Influence of Platelet Reactivity on Clinical Outcomeof Patients with Stable Coronary Artery Disease

Annunziata Nusca & Giuseppe Patti &Germano Di Sciascio

Received: 19 October 2012 /Accepted: 11 December 2012 /Published online: 3 January 2013# Springer Science+Business Media New York 2012

Abstract Single antiplatelet therapy with aspirin is actuallyrecommended for cardiovascular prevention in patients withstable coronary disease, whereas dual antiplatelet therapy(aspirin and clopidogrel) represents the established treat-ment in patients with acute coronary syndromes or stableangina undergoing percutaneous coronary intervention.However, recurrent ischemic events occur in patients ontreatment with clopidogrel; this may be due to low respon-siveness to this agent, a phenomenon influenced by envi-ronmental, clinical, and genetic factors. Different strategieshave been tested to overcome this phenomenon, such asincrease in clopidogrel loading and maintenance doses anduse of newer P2Y12 inhibitors (prasugrel and ticagrelor),which are by now indicated for patients with acute coronarysyndromes; the latter agents have been associated withstronger antiplatelet effect than clopidogrel even in patientswith stable coronary disease, but further studies are neededto test their net clinical benefit in this setting (reduction ofischemic events without increase in bleeding).

Keywords Platelet reactivity . Antiplatelet therapy .

Clopidogrel . Prasugrel . Ticagrelor . Stable coronary arterydisease

Platelets play a crucial role in the pathogenesis of atheroscle-rosis and thrombosis [1–3]. In response to vascular damage,such as rupture of atherosclerotic plaque or stent deployment,prothrombotic materials are exposed to the circulating blood,and platelets adhere to the subendothelium and release

agonists promoting development of a platelet-rich thrombusover the vascular lesion [1–4]. On the basis of these mecha-nisms, platelet activation contributes to the precipitation ofacute vascular events, such as myocardial infarction, stroke,and peripheral vascular occlusion. Thus, antiplatelet therapyrepresents a cornerstone for therapy of patients with acutecoronary syndromes [5] and stable atherosclerotic disease [6].

Previous investigations have documented an enhancednumber of activated platelets in patients with acute coronarysyndromes [7, 8]; however, evidence of platelet hyperactivityhas been also demonstrated in patients with stable coronaryartery disease (CAD). Furman et al. [9], analyzing peripheralvenous blood from 19 healthy subjects and 19 patients withstable coronary disease, observed in the latter an increasednumber of circulating degranulated platelets and an enhancedplatelet reactivity, as expressed by elevated surface P-selectinin response to stimulation with low concentrations of agonists.Furthermore, platelet reactivity has been correlated with theextent of the atherosclerotic disease, and patients with largeratherosclerotic burden disease (coronary, cerebral, and periph-eral disease) have higher baseline platelet reactivity [10].These results were confirmed by another study showing asignificant association between extent of coronary atheroscle-rosis and residual platelet activation after clopidogrel admin-istration in patients with stable CAD undergoing percutaneouscoronary intervention (PCI): Those with multivessel coronarydisease had increased rate of high on-treatment platelet reac-tivity (HPR), defined as P2Y12 reaction units (PRU)≥240 bythe VerifyNow assay, as compared with patients with single-vessel disease (40.5 % vs 21.6 %; OR, 2.47; 95 % CI, 1.53–3.98; p<0.001). Moreover, higher platelet reactivity was as-sociated with enhanced risk of periprocedural myocardialinfarction [11]. Other studies observed an inadequate plateletinhibition in the steady-state phase of treatment with clopi-dogrel in patients with stable coronary disease. Among 150patients with stable CAD undergoing elective PCI, incidence

A. Nusca :G. Patti :G. Di Sciascio (*)Department of Cardiovascular Sciences, Campus Bio-MedicoUniversity, Via E. Longoni, 83,00155 Rome, Italye-mail: g.disciascio@unicampus.it

J. of Cardiovasc. Trans. Res. (2013) 6:346–354DOI 10.1007/s12265-012-9439-7

of nonresponders at light transmittance aggregometry (plateletinhibition, <10 %) after 600 mg loading dose was 5 % (withADP, 5 mol/L) and 11 % (with ADP, 20 mol/l), whereas 9 and26 % of patients were semi-responders (platelet inhibition of10–29 %) [12]. Recently, in the Gauging ResponsivenessWith a VerifyNow Assay: Impact of Thrombosis and Safety(GRAVITAS) trial, percentage of patients with HPR (PRU>230) while on clopidogrel therapy was 40 % at 30 days afterPCI [13]. Alexopoulos et al. [14] found on 99 clopidogrel-treated (>12 months) patients elevated platelet reactivity dur-ing follow-up (PRU≥235). However, rates of patients non- orlow responders to clopidogrel depends not only by the defi-nition of HPR used but also by the coexistence of environ-mental, clinical, and genetic factors [15, 16]; among theclinical factors, older age, high body mass index, smoking,diabetes, drug–drug interactions, and patient compliance mayplay a role. In particular, a growing body of evidence hasdemonstrated low clopidogrel responsiveness in diabeticpatients. Angiolillo et al. [17] observed increased plateletaggregation and activation in patients with vs without diabetesmellitus at baseline and up to 24 h following administration of300-mg clopidogrel load persisting over long-term duringclopidogrel plus aspirin therapy. Moreover, a higher propor-tion of low responders to standard clopidogrel maintenancedose was also observed in the diabetic population (8 vs 38 %in patients without diabetes, p=0.04). The same authors dem-onstrated in patients with diabetes mellitus that, as comparedwith 600-mg clopidogrel load and 150mg/daymaintenance ofclopidogrel, use of prasugrel may provide an additional, sig-nificant level of platelet inhibition [18]. Of note, this impairedresponse to antiplatelet drugs in diabetic patients, especially toclopidogrel, may be also related to other factors beside analtered platelet function, such as accelerated platelet turnover,endothelial dysfunction, impaired fibrinolysis, and increasedlevels and activity of coagulation factors. Percutaneous coro-nary revascularization by itself significantly increases plateletactivation proportionally to procedural complexity and extentof vascular damage [19]. Procedural-induced platelet reactiv-ity may play an important role in determining peri-proceduralmyocardial injury, suggesting that “more aggressive” antipla-telet strategies in the setting of complex PCI may be benefi-cial. Furthermore, recent findings suggested that geneticpolymorphisms, influencing drug absorption, variations inbiotransformation rate into active metabolite, and linkage toP2Y12 receptor, may have a role in determining high residualplatelet reactivity and consequent low clopidogrel response.Clopidogrel is a pro-drug, converted into the active metabolitein a two-step oxidative process catalyzed by different CYPenzymes [20]. Genes encoding for these enzymes are poly-morphic, and there is evidence that some allelic variants ofthese enzymes influence clopidogrel response and are linkedto an increased risk of adverse cardiovascular events inpatients with CAD. This is the case of the CYP2C19 variants,

an enzyme contributing to both oxidative steps leading togeneration of the active clopidogrel metabolite. TheCYP2C19 gene is located on chromosome 10, and at least25 genetic variants have been described. Among these, a loss-of-function (LoF) variant allele, CYP2C19*2, represents themajority of the defective genotypes, and in patients undergo-ing elective PCI for stable CAD, carriers of LoF CYP2C19*2allele had a 2.4-fold higher risk of cardiovascular events vsnoncarriers [21, 22].

The great emphasis linked to low response to clopidogrelis related to the clinical impact that this phenomenon mayhave on short- and long-term prognosis of patients withcoronary artery disease. In the Antiplatelet Therapy forReduction of Myocardial Damage During Angioplasty—Platelet Reactivity Predicts Outcome (ARMYDA-PRO)study [23], HPR after clopidogrel administration, definedas PRU ≥240 at the time of procedure, was associated with6-fold higher incidence of 30-day major adverse cardiacevents (MACE) after PCI (20 % in patients with HPR vs3 % in those without, p=0.034); this outcome was mainlydriven by an increased occurrence of periprocedural myo-cardial infarction. The clinically driven threshold of plateletreactivity (PRU≥240) discriminated patients at higher riskof events at 1 month, with a sensitivity of 81 % and apositive predictive value of 81 %. This threshold was similarto that observed by Price et al. [24] in another series of 380patients undergoing PCI; in this study, a PRU cut-off≥235was predictive of cardiovascular death and stent thrombosisat 6 months. Aradi et al. [25], analyzing data from 20 studiesand 9.187 patients, found that HPR after PCI, detected byvarious laboratory assays with different cut-off definitions,was associated with a significant 3-fold increase in nonfatalmyocardial infarction (p<0.00001), a 4-fold increase instent thrombosis (p<0.0001), and a 3.4-fold increase incardiovascular mortality (p<0.00001) vs patients with nor-mal on-treatment reactivity. Recently, a large collaborativepatient-level meta-analysis from six studies [26] has con-firmed the prognostic role of platelet reactivity measured byVerifyNow assay on adverse cardiovascular events in 3,059patients undergoing PCI. The primary end point (death,myocardial infarction, and stent thrombosis) occurred morefrequently in higher quartiles of PRU (5.8 % in quartile I,6.9 % in quartile II, 10.9 % in quartile III, and 15.8 % inquartile IV; p<0.001); every 10-U increase in PRU wasassociated with increased incidence of the primary end point(HR, 1.04; 95% CI, 1.03–1.06; p<0.0001), and patientswith PRU≥230 had 2-fold higher rates of MACE vs thosewith PRU<230 (HR, 2.10; 95% CI, 1.62–2.73; p<0.0001).Of note, also mortality was significantly increased inpatients with HPR (HR, 1.66; 95 % CI, 1.04–2.68; p=0.04). An enhanced prevalence of low response to antipla-telet drugs was also observed in patients with stent throm-bosis in the Clopidogrel Resistance in Stent Thrombosis

J. of Cardiovasc. Trans. Res. (2013) 6:346–354 347

registry [27]. Oppositely, the recent Antiplatelet Drug Resis-tances and Ischemic Events study did not support plateletfunction testing for the evaluation of the risk of MACE inlow-risk patients with coronary disease: Among 771patients, 15 % of patients with poor response to aspirinand/or clopidogrel (measured by assessment of thrombox-ane B2 and vasodilator phosphoprotein-platelet reactivityindex) experienced an adverse event vs 16 % of those withnormal response [28]. This lack of correlation betweenplatelet reactivity and clinical endpoints was also observedin a recent large trial comparing prasugrel vs clopidogrel inpatients with unstable angina or non-ST segment myocardialinfarction, who were managed medically without plannedrevascularization [29]. In the Targeted Platelet Inhibition toClarify the Optimal Strategy to Medically Manage AcuteCoronary Syndromes study, despite stronger antiplateleteffects of prasugrel than clopidogrel, no difference wasobserved at 30 months between the two antiplatelet agentsin the occurrence of MACEs and no association betweenplatelet reactivity and occurrence of ischemic outcomes [29]in medically managed patients with ACS. The study remainsrelevant, though, for an apparent advantage of prasugrelemerging after the first year of treatment and the lack ofexcess bleeding with prasugrel with the reduced mainte-nance dose of 5 mg, utilized in patients with low bodyweight (<60 kg) and/or aged >75 .

Current Status of Antiplatelet Therapy in StablePatients

Single antiplatelet therapy with aspirin is actually recommen-ded for cardiovascular prevention in patients with chronicstable angina, whereas dual antiplatelet therapy (aspirin anda P2Y12 inhibitor) represents the established treatment inpatients with stable CAD undergoing coronary stent implan-tation to prevent stent thrombosis. Beneficial effects of clopi-dogrel in addition to aspirin have been well established inpatients with CAD (Table 1 summarizes the main character-istics of the presented studies on clopidogrel antiplatelet strat-egy in patients with stable CAD). The Clopidogrel for theReduction of Events During Observation trial [30] showed a38 % relative risk reduction of death, MI, and urgent targetvessel revascularization (TVR) at 28 days in patients under-going elective or urgent PCI and pre-treated with 300-mgloading dose of clopidogrel before the procedure vs assump-tion of clopidogrel, without loading dose, at the time ofintervention (p=0.05). Accordingly, 300-mg clopidogrel load-ing dose has represented for several years the conventionaltherapy for P2Y12 inhibition in patients undergoing electivecoronary angioplasty. Following pharmacodynamic studiesdemonstrating greater platelet inhibition with an increased(600 mg) clopidogrel load, the ARMYDA-2 trial [31] was

the first randomized study of head-to-head comparison be-tween pretreatment with 600 vs 300 mg loading dose ofclopidogrel in low- to moderate-risk patients undergoingPCI; primary end point (30-day occurrence of death, MI,TVR) was detected in 4 % of patients in the high vs 12 % ofpatients in the conventional loading dose group (p=0.041).Multivariable analysis showed a 52 % risk reduction of peri-procedural myocardial infarction in patients pretreated with600-mg clopidogrel (OR, 0.48; 95 % CI, 0.15–0.97; p=0.044). Interestingly, no further benefit of a clopidogrel load-ing dose >600 mg was demonstrated in clinical and plateletfunction studies; in particular, in the Assessment of the BestLoading Dose of Clopidogrel to Blunt Platelet Activation,Inflammation and Ongoing Necrosis (ALBION) [32] andIntracoronary Stenting and Antithrombotic Regimen: ChooseBetween 3 High Oral Doses for Immediate Clopidogrel Effect(ISAR-CHOICE) [33] studies, a 900-mg load does not pro-vide a higher inhibition of platelet aggregation vs 600 mg.Moreover, in the ARMYDA-4 study [34], a further 600-mgloading dose in patients on chronic therapy with 75 mg/dayclopidogrel did not translate into significant clinical benefit inpatients with stable CAD undergoing PCI, whereas it wasassociatedwith decreased incidence of 30-dayMACE in thosewith acute coronary syndromes. Finally, various authors in-vestigated the potential benefit of intensifying platelet inhibi-tion with peri-procedural glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa) on short- and long-term outcome of patients under-going elective PCI. Use of abciximab on top of dual antipla-telet therapy, although it was associated with strongerantiplatelet effects, in the Intracoronary Stenting and Antith-rombotic Regimen-Rapid Early Action for Coronary Treat-ment (ISAR-REACT) study [35], failed to demonstrate anyadditional cardiovascular protective effect at 30 days afterelective PCI. However, the more recent Tailoring Treatmentwith Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) trial [36] observed that,in patients with poor responsiveness to standard oral antipla-telet therapy (aspirin, clopidogrel or both), intensification ofplatelet inhibition with tirofiban significantly decreased theincidence of periprocedural myocardial infarction after PCIand 30-day MACE, suggesting a potential additional benefitof these antiplatelet agents in high-risk subsets of patients,such as those with diabetes mellitus or undergoing complexprocedures.

Given the high percentage of patients with HPR also duringthe maintenance phase of clopidogrel treatment, investigationsusing increased maintenance doses of this drug have beenperformed in order to optimize results of long-term antiplatelettherapy in patients with stable CAD after coronary stentimplantation. In the ISAR-CHOICE 2 study [37], administra-tion of 150 mg/day clopidogrel resulted in higher inhibition ofADP platelet aggregation vs the standard 75 mg/day chronicdose at 1 month after intervention. In the Optimizing

348 J. of Cardiovasc. Trans. Res. (2013) 6:346–354

Tab

le1

Principal

trialsinvestigatingop

timal

antip

latelettherapyin

stable

coronary

artery

disease

Trials

Designandstud

ypo

pulatio

nAntiplateletstrategies

Laboratorymetho

dsandHPR

definitio

nMainresults

Clopido

grel

loadingdo

se

ARMYDA-2

[31]

255patientsschedu

ledfor

electiv

ePCI

600mg(n=12

6)vs

300mg(n=12

9)loadingregimen

ofclop

idog

rel

given4–

8hbefore

theprocedure

Noaggregom

etry

data

available

600mgloadingregimen

was

associated

with

sign

ificantrisk

redu

ctionof

periprocedural

MIand30

-day

MACE

ALBIO

N[32]

103low-to-mod

eraterisk

patients

with

non–

ST-elevationacute

coronary

synd

romes

undergoing

PCI

300-

(n=35

)vs

600-

(n=34

)vs

900-mg(n=34

)oral

clop

idog

rel

loadingdo

se

LTA,IPA

<10

%at

6h

900-mgmay

indu

ceagreaterantip

latelet

effect

than

600mg,

whencompared

with

thestandard

300-mgregimen,

with

outsign

ificantredu

ctionof

clinical

endp

oints

ISAR-CHOICE[33]

60patientswith

stable

coronary

artery

diseaseun

dergoing

electiv

ePCI

300-

(n=20

)vs

600-

(n=20

)vs

900-mg(n=20

)oral

clop

idog

rel

loadingdo

se

Optical

aggregom

etry

Loading

doseshigh

erthan

600mgare

notassociated

with

anadditio

nal

platelet

inhibitio

nbecauseof

limited

clop

idog

relabsorptio

n

ARMYDA-4

[34]

503patientson

>10

days

clop

idog

reltherapy(60%

with

stable

coronary

disease)

600mgclop

idog

relre-loading

4–8hbefore

PCI(n=25

2)vs

placebo(n=25

1)

Noaggregom

etry

data

available

Nosign

ificantbenefitfrom

reloading

patientswith

stable

coronary

disease

onchronicclop

idog

reltherapyprior

toPCI

Add

ition

albenefitof

GpIIb/IIIainhibitors

ISAR-REACT[35]

2,15

9patientswith

coronary

artery

diseasewho

underw

ent

PCIreceiving60

0mg

clop

idog

relload

Abcixim

ab(n=1,07

9)vs

placebo

(n=1,08

0)Noaggregom

etry

data

available

Abcixim

abisassociated

with

noclinically

measurablebenefitwith

inthefirst30

days

3T/2R[36]

263patientsaspirinand/or

clop

idog

relpo

orrespon

ders

undergoing

electiv

ePCI

Tirofiban

(n=13

2)vs

placebo(n=13

1)VerifyN

owassay,ASA

resistance

≥550

ARU

Clopido

grel

resistance

<40

%IPA

Intensifiedplatelet

inhibitio

nwith

tirofiban

lowerstheincidenceof

periprocedural

MIand30

-day

MACEin

poor

respon

ders

patients

Maintenance

clop

idog

reldo

se

ISAR-CHOICE2[37]

60patientsafterpre-treatm

ent

with

600mgof

clop

idog

rel

andwith

in12

haftersuccessful

PCI

Clopido

grel

75mgmaintenance

dose

(n=29

)vs

150mgmaintenance

dose

(n=31

)

Optical

aggregom

etry

and

VerifyN

owTM

P2Y

12assay

150mgdaily

maintenance

dose

ofclop

idog

relresults

inmoreintense

platelet

inhibitio

ncomparedto

75mg

OPTIM

US[38]

40patientswith

diabetes

mellitus

andstable

CAD,subo

ptim

alclop

idog

relrespon

ders

Clopido

grel

150mg/day(n=20

)Clopido

grel

75mg/day(n=20

)for30

days

LTA,subo

ptim

alrespon

der

20μm

ol/L

ADP-ind

uced

Agg

max>50

%

A15

0-mgmaintenance

dose

was

associated

with

enhanced

antip

lateleteffectscomparedto

75mg

ARMYDA-150

mg[39]

50patientsrand

omized

1mon

thafterinterventio

naftersuccessful

PCI

Clopido

grel

75mgmaintenance

dose

(n=25

)vs

150mg(n=25

)for30

days,than

cross-ov

er,the

assign

edclop

idog

relmaintenance

regimen

was

switchedand

continuedforafurther30

days

VerifyN

owassay,PRU

≥240

150mg/dayclop

idog

relmaintenance

dose

isassociated

with

strong

erplatelet

inhibitio

n,im

prov

ement

ofendo

thelialfunctio

n,and

redu

ctionof

inflam

mation,

comparedwith

75mg/day

J. of Cardiovasc. Trans. Res. (2013) 6:346–354 349

Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study[38], Angiolillo et al. showed that 150 mg/day clopidogrelmaintenance dose was associated with stronger antiplateleteffects (vs 75 mg/day) in patients with diabetes mellitus;however, suboptimal clopidogrel response (defined as20 μmol/L ADP-induced maximal aggregation >50 %) wasstill present in 60 % of patients in the high-dose arm. Finally,in a recent randomized trial from the ARMYDA group [39],50 patients were randomly assigned after PCI to receivestandard (75 mg/day; n=25) or high (150 mg/day; n=25)clopidogrel maintenance dose for 30 days; after 1 month,cross-over was performed, and the assigned clopidogrel reg-imen was switched and continued for further 30 days. Patientswith higher maintenance dose showed higher platelet inhibi-tion (i.e., lower platelet reactivity as evaluated by PRU), betterflow-mediated vasodilation, and lower high-sensitive C-reactive protein. The percentage of low-responder patientswas also significantly decreased in the 150-mg group (12 vs32 %; p=0.001). However, recent studies indicated that ther-apy with high maintenance dose clopidogrel (150 mg daily)was not effective to overcome the influence of LoF allele. In amulticenter study on 333 patients with cardiovascular disease,tripling the standard dose of clopidogrel (225 mg) inCYP2C19*2 heterozygotes, but no 300 mg daily dose inhomozygotes, achieved a level of platelet reactivity similarto the level observed in noncarriers treated with the standarddose [40]. These findings confirm that some patients maycontinue to have elevated HPR despite increase in clopidogrelmaintenance doses, suggesting the need for new antiplateletdrugs able to definitely overcome the phenomenon of lowresponsiveness.

As patients with HPR are at increased risk for both short-and long-term ischemic events occurrence, also includingstent thrombosis, a recent consensus statement has consideredthe possibility of evaluating thresholds of platelet reactivity topersonalize antiplatelet therapy according to the individualresponse to clopidogrel [41]. Moreover, on the other hand,observational studies indicated that very low platelet reactivitywhile on antiplatelet therapy may be associated with higherrates of bleeding complications [42, 43], raising the concept ofa “therapeutic window” of P2Y12 inhibition, measured byresidual platelet reactivity, with thrombotic/ischemic riskabove the upper threshold and bleeding risk below the lowerthreshold. Mangiacapra et al. recently proposed specificthresholds to identify this “therapeutic window” (PRU 179to 238) in the ARMYDA-PROVE study, demonstrating thatPRU values included in this interval of platelet reactivity werean independent predictor of reduced risk for 30-day net ad-verse clinical events (odds ratio, 0.47; 95 % CI, 0.27–0.81)[44]. This emerging approach to increase efficacy of antipla-telet therapy performing an individual, “tailored” strategy wasevaluated by Bonello et al. [45], who adjusted clopidogrelloading dose according to platelet monitoring usingT

able

1(con

tinued)

Trials

Designandstud

ypo

pulatio

nAntiplateletstrategies

Laboratorymetho

dsandHPR

definitio

nMainresults

“Tailoredstrategy

”

GRAVITAS[13]

2,21

4patientswith

high

on-

treatm

entreactiv

ity12–24

hafterPCIwith

drug

-elutin

gstents

High-do

seclop

idog

rel(600

-mginitial

dose,15

0mgdaily

thereafter)or

standard-doseclop

idog

rel(no

additio

nalloadingdo

se,75

mgdaily

)for6mon

ths

VerifyN

owassay,PRU

≥230

Use

ofhigh

-doseclop

idog

rel

comparedwith

standard-dose

clop

idog

reldidno

tredu

cethe

incidenceof

deathfrom

cardiovascular

causes,no

nfatal

myo

cardialinfarctio

n,or

stent

thrombo

sis

ARCTIC

[14]

2,44

0patientsschedu

ledforelectiv

ePCI

Mon

itoring

grou

p(n=1,21

3)—

adjustmentof

antip

latelettherapy

accordingplatelet

functio

nevaluatio

n;conv

entio

nalgrou

p(n=1,22

7)—

conv

entio

naltreatm

entwith

outplatelet

functio

nmon

itoring

VerifyN

owassay,ASA

resistance

≥550

ARU

Clopido

grel

resistance

≥235

PRU

1-year

incidenceof

death,

MI,stent

thrombo

sis,stroke

orurgent

revascularizationwas

notdifferent

betweenthetwogrou

ps

PCIpercutaneous

coronary

interventio

n,MImyo

cardialinfarction,MACEmajor

cardiacadverseevents,L

TAlig

httransm

ittance

aggregom

etry,IPA

inhibitio

nplateletaggregation,ASA

aspirin,ARU

aspirinreactio

nun

its,PRU

platelet

reactio

nun

its

350 J. of Cardiovasc. Trans. Res. (2013) 6:346–354

vasodilator-stimulated phosphoprotein (VASP) index; despitethe small sample size enrolled (n=162), VASP-guided clopi-dogrel dosing (up to 2.4 g/day) significantly improved clinicaloutcome after PCI in patients with low response to the drug ontop of 600-mg loading dose, without increase in the risk ofmajor bleeding. Recently, the GRAVITAS trial [13] evaluatedwhether high-dose clopidogrel is superior to standard-dosetherapy for the prevention of cardiovascular events after PCIin patients with HPR according to VerifyNow measurements:2,214 patients with PRU>230 were randomly assigned tohigh-dose (600-mg load followed by 150 mg/day for6 months) or standard-dose clopidogrel (no additional loadingdose followed by 75 mg daily); 6-month results demonstratedequal rates of the primary end point (death from cardiovascu-lar causes, nonfatal myocardial infarction or stent thrombosis)in the two arms (2.3 vs 2.3 %; HR, 1.01; 95 % CI, 0.58–1.76;p=0.97), without bleeding excess in the high-dose group.Thus, this study questioned the clinical value of improvingplatelet inhibition by increasing clopidogrel dose accordingplatelet-function testing, suggesting that this may not be aneffective alternative approach in patients with HPR and con-firming the high proportion of patients low responder even tohigh clopidogrel doses. The Assessment with a Double Ran-domization of a Fixed Dose vs a Nonitoring-Guided Dose ofAspirin and Clopidogrel after DES Implantation, and Treat-ment Interruption vs Continuation, 1 Year After Stenting(ARCTIC) study recently failed to demonstrate the benefitof an antiplatelet “tailored” therapy in patients undergoingelective PCI [46]; in this study, 2,440 patients with stableangina were assigned to a strategy of platelet-function evalu-ation with adjustment of antiplatelet drugs and doses in pres-ence of inadequate platelet-inhibitory response (monitoringgroup, receiving increased loading andmaintenance clopidog-rel dose or switching to prasugrel) or conventional treatmentwithout platelet function assessment (conventional group). At1-year after the intervention, adjustment of antiplatelet thera-py, before and after stenting, according to platelet-functionmonitoring, did not reduce the rate of the primary endpoint(death from any cause, myocardial infarction, stent thrombo-sis, stroke or urgent revascularization: 34.6 vs 31.1 %, p=0.10). Thus, other studies enrolling patients with higher riskprofile as well as using other functional assays or other defi-nitions of impaired response to antiplatelet agents or differenttiming of platelet function assessment are needed in order tosolve the paradox of high platelet reactivity as a risk markerfor poorer clinical outcome and its failure to guide the anti-platelet therapy.

Prasugrel and Ticagrelor in Stable CAD

Prasugrel and ticagrelor are newer and more potent P2Y12inhibitors recently approved in clinical practice. Prasugrel is athird-generation thienopyridine and an irreversible platelet

receptor blocker; after ingestion, it is hydrolyzed into an inter-mediary metabolite, a prodrug requiring hepatic conversionwith only one CYP450-dependent oxidative step to generatethe active metabolite. This difference explains the more rapidonset of action compared to clopidogrel, the greater inhibitionof platelet aggregation, the lower incidence of nonresponders,and the lesser influence of genetic polymorphisms. Peak con-centrations of prasugrel are reached after 30 min and 60–70 %of platelet inhibition is usually achieved after 2–4 h followingdrug administration [47]. Ticagrelor is an oral, reversible,short-acting, nonthienopyridine P2Y12 antagonist; it is not aprodrug and maximal platelet inhibition is reached in 1–3 h. Inplatelet aggregation studies, ticagrelor inhibited platelet aggre-gation more effectively than clopidogrel, with lower degree ofinterindividual response variability [48]. In the last version ofboth ACCF/AHA/SCAI [49] and ESC Guidelines for PCI[50], these newer antiplatelet agents have been approved forthe management of patients with acute coronary syndromesundergoing (both agents) or not coronary stenting (ticagrelor).Given the absence of clinical studies, they are not jet recom-mended for the antiplatelet treatment of patients with chronicstable angina. However, observational evidences suggesting apotential their benefit also in this subset are increasing, espe-cially in high-risk patients with persistent HPR on clopidogrelafter percutaneous revacularization.

Jenberg et al. [51] evaluated the dose-dependent pharma-codynamic effects of prasugrel, randomly assigned to fourdifferent dosing regimens (loading and maintenance of 40/5,40/7.5, 60/10, 60/15 mg vs clopidogrel 75 mg), in an aspirin-treated population with stable CAD. After loading (6 h) andmaintenance phase (28 days), use of prasugrel was associatedwith significantly higher inhibition of platelet activity (IPA) ascomparedwith clopidogrel; in particular, on day28, there wereno nonresponders (IPA<20%)with prasugrel 10 and 15mg vs45 % in the clopidogrel group (p=0.007). In the OPTIMUS 3study [18], 35 patients with diabetes mellitus were random-ized to either prasugrel 60 mg loading dose/10 mg mainte-nance dose or clopidogrel 600 mg/150 mg; greater plateletinhibition by the VerifyNow assay was observed with prasu-grel after loading and during maintenance therapy, with fewerlow responders at all time points, irrespective of the definitionused. Finally, similar results were recently observed in theaggregometric substudy of the Testing Platelet Reactivity inPatients Undergoing Elective Stent Placement on Clopidogrelto Guide Alternative Therapy with Prasugrel trial [52], whichconfirmed the effectiveness of switching from clopidogrel toprasugrel to reduce incidence of low responders (defined asPRU >208) in patients with stable CAD. Ticagrelor wasassociated with higher platelet inhibition vs clopidogrel inthe ONSET/OFFSET study [53], in which 123 patients withstable coronary disease on aspirin were randomized to tica-grelor (180 mg loading dose and 90 mg BID maintenancedose) or clopidogrel (600 mg, and then 75 mg/day) for

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6 weeks. Ticagrelor achieved more rapid and greater inhibi-tion than clopidogrel; this inhibition was sustained during themaintenance phase and was faster in offset after drug discon-tinuation, another key point for patients who eventually needunanticipated surgical procedures.

Despite these positive results from aggregometry studiesdemonstrating stronger antiplatelet effects of prasugrel andticagrelor than clopidogrel, the net clinical benefit (possiblereduction of ischemic events without significant increase inbleeding) of these new antiplatelet drugs in patients with stableCAD has not been demonstrated yet. Moreover, in stablepatients, the clinically driven threshold for defining HPRmightbe different from those observed in patients with acute coro-nary syndromes. The randomized, phase III Prevention withTicagrelor Of Secondary Thrombotic Events in High-RiskPatients with Prior Acute Coronary Syndrome trial, comparingclinical outcome of ticagrelor vs clopidogrel in patients withprevious myocardial infarction 12–36 months in the past, willhopefully provide more information on the use of this newer,more potent antiplatelet agent in patients with stable CAD.

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