Portal de Periódicos da CAPES

New Antithrombotic Drugs

2012; Elsevier BV; Volume: 141; Issue: 2 Linguagem: Inglês

10.1378/chest.11-2294

1931-3543

Jeffrey I. Weitz, John W. Eikelboom, M Samama,

Atrial Fibrillation Management and Outcomes

This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents. This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents. acute coronary syndrome adenosine diphosphate activated partial thromboplastin time cytochrome P450 hazard ratio low-molecular-weight heparin myocardial infarction nematode anticoagulant peptide c2 peripheral arterial disease type 1 plasminogen activator inhibitor protease-activated receptor percutaneous coronary intervention pulmonary embolism platelet factor 4 Study of Platelet Inhibition and Patient Outcomes relative risk thrombin activatable fibrinolysis inhibitor thrombolysis in myocardial infarction thrombin receptor agonist peptide tissue plasminogen activator urokinase plasminogen activator Arterial and venous thrombosis is a major cause of morbidity and mortality. Arterial thrombosis is a common cause of myocardial infarction (MI), ischemic stroke, and limb gangrene; venous thrombosis includes DVT, which can be complicated by the postthrombotic syndrome, and pulmonary embolism (PE), which can be fatal or can lead to chronic thromboembolic pulmonary hypertension. Arterial thrombi, which form under high shear conditions, consist of platelet aggregates held together by small amounts of fibrin.1Freiman D The structure of thrombi.in: Colman RW Hirsh J Marder VJ Salzman EW Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 2nd ed. JB Lippincott, Philadelphia, PA1987: 1123-1135Google Scholar Because of the predominance of platelets, strategies to inhibit arterial thrombogenesis focus mainly on drugs that block platelet function but include anticoagulants for prevention of cardioembolic events in patients with atrial fibrillation or mechanical heart valves. Fibrinolytic drugs are used for rapid restoration of antegrade blood flow in patients with acute MI who do not undergo a primary percutaneous coronary intervention (PCI) and for treatment of acute ischemic stroke. Venous thrombi, which form under low shear, are composed mainly of fibrin and trapped RBCs and contain relatively few platelets.1Freiman D The structure of thrombi.in: Colman RW Hirsh J Marder VJ Salzman EW Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 2nd ed. JB Lippincott, Philadelphia, PA1987: 1123-1135Google Scholar With the predominance of fibrin in venous thrombi, anticoagulants are the mainstay for the prevention and treatment of VTE. Systemic or catheter-directed fibrinolytic therapy is used for treatment of massive PE and for management of selected patients with submassive PE, whereas catheter-directed fibrinolytic therapy is used in some patients with extensive iliofemoral DVT. Limitations of existing antithrombotic drugs have prompted a search for novel agents. Focusing on new drugs for the prevention and treatment of arterial and venous thrombosis, this chapter (1) outlines the rationale for development of new antithrombotic drugs; (2) describes the new antithrombotic drugs, focusing primarily on those in phase 2 or 3 clinical testing; and (3) provides perspective on the unmet needs in antithrombotic therapy. New antithrombotic drugs have been developed to overcome the limitations of existing agents. Most of the advances have been in the area of antiplatelet drugs and anticoagulants. The development of new fibrinolytic agents has lagged. Although IV glycoprotein IIb/IIIa antagonists have a role in patients undergoing PCI, the need for these agents has declined because of the development of more potent oral antiplatelet drugs. Currently available oral antiplatelet drugs include aspirin, clopidogrel, prasugrel, and dipyridamole. The efficacy of aspirin and clopidogrel has clearly established cyclooxygenase-1, a key enzyme in thromboxane A2 synthesis, and P2Y12, the major adenosine diphosphate (ADP) receptor on platelets, as important targets for antiplatelet drugs. Although the benefits of aspirin for secondary prevention of atherothrombotic cardiovascular events clearly outweigh the risk of bleeding, aspirin is of limited usefulness for primary prevention, including primary prevention in patients with type 2 diabetes mellitus.2Baigent C Blackwell L Collins R Antithrombotic Trialists' (ATT) Collaboration et al.Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-1860Abstract Full Text Full Text PDF PubMed Scopus (1600) Google Scholar In addition, recent meta-analyses question the usefulness of aspirin for prevention of cardiovascular events in patients with peripheral arterial disease (PAD).3Berger JS Krantz MJ Kittelson JM Hiatt WR Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials.JAMA. 2009; 301: 1909-1919Crossref PubMed Scopus (0) Google Scholar Building on this latter information, an expert panel of the US Food and Drug Administration found insufficient evidence to support over-the-counter use of aspirin for prevention of cardiovascular events in such patients.4Food and Drug Administration Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; final rule for professional labeling of aspirin, buffered aspirin, and aspirin in combination with antacid drug products.Fed Regist. 1998; 63: 56802-56809Google Scholar These issues highlight the limitations of aspirin. On its own, clopidogrel has been shown to be only marginally more effective than aspirin.5CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).Lancet. 1996; 348: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (4839) Google Scholar The combination of aspirin plus clopidogrel is superior to aspirin alone in patients at high risk for cardiovascular events,6Yusuf S Zhao F Mehta SR Chrolavicius S Tognoni G Fox KK Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med. 2001; 345: 494-502Crossref PubMed Scopus (4924) Google Scholar, 7Chen ZM Jiang LX Chen YP COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group et al.Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.Lancet. 2005; 366: 1607-1621Abstract Full Text Full Text PDF PubMed Scopus (1402) Google Scholar, 8Sabatine MS Cannon CP Gibson CM CLARITY-TIMI 28 Investigators et al.Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.N Engl J Med. 2005; 352: 1179-1189Crossref PubMed Scopus (1454) Google Scholar, 9Mehta S Tanguay J-F Eikelboom JW et al.Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS): a randomised factorial trial.Lancet. 2010; 376: 1233-1243Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but combination therapy is associated with a significant risk of bleeding and has yielded disappointing results in patients with stable cardiovascular disease.10Bhatt DL Fox KA Hacke W CHARISMA Investigators et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354: 1706-1717Crossref PubMed Scopus (1842) Google Scholar, 11Diener H-C Bogousslavsky J Brass LM MATCH investigators et al.Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial.Lancet. 2004; 364: 331-337Abstract Full Text Full Text PDF PubMed Scopus (1527) Google Scholar Although the combination of aspirin plus dipyridamole is superior to aspirin alone for secondary prevention in patients with cerebrovascular disease,12Verro P Gorelick P Nguyen D Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis.Stroke. 2008; 39: 1358-1363Crossref PubMed Scopus (79) Google Scholar the efficacy of this combination is similar to that of clopidogrel.13Sacco RL Diener H-C Yusuf S PRoFESS Study Group et al.Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.N Engl J Med. 2008; 359: 1238-1251Crossref PubMed Scopus (564) Google Scholar The limitations of existing antiplatelet drugs reflect, at least in part, their capacity to attenuate only a single pathway of platelet activation. Because platelets can be activated via multiple pathways, the potential for bypassing the inhibitory effects of these drugs remains high when there is a potent stimulus for platelet activation. Consequently, it is not surprising that breakthrough cardiovascular events occur, and these should not necessarily be labeled as simple treatment failures. Another factor that may contribute to breakthrough cardiovascular events is individual variability in the response to antiplatelet drugs. Such variability may reflect poor compliance, pharmacogenetic factors, increased platelet turnover, drug interactions, baseline and residual platelet hyperreactivity, and other factors.14Hankey GJ Eikelboom JW Aspirin resistance.Lancet. 2006; 367: 606-617Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, 15Armero B Ait Mokhtar O Mancini JAP et al.Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism.J Am Coll Cardiol. 2010; 56: 1630-1636Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Decreased responsiveness to aspirin and/or clopidogrel is common in patients with acute coronary syndromes, particularly in those with diabetes.16Braunwald E Angiolillo DJ Bates ER et al.Assessing the current role of platelet function testing.Clin Cardiol. 2008; 31: I10-I16Crossref PubMed Scopus (21) Google Scholar In patients undergoing PCI, a reduced biologic response to aspirin plus clopidogrel has been associated with a poorer outcome. The decreased response may reflect, at least in part, reduced metabolic activation of clopidogrel.15Armero B Ait Mokhtar O Mancini JAP et al.Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism.J Am Coll Cardiol. 2010; 56: 1630-1636Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar The cytochrome P450 (CYP) 2C19 enzyme plays a critical role in this process, and clopidogrel-treated patients with reduced function variants of the CYP2C19 gene have lower levels of clopidogrel metabolites and diminished platelet inhibition.17Mega JL Simon T Collet JP et al.Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.JAMA. 2010; 304: 1821-1830Crossref PubMed Scopus (589) Google Scholar It is estimated that 26% of the white population carries one loss-of-function variant of this gene, and about 2% carry two such alleles. These percentages are slightly higher in blacks and substantially higher in Asians. In patients undergoing PCI, those with one or two CYP2C19 loss-of-function alleles are at increased risk of subsequent cardiovascular events compared with noncarriers.17Mega JL Simon T Collet JP et al.Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.JAMA. 2010; 304: 1821-1830Crossref PubMed Scopus (589) Google Scholar These findings have prompted some experts to recommend tailored antiplatelet therapy based on periprocedural platelet function or genetic testing.18Verstuyft C Simon T Kim RB Personalized medicine and antiplatelet therapy: ready for prime time?.Eur Heart J. 2009; 30: 1943-1963Crossref PubMed Scopus (27) Google Scholar, 19Damani SB Topol EJ The case for routine genotyping in dual-antiplatelet therapy.J Am Coll Cardiol. 2010; 56: 109-111Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar However, the value of this approach has not been established. Instead, the limitations of existing antiplatelet agents has prompted the development of newer and more potent drugs, some directed against proven targets involved in platelet activation and others against new targets. These agents include novel inhibitors of the thromboxane A2 receptor, new P2Y12 antagonists, and inhibitors of protease activated receptor-1 (PAR-1), the major thrombin receptor on platelets. On the anticoagulant front, most of the recent attention has focused on the development of new oral agents to replace vitamin K antagonists.20Eikelboom JW Weitz JI New anticoagulants.Circulation. 2010; 121: 1523-1532Crossref PubMed Scopus (0) Google Scholar Rivaroxaban, a direct factor Xa inhibitor, and dabigatran etexilate, a direct thrombin inhibitor, have been licensed in many countries for short-term thromboprophylaxis after elective hip or knee arthroplasty, and dabigatran etexilate has recently been licensed in the United States and Canada for stroke prevention in patients with atrial fibrillation. Several other direct factor Xa inhibitors, including apixaban and edoxaban, are in advanced stages of development for these and other indications (Table 1).Table 1[Section 1.0] Comparison of the Pharmacologic Properties of the New Oral Anticoagulants That Are Approved or in the Most Advanced Stages of Clinical DevelopmentPropertyDabigatranRivaroxabanApixabanEdoxabanTargetThrombinFactor XaFactor XaFactor XaMolecular weight628436460548Bioavailability, %6805050Dose frequencyod/bidod/bidbidodTmax, h2331-2Half-life, h12-177-119-149-11Protein binding, %35958754CYP metabolism, %None3215 10 ng/mL; a concentration that can be achieved with daily doses of 10 to 30 mg.28Gaussem P Reny J-L Thalamas C et al.The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies.J Thromb Haemost. 2005; 3: 1437-1445Crossref PubMed Google Scholar Single-dose administration of 10 mg of terutroban to 12 patients with coronary artery disease who were receiving aspirin (100 mg/d) improved forearm blood flow after acetylcholine infusion compared with the results in eight aspirin-treated patients who received placebo.29Belhassen L Pelle G Dubois-Rande JL Adnot S Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin.J Am Coll Cardiol. 2003; 41: 1198-1204Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar In patients with PAD randomized to terutroban, aspirin, or placebo, terutroban produced dose-dependent inhibition of platelet aggregation in response to thromboxane, ADP, or collagen and was at least as potent as aspirin.30Fiessinger JN Bounameaux H Cairols MA TAIPAD investigators et al.Thromboxane antagonism with terutroban in peripheral arterial disease. The TAIPAD study.J Thromb Haemost. 2010; 8: 2369-2376Crossref PubMed Scopus (21) Google Scholar These phase 2 findings prompted the phase 3, double-blind Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial, which compared terutroban (30 mg/d) with aspirin (100 mg/d) for secondary prevention in 19,119 patients with a recent history of ischemic stroke or transient ischemic attacks.31Bousser M-G Amarenco P Charmorro A et al.Rationale and design of a randomized, double-blind, parallel group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.Cerebrovasc Dis. 2009; 27: 509-518Crossref PubMed Scopus (56) Google Scholar, 32Bousser M-G Amarenco P Chamorro A PERFORM Study Investigators et al.The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study: baseline characteristics of the population.Cerebrovasc Dis. 2009; 27: 608-613Crossref PubMed Scopus (26) Google Scholar The primary efficacy end point, a composite of fatal or nonfatal ischemic stroke or MI or vascular death, occurred in 11% of patients receiving either terutroban or aspirin (hazard ratio [HR], 1.02; 95% CI, 0.94–1.12). There was a small increase in minor bleeding with terutroban compared with aspirin (12% and 11%, respectively; HR, 1.11; 95% CI, 1.02–1.12), but no difference in other safety end points.33Bousser M-G Amarenco P Chamorro A PERFORM Study Investigators et al.Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial.Lancet. 2011; 377: 2013-2022Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar A derivative of methoxy-isophthalic acid, picotamide not only inhibits the thromboxane A2 receptor but also inhibits thromboxane synthetase at equivalent concentrations.34Modesti PA Cecioni I Colella A Costoli A Paniccia R Neri Serneri GG Binding kinetics and antiplatelet activities of picotamide, a thromboxane A2 receptor antagonist.Br J Pharmacol. 1994; 112: 81-86Crossref PubMed Scopus (22) Google Scholar In contrast to aspirin, picotamide does not interfere with prostacyclin production. In a double-blind, placebo-controlled study in 2,304 patients with PAD, treatment with picotamide (300 mg bid) or placebo was administered for 18 months.35Balsano F Violi F The ADEP Group. Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study.Circulation. 1993; 87: 1563-1569Crossref PubMed Google Scholar End points of the study included major events (cardiovascular death, MI, stroke, or amputation) and minor events (unstable angina, transient ischemic attacks, hypertension, renal failure, or worsening of PAD symptoms). Although the intention-to-treat analysis revealed an 18.9% reduction in major plus minor events with picotamide, this difference was not statistically significant. However, the on-treatment analysis showed a 22.8% reduction in the same end points. Bleeding side effects were similar in the two groups. A post hoc subgroup analysis of the data from the 438 patients with diabetes included in the study revealed a 45.2% reduction in major and minor end points with picotamide compared with placebo.36Milani M Longoni A Maderna M Effects of picotamide, an antiplatelet agent, on cardiovascular, events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study.Br J Clin Pharmacol. 1996; 42: 782-785Crossref PubMed Google Scholar These findings prompted a randomized trial comparing picotamide (600 mg bid) with aspirin (320 mg/d) in 1,209 patients with diabetes with PAD.37Neri Serneri GG Coccheri S Marubini E Violi F Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.Eur Heart J. 2004; 25: 1845-1852Crossref PubMed Scopus (0) Google Scholar The primary efficacy end point was overall mortality, whereas the secondary end point was the composite of death and cardiovascular events. At 2 years, the overall mortality rates with picotamide and aspirin were 3.0% and 5.5%, respectively (relative risk [RR], 0.55; 95% CI, 0.31–0.98). Cardiovascular events occurred in 7.1% of patients given picotamide and 8.7% of those treated with aspirin. The difference in the combined end point of mortality plus cardiovascular events between the two groups did not reach statistical significance. Bleeding events were infrequent with both picotamide and aspirin (1.3% and 2.0%, respectively). Although these results are promising, additional studies are needed to establish the role of picotamide in patients with diabetes with PAD. Three reversible P2Y12 inhibitors are in phase 3 development: cangrelor, ticagrelor, and elinogrel (Table 2). Although these agents are chemically distinct and have different pharmacologic profiles, they share certain properties. In contrast to the thienopyridines, the reversible P2Y12 inhibitors do not require metabolic activation and they bind directly and reversibly to the P2Y12 receptor. Because of the reversible binding, their inhibitory effects decrease as drug concentrations fall.Table 2[Section 2.2] Pharmacologic Characteristics of Direct-Acting Reversible P2Y12 InhibitorsCharacteristicCangrelorTicagrelorElinogrelMolecular weight776523562Route of administrationIVOralIV or oralSite of actionADP binding siteSite distinct from ADP binding siteADP binding siteType of inhibitionCompetitiveNoncompetitiveCompetitiveTime to peak activity30 min2 h20 min and 12 h for IV and oral formulation, respectivelyFrequency of oral administrationInactivebidbidHalf-life3-5 min6-12 hNot reportedMetabolismDephosphorylationO -deethylation and oxidationNoneElimination27% Renal; 58% feces30% Renal; 70% feces40% Renal; 60% fecesTime to recovery of platelet function60 min3-5 dNot reportedStage of developmentPhase 3Completed phase 3; licensed in United States, Europe, and CanadaPhase 2ADP = adenosine diphosphate. Open table in a new tab ADP = adenosine diphosphate. An adenosine triphosphate analog, cangrelor is a direct competitive inhibitor of P2Y12.37Neri Serneri GG Coccheri S Marubini E Violi F Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.Eur Heart J. 2004; 25: 1845-1852Crossref PubMed Scopus (0) Google Scholar In contrast to clopidogrel or prasugrel, cangrelor does not require hepatic conversion to an active metabolite. The drug is only active when administered IV and it produces almost immediate and dose-proportional inhibition of ADP-induced platelet aggregation. Cangrelor is rapidly inactivated by dephosphorylation and has a half-life of 3 to 5 min. Upon cessation of therapy, therefore, there is recovery of platelet function within 60 min.37Neri Serneri GG Coccheri S Marubini E Violi F Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.Eur Heart J. 2004; 25: 1845-1852Crossref PubMed Scopus (0) Google Scholar, 38Fugate SE Cudd LA Cangrelor for treatment of coronary thrombosis.Ann Pharmacother. 2006; 40: 925-930Crossref PubMed Scopus (0) Google Scholar The interaction of cangrelor with P2Y12 prevents the binding of the active metabolites of clopidogrel or prasugrel. This phenomenon complicates the transitioning of patients from cangrelor to clopidogrel or other thienopyridines, which can only exert their inhibitory effects once cangrelor dissociates from P2Y12. Cangrelor has been evaluated in a two-part phase 2 trial in patients undergoing PCI.39Greenbaurm AB Grines CL Bittl JA et al.Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase 2, multicenter, randomized, placebo- and active-controlled trial.Am Heart J. 2006; 151: 689.e1-689.e10Abstract Full Text Full Text PDF Scopus (137) Google Scholar For part one, 200 patients were randomized to an 18- to 24-h infusion of cangrelor (in doses of 1, 2, or 4 μg/kg/min) or placebo in addition to aspirin plus heparin. In the second part, an additional 199 patients were randomized to IV cangrelor (at a dose of 4 μg/kg/min) or abciximab prior to PCI. In the first part of the study, the primary end point, the combination of major and minor bleeding up to 7 days, occurred in 13% of patients given cangrelor and in 8% of those given placebo, a difference that was not statistically significant.39Greenbaurm AB Grines CL Bittl JA et al.Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: