Thrombotic and bleeding events after coronary stenting according to clopidogrel and aspirin platelet...

© 2014 Elsevier Masson SAS.

Archives of Cardiovascular Disease (2014) 107, 225—235

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CLINICAL RESEARCH

Thrombotic and bleeding events aftercoronary stenting according to clopidogreland aspirin platelet reactivity: VerifyNowFrench Registry (VERIFRENCHY)

Incidence des événements ischémiques et hémorragiques aprèsstenting coronaire selon la réactivité plaquettaire à l’aspirine etau clopidogrel : VerifyNow French Registry (VERIFRENCHY)

Grégoire Rangéa,∗, Komlavi Yayehdb, Loic Belleb,Christophe Thuairea, Pascal Richardc,Pierre Cazauxd, Franck Barboue, René Köning f,Stephan Chassaingg, Emmanuel Teigerh,Romain Berthier i, Marie-Pascale Decomis j,Jean-Philippe Claudelk, Nicolas Delarche l,Philippe Brunelm, Fabien De Polin, Patrick Dupouyo,Farzin Beyguip, Franck Alberta,Jean-Philippe Colletp, Gilles Montalescotp, on behalfof the VERIFRENCHY investigators

a Department of Cardiology, les hôpitaux de Chartres, Eure-et-Loir, 4, rue Claude-Bernard,28630 Le Coudray, Franceb Department of Cardiology, centre hospitalier de la région d’Annecy, Annecy, Francec Department of Cardiology, clinique Saint-Martin, Caen, Franced Department of Cardiology, centre hospitalier Lorient, Lorient, Francee Department of Cardiology, hôpital d’instruction des armées du Val-de-Grâce, Paris, Francef
Department of Cardiology, clinique Saint-Hilaire, Rouen, France
Abbreviations: %PI, percentage of platelet inhibition; ACS, acute coronary syndrome; ARU, aspirin reaction units; BMS, bare-metalstent; CI, confidence interval; DES, drug-eluting stent; HR, hazard ratio; OAR, on-aspirin platelet reactivity; OCR, on-clopidogrel plateletreactivity; PCI, percutaneous coronary intervention; VERIFRENCHY, VerifyNow French Registry.

∗ Corresponding author.E-mail address: [email protected] (G. Rangé).

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226 G. Rangé et al.

g Department of Cardiology, clinique Saint-Gatien, Tours, Franceh Department of Cardiology, hôpital Henri-Mondor, Créteil, Francei Department of Cardiology, hôpital de Corbeil, Corbeil, Francej Department of Cardiology, clinique de la Reine-Blanche, Orléans, Francek Department of Cardiology, infirmerie protestante, Lyon, Francel Department of Cardiology, hôpital de Pau, Pau, Francem Department of Cardiology, nouvelles cliniques nantaises, Nantes, Francen Department of Cardiology, hôpital Haguenau, Haguenau, Franceo Department of Cardiology, hôpital privé d’Antony, Antony, Francep Institut de cardiologie, hôpital la Pitié-Salpêtrière, Paris, France

Received 7 January 2014; received in revised form 5 March 2014; accepted 20 March 2014Available online 29 April 2014

KEYWORDSOn-plateletreactivity;VerifyNow assay;Ischaemic events;Bleeding

SummaryBackground. — Dual antiplatelet therapy, comprising aspirin and clopidogrel, is recommendedin patients undergoing coronary stenting to avoid the occurrence of stent thrombosis and othersischaemic events. Interindividual response to clopidogrel varies, however, with poor responseassociated with an increased risk of ischaemic events. New assays are available for testingaspirin and clopidogrel response routinely at the bedside.Aim. — To evaluate the prognostic value of testing antiplatelet response in an intermediate-riskpopulation undergoing stent implantation.Methods. — We prospectively assessed clopidogrel and aspirin response using the VerifyNowassay at the time of coronary stenting in 1001 patients who presented with stable coronary dis-ease or non-ST-segment elevation acute coronary syndrome. The main ischaemic endpoint wasthe composite of definite and probable stent thrombosis, cardiovascular death or spontaneousmyocardial infarction at one year. The safety endpoint was major bleeding.Results. — Overall, 36.0% of patients had high on-clopidogrel platelet reactivity (OCR) and 8.6%had high on-aspirin platelet reactivity (OAR). The main ischaemic composite endpoint occurredin 3.9% of patients with high vs. 2.3% of patients with normal OCR (hazard ratio 1.66, 95%confidence interval 0.78—3.54; P = 0.18). Definite or probable stent thrombosis occurred in 1.1%of patients with high vs. 0.3% of patients with normal OCR (P = 0.86). There was no significantdifference in ischaemic endpoints according to OAR and there was no difference in rates ofmajor bleeding between patients with high versus normal on-treatment platelet reactivity.Conclusions. — On-treatment platelet reactivity was not associated with 1-year ischaemic orbleeding events in an intermediate-risk population undergoing stent implantation.© 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSRéactivitéplaquettaire ;VerifyNow ;Évènementsischémiques ;Saignements

RésuméRationnel. — La bithérapie antiplaquettaire, comprenant l’aspirine et le clopidogrel, estrecommandée chez tous les patients après stenting coronaire pour prévenir les évènementsischémiques dont la thrombose de stent. La réponse individuelle au clopidogrel est très variableet une faible réponse est associée à une augmentation des évènements ischémiques. De nou-veaux tests sont maintenant disponibles pour évaluer cette réponse à l’aspirine et au clopidogrelde manière routinière et délocalisée.Objectif. — Évaluer la valeur pronostique de ces tests de réponse aux antiplaquettaires chezune population à risque intermédiaire bénéficiant d’un stenting coronaire.Méthode. — Nous avons mesuré de facon prospective la réponse à l’aspirine et au clopidogrelpar VerifyNow lors de la procédure de stenting coronaire chez 1001 patients présentant un angorstable ou un syndrome coronarien aigu sans sus-décalage du segment ST. Le critère compos-ite principal d’évaluation des événements ischémiques était l’apparition d’une thrombose destent certaine ou probable et/ou d’un décès cardio-vasculaire et/ou d’un infarctus spontanédu myocarde à 1 an. Le critère d’évaluation de sécurité était les saignements majeurs.Résultats. — Sur l’ensemble de la population, 36 % des patients gardait une hyperréactivitéplaquettaire sous clopidogrel (HPC) et 8,6 % gardait une hyperréactivité plaquettaire sousaspirine (HPA). Le critère composite d’évaluation principal a été observé dans 3,9 % des caschez les patients avec hyperréactivité vs 2,3 % avec normoréactivité plaquettaire sous clopid-ogrel (NPC)(hazard ratio 1,66, 95 % intervalle de confiance 0,78—3,54 ; p = 0,18). La thrombose

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Events after stenting according to clopidogrel and aspirin platelet reactivity 227

de stent certaine ou probable a été observée dans 1,1 % des HPC vs 0,3 % chez les NPC (p = 0,86).Il n’a pas été observé de différence significative tant des évènements ischémiques que hémor-ragiques entre le groupe des hyper- vs normorépondeurs au traitement antiplaquettaire.Conclusion. — La réactivité plaquettaire sous clopidogrel et aspirine n’est pas corrélée àl’incidence des évènements ischémiques et hémorragique à 1 an d’un stenting coronaire dansune population à risque intermédiaire.© 2014 Elsevier Masson SAS. Tous droits réservés.

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Background

Dual antiplatelet therapy with aspirin and clopidogrel is rec-ommended in patients undergoing coronary stenting to avoidthe occurrence of stent thrombosis and ischaemic events[1]. Interindividual response to clopidogrel varies widely,however, due to drug-related factors and genetic mutations,but also to several other clinical factors including diabetesmellitus, acute coronary syndrome and high body massindex [2]. Several studies have demonstrated a relation-ship between clopidogrel and/or aspirin poor response andincreased risk of ischaemic events after coronary stenting[3—5]. Most were performed using light transmission aggre-gometry, an assay that is not widely available in practicedue to laboratory constraints. New and reliable assays arenow available for testing aspirin and clopidogrel responseroutinely at the bedside, including the VerifyNowTM P2Y12assay (Accumetrics, San Diego, CA, USA) [6].

The aim of the multicentre VerifyNow French Registry(VERIFRENCHY) was to assess the prognostic value of testingon-treatment platelet reactivity using aspirin and clopid-ogrel with the VerifyNow assay at the time of coronarystenting.

Methods

Study population

VERIFRENCHY was a multicentre prospective observationalstudy that recruited patients in 20 high-volume percuta-neous coronary intervention (PCI) centres in France. Thestudy population included adults (≥ 18 years) with stableangina, silent ischaemia or non-ST-segment elevation acutecoronary syndrome (ACS; unstable angina or non-ST-segmentelevation myocardial infarction) undergoing planned PCIwith stenting. Exclusion criteria were periprocedural gly-coprotein IIb/IIIa inhibitors, bivalirudin treatment beforePCI, contraindications to aspirin or clopidogrel, use of oralanticoagulation and lack of available clopidogrel responseat inclusion. Written informed consent was obtained fromall patients before the index procedure. The study wasapproved by the French Authorities (AFSSAPS [2008-A00411-54] and CPP [n◦ 2008-N2]).

Procedures

Eligible patients were screened at the time of the coro-
nary angiogram. Patients were loaded with clopidogrel600 mg ≥ two hours before PCI unless they had been on amaintenance clopidogrel dose of 75 mg for > one week. Anintravenous loading dose of aspirin was given according
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o the investigators’ usual practices in patients in whomspirin was started < one week before angiography. Patientsere tested for both aspirin and clopidogrel response before

tent implantation. A valid biological measure of clopido-rel/aspirin response was requested before inclusion in thetudy.

After stent implantation, aspirin (75—160 mg) and clo-idogrel (75 mg) maintenance doses were recommended forne month after bare-metal stent (BMS) implantation and forne year after drug-eluting stent (DES) implantation or if thelinical presentation was an ACS. In this registry, we com-ared the rate of primary and secondary endpoints at oneear according to treatment response to both clopidogrelnd aspirin.

Data were collected prospectively on-site and analysedy the Peter Holmes Company. Blood samples were drawnoth before PCI and 24 hours after PCI to measure troponinoncentrations. Follow-up data were obtained by clinicalxamination at hospital discharge and by telephone contactt one month and one year after discharge.

Whole blood was obtained at the time of catheterization.latelet function testing was performed with the VerifyNowssay after the decision was made to perform stenting,ut before starting PCI [7,8]. The selection of VerifyNowlatelet inhibition (%PI) with a cut-off of ≤ 15% was basedn data from Bouman et al., who demonstrated a goodorrelation between P2Y12 reaction unit values and %PIith plasma concentrations of active metabolite clopidogrel

9]. High on-aspirin platelet reactivity (OAR) was defineds an aspirin reaction unit (ARU) ≥ 550, and normal OARas defined as ARU < 550 [7,8]. High on-clopidogrel platelet

eactivity (OCR) was defined as %PI ≤ 15% and normal OCRs %PI > 15%, based on data from Godino et al. [3]. Investi-ators were strongly encouraged not to modify antiplateletherapy according to the results of platelet function tests.

Patients were also classified according to the VerifyNowPI and ARU quartiles to assess bleeding events; the lowestlatelet reactivity quartiles of clopidogrel and aspirin wereompared with the other three quartiles.

ndpoints

schaemic endpoints were defined as definite and proba-le stent thrombosis, myocardial infarction (spontaneousnd/or periprocedural), all-cause death, cardiovasculareath and stroke. The main ischaemic composite endpointas a combination of definite and probable stent throm-osis, cardiovascular death and spontaneous myocardial
nfarction at one year. The secondary composite ischaemicndpoint included the combination of definite and proba-le stent thrombosis, all-cause death, non-fatal myocardialnfarction (spontaneous and periprocedural) and stroke.

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28

Periprocedural myocardial infarction was defined as aostprocedural increase in troponin concentration > threeimes the 99th percentile upper reference limit in patientsith normal baseline concentrations of troponin (type 4a

10]); in patients with an ACS and raised baseline troponinoncentrations, the definition of a subsequent elevation

20% of the baseline value was applied [11]. Sponta-eous myocardial infarction was defined as ≥ 1 value ofroponin > 99th percentile upper reference limit togetherith evidence of myocardial ischaemia (type 1) [10,11].tent thrombosis included definite, probable and possibletent thrombosis [11]. Ischaemic stroke was defined as focaloss of neurological function caused by an ischaemic event.

The main safety endpoint was defined according tohe International Society of Thrombosis and Haemostasisefinitions [12]. Major bleeding was defined as: fatal bleed-ng; symptomatic bleeding in a critical area or organ (i.e.ntracranial, intraspinal, intraocular, retroperitoneal, intra-rticular or pericardial), or intramuscular bleeding withompartment syndrome; and bleeding causing a fall inaemoglobin concentration of ≥ 20 g/L or leading to trans-usion of ≥ two units of whole blood. Minor bleeding wasefined as any clinically overt sign of haemorrhage that wasctionable, but did not meet the criteria for major bleeding.

tatistical analysis

power calculation was performed to determine the studyample size. Anticipating a 35% rate of high OCR and annnual stent thrombosis rate of 1.7% [13] (� risk at 5% andrror at 80%, bilateral test), 800 patients would be needed;llowing for loss to follow-up, a population of 1000 patientsas chosen.

Continuous variables and categorical variables arexpressed as mean ± standard deviations and counts andercentages, respectively. Student’s t test was used toompare continuous variables and the Chi2 test or Fisher’sxact test was used to compare categorical variables. Sur-ival analysis was performed by the Kaplan—Meier methodith a log-rank test-group comparison. A P value < 0.05 wasonsidered statistically significant. Statistical analysis waserformed using SPSS version 20.0 (IBM Corp, Somers, NY,SA).

esults

total of 1053 patients were pre-treated with clopidogrelnd aspirin and underwent PCI with stenting. A VerifyNowest result was not available in 52 (4.9%) patients due toechnical issues (bubbling or calibration problem); conse-uently, 1001 patients were included in the analysis. In 292.9%) of these patients, the aspirin test result was notvailable; therefore 972 patients were included in the com-arison of aspirin response (Fig. 1). Among the 1001 patientsith P2Y12 VerifyNow test results available, 360 (36.0%) hadigh OCR and 641 (64.0%) had normal OCR. Among the 972atients with aspirin test results available, 84 (8.6%) had
igh OAR and 888 (91.4%) had normal OAR.
Patients with high OCR were on average older, had aigher body mass index, were more often diabetic and lessrequently smokers compared to patients with normal OCR

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ition; ARU: aspirin reaction units; BMS: bare-metal stent; DES:rug-eluting stent; PCI: percutaneous coronary intervention.

Table 1). High OAR patients were more frequently men andisplayed a higher creatinine clearance than patients withormal OAR.

No differences were observed in the angiographic androcedural characteristics between high and normal OCRatients, except for less frequent use of DES in high OCRatients (Table 2). Despite strong recommendations not tohange treatment, patients with high OCR were more fre-uently given glycoprotein IIb/IIIa inhibitors and reloadedith clopidogrel during the post-PCI period compared with

hose with normal OCR. In addition, almost one-quarter ofhe patients had a double maintenance clopidogrel dose atischarge from hospital, with no statistically significant dif-erence between the high versus normal platelet reactivityroups (Table 2).

At 1-year follow-up, the main ischaemic composite end-oint occurred in 3.9% of patients with high vs. 2.3% of thoseith normal OCR (hazard ratio [HR] 1.66, 95% confidence

nterval [CI] 0.78—3.54; log rank P = 0.18) (Fig. 2A), while theecondary ischaemic composite endpoint occurred in 15.8%f patients with high vs. 18.6% with normal OCR (HR 0.84,
5% CI 0.61—1.16; log rank P = 0.25) (Fig. 2B).
Ten cases of stent thrombosis occurred (1.0% of the wholeohort), of which two were definite, four probable and fourossible (Table 3). Definite and probable stent thrombosis


Table 1 Patient baseline characteristics.

Variables On-clopidogrel platelet reactivity On-aspirin platelet reactivity

Totalcohortn = 1001)

High(n = 360)

Normal(n = 641)

P Totalcohort(n = 972)

High(n = 84)

Normal(n = 888)

P

Age (years) 66.5 ± 11.4 68.3 ± 11.6 65.5 ± 11.2 < 0.001 66.6 ± 11.5 66.1 ± 12.4 66.6 ± 11.4 0.69Men 833 (83.2) 298 (82.8) 535 (83.5) 0.78 809 (83.2) 78 (92.9) 731 (82.3) 0.01Body mass index(kg/m2)

26.5 ± 4.0 27.2 ± 4.4 26.2 ± 3.7 < 0.001 26.5 ± 4.1 27.0 ± 4.2 26.5 ± 4.0 0.30

Current smoker 181 (18.1) 49 (13.6) 132 (20.6) 0.02 177 (18.2) 17 (20.2) 160 (18.0) 0.38Hypertension 594 (59.3) 223 (61.9) 371 (57.9) 0.20 579 (59.6) 51 (60.7) 528 (59.5) 0.80Family history 312 (31.2) 100 (27.8) 212 (33.1) 0.08 304 (31.3) 21 (25.0) 283 (31.9) 0.19Diabetes mellitus 261 (26.1) 127 (35.3) 134 (20.9) < 0.001 249 (25.6) 23 (27.4) 226 (25.5) 0.69Hypercholesterolemia 665 (66.4) 227 (63.1) 438 (68.3) 0.09 649 (66.8) 52 (61.9) 597 (67.2) 0.33Creatinine clearance(mL/min/m2)

81.8 ± 31.2 79.5 ± 31.3 83.1 ± 31.1 0.08 81.6 ± 31.0 88.1 ± 32.5 81.0 ± 30.8 0.04

Acute coronarysyndromes

216 (21.6) 82 (22.8) 134 (20.9) 0.49 208 (21.4) 16 (19.0) 192 (21.6) 0.58

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Data are mean ± standard deviation or number (%).

occurred in 1.1% of patients with high vs. 0.3% with normalOCR (log rank P = 0.86). None of the 84 patients with highOAR had stent thrombosis vs. 0.7% of patients in the normalOAR group (P = 0.58) (Table 4). No differences were observedin the rates of other ischaemic or bleeding events accordingto OCR or OAR (Table 4).

No differences were found in the rates of major bleedingbetween the OCR or OAR quartiles (Table 5). The rates ofminor bleeding were greater in the highest quartiles of OCRand OAR, but the difference was statistically significant only

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Figure 2. Cumulative incidence of the (A) primarya and (B) secondahigh on-treatment platelet reactivity as measured by the VerifyNow P2Yratio; OCR: on-clopidogrel platelet reactivity. aComposite of cardiovascmyocardial infarction. bComposite of definite and probable stent thromyocardial infarction.


or OAR (P = 0.002). Conversely and of interest, major bleed-ng was decreased by threefold in the top quartile of OCRTable 5).

iscussion

n this multicentre French registry of patients with stableoronary disease or non-ST-segment elevation ACS under-oing planned PCI with stenting and pre-treated with

ryb combined ischaemic outcomes in patients with and without12 assay at 1-year follow-up. CI: confidence interval; HR: hazardular death, definite and probable stent thrombosis, spontaneous

mbosis, all-cause death, spontaneous, stroke and periprocedural


Table 2 Angiographic and procedural characteristics.

Variable On-clopidogrel platelet reactivity On-aspirin platelet reactivity

Totalcohort(n = 1001)

High(n = 360)

Normal(n = 641)

P Totalcohort(n = 972)

High(n = 84)

Normal(n = 888)

P

Radial access 767 (76.6) 279 (77.5) 488 (76.1) 0.88 745 (76.6) 67 (79.8) 678 (76.4) 0.86Number of diseased

vesselsOne 434 (43.4) 155 (43.1) 279 (43.5) 0.88 423 (43.5) 40 (47.6) 383 (43.1) 0.43Two 345 (34.5) 114 (31.7) 231 (36.0) 0.16 329 (33.8) 20 (23.8) 309 (34.8) 0.04Three 199 (19.9) 81 (22.5) 118 (18.4) 0.12 197 (20.3) 23 (27.4) 174 (19.6) 0.09

Left main disease 32 (3.2) 11 (3.1) 21 (3.3) 0.85 32 (3.3) 2 (2.4) 30 (3.4) 0.62Number of lesions

per patient1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.6 0.26 1.3 ± 0.5 1.3 ± 0.6 1.3 ± 0.5 0.79

Lesion type B2/C 573 (57.2) 199 (55.2) 374 (58.3) 0.68 559 (57.5) 51 (60.7) 508 (57.2) 0.53Thrombus-

containinglesion

42 (4.2) 19 (5.3) 23 (3.6) 0.20 42 (4.3) 5 (6.0) 37 (4.2) 0.40

Number of vesselstreated perpatient

1.2 ± 0.4 1.2 ± 0.4 1.2 ± 0.4 0.11 1.2 ± 0.4 1.2 ± 0.4 1.2 ± 0.4 0.99

Number of stentsper patient

1.5 ± 0.8 1.5 ± 0.8 1.5 ± 0.8 0.68 1.5 ± 0.8 1.5 ± 0.7 1.5 ± 0.8 0.55

At least oneDES/patient

573 (57.2) 190 (52.8) 383 (59.8) 0.03 557 (57.3) 44 (52.4) 513 (57.8) 0.34

Minimal stentdiameter (mm)

3.7 ± 16.2 3.9 ± 18.6 3.6 ± 14.7 0.76 3.7 ± 16.5 2.9 ± 0.5 3.8 ± 17.2 0.63

Maximal length ofstent (mm)

21.7 ± 12.4 22.0 ± 14.9 21.5 ± 10.7 0.61 21.6 ± 12.4 23.2 ± 21.7 21.5 ± 11.1 0.47

Thrombectomy 6 (0.6) 4 (1.1) 2 (0.3) 0.19 5 (0.5) 0 5 (0.6) 0.49Rotablator 10 (1.0) 1 (0.3) 9 (1.4) 0.10 9 (0.9) 0 9 (1.0) 0.35Post stent inflation 208 (20.8) 78 (21.7) 130 (20.3) 0.60 202 (20.2) 14 (16.7) 188 (21.2) 0.33GPI peri or post PCI 42 (4.2) 18 (5.0) 24 (3.7) 0.05 42 (4.3) 4 (4.8) 38 (4.3) 0.83GPI reloading dose

post PCI92 (9.2) 55 (15.3) 37 (5.8) < 0.001 90 (9.3) 16 (19.0) 74 (8.3) 0.001

Clopidogrelmaintenanceregimen post PCI75 mg 776 (77.5) 273 (75.8) 503 (78.5) 0.33 754 (77.6) 63 (75) 691 (77.8) 0.55≥ 150 mg 225 (22.5) 87 (24.2) 138 (21.5) 0.33 218 (22.4) 21 (25.0) 197 (22.2) 0.55

Data are mean ± standard deviation or number (%). DES: drug-eluting stent; GPI: glycoprotein IIb/IIIa inhibitor; PCI: percutaneouscoronary intervention.

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lopidogrel and aspirin, the 1-year rate of ischaemic andajor bleeding events did not differ according to residuallatelet reactivity.

The analytical validity of the VerifyNow assay in com-arison with light transmission aggregometry has beenemonstrated in previous investigations [14,15]. The resultsrom several studies (Table 6) [16—21] and a meta-analysis22] have suggested that the level of on-treatment plateleteactivity according to the VerifyNow assay is associatedith cardiovascular events, including stent thrombosis,
fter PCI. Randomized clinical trials have, however,rovided controversial findings on adjusting antiplateletherapy on the basis of on-treatment platelet reactivityesults. The ARCTIC study reported no improvement in
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linical outcomes with platelet function monitoring andreatment adjustment for coronary stenting using the Ver-fyNow assay [23]. In the GRAVITAS study, the use ofigh-dose versus standard-dose clopidogrel in patients withigh on-treatment reactivity after PCI with DES did noteduce the incidence of ischaemic events [24]. Also, theRIGGER-PCI study was interrupted prematurely due to futil-

ty (low number of cardiac deaths or myocardial infarctions)25]. Finally, the TRILOGY study, one of the largest recentrials of patients with medically managed ACS without
T-segment elevation, also found no significant relation-hip between the occurrence of ischaemic events andontinuous P2Y12 reaction unit (PRU) values [26]. Theesults of these randomized trials bring into question the

Events after

stenting according

to clopidogrel

and aspirin

platelet reactivity

231

Table 3 Characteristics of patients with definite, probable or possible stent thrombosis.

Stent thrombosiscategory

PRU value(%PI)

ARU value Clinicalpresentation

Stent type Pre-treatmentinterval

Time to stentthrombosis (daysafter PCI)

Stent thrombosis presentation

Definite stentthrombosis

Patient 1 (male,53 years)

284 (14) 414 Post MI DES < 48 hours 11 Angiographically proven


431 (0) 511 ACS (NSTEMI) DES < 48 hours 2 Angiographically proven

Probable stentthrombosis


244 (24) 442 Post MI BMS < 1 week 4 Unexplained sudden death


214 (0) 10 Post MI DES > 1 week 15 Unexplained sudden death


371 (3) 491 Silentischaemia

DES < 48 hours 159 Documented MI in the territoryof the implanted stent withoutangiographic confirmation


219 (40) 409 ACS (unstableangina)

DES > 1 week 53 Documented MI in the territoryof the implanted stent withoutangiographic confirmation

Possible stentthrombosis


427 (46) 418 Stable angina BMS > 1 week 72 Unexplained sudden death

Patient 8 (female,75 years)

284 (25) 525 Stable angina DES 5 days 82 Unexplained sudden death


356 (0) 520 Stable angina DES > 1 week 50 Unexplained sudden death


374 (0) 546 Unstableangina

DES > 1 week 327 Unexplained sudden death

%PI: percentage of platelet inhibition; ACS: acute coronary syndrome; ARU: aspirin reaction units; BMS: bare-metal stent; DES: drug-eluting stent; MI: myocardial infarction; NSTEMI:non-ST-segment elevation myocardial infarction; PRU: P2Y12 reaction units.

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Table 4 Clinical outcomes at 1-year follow-up.

Endpoints On-clopidogrel platelet reactivity On-aspirin platelet reactivity


High(n = 360)

Normal(n = 641)

Pa Totalcohort(n = 972)

High(n = 84)

Normal(n = 888)

Pa

Ischaemic endpointsDefinite and probable ST 6 (0.6) 4 (1.1) 2 (0.3) 0.86 6 (0.6) 0 6 (0.7) 0.58Definite, probable andpossible ST

10 (1.0) 6 (1.7) 4 (0.6) 0.80 10 (1.0) 0 10 (1.1) 0.40

All-cause death 18 (1.8) 10 (2.8) 8 (1.2) 0.28 18 (1.8) 1 (1.2) 17 (1.9) 0.27Cardiovascular death 11 (1.1) 5 (1.4) 6 (0.9) 0.57 11 (1.1) 1 (1.2) 10 (1.1) 0.35MI (ESC type 1) 18 (1.8) 7 (1.9) 11 (1.7) 0.36 17 (1.7) 1 (1.2) 16 (1.8) 0.88MI (ESC type 4a) 149 (14.9) 45 (12.5) 104 (16.2) 0.11 145 (14.9) 8 (9.5) 137 (15.4) 0.15MI (types 1 and 4a) 165 (16.5) 50 (13.9) 115 (17.9) 0.17 160 (16.5) 8 (9.5) 152 (17.1) 0.08Stroke 5 (0.5) 3 (0.83) 2 (0.31) 0.35 4 (0.41) 0 4 (0.45) 0.69Main ischaemic compositeendpointb

29 (2.9) 14 (3.9) 15 (2.3) 0.18 28 (2.9) 2 (2.4) 26 (2.9) 0.87

Secondary ischaemiccomposite endpointc

176 (17.6) 57 (15.8) 119 (18.6) 0.25 171 (17.6) 8 (9.5) 163 (18.4) 0.05

Safety endpointsMajor haemorrhage 11 (1.1) 3 (0.8) 8 (1.2) 0.70 11 (1.1) 0 11 (1.2) 0.37Minor haemorrhage 61 (6.1) 15 (4.2) 46 (7.2) 0.94 61 (6.3) 1 (1.2) 60 (6.7) 0.20Major and minorhaemorrhage

72 (7.2) 18 (5.0) 54 (8.4) 0.92 72 (7.4) 1 (1.2) 71 (8.0) 0.13

Data are number (%). ESC: European Society of Cardiology; MI: myocardial infarction; ST: stent thrombosis.a Log-rank P-value.b Cardiovascular death, stent thrombosis, MI ESC type 1.c All-cause death, stent thrombosis, MI ESC types 1 and 4a, stroke.

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elevance of research into antiplatelet therapy resistancen ACS.

Previous studies on the prognostic value of the VerifyNowssay found an association between high on-platelet reac-ivity and clinical outcomes, and reported higher rates ofschaemic events than in the VERIFRENCHY study. In thetudy by Price et al. [20], the rate of definite or proba-le stent thrombosis was 1.6% (vs 0.6% in VERIFRENCHY);reet et al. [16] reported a rate of spontaneous myocar-ial infarction of 7.1% (vs. 1.8% in VERIFRENCHY); and in
he study by Marcucci et al. [18], the rate of cardiovas-ular deaths was 3.5% (vs. 1.1% in VERIFRENCHY). Therere several possible reasons for these discrepancies. First,
gop

Table 5 Haemorrhagic events at one1 year according to quar

Haemorrhagic events On-clopidogrel platelet reactivity


Q1—Q3(n = 749)

Q4 highresponse(n = 252)

All haemorrhage 72 (7.2) 50 (6.7) 22 (8.7)

Major haemorrhage 11 (1.1) 10 (1.3) 1 (0.4)

Minor haemorrhage 61 (6.1) 40 (5.3) 21 (8.3)

Data are number (%). Q: quartile.a Log-rank p-value.


nly 22% of the VERIFRENCHY population was diagnosed withCS at presentation, a condition associated with a threefoldigher rate of stent thrombosis compared with that in a sta-le coronary artery disease population undergoing PCI [27].ndeed, the recent ADAPT-DES study showed a correlationetween high OCR and ischaemic events in ACS patients,hereas no such effect was present in those with a stablelinical presentation [28]. Second, we may have excludedigh-risk procedures, a selection bias that may account forhe low rate of ischaemic events. Third, systematic clopido-
rel pre-treatment and high rates of use of a double dosef clopidogrel after hospital discharge (22.5%) may haverevented the development of acute and subacute stent
tile of response to clopidogrel or aspirin.

On-aspirin platelet reactivity

Pa Totalcohort(n = 972)

Q1—Q3(n = 719)

Q4 highresponse(n = 253)

Pa

0.28 72 (7.4) 44 (6.1) 28 (11.1) 0.010.19 11 (1.1) 9 (1.3) 2 (0.8) 0.420.09 61 (6.3) 35 (4.9) 26 (10.3) 0.002


Table 6 Outcomes with the VerifyNow assay.

Studies ACS (%) Cut-off High on-clopidogrelplatelet reactivity (%)

Endpoints: high vs. normalon-clopidogrel platelet reactivity

Price et al., 2008 [20] 6.3 PRU > 235 34.1 CV death: 2.8% vs. 0% (P = 0.004)ST: 4.6% vs. 0% (P = 0.004)Composite of CV death/MI/ST: 6.5%vs. 1.0% (P = 0.008)

Breet et al., 2010 [16] 0 PRU > 236 38.6 ST: 2.0% vs. 0.8% (P = 0.09)CV death: 2.2% vs. 1.4% (P = 0.32)

Patti et al., 2008 [19] 54.4 PRU > 240 — Composite of CV death/MI1/TVR:20% vs. 3% (P = 0.034)

Campo et al., 2010 [17] 32.5 %PI < 40% 38.2 Death: 2.2% vs. 1.7% (P = 0.4)Stroke: 1.1% vs. 0% (P = 0.2)MI1: 4.5% vs. 16.2% (P = 0.001)

Marcucci et al., 2009 [18] 100 PRU > 240 32.1 CV death: 3.5%; HR: 2.38 (P = 0.031)MI1: 3.9%; HR: 2.73 (P = 0.006)

Suh et al., 2011 [21] 38 PRU > 252 — ST: 0.87%Composite of CV death/ST/MI/TVR:11.8% vs. 7.1% (P = 0.03)

This study 21.6 %PI < 15% 36 ST: 1.1% vs. 0.3% (P = 0.86)(VERIFRENCHY) MI1: 1.9% vs. 1.7% (P = 0.36)

Composite of ST/CV death/MI: 3.9%vs. 2.3% (P = 0.18)

%PI: percentage of platelet inhibition; ACS: acute coronary syndrome; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarctiontype 1; PRU: P2Y12 reaction units; ST: stent thrombosis; TVR: target vessel revascularization.

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thrombosis [29]. Fourth, recent improvements in techni-cal procedures associated with PCI, such as high pressuredeployment and advances in stent configuration, have beenassociated with lower rates of stent thrombosis [23] (ran-ging from 1.3 to 1.7% in 2005 [13], when the first DES wereintroduced, compared with 0—0.6% in 2011, with the intro-duction of second-generation DES [24,25]). The low rate ofischaemic events in the present study is similar to thosefound in the no-monitoring groups of other studies [23—25].The cut-off level used may possibly explain the negativeresults of this study; however, to date, there is no consensuson this issue. The results of the GRAVITAS [24] and TRIGGER-PCI [25] studies were negative using cut-off PRU values of230 and 208, respectively, while ARCTIC reported the sameresults with a PRU cut-off of 235 and 15% for the %PI [23].The ongoing ANTARCTIC study (NCT01538446) is expected toprovide more consistent answers in patients with an ACS.

While the results of one study reported an increased rateof major bleeding in clopidogrel high responders [30], thisfinding was not supported by our results. The absence ofan increase in major bleeding observed in clopidogrel goodresponders may be due to the high rate of use of radialaccess in the study, which is associated with a very lowincidence of major bleeding [31].

This study has some limitations. Higher rates of use ofa clopidogrel reloading dose and of glycoprotein IIb/IIIainhibitors in patients with high OCR may have introducedbias, with the potential to reduce the difference between
event rates between high and low OCR groups.
The rate of high on-treatment platelet reactivity toadenosine diphosphate could be partially explained byauthorization of a 600 mg clopidogrel loading dose two hours

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efore PCI, as supported by data from the ALBION study32]. In our study, however, 74.4% of patients were treated

48 hours before PCI and 54.3% were treated > one weekefore PCI. When the study was designed there was nogreement on the optimal cut-off for detecting bleedingvents; recently, however, there has been a trend towardselecting a cut-off of ≤85 PRU, based on data from the studyy Campo et al. [33].

onclusions

n this prospective multicentre study, on-treatment plateleteactivity using aspirin and clopidogrel was not associatedith 1-year ischaemic or bleeding events in an intermediate-

isk population undergoing stent implantation. These resultsay either accurately reflect the lower than expected event

ates; conversely, the VerifyNow assay may be unable to dis-inguish patients undergoing coronary stenting at increasedisk of an ischaemic event.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

cknowledgements

he study was sponsored by Association pour le développe-ent de la cardiologie dans la ville de Chartres. Research

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34

rants were obtained from Medtronic, Boston Scientificorporation, Abbott, Stago and Cordis Corporation. Wehank Christophe Laure, Patrick Piesvaux, Christelle Vas-aliere, Martin Kappler and Cécile Ricard for their importantontributions, especially in data management. Sophieushton-Smith provided editorial assistance and was fundedy the authors.

Trial registration: NCT00753753 (http://clinicaltrials.ov).

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