9-Updates in Antiplatelet Agents 2013 RCT

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Cardiovascular Pharmacology Core Review

Updates in Antiplatelet AgentsUsed in Cardiovascular Diseases

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

Abstract

Background: Antiplatelet therapy is a cornerstone in coronary artery disease management. However, patients with acutecoronary 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 Contentdatabase (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-ST-

segment elevation myocardial infarction (MI), dual antiplatelet therapy (aspirin and clopidogrel) demonstrated a reduction in deathfrom cardiovascular causes, nonfatal MI, or stroke (relative risk 0.80; 95% confidence interval [CI], 0.72-0.90). In ST-segment ele-vation 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 patientsundergoing percutaneous coronary intervention (PCI; hazard ratio [HR], 0.81; 95% CI 0.73-0.90) but not in those receiving med-ical 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 riskof bleeding in certain patient population. Conclusions: In the last 5 years, newer antiplatelet agents, including prasugrel andticagrelor, have been demonstrated to reduce recurrent cardiovascular events compared to standard therapy and, however, alsocaused increase bleeding in selected patient populations. Newer agents including shorter acting P2Y12 inhibitor or antiplateletsthat 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 vasocon-

striction 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, app-

roximately 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 dis-

ease 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, thieno-

pyridine P2Y12 receptor antagonists (eg, clopidogrel), and gly-

coprotein 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 anti-

platelet agent (aspirin second generation thienopyridine, and

clopidogrel) in the management of ACS, especially in patients

receiving percutaneous coronary intervention (PCI), are alsowell established.57 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]

Journal of Cardiovascular

Pharmacology and Therapeutics

18(6) 514-524

The Author(s) 2012

Reprints and permission:

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DOI: 10.1177/1074248413499971

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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 andMetoprolol in Myocardial Infarction Trial study also demon-

strated that clopidogrel added to aspirin therapy reduces death,

reinfarction, and stroke (9.2% clopidogrel vs 10.1% placebo,

P .002).8 In the last 5 years, newer antiplatelet agents have

also become available, and even more agents are in the develop-

mental pipeline. This continues to refine the role of antiplatelet

agents used in cardiovascular diseases (CVDs). The latest Amer-

ican 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, bothclopidogrel 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 treat-

ment guidelines were identified from MEDLINE and CurrentContent database (both from 1966 to April 15, 2013) using

search terms aspirin, clopidogrel, prasugrel, ticagrelor, glyco-

protein IIb/IIIa inhibitors, antiplatelet agents, coronary artery

disease, acute coronary syndrome, pharmacology, pharmacoki-

netics, and pharmacodynamics. Citations from available arti-

cles were also reviewed for additional references.

Clinical Pharmacology of Antiplatelet Agents

Table 1 summarizes the mechanism of action, pharmacoki-

netics, and optimal dosing of different antiplatelet agents on the

US market.

Aspirin

Aspirin is the first antiplatelet agent established for its cardio-

vascular 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, respec-

tively).9 The COX isozymes catalyze the conversion of arachi-

donic acid to prostaglandin H2 (PGH2). The PGH2 is the

immediate precursor of thromboxane A2 (TXA2) and prostacy-

clin (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 intes-

tine. Plasma levels peak 30 to 40 minutes after ingestion, and

inhibition of platelet function is evident within an hour. In con-trast, 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 irrever-

sibly inactivates platelet COX-1. Aspirin also acetylates mega-

karyocyte COX-1, thereby inhibiting thromboxane production

in newly released platelets as well as those already in the circu-

lation. The mean life span of human platelets is approximately10 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 deci-

sion of use of aspirin as primary prevention therapy is depen-

dent on a balance of an individuals risk of cardiovascularevents and adverse treatment effects, such as bleeding.15 Odd

ratios for bleeding, in casecontrol studies of low-dose aspirin,

range between 1.3 and 3.2.16 The US Food and Drug Admin-

istration has not been adequately persuaded that there is suf-

ficient 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 estimated10% 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 ben-

efit 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 aggrega-

tion by blocking fibrinogen binding to the GpIIb/IIIa

Cheng 515


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receptors on the platelet, thus preventing linking of platelets,

the final step of platelet aggregation. Three parenteral glyco-

protein IIb/IIIa inhibitors are available on the US market.

Abciximab is a humanized version of a Fab fragment of a

murine antibody directed against GpIIb-IIIa. Platelet aggre-

gation is nearly completely abolished with >80% receptor

blockade.22 After intravenous bolus administration, pharma-cokinetic data indicate that free plasma abciximab concentra-

tions 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 plate-

let 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 1101), death

or reinfarction was also reduced in patients receiving abcixi-

mab 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 tirofi-

ban clearance with unchanged tirofiban found in urine and

feces.

25

Dose adjustment is required in patients with renalinsufficiency 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 meta-

analysis (n 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 heptapep-

tide. 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 impair-

ment exhibit prolonged inhibition of platelet function after

receiving eptifibatide and required dosage adjustment.28 Eptifi-

batide treatment has also been associated with thrombocytope-

nia, 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 signif-

icant benefit when compared with placebo.29 However, in a

subsequent trial investigating higher doses, a significant reduc-

tion in the risk of death, MI, urgent coronary revascularization,

and bail-out use of GPIIb/IIIa inhibitors was demonstrated ver-

sus 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 vasodi-

lator 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 recep-

tors, 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 bioavailabil-

ity 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 con-

jugate, 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 phosphodies-

terase 3 inhibitory effect, as well as antiproliferative properties

reducing smooth muscle cell proliferation and neointimal

hyperplasia after endothelial injury. Cilostazol is contraindi-

cated 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 meta-

bolites 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-genera-

tion 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 under-

going PCI. However, clopidogrel also has limitations, includ-

ing 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 pro-

drugs that must undergo metabolic activation through the

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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 rap-

idly 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, primarilyalbumin. 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 metabo-

lized 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 inhibitedfrom 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 anti-

platelet 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 car-

boxyl metabolite compared with a loading dose of 300 mg.

36

Inhibition of ADP-induced platelet aggregation was also signif-

icantly greater with a 600 mg loading dose of clopidogrel

compared with a 300 mg loading dose.37 The incremental anti-

platelet 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 once-

daily 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 meta-

bolite has a half-life of approximately 4 hours, and renal excre-

tion is the major route for elimination.39 Initial pharmaco-

logical studies with prasugrel in healthy individuals39 and in

patients with stable coronary artery disease32 showed that pra-

sugrel has a more rapid onset of action than clopidogrel and

achieves more consistent and complete inhibition of ADP-

induced 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, evi-

dence 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, inhi-

biting ADP-mediated platelet response. Ticagrelor demon-

strates noncompetitive antagonistic activity for ADP-induced

platelet aggregation.46 Unlike clopidogrel and prasugrel, tica-

grelor 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 metabo-

lite, 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 Fromthe 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 Prasugrel-

Thrombolysis 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 ran-

domized to receive either clopidogrel 300 mg loading dose

followed by 75 mg daily or prasugrel 60 mg loading dose fol-

lowed 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 revasculari-

zation (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 75 years of age, 9 spontaneous fatal hemorrhages

were observed with prasugrel and 0 with clopidogrel. In patients


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in intensity and often resolved during continued treatment.57 In

a substudy,199 patients from PLATO (101 ticagrelor and 98

clopidogrel) underwent pulmonary function testing irrespective

to whether they reported dyspnea.58 There was no significant

difference between treatment groups for forced expiratory

volume in the first second of expiration (ticagrelor 2.81 L and

clopidogrel 2.70 L). There was no indication of an adverseeffect on pulmonary function assessed after 1 month or after

at least 6 months of chronic treatment.

Ticagrelor has also been shown to increase the occurrence of

Holter-detected bradyarrhythmias (including ventricular

pauses).59 In a Holter substudy, a total of 2908 patients were

included in the continuous electrographic assessment, of whom

2866 (98.5%) had week 1 recordings, 1991 (68.4%) had

1-month recordings, and 1949 (67.0%) had both. During the

first week after randomization, ventricular pauses 3 seconds

occurred more frequently in patients receiving ticagrelor than

clopidogrel (5.8% vs 3.6%; RR: 1.61; P .006). At 1 month,

pauses 3 seconds occurred overall less frequently and weresimilar between treatments (2.1% vs 1.7%). There were no dif-

ferences between ticagrelor and clopidogrel in the incidence of

clinically reported bradycardic adverse events. Ticagrelor is

structurally similar to adenosine57 and therefore may partially

explain some of its side effects similar to that of adenosine such

as dyspnea and bradyarrhythmia.

Several subanalyses were performed with PLATO. One sub-

analysis was performed in patients who underwent planned

invasive strategy (PCI or CABG) for management of their

ACS.60 In all, 6732 patients undergoing invasive strategy were

assigned to ticagrelor and 6676 patients were assigned to clopi-

dogrel. The primary composite end point occurred in fewerpatients in the ticagrelor group than in the clopidogrel group

(9.0% vs 10.7%, HR 0.84, 95% CI 0.75-0.94; P .0025).

There was no difference between clopidogrel and ticagrelor

groups in the rates of total major bleeding (11.6% vs 11.5%,

HR 0.99, 95% CI 0.89-1.10; P .8803) or severe bleeding

(3.2% vs 2.9%, HR 0.91, 95% CI 0.74-1.12; P .3785).

Another PLATO substudy was also performed looking at

patients with ACS who were managed by medical treatment

only.61 In all, 3143 patients were managed noninvasively. The

incidence of the primary end point was lower with ticagrelor

than with clopidogrel (12.0% vs 14.3%; HR 0.85, 95% CI

0.73-1.00; P .04). Overall mortality was also lower (6.1%

vs 8.2%; HR 0.75, 95% CI 0.61-0.93;P .01). The incidence

of total major bleeding (11.9% vs 10.3%; HR 1.17, 95% CI

0.98-1.39; P .08) and non-CABG-related major bleeding

(4.0% vs 3.1%; HR 1.30, 0.95-1.77; P .10) was not signifi-

cantly different between ticagrelor and clopidogrel.

The subpopulation in the PLATO trial that underwent

CABG was also examined in a separate subanalysis.62 The pro-

tocol recommended ticagrelor to be withheld for 24 to 72 hours

and clopidogrel for 5 days preoperatively. In all, 1261 patients

underwent CABG and were receiving study drug treatment


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majority of patients (*70%) recovered more than 60% of their

baseline aggregation response by 1 hour after infusion.67 The

potential advantage of a short-acting P2Y12 inhibitor is that

there will be less delay should patients require bypass surgery.

Cangrelor was studied in 2 large phase III trials with PCI

(CHAMPION-PLATFORM and CHAPMION-PHEONIX) and

demonstrated significant reduction in rate of ischemic event,including stent thrombosis.68,69 Compared with placebo, major

bleeding appeared to be more frequent due to increased groin

hematomas.68 Similar to ticagrelor, cangrelor is associated with

higher frequencies of dyspnea.68,69 The fast onset and offset of

action of cangrelor may make it a desirable therapeutic option

for patients with ACS undergoing PCI before committing

patients to one of the longer acting oral antiplatelet agents for

chronic therapy.

Protease Activated Receptor 1 Inhibitors. Thrombin is one of the

most potent platelet activators, and protease activated recep-

tor 1 (PAR-1) is the principal thrombin receptor on human

platelets. However, unlike ADP and TXA2 pathways, which

are crucial in both physiological hemostasis and pathological

thrombosis, preclinical evidence suggests PAR-1-mediated

platelet activation does not appear to be involved in protective

hemostasis. It has been hypothesized that combining a PAR-1

inhibitor with existing treatment may increase platelet inhibi-

tion without further increasing the risk of bleeding.70 Cur-

rently, 2 PAR-1 inhibitors are under clinical investigation,

vorapaxar and atopaxar, and vorapaxar has entered Phase III

clinical trials. Vorapaxar is a high affinity, oral antagonist

of the PAR-1 receptor.71 In a recent large clinical trial,

Thrombin Receptor Antagonist for Clinical Event Reduction

in Acute Coronary Syndrome patients (n 13 000) receiving

vorapaxar did not experience improvement in the primary

efficacy end point (a composite of death from cardiovascular

causes, MI, stroke, recurrent ischemia with rehospitalization,

or urgent coronary revascularization) versus placebo. Further-

more, vorapaxar significantly increased the incidence of

moderate and severe bleeding as well as intracranial haemor-

rhage.72 This is consistent with a large-scale secondary pre-

vention trial (Thrombin Receptor Antagonist in Secondary

Prevention of Atherothrombotic Ischemic Events [TRA-2P/

TIMI 50]), where an increase in intracranial hemorrhage was

detected in patients with a history of stroke. This trend contin-ued in patients in the TRA-2P/TIMI 50 trial, where the data

and safety monitoring board recommended the discontinua-

tion of vorapaxar in patients with a history of stroke on the

basis of an excess of intracranial hemorrhage. The overall

trial, however, showed that in 26 449 patients with a history

of MI, ischemic stroke, or peripheral arterial disease (PAD),

vorapaxar 2.5 mg daily significantly reduced the primary

efficacy end point, a composite of death from cardiovascular

causes, MI, or stroke compared with placebo (9.3% vs 10.5%,

respectively; HR 0.87 [95% CI 0.80, 0.94]; P < .001).73 The

role of PAR-1 inhibitor in management of coronary artery dis-

ease needs to be further defined.

Conclusions

Antiplatelet therapy, including aspirin, clopidogrel, and glyco-

protein IIb/IIIa inhibitors, is a cornerstone in coronary artery

disease management. However, with the advances made in the

area of antiplatelet therapy in the last few years, patients with

ACS still remain at risk of recurrent cardiovascular events. In

the last 5 years, newer antiplatelet agents including prasugrel

and ticagrelor have become available. Each has demonstrated

reduced recurrent cardiovascular events compared to standard

therapy and, however, also caused increased bleeding in

selected patient populations. Newer agents including shorter

acting P2Y12 inhibitors, such as cangrelor or antiplatelets that

target other receptors, are being evaluated to attempt to

improve/maintain therapeutic efficacy yet minimize the risk

of bleeding.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect tothe research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

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