Volume 103, Issue 3, Supplement , Pages 1A-3A, 2 February 2009
Introduction
Article Outline
This supplement to The American Journal of Cardiology reports on the proceedings of a Scientific and Clinical Expert Panel, which was convened on November 17, 2007, in Detroit, Michigan to review current clinical evidence and expert opinion on the use of antiplatelet therapy in the treatment of patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous coronary intervention (PCI). This supplement also reviews the currently available information on antiplatelet agents in advanced clinical testing.
In the first article, Dr. Lisa K. Jennings discusses the pathophysiologic role of platelets in atherothrombosis. Platelets release preformed substances—including adhesive proteins, such as thrombospondin, fibrinogen, and von Willebrand factor; chemokines; coagulation factors; and growth factors—from their granules and synthesize the potent vasoconstrictor and activator thromboxane A2 by converting arachidonic acid to prostaglandin H2 in a process catalyzed by cyclooxygenase-1. Both thromboxane A2 and adenosine diphosphate (ADP) are released when platelets adhere to vessel walls, and together, they start a chain reaction that leads to platelet activation and aggregation. Thrombin binding to platelet receptors promotes hemostasis or thrombosis and catalyzes the conversion of fibrinogen into fibrin. Thrombin exerts its activities on platelets by cleaving protease-activated receptor–1 (PAR-1) and PAR-4, which points toward the utility of PAR-1 inhibitors (ie, thrombin receptor antagonists) as antiplatelet agents. The ability of ADP to stimulate platelet receptors P2Y1 and P2Y12 (especially the latter) facilitates platelet aggregation and thrombosis and is therefore the target of irreversible binding by clopidogrel and other thienopyridines and of reversible binding by nonthienopyridines, such as ticagrelor and cangrelor.
In the next article, Dr. Deepak L. Bhatt surveys the role of antiplatelet therapy across a spectrum of patients with coronary artery disease. As demonstrated in a meta-analysis by the Antithrombotic Trialists' Collaboration,1 aspirin unquestionably reduces mortality in patients with various manifestations of vascular disease. Although monotherapy with clopidogrel (and, presumably, other drugs that block ADP activation of the platelet P2Y12 receptor) has been known to be significantly more effective than aspirin in patients with a previous myocardial infarction or stroke (14.9% relative risk reduction) since the Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study,2 acceptance has been slow. However, because the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study3 showed that the addition of clopidogrel to aspirin conferred a 20% relative risk reduction and 2% absolute risk reduction compared with aspirin alone, dual antiplatelet therapy with aspirin and clopidogrel has become the “gold standard.” The potential for serious bleeding with drugs that blunt platelet activity needs to be considered.
The necessity for dual antiplatelet therapy has come to the forefront again because of the widespread use of intracoronary stents in PCI. The 2 main concerns with stents are restenosis and stent thrombosis. Although the value of antiplatelet therapy in preventing restenosis is uncertain, dual antiplatelet therapy clearly reduces the risk of stent thrombosis. This is especially critical with drug-eluting stents, which have been associated with a higher risk of late thrombosis than have bare metal stents.
Dominick J. Angiolillo, MD, PhD
In his article, Dr. Alan D. Michelson compares standard and advanced tests for measuring platelet function in vitro. The tests he describes are platelet aggregometry; impedance aggregometry; VerifyNow (Accumetrics, San Diego, CA); Plateletworks (Helena Laboratories, Beaumont, TX); platelet surface P-selectin, platelet surface–activated glycoprotein IIb/IIIa, and leukocyte–platelet aggregates; TEG Platelet Mapping system (Haemoscope Corporation, Niles, IL); Impact Cone and Plate(let) Analyzer (Diamed, Cressier, Switzerland); Platelet Function Analyzer-100 (Siemens Healthcare Diagnostics, Deerfield, IL); phosphorylation of vasodilator-stimulated phosphoprotein; serum thromboxane B2; and urinary 11-dehydro thromboxane B2. The most specific tests for the effect of aspirin measure cyclooxygenase-1 using either thromboxane as the end point or arachidonic acid as the agonist. The most specific test for the effect of clopidogrel is the vasodilator-stimulated phosphoprotein. Point-of-care assays (ie, available at the bedside and easy to conduct and read), such as VerifyNow, have potentially great practical advantages over central laboratory tests.
In my article, I review the variability in responsiveness to antiplatelet therapy from patient to patient. Platelet hyperreactivity plays an important pathogenetic role in intracoronary thrombus formation after intervention for ACS. Although dual antiplatelet therapy with aspirin and clopidogrel is credited with a 20% reduction over aspirin alone in the number of patients who experience adverse outcomes, approximately 10% of patients receiving dual antiplatelet therapy experience further ischemic events. The occurrence of ischemic events despite the use of dual therapy suggests that some patients may respond inadequately to treatment. Variable response to oral antiplatelet therapy is well documented. However, a distinction must be made between resistance (the failure to inhibit platelet activity in vitro) and treatment failure (the recurrence of ischemic events despite antiplatelet therapy). The nature of variable responsiveness differs between aspirin and clopidogrel because they have dissimilar and complementary pharmacologic profiles. However, it is now appreciated that observations of clopidogrel response that rely on baseline platelet reactivity are less reliable predictors than posttreatment platelet reactivity. The mechanisms underlying interindividual variability in response to clopidogrel have not been fully elucidated but are probably multifactorial. Potential factors may be genetic, cellular, and/or clinical. Managing an inadequate response to antiplatelet therapy still represents a major challenge.
In the next article, Dr. Matthew J. Price discusses how monitoring of platelet function in response to antiplatelet therapy can reduce ischemic and bleeding complications of PCI. The principal objections to monitoring are cost, general unavailability of convenient point-of-care assays, lack of standardization, and the fact that complications, such as stent thrombosis, are relatively infrequent (although with serious consequences). However, although the positive predictive value may be low, the negative predictive value is excellent with some assays. The identification of patients who are at a low rather than high risk of nonresponsiveness can provide the clinician with confidence regarding the decision to implant a drug-eluting stent and the probable effectiveness of the patient's antiplatelet regimen.
Prospective, randomized studies are required to determine whether platelet function monitoring to guide antiplatelet therapy in high-risk patients is a safe and cost-effective approach to improving outcomes after PCI. Platelet function monitoring may also play an important role in determining the risk of bleeding events in patients receiving antiplatelet therapy who are candidates for noncardiac surgery and the minimum “washout” interval that should be observed before proceeding to surgery.
Finally, Dr. Bhatt, Paul Gurbel, MD, Dr. Jennings, and I review 4 antiplatelet agents in various stages of clinical development. I describe the benefits and limitations of prasugrel, a new thienopyridine that has been assessed in several large-scale clinical trials.4, 5 In every comparative trial, both 60-mg loading doses and 10–mg/day maintenance doses produced a more thorough inhibition of platelet aggregation than did the corresponding 300-mg and 75–mg/day recommended doses of clopidogrel, with the difference resulting in a lower rate of the combined primary outcome of cardiac death, nonfatal myocardial infarction, and stroke in patients with high-risk ACS. The ability of prasugrel to reduce the risk of stent thrombosis by >50% in one trial was particularly noteworthy.6 In another study, the relative advantage of prasugrel in the inhibition of platelet aggregation is preserved, even when the clopidogrel loading and maintenance doses are doubled to 600 mg and 150 mg/day, respectively.7 Somewhat offsetting the superior antithrombotic efficacy of prasugrel is its tendency to increase the risk of bleeding, including life-threatening bleeding. A benefit analysis suggests that although this risk is significant, it does not entirely outweigh the advantages of prasugrel in patients undergoing PCI.
Dr. Bhatt reports on cangrelor, a candidate agent requiring intravenous administration. Cangrelor is a modified adenosine triphosphate analogue that antagonizes the ADP–induced activation of platelet P2Y12 receptors with high receptor specificity. The blockade of cangrelor, unlike that of the thienopyridines, is reversible, permitting full recovery of platelet function approximately 1 hour after infusion. Because cangrelor is not a prodrug that requires hepatic metabolism to become active, its pharmacologic effect is immediate. It has a predictable steady-state dose–concentration effect relation, an ultrashort onset, a short plasma half-life, and clearance that is independent of renal or hepatic function. A bolus dose can be titrated to achieve up to 100% inhibition of ADP–induced platelet aggregation. Cangrelor is currently in large-scale phase 3 clinical trials for the suppression of periprocedural ischemic events.
Dr. Gurbel examines ticagrelor (AZD6140), another reversible, highly selective nonthienopyridine antagonist of ADP at the platelet P2Y12 receptor that does not depend on biotransformation into an active metabolite. Ticagrelor can therefore become biologically available much faster than can clopidogrel or other drugs in that class, and unlike cangrelor, it is not an adenosine triphosphate analogue and is administered orally. Phase 2 studies indicate that ticagrelor has a safety and efficacy profile similar to that of clopidogrel, although the studies were not powered to demonstrate superiority.8, 9 An ongoing large-scale phase 3 trial is evaluating whether ticagrelor is superior to clopidogrel in patients with ACS.
Lastly, Dr. Jennings looks at the PAR-1 antagonists. Thrombin is an important agonist, as small amounts of thrombin are generated on expression of tissue factor (tissue factor that may be expressed by damaged endothelium or activated monocytes). Thus, the generation of thrombin may be among the earliest events leading to platelet activation. Thrombin via its effect on PAR-1 also has a synergistic effect on collagen-induced platelet procoagulant by the induction of a sustained elevation of platelet Ca2+. When PAR-1 signaling is inhibited, the combined effects of collagen, thrombin-induced Ca2+ signals, and the generation of platelet procoagulant activity are reduced to the level associated with collagen alone. Of the 4 PARs thus far identified, PAR-1 was singled out as a therapeutic target because it is a high-affinity receptor for platelet activation at low thrombin levels. PAR-1 inhibitors (of which SCH 530348 is representative, although it is structurally different from others in its class) are thrombin receptor antagonists with no measurable effect on platelet aggregation induced by ADP, thromboxane A2, or collagen. SCH 530348 has been given a fast track designation by the US Food and Drug Administration (FDA) in the expectation that it will reduce the incidence of recurrent ischemic events and serious bleeding in patients undergoing PCI. Compared with the thienopyridines, SCH 530348 is associated with less bleeding.
It is anticipated that these new antiplatelet agents will show the potential both to overcome the limitations of currently available agents and to provide improved clinical outcomes in patients with ACS and patients who are undergoing PCI.
Author Disclosures
The author who contributed to this article has disclosed the following industry relationships.
Dominick J. Angiolillo, MD, PhD, has served on the advisory boards of Accumetrics, Inc, Avena Pharmaceuticals, Inc, Bristol-Myers Squibb Company/sanofi-aventis, Eli Lilly and Company/Daiichi Sankyo, Inc, Medicure, Inc, The Medicines Company, Novartis, and Portola Pharmaceuticals, Inc; acted as an investigator for Accumetrics, Inc, AstraZeneca PLC, Eisai Inc, Eli Lilly and Company/Daiichi Sankyo, Inc, GlaxoSmithKline PLC, The Medicines Company, Otsuka, Portola Pharmacuticals, Inc, and Schering-Plough Corporation and has served as a speaker for Bristol-Myers Squibb Company/sanofi-aventis and Eli Lilly and Company/Daiichi Sankyo, Inc.
References
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- . Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–1047
- . Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50:1844–1851
Statement of author disclosure: Please see the Author Disclosures section at the end of this article.
PII: S0002-9149(08)02026-2
doi:10.1016/j.amjcard.2008.11.015
© 2009 Elsevier Inc. All rights reserved.
Volume 103, Issue 3, Supplement , Pages 1A-3A, 2 February 2009
