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Updates in Antiplatelet Agents Used in Cardiovascular Diseases Judy W. M. Cheng J CARDIOVASC PHARMACOL THER 2013 18: 514 DOI: 10.1177/1074248413499971 The online version of this article can be found at: http://cpt.sagepub.com/content/18/6/514

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Cardiovascular Pharmacology Core Review

Updates in Antiplatelet Agents Used in Cardiovascular Diseases

Journal of Cardiovascular Pharmacology and Therapeutics 18(6) 514-524 ª The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413499971 cpt.sagepub.com

Judy W. M. Cheng, BS, PharmD, MPH, FCCP, BCPS1

Abstract Background: Antiplatelet therapy is a cornerstone in coronary artery disease management. However, patients with acute coronary syndrome still remain at risk of recurrent cardiovascular events despite the advance of medical therapy. Objective: This article provides a review of antiplatelet agents used in cardiovascular diseases and focus on updates in the past 5 years. Method: Peer-reviewed clinical trials and relevant treatment guidelines were identified from MEDLINE and Current Content database (from 1966 to April 15, 2013) using search terms aspirin, clopidogrel, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, antiplatelet agents, coronary artery disease, acute coronary syndrome, pharmacology, pharmacokinetics, and pharmacodynamics. Citations from the available articles were also reviewed for additional references. Results: In unstable angina and non-STsegment elevation myocardial infarction (MI), dual antiplatelet therapy (aspirin and clopidogrel) demonstrated a reduction in death from cardiovascular causes, nonfatal MI, or stroke (relative risk 0.80; 95% confidence interval [CI], 0.72-0.90). In ST-segment elevation MI, dual antiplatelet therapy reduced the rate of occluded infarct-related artery/death or recurrent MI (95% CI, 24%-47%). Newer agents such as prasugrel, when compared to clopidogrel, reduced death from vascular causes, MI, or stroke in patients undergoing percutaneous coronary intervention (PCI; hazard ratio [HR], 0.81; 95% CI 0.73-0.90) but not in those receiving medical management only. When compared to clopidogrel, ticagrelor reduces death from vascular causes, MI, or stroke (HR: 0.84; 95% CI, 0.77-0.92) in patients undergoing PCI or receiving medical management only. Both the agents, however, increase the risk of bleeding in certain patient population. Conclusions: In the last 5 years, newer antiplatelet agents, including prasugrel and ticagrelor, have been demonstrated to reduce recurrent cardiovascular events compared to standard therapy and, however, also caused increase bleeding in selected patient populations. Newer agents including shorter acting P2Y12 inhibitor or antiplatelets that target other receptors are being evaluated to improve/maintain therapeutic efficacy yet minimize the risk of bleeding. Keywords antiplatelet agents, prasugrel, ticagrelor, acute coronary syndrome

Introduction Platelets play an important role in normal homeostasis and atherothrombosis by adhering to injured vascular wall, releasing vasoactive and prothrombotic mediators that trigger vasoconstriction and promote coagulation.1 However, uncontrolled progression of this process can lead to intraluminal thrombus formation, vascular occlusion, and subsequent ischemia or infarction. Coronary artery diseases including stable angina and acute coronary syndromes (ACS) are the leading causes of morbidity and mortality in the United States.2 In 2010, approximately 8 million cases of myocardial infarction (MI) were diagnosed.2 Thrombotic occlusion of the coronary arteries underlies the pathophysiology of each of these conditions. This occlusion occurs when atherosclerotic plaque ruptures, and platelet aggregation takes place at the site of rupture.1 Antiplatelet therapy is a cornerstone in coronary artery disease management. They interfere with one or more steps of the process of platelet release and aggregation and reduce the risk of thrombosis. However, the beneficial effect cannot be

dissociated from an increased risk of bleeding. Aspirin, thienopyridine P2Y12 receptor antagonists (eg, clopidogrel), and glycoprotein IIb/IIIa inhibitors (eg, abciximab and eptifibatide) are standard therapy, well established to prevent and manage arterial thrombotic events.3,4 The clinical benefits of dual antiplatelet agent (aspirin þ second generation thienopyridine, and clopidogrel) in the management of ACS, especially in patients receiving percutaneous coronary intervention (PCI), are also well established.5–7 In unstable angina and non-ST-segment elevation MI (NSTEMI), dual antiplatelet therapy with aspirin and clopidogrel has been demonstrated to reduce death from

1

Department of Pharmacy Practice

Manuscript submitted: April 27, 2013; accepted: July 03, 2013. Corresponding Author: Judy W. M. Cheng, MCPHS University, 179 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]

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cardiovascular causes, nonfatal MI, or stroke by a relative risk of 20% (clopidogrel: 9.3%, placebo: 11.4%: relative risk [RR] 0.80; 95% confidence interval [CI], 0.72-0.90; P < .001).5,6 In STEMI, dual antiplatelet therapy reduces the rate of occluded infarct-related artery on angiography or death or recurrent MI before angiography by 36% (placebo: 21.7%, clopidogrel: 15.0%, (95% CI, 24%-47%; P < .001).7 The ClOpidogrel and Metoprolol in Myocardial Infarction Trial study also demonstrated that clopidogrel added to aspirin therapy reduces death, reinfarction, and stroke (9.2% clopidogrel vs 10.1% placebo, P ¼ .002).8 In the last 5 years, newer antiplatelet agents have also become available, and even more agents are in the developmental pipeline. This continues to refine the role of antiplatelet agents used in cardiovascular diseases (CVDs). The latest American College of Cardiology Foundation and American Heart Association (AHA) Guidelines on unstable angina and NSTEMI management recommend that dual antiplatelet agents be used for either medical management or patients undergoing PCI.3 For medical management patients, in addition to aspirin, both clopidogrel and ticagrelor are therapeutic options as the second antiplatelet agent. For patients undergoing PCI, in addition to aspirin, clopidogrel, prasugrel, or ticagrelor are all acceptable therapeutic option as the second antiplatelet agent.3 This article provides a review of the pharmacology and clinical efficacy/ adverse effects of these agents with focus on update of the newer antiplatelet agents used in this area in the past 5 years.

Method Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Content database (both from 1966 to April 15, 2013) using search terms aspirin, clopidogrel, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, antiplatelet agents, coronary artery disease, acute coronary syndrome, pharmacology, pharmacokinetics, and pharmacodynamics. Citations from available articles were also reviewed for additional references.

Clinical Pharmacology of Antiplatelet Agents Table 1 summarizes the mechanism of action, pharmacokinetics, and optimal dosing of different antiplatelet agents on the US market.

Aspirin Aspirin is the first antiplatelet agent established for its cardiovascular beneficial effect and is the most widely studied and used antiplatelet drug. The best-characterized mechanism of action of aspirin is related to its capacity to permanently inhibit the cyclooxygenase (COX) activity of prostaglandin H-synthase 1 and prostaglandin H-synthase 2 (COX-1 and COX-2, respectively).9 The COX isozymes catalyze the conversion of arachidonic acid to prostaglandin H2 (PGH2). The PGH2 is the immediate precursor of thromboxane A2 (TXA2) and prostacyclin (PGI2). The TXA2 induces platelet aggregation and

vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilation. Because TXA2 is largely derived from COX-1 (mostly from platelets), it is highly responsive to aspirin inhibition.9 Aspirin is rapidly absorbed in the stomach and upper intestine. Plasma levels peak 30 to 40 minutes after ingestion, and inhibition of platelet function is evident within an hour. In contrast, it can take 3 to 4 hours to reach peak plasma levels after administration of enteric-coated aspirin. Therefore, if a rapid effect is required and only enteric-coated tablets are available, the tablets should be chewed instead of swallowed intact. The oral bioavailability of regular aspirin tablets is 40% to 50%. Aspirin has a half-life of 15 to 20 minutes.10 Despite rapid clearance of aspirin from the circulation, the platelet inhibitory effects last the life span of the platelet, because aspirin irreversibly inactivates platelet COX-1. Aspirin also acetylates megakaryocyte COX-1, thereby inhibiting thromboxane production in newly released platelets as well as those already in the circulation. The mean life span of human platelets is approximately 10 days, which means that approximately 10% to 12% of the circulating platelets are replaced every day.9 Major side effect of aspirin is dose-related bleeding and gastrointestinal distress. Low-dose aspirin (75-325 mg per day) use has been long established to be associated with a significant reduction in the risk of cardiovascular events.11,12 The role of low-dose aspirin for the secondary prevention (in individuals with coronary artery disease, peripheral vascular disease, or cerebrovascular disease) of cardiovascular events is well established, while its use in primary prevention is more controversial.13,14 The decision of use of aspirin as primary prevention therapy is dependent on a balance of an individual’s risk of cardiovascular events and adverse treatment effects, such as bleeding.15 Odd ratios for bleeding, in case–control studies of low-dose aspirin, range between 1.3 and 3.2.16 The US Food and Drug Administration has not been adequately persuaded that there is sufficient evidence of a net benefit for aspirin use in primary prevention in all patients.17 The AHA, however, recommends low-dose aspirin in individuals with an estimated 10% risk of a cardiovascular event over a 10-year period.18 Similarly, the US Preventive Services Taskforce recommends aspirin in men aged 45 to 79 years in whom the benefit of a reduction in MI outweighs the harm of an increased risk of gastrointestinal bleeding, and in women aged 55 to 79 years in whom the benefit of a reduction in the risk of ischemic stroke outweighs the same risk of harm.19 For older adults, they recommend a 12% risk of a cardiovascular event over 10 years as the cutoff when the benefit exceeds the risk in those aged 70 to 79 years. For people with diabetes, the American Diabetes Association acknowledges the lack of a clear role for aspirin in primary prevention and currently recommends its use in patients with diabetes who have a 10-year CVD risk of over 10%.20,21

Glycoprotein IIb/IIIa Inhibitors Glycoprotein (Gp) IIb/IIIa inhibitors prevent platelet aggregation by blocking fibrinogen binding to the GpIIb/IIIa

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Eptifibatide

10 hours

200 mg extended100 mg po 0.25 mg/kg bolus 180 mg/kg bolus IV release dipyridatwice daily IV þ 0.125 mg/kg/ (repeat in 10 mole and 25 mg min minutes for PCI) aspirin twice daily þ 2 mg/kg/min (for stroke prevention only)

15-20 minutes

75-325 mg po daily

Gastrointestinal upsets

Half-life

Dosage (for coronary artery disease unless otherwise specified)

Side effects besides bleeding

11 hours

Metabolized primarily CYP3A4 and, to a lesser extent, CYP2C19

1-2 hours

Deaminated

0.4 mg/kg bolus IV þ 0.1 mg/kg/min

1-2 hours

Not metabolized

NA (bind to platelets)

NA

500 mg loading po, 250 mg po twice daily

12-13 hours

Metabolized through N-dealkylation, N-oxidation, and oxidation of the thiophene ring

98%

80%-90%

98% bound to albumin

79%

Irreversible P2Y12 receptor antagonist (via its active metabolite only)

Prasugrel

>99% bound to plasma protein

36%

Reversible P2Y12 receptor antagonist (both ticagrelor itself and its active metabolite)

Ticagrelor

300-600 mg loading po, then 75 mg po once daily

Clopidogrel: 6 hours. Active metabolite: 30 minutes

60 mg loading, then 10 mg daily (5 mg if patient is 80% receptor blockade.22 After intravenous bolus administration, pharmacokinetic data indicate that free plasma abciximab concentrations decrease rapidly (initial half-life of about 30 minutes), reflecting the rapid binding of the antibody to GpIIb-IIIa.22 Peak effects on receptor blockade, platelet aggregation, and bleeding time were observed at 2 hours. This was followed by gradual recovery of platelet function, with bleeding times returning to baseline by 12 hours.22,23 Thrombocytopenia occurs in 1% to 2% of the patients treated with abciximab. The risk of thrombocytopenia appears to be increased with abciximab readministration. Typically, the decrease in platelet count occurs within 24 hours of initiation of treatment but may begin to fall as early as 2 hours after the treatment starts.9 Abciximab has been demonstrated to decrease the risk of events compared with placebo in high-risk patients with NSTEMI scheduled for PCI after treatment with clopidogrel. In a meta-analysis of studies assessing patients presenting for primary PCI and stenting of STEMI (n ¼ 1101), death or reinfarction was also reduced in patients receiving abciximab versus placebo.24 Tirofiban is a nonpeptide tyrosine derivative that selectively binds to GpIIb-IIIa. The plasma half-life of tirofiban is 1.5 to 2 hours, and both renal and biliary excretion contribute to tirofiban clearance with unchanged tirofiban found in urine and feces.25 Dose adjustment is required in patients with renal insufficiency but not in patients with hepatic disease. Severe, but reversible, thrombocytopenia has been reported in a small percentage of patients treated with tirofiban.26 In a metaanalysis (n ¼ 20 006), tirofiban used in patients with unstable angina and NSTEMI scheduled for PCI was significantly more effective than placebo at reducing the risk of mortality or the composite of death and MI at 30 days.27 Eptifibatide is a synthetic disulfide-linked cyclic heptapeptide. It is formulated after the KGD sequence found in the snake venom disintegrin obtained from Sistrurus miliarius barbouri (barbourin) and has high specificity for GpIIb-IIIa.9 Because the drug is cleared by the kidneys, patients with renal impairment exhibit prolonged inhibition of platelet function after receiving eptifibatide and required dosage adjustment.28 Eptifibatide treatment has also been associated with thrombocytopenia, and an immunologic mechanism has been identified in some patients.26 In one study in patients with unstable angina and NSTEMI undergoing PCI, eptifibatide did not show significant benefit when compared with placebo.29 However, in a subsequent trial investigating higher doses, a significant reduction in the risk of death, MI, urgent coronary revascularization, and bail-out use of GPIIb/IIIa inhibitors was demonstrated versus placebo.30 More recently, it has been shown that early administration of eptifibatide presented no advantage over postangiographic administration.31

Dipyridamole Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent is controversial. Both inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine monophosphate [cAMP]) and blockade of the uptake of adenosine (which binds to A2 receptors, stimulates platelet adenylyl cyclase, and increases cAMP) have been suggested.9 The cAMP is an inhibitor for platelet aggregation. The absorption of dipyridamole is variable and results in low-systemic bioavailability of the drug. A modified release formulation of dipyridamole with improved bioavailability has been developed in a combination pill with low-dose aspirin.32 Dipyridamole is highly protein bound to albumin, eliminated primarily by biliary excretion as a glucuronide conjugate, and is subject to enterohepatic recirculation. Half-life of dipyridamole is 10 hours.9 The use of dipyridamole for primary or secondary prevention of coronary artery disease is not well established.

Cilostazil Cilostazol is a 2-oxoquinolone derivative that is reported to have vasodilatory and antiplatelet properties, via phosphodiesterase 3 inhibitory effect, as well as antiproliferative properties reducing smooth muscle cell proliferation and neointimal hyperplasia after endothelial injury. Cilostazol is contraindicated in patients with heart failure because of the potential to trigger ventricular tachycardia. There is substantial variability in the absorption of orally administered cilostazol. Cilostazol is highly albumin bound and is extensively metabolized by cytochrome P450 (CYP450) enzymes with excretion of metabolites in the urine. It has a half-life of 11 hours.9 Cilostazil is indicated for symptomatic peripheral arterial disease, but its role in primary or secondary prevention of coronary artery disease is not well established.

P2Y12 receptor antagonists Ticlopidine, clopidogrel, and prasugrel represent 3 generations of oral thienopyridines that inhibit adenosine diphosphate (ADP)-induced platelet aggregation. The use of first-generation agent ticlopidine was limited by its bone marrow toxicity (neutropenia) and has largely been replaced by clopidogrel that has become established as standard therapy across the spectrum of patients with coronary artery disease and in those undergoing PCI. However, clopidogrel also has limitations, including variable absorption; variable antiplatelet effects related, at least in part, to common polymorphisms in the genes that regulate the metabolic activation of clopidogrel; and a delayed onset and offset of action. Prasugrel, a more recently available, third-generation thienopyridine, has a more rapid onset of action, is more potent than clopidogrel, and produces more consistent platelet inhibition. All 3 thienopyridines are prodrugs that must undergo metabolic activation through the

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Journal of Cardiovascular Pharmacology and Therapeutics 18(6)

hepatic CYP450 system to generate the active metabolites that exert their pharmacologic action. Ticlopidine. Up to 90% of a single oral dose of ticlopidine is rapidly absorbed.18 Plasma concentrations peak 1 to 3 hours after a single-oral dose of 250 mg. More than 98% of the absorbed ticlopidine is reversibly bound to plasma proteins, primarily albumin. Ticlopidine is metabolized rapidly and extensively. A total of 13 metabolites have been identified in humans.18 The apparent half-life of ticlopidine is 24 to 36 hours after a single oral dose and up to 96 hours after 14 days of repeated dosing. The standard dosing regimen of ticlopidine is 250 mg twice a day.33 Clopidogrel. Clopidogrel is also rapidly absorbed and metabolized through a 2-step process to generate an active metabolite that irreversibly binds to the platelet P2Y12 receptor.34 On repeated daily dosing of 50 to 100 mg of clopidogrel in healthy volunteers, ADP-induced platelet aggregation was inhibited from the second day of treatment (25%-30% inhibition) and reached a steady state (50%-60% inhibition) after 4 to 7 days. Such a level of inhibition was comparable to that achieved with ticlopidine (500 mg/d), although the antiplatelet effects of the latter were more delayed than that of clopidogrel.34 Loading dose (eg, 300 mg) of clopidogrel results in more rapid platelet inhibition (6-12 hours) than that achieved with the 75 mg dose.35 After loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug was achieved after 2 to 4 hours.36 Moreover, a loading dose of 600 mg resulted in higher plasma concentrations of the active metabolite and the inactive carboxyl metabolite compared with a loading dose of 300 mg.36 Inhibition of ADP-induced platelet aggregation was also significantly greater with a 600 mg loading dose of clopidogrel compared with a 300 mg loading dose.37 The incremental antiplatelet effect of 900 mg over 600 mg of clopidogrel appears marginal.37,38 Platelet function returns to baseline 7 to 10 days after the last dose of clopidogrel. This also justifies a oncedaily regimen for aspirin and clopidogrel in patients with normal rates of platelet turnover despite short half-life of both the drugs in the circulation. Prasugrel. Prasugrel is rapidly absorbed after oral administration and converted into its active metabolite, which reaches peak concentrations within 30 minutes of dosing. The active metabolite has a half-life of approximately 4 hours, and renal excretion is the major route for elimination.39 Initial pharmacological studies with prasugrel in healthy individuals39 and in patients with stable coronary artery disease32 showed that prasugrel has a more rapid onset of action than clopidogrel and achieves more consistent and complete inhibition of ADPinduced platelet aggregation.40,41 The more rapid onset of action of prasugrel may in part reflect the hepatic conversion to its active metabolite by CYP450 enzymes in a single step, which contrasts with that of clopidogrel that undergoes a 2-step hepatic conversion process.42 Unlike clopidogrel, evidence showed that polymorphisms in CYP2C19 or the

concomitant use of proton-pump inhibitors did not interfere with the metabolism of prasugrel.43,44 Clinical studies on the use of prasugrel in patients with coronary artery disease will be discussed in greater depth in the clinical trial section.

Ticagrelor Ticagrelor is the first member of a new class of antiplatelet agent, the cyclopentyl-triazolopyrimidines.45 Ticagrelor is an orally active, selective antagonist of the P2Y12 receptor, inhibiting ADP-mediated platelet response. Ticagrelor demonstrates noncompetitive antagonistic activity for ADP-induced platelet aggregation.46 Unlike clopidogrel and prasugrel, ticagrelor demonstrates platelet inhibitory activity without the need for metabolic activation. In addition, its active metabolite (AR-C124910XX) is also active and demonstrates P2Y12 receptor antagonism activity equipotent to ticagrelor.47,48 Ticagrelor was rapidly absorbed with a maximum plasma concentration occurring at 1.5 hours. The major active metabolite, AR-C124910XX, is formed by O-deethylation (via CYP3A4) and represents approximately 40% of the parent concentration. The plasma elimination half-life of ticagrelor was found to be 7.2 hours.49 Clinical trials evaluating the use of ticagrelor in patients with coronary artery disease will be discussed subsequently.

Clinical Trials Updates: Updates From the Last 5 years Prasugrel The majority of the clinical outcomes data for prasugrel comes from the phase III Trial to Access Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial. In this study, 13 608 patients with ACS with planned PCI (10 074 patients with moderate to high-risk unstable angina and NSTEMI and 3534 patients with STEMI) were randomized to receive either clopidogrel 300 mg loading dose followed by 75 mg daily or prasugrel 60 mg loading dose followed by 10 mg daily.50 Patients were treated for a median of 14.5 months. The primary end point was the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Patients randomized to prasugrel had fewer primary end point events compared with clopidogrel (9.9% vs 12.1%; hazard ratio [HR], 0.81; 95% CI, 0.73 to 0.90; P < .001). The reduction in clinical ischemic events was also notable for a reduction in MI (7.4% vs 9.7%, P < .001) and urgent target vessel revascularization (2.5% vs 3.7%; P < .001). The major safety end point of noncoronary artery bypass graft (CABG)-related TIMI major bleeding was significantly higher with prasugrel (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03-1.68; P < .03). There was also significant increase in non-CABG-related TIMI major or minor bleeding (5.0% vs 3.8%; HR, 1.31; 95% CI, 1.11-1.56; P < .002) and bleeding requiring transfusion (4.0% vs 3.0%; HR, 1.34; 95% CI, 1.11-1.63; P < .001). Among non-CABG-related

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bleeding, the excess was predominantly spontaneous bleeding (1.6% vs 1.1%; HR, 1.51; 95% CI, 1.09-2.08; P < .01). Intracranial bleeding was not significantly increased (0.3% of both treatment arms). Patients with known history of stroke or transient ischemic attacks (n ¼ 518) before enrollment in TRITON-TIMI 38 trial had a higher rate of primary efficacy events (19.1% vs 14.4%; HR, 1.37; P < .15) driven by an increase in stroke, which differed significantly from the nonstroke cohort (P for interaction 75 years of age (n ¼ 1809), a smaller relative reduction in primary efficacy events (17.2% vs 18.3%; HR, 0.94; P ¼ .60) and an absolute TIMI major bleeding rates (4.2% vs 3.4%; HR, 1.36; P ¼ .24) were observed. This resulted in a neutral net outcome (21.7% vs 21.5%; HR, 0.99; P ¼ .92). Similar bleeding concern was also observed in the elderly patients. In patients >75 years of age, 9 spontaneous fatal hemorrhages were observed with prasugrel and 0 with clopidogrel. In patients

Updates in antiplatelet agents used in cardiovascular diseases.

Antiplatelet therapy is a cornerstone in coronary artery disease management. However, patients with acute coronary syndrome still remain at risk of re...
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