infusion). Major non-CABG bleeding at 96 h (primary safety outcome) was significantly lower among enoxaparin-treated patients than those receiving UFH (1.8% vs 4.6%, p = 0.03). Minor bleeding occurred more often in the enoxaparin group (30.3% vs 20.8%, p = 0.003). Patients receiving enoxaparin were less likely to experience ischemia (determined by continuous ECG monitoring) [primary outcome] during the initial (14.3% vs 25.4%, p = 0.002) and subsequent (12.7% vs 25.9%, p < 0.0001) 48-h monitoring periods. Combined death or MI at 30 days was also lower in enoxaparin-treated patients (5% vs 9%, p = 0.03).

In PARAGON B,⁶⁵ 5,225 patients with NSTE MI received either lamifiban or placebo in combination with aspirin and heparin, 805 patients received a LMWH preparation, while the remainder received UFH. The incidence of death, MI, or severe recurrent ischemia was 12.2% for the overall cohort and lowest in the lamifiban-plus-LMWH group (10.2%). The incidence of death or MI was 11.0% and 9.0%, respectively. The benefit for those receiving lamifiban plus LMWH was sustained at 6 months with lower revascularization rates (42.8% vs 51.5%) and a lower composite of death or MI (11.9% vs 13.8%). After correcting for baseline differences, there was a significantly lower revascularization rate at 30 days with use of LMWH (p = 0.001). Major bleeding was 1.6% for patients receiving UFH and lamifiban, and 1.5% in those receiving LMWH and lamifiban.

Anticoagulation monitoring with LMWHs. LMWH preparations catalyze thrombin inhibition to a lesser extent than UFH and, as a result, they induce less prolongation of the aPTT. Because prolongation of the aPTT correlates inversely with the anti-Xa:anti-IIa ratio, tinzaparin (ratio 1.5:1) produces a higher aPTT (for an equivalent dose) than enoxaparin (ratio 3.0:1). The more rapid dissipation of anti-IIa activity following LMWH administration also contributes to a weaker effect of LMWH preparations on the aPTT.

Anti-Xa activity can be measured by chromogenic and chronometric assays. As with other coagulation tests, variability does exist. A majority of clinical trials, whether based on deep vein thrombosis prophylaxis, venous thromboembolism treatment, or ACS, have not required drug titration according to anti-Xa monitoring; however, an ability to define safe and effective levels of anticoagulation is important for clinical reasons. Defining a target level of factor Xa inhibition is also important in patients with altered drug clearance such as renal insufficiency (particularly with LMWH preparations characterized by a high anti-Xa:anti-IIa ratio). Lastly, monitoring capabilities may be useful when drug reversal is required because of the possibility of hemorrhagic complications during invasive procedures with inherent bleeding risks.

In the TIMI 11A study,⁶⁶ there was a relationship between enoxaparin dose and hemorrhagic complications, particularly in those undergoing coronary angiography, PCI, or CABG. Patients receiving enoxaparin at a dose of 1.25 mg/kg q12h had a peak anti-Xa activity (chromogenic assay) of 1.5 IU/mL, while those receiving 1.0 mg/kg q12h averaged 1.0 IU/mL. Anti-Xa activity among patients with major hemorrhage was 1.8 to 2.0 IU/mL. An analysis of anti-Xa inhibition pharmacokinetics revealed that high trough and peak activity (upper quintiles) was associated with major hemorrhagic events.⁶⁶

The optimal level of factor Xa inhibition has not been determined for patients with ACS receiving LMWH. The available information derived from nonrandomized clinical studies of PCI suggests that anti-Xa activity > 0.5 IU/mL is associated with a low incidence of ischemic/thrombotic and hemorrhagic events.⁶⁷⁶⁸ Global coagulation tests, including traditional aPTT and activated clotting time (ACT) assays, may provide some insight for LMWH preparations characterized by low anti-Xa:anti-IIa activity.⁶⁹

Antithrombin therapies and renal function. The mechanism of LMWH clearance is predominantly renal (nonsaturable), which explains the linear characteristics of reported elimination curves.⁷⁰⁷¹ Renal performance may not influence pharmacokinetics following single-dose IV administration of enoxaparin.⁷²⁷³

The anti-Xa pharmacokinetics of several other LMWH preparations have been investigated in small-scale, multiple-dose trials. The findings suggest that severe renal insufficiency (CrCl < 30 mL/min) is associated with reduced drug clearance, particularly with lower molecular weight (or proportion of short-chain molecules) preparations. Studies evaluating appropriate dose titration to established target levels of anti-Xa activity in patients with end-stage renal disease should be undertaken to provide guidance in achieving optimal patient care.

	Recommendations

TOP Abstract Introduction 1.0 Acute Management of... Recommendations Recommendations Recommendations 1.2 Antithrombin Therapies Recommendation Recommendations Recommendation 2.0 Post MI and... Recommendations 2.3 Comparisons of antiplatelet... Recommendations 3.0 Chronic, Stable CAD Recommendations 4.0. Congestive Heart Failure... 4.1 VKA, aspirin Recommendations 5.0. Primary Prevention Recommendations Summary of Recommendations References

 
1.2.2.1. For the acute treatment of patients with NSTE ACS, we recommend LMWHs over UFH (Grade 1B).

1.2.2.2. We recommend against routine monitoring of the anticoagulant effect of the LMWHs (Grade 1C).

1.2.2.3. We suggest continuing LMWHs during PCI treatment of the NSTE ACS patient when it has been started as the "upstream" anticoagulant (Grade 2C).

1.2.2.4. For patients receiving GP IIb/IIIa inhibitors as upstream treatment of NSTE ACS, we suggest LMWH over UFH as the anticoagulant of choice (Grade 2B).

1.2.3 Indirect, selective factor Xa inhibitors: synthetic pentasaccharide
The pentasaccharide sequence contained within heparin molecules is a prerequisite for antithrombin binding and subsequent coagulation protease neutralization. Fondaparinux (molecular weight, 1,728 d) is a synthetic pentasaccharide that facilitates antithrombin (indirect)-mediated factor Xa (selective) inhibition. It does not inactivate thrombin. The anti-Xa activity of the drug increases with increasing plasma concentrations, peaking within 3 h of SC administration. Elimination occurs solely through renal mechanisms, and the plasma half-life is 17 to 21 h.

Fondaparinux is currently US Food and Drug Administration approved for prophylaxis of deep vein thrombosis in patients undergoing hip fracture, hip replacement, or knee replacement surgery. Its use in patients with NSTE ACS is limited to a single phase II study. In the Pentasaccharide in Unstable Angina study,⁷⁴ 1,147 patients were randomized to receive either enoxaparin (1 mg/kg SC bid) or fondaparinux (2.5 mg, 4 mg, 8 mg, or 12 mg/d SC) for 3 to 7 days. The primary efficacy end point was a composite of death, MI, or recurrent ischemia at 9 days and 30 days. The composite end point was reached in 40.2%, 30.0%, 43.5%, 41.0%, and 34.8%, respectively, and major and minor bleeding at day 30 occurred in 3.9%, 5.4%, 5.4%, 4.6%, and 4.8% of patients, respectively.

In a pilot trial,⁷⁵ 61 patients undergoing balloon angioplasty received a single, 5-min IV infusion of 12 mg of pentasaccharide. Two patients (3.28%; 95% CI, 0.4 to 11.4%) experienced abrupt vessel closure. ACT and aPTT measurements remained within the normal range; however, thrombin-antithrombin complex, prothrombin fragment 1.2 and factor VIIa levels decreased by 50 to 60% within 2 h of injection of the test drug. There were no major hemorrhagic events.

Fondaparinux elimination is prolonged in patients with renal impairment. Total clearance is reduced by 25% in patients with mild renal impairment (CrCl, 50 to 80 mL/min), approximately 40% lower among patients with moderate renal impairment (CrCl, 30 to 50 mL/min) and 55% lower in the setting of severe renal impairment (CrCl < 30 mL/min). Fondaparinux elimination is also reduced (by 25%) in patients > 75 years old (compared with patients < 65 years old). There are insufficient data to recommend fondaparinux in patients presenting with NSTE ACS. Large, randomized trials are underway evaluating the safety and efficacy of fondaparinux among patients presenting with both ST-segment elevation and NSTE ACS.

1.2.4 Direct, selective factor Xa inhibitors: DX-9065a
DX-9065a is the first in a class of small molecule, direct, specific, and reversible factor Xa inhibitors. It is a synthetic, nonpeptide amidinoaryl derivative (571 d) with rapid binding kinetics for factor Xa but not thrombin.⁷⁶⁷⁷ The cumulative experience with it among patients with CAD is limited to a single phase 1B study and a phase II study in the setting of PCI. The Xa Neutralization for Atherosclerotic Disease Understanding 1B trial⁷⁸ included 73 patients aged 55 to 75 years with clinically stable CAD. They were randomized to receive either placebo or a 72-h IV infusion of DX-9065a in doses required to achieve plasma concentrations of 15, 50, 100, or 200 ng/mL. All patients received aspirin. Based on a three-compartment model, plasma<