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The current state of antiplatelet therapy in acute coronary syndromes: The data and the real world

April 1, 2009|Cleveland Clinic Journal of Medicine
John H. Alexander, MD, MHSc
Author and Disclosure Information

John H. Alexander, MD, MHSc
Associate Professor of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC

Correspondence: John H. Alexander, MD, MHSc, Duke University Medical Center, Duke Clinical Research Institute, DUMC Box 3850, Durham, NC 27715; john.h.alexander@duke.edu

Dr. Alexander reported financial relationships with Adolor (consulting), Bristol-Myers Squibb (research support), Daiichi Sankyo (consulting), Medicure (consulting and research support), Medtronic Japan (research support), Millennium Pharmaceuticals (equity interest and research support), Momenta Pharmaceuticals (research support), the National Institutes of Health (consulting and research support), Novartis (consulting), Pfizer (consulting), Regado Biosciences (research support), and Schering-Plough (research support).

This article was developed from an audio transcript of Dr. Alexander’s lecture at the CME course that formed the basis of this supplement. The transcript was edited and formatted by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Alexander.

Dr. Alexander received honoraria for contributing to this supplement and the CME course on which it was based. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from the educational grant from Daiichi Sankyo, Inc., and Eli Lilly and Co. that supported the course and this supplement. These grantors had no input on the content of the course or this supplement.

ABSTRACT

Managing antiplatelet therapy for patients with acute coronary syndromes (ACS) is complex, and current therapy options and approaches for these patients are suboptimal. Despite the use of available antiplatelet therapies—aspirin, clopidogrel, and the parenteral glycoprotein IIb/IIIa inhibitors—recurrence of ischemic events in patients with ACS continues to rise over time. Moreover, bleeding remains an important—and often underappreciated—risk with these therapies, and national registries demonstrate that dosing of antiplatelet therapies frequently strays from evidence-based guidelines. Recent quality-improvement initiatives developed in conjunction with national registries of patients with ACS promise to improve adherence to guidelines through hospital-specific performance reports. More evidence-based use of existing and emerging antiplatelet agents has the potential to improve both ischemic and bleeding outcomes in patients with ACS.

KEY POINTS

  • Recurrent ischemic events have been observed in all antiplatelet trials to date, in spite of the addition of more potent antiplatelet regimens.
  • There appears to be a gradient of benefit from dual antiplatelet therapy depending on patients’ risk of thrombotic events (the greater the risk, the greater the benefit).
  • Local practice patterns in interventional therapy for ACS should be taken into consideration when applying results from clinical trials to clinical practice.
  • ACS patients who stand to benefit most from antiplatelet therapies also are at the greatest risk of bleeding from those therapies.
  • The importance of a tailored approach to antiplatelet therapy and dosing is becoming more widely recognized.

Glycoprotein IIb/IIIa inhibitors

The glycoprotein IIb/IIIa inhibitors—abciximab, eptifibatide, and tirofiban—are parenteral drugs that block the final common pathway of platelet aggregation. With increased focus on the upstream inhibition of platelet activation and the wider availability of more potent oral antiplatelet drugs, the use of glycoprotein IIb/IIIa inhibitors has been declining in recent years.

Efficacy in ACS. A number of placebo-controlled trials of glycoprotein IIb/IIIa inhibitors have been conducted in the setting of ACS without ST-segment elevation. In each trial, the glycoprotein IIb/IIIa inhibitor was associated with a significant reduction in 30-day rates of a composite of death and nonfatal MI. A 2002 pooled analysis of these trials demonstrated an overall 8% relative risk reduction in this end point with active glycoprotein IIb/IIIa inhibitor therapy (P = .037).14 Interpreting the benefit of glycoprotein IIb/IIIa blockade in the setting of clopidogrel therapy, however, is more challenging since upstream use of clopidogrel was rare at the time these studies were performed.

An outlier in the aforementioned pooled analysis was the GUSTO IV-ACS study (Global Utilization of Strategies to open Occluded coronary arteries trial IV in Acute Coronary Syndromes), in which abciximab showed no significant benefit over placebo on the primary end point of death or MI at 30 days.15 This study included 7,800 patients with ACS without ST-segment elevation who were being treated with aspirin and unfractionated or low-molecular-weight heparin and were then randomized to placebo or abciximab. Abciximab was given as a front-loaded bolus followed by an infusion lasting either 24 or 48 hours.

A trend toward higher all-cause mortality was observed with longer infusions of abciximab in the GUSTO IV-ACS trial.15 A hypothesis emerged that a front-loaded regimen of abciximab is suitable for patients undergoing PCI, in whom platelet activation and the risk of adverse outcomes is greatest in the catheterization laboratory, but is less well suited for medically managed patients, in whom levels of platelet aggregation and risk are ongoing.

Timing of treatment. The optimal timing of glyco­protein IIb/IIIa inhibitor initiation remains controversial. Boersma et al pooled data from three randomized placebo-controlled trials and stratified the results into outcomes before PCI and outcomes immediately following PCI.16 Glycoprotein IIb/IIIa inhibition was associated with a 34% relative reduction in the risk of death or MI during 72 hours of medical management prior to PCI (P = .001) and an enhanced 41% relative reduction in this end point in the 48 hours following PCI when PCI was performed during administration of the study drug (P = .001). The investigators concluded that glycoprotein IIb/IIIa blockade should be initiated early after hospital admission and continued until after PCI in patients who undergo the procedure.

The effect of upstream glycoprotein IIb/IIIa inhibitor use was more ambiguous in the recent Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial of patients with ACS being managed invasively. At 1 year, upstream use—as compared with in-lab use—of glycoprotein IIb/IIIa inhibitors was associated with a reduction in the rate of ischemic events among patients treated with the direct thrombin inhibitor bivalirudin (17.4% vs 21.5%, respectively; P < .01) but not among patients treated with unfractionated heparin or low-molecular-weight heparin (17.2% vs 18.4%; P = .44).17

Ongoing clinical trial results may shed further light on the considerable clinical uncertainty that remains regarding the benefits of upstream glycoprotein IIb/IIIa inhibitor use in patients with ACS.

Enrollment has just been completed in a large randomized trial designed to prospectively assess the optimal timing of glycoprotein IIb/IIIa inhibitor initiation in patients with high-risk ACS without ST-segment elevation in whom an invasive strategy is planned no sooner than the next calendar day.18 The study, known as EARLY-ACS, is randomizing patients to eptifibatide or placebo begun within 8 hours of hospital arrival, with provisional eptifibatide available in the catheterization laboratory. The primary end point is a 96-hour composite of all-cause mortality, nonfatal MI, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout with a glycoprotein IIb/IIIa inhibitor during PCI. Data should be available in 2009.

ANTIPLATELET THERAPY GUIDELINES IN NON-ST-ELEVATION ACUTE CORONARY SYNDROMES

In 2007, the American College of Cardiology (ACC) and American Heart Association (AHA) updated their joint guidelines for the use of antiplatelet therapy in the management of patients with unstable angina or MI without ST-segment elevation.19 These guidelines incorporate a large degree of flexibility in the choice of antiplatelet therapy, which can make implementation of their recommendations challenging.

The guidelines contain classes of recommendations based on the magnitude of benefit (I, IIa, IIb, III) and levels of evidence (A, B, C). Following here are key recommendations from the updated guidelines (bulleted and in italics, with the class and level of the recommendation noted in parentheses),19 supplemented with additional commentary where appropriate.

Antiplatelet therapy: General recommendations

  • Aspirin should be given to all patients as soon as possible after presentation and continued indefinitely in patients not known to be intolerant of aspirin (class I, level A).
  • Clopidogrel should be given to patients unable to take aspirin because of hypersensitivity or major gastro­intestinal (GI) intolerance (class I, level A).

This recommendation is based on data from the CURE trial7 and the earlier CAPRIE study.10 The clopidogrel regimen recommended is a 300-mg loading dose followed by a maintenance dosage of 75 mg/day. The incidence of aspirin intolerance is approximately 5%, depending on how intolerance is defined. A significant proportion of patients will stop aspirin because of GI upset or trivial bleeding, failing to understand the true benefits of aspirin. A much smaller subset—perhaps 1 in 1,000—has a true allergy to aspirin.

  • Patients with a history of GI bleeding with the use of either aspirin or clopidogrel should be prescribed a proton pump inhibitor or another drug that has been shown to minimize the risk of bleeding (class I, level B).

Initial invasive strategy

  • For patients in whom an early invasive strategy is planned, therapy with either clopidogrel or a glycoprotein IIb/IIIa inhibitor should be started upstream (before diagnostic angiography) in addition to aspirin (class I, level A).

This recommendation does not give preference to either agent because head-to-head comparisons of antiplatelet and antithrombotic therapies in this setting are not available.

  • Unless PCI is planned very shortly after presentation, either eptifibatide or tirofiban should be the glycoprotein IIb/IIIa inhibitor of choice; if there is no appreciable delay to angiography and PCI is planned, abciximab is indicated (class I, level B).

This recommendation is based on findings of the GUSTO IV-ACS study.15

  • When an initial invasive strategy is selected, initiating therapy with both clopidogrel and a glycoprotein IIb/IIIa inhibitor is reasonable (class IIa, level B).

Clearly, the guidelines offer some leeway to allow for different practice patterns in the use of an initial invasive strategy. In my practice, if a patient is high risk and has a low likelihood of early CABG, I use both clopidogrel and a glycoprotein IIb/IIIa inhibitor upstream (prior to going to the catheterization laboratory). If a patient has a reasonable likelihood of requiring CABG, I eliminate the thienopyridine and treat with a glycoprotein IIb/IIIa inhibitor. If a patient is at increased risk of bleeding, I forgo the glyco­protein IIb/IIIa inhibitor in favor of clopidogrel.

  • In patients who are going to the catheterization laboratory, omitting a glycoprotein IIb/IIIa inhibitor upstream is reasonable if a loading dose of clopidogrel was given and the use of bivalirudin is planned (class IIa, level B).

This recommendation takes into account the duration of clopidogrel’s antiplatelet effect and recognizes the likely limited benefit of glycoprotein IIb/IIIa inhibitors in patients who proceed rapidly to the catheterization laboratory.

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