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High-on-treatment platelet reactivity predicts adverse outcome after carotid artery stenting: A prospective study

  • Author Footnotes
    1 These authors share first authorship.
    G. Simonte
    Footnotes
    1 These authors share first authorship.
    Affiliations
    Unit of Vascular Surgery, S. Maria della Misericordia Hospital, Perugia, Italy
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  • Author Footnotes
    1 These authors share first authorship.
    G. Guglielmini
    Footnotes
    1 These authors share first authorship.
    Affiliations
    Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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  • E. Falcinelli
    Affiliations
    Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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  • G. Isernia
    Affiliations
    Unit of Vascular Surgery, S. Maria della Misericordia Hospital, Perugia, Italy
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  • A.M. Mezzasoma
    Affiliations
    Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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  • Author Footnotes
    2 These authors share senior authorship.
    P. Gresele
    Correspondence
    Corresponding author at: Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Strada Vicinale Via delle Corse, 06126 Perugia, Italy.
    Footnotes
    2 These authors share senior authorship.
    Affiliations
    Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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  • Author Footnotes
    2 These authors share senior authorship.
    M. Lenti
    Footnotes
    2 These authors share senior authorship.
    Affiliations
    Unit of Vascular Surgery, S. Maria della Misericordia Hospital, Perugia, Italy
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  • Author Footnotes
    1 These authors share first authorship.
    2 These authors share senior authorship.
Published:December 27, 2022DOI:https://doi.org/10.1016/j.thromres.2022.12.015

      Highlights

      • While the predictive value of HTPR for PCI is known no data are available for CAS.
      • 300 patients undergoing CAS were enrolled in a prospective clinical study.
      • HTPR to DAPT was evaluated with 5 different laboratory assays.
      • HTPR detected by MEA and VASP test was associated with risk of MACE.
      • HTPR to three tests was strongly predictive of increased MACE risk.

      Abstract

      Background and purpose

      High-on-treatment platelet reactivity (HTPR) has been established as a predictor of major adverse cardiovascular events (MACE) in patients undergoing percutaneous coronary interventions on dual antiplatelet therapy (DAPT), but no data are available on its predictive value in patients on DAPT after carotid artery stenting (CAS). We aimed to evaluate the possible association between HTPR in patients on aspirin plus clopidogrel therapy after CAS and subsequent MACE.

      Methods

      All consecutive patients treated with CAS in a single institution were enrolled in a prospective clinical study. HTPR was evaluated with 5 different laboratory assays carried out just before CAS. MACE incidence (cerebral ischemia, myocardial infarction, stent thrombosis, acute limb ischemia and vascular death) was evaluated at 30 days and thereafter at yearly visits.

      Results

      A total of 300 patients were enrolled in the study, and eight were then excluded because blood samples resulted unsuitable for the laboratory testing or CAS aborted for technical problems. Median follow-up was 5.8 years and during this period 47 MACE occurred.
      HTPR detected by multiplate electronic aggregometry (MEA) and the VASP phosphorylation assay (VASP) were associated with a significantly enhanced risk of MACE (p = 0.048 and p = 0.038, respectively). However, HTPR to three tests (HTPR3) was more strongly predictive of increased risk of a vascular event at follow up (p = 0.005) at bivariate analysis and also at Cox regression multivariate analysis (p = 0.002).

      Conclusions

      HTPR to three different assays (mainly to VASP + PFA P2Y+ VerifyNow) in patients on DAPT after CAS has predictive value for subsequent MACE. Prospective studies to assess whether platelet function testing-guided antiplatelet therapy is superior to standard DAPT in patient undergoing CAS should be considered.

      Keywords

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      References

        • Noiphithak R.
        • Liengudom A.
        Recent update on carotid endarterectomy versus carotid artery stenting.
        Cerebrovasc. Dis. 2017; 43: 68-75https://doi.org/10.1159/000453282
        • De Rango P.
        • Caso V.
        • Leys D.
        • Paciaroni M.
        • Lenti M.
        • Cao P.
        The role of carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.
        Stroke. 2008; 39: 3116-3127https://doi.org/10.1161/STROKEAHA.108.518357
        • Sardar P.
        • Chatterjee S.
        • Aronow H.D.
        • Kundu A.
        • Ramchand P.
        • Mukherjee D.
        • et al.
        Carotid artery stenting versus endarterectomy for stroke prevention: a meta-analysis of clinical trials.
        J. Am. Coll. Cardiol. 2017; 69: 2266-2275https://doi.org/10.1016/j.jacc.2017.02.053
        • Antoniou G.A.
        • Georgiadis G.S.
        • Georgakarakos E.I.
        • Antoniou S.A.
        • Bessias N.
        • Smyth J.V.
        • et al.
        Meta-analysis and meta-regression analysis of outcomes of carotid endarterectomy and stenting in the elderly.
        JAMA Surg. 2013; 148: 1140-1152https://doi.org/10.1001/jamasurg.2013.4135
        • Naqvi T.Z.
        • Lee M.S.
        Carotid intima-media thickness and plaque in cardiovascular risk assessment.
        JACC Cardiovasc. Imaging. 2014; 7: 1025-1038https://doi.org/10.1016/j.jcmg.2013.11.014
        • Gresele P.
        • Paciullo F.
        • Migliacci R.
        Antithrombotic treatment of asymptomatic carotid atherosclerosis: a medical dilemma.
        Intern. Emerg. Med. 2020; 15: 1169-1181https://doi.org/10.1007/s11739-020-02347-7
        • Huibers A.
        • Halliday A.
        • Bulbulia R.
        • Coppi G.
        • de Borst G.J.
        • ACST-2 Collaborative Group
        Antiplatelet therapy in carotid artery stenting and carotid endarterectomy in the asymptomatic carotid surgery trial-2.
        Eur. J. Vasc. Endovasc. Surg. 2016; 51: 336-342https://doi.org/10.1016/j.ejvs.2015.11.002
        • Bertrand M.E.
        • Rupprecht H.J.
        • Urban P.
        • Gershlick A.H.
        • CLASSICS Investigators
        Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS).
        Circulation. 2000; 102: 624-629https://doi.org/10.1161/01.cir.102.6.624
        • Park K.W.
        • Kang S.H.
        • Kang J.
        • Jeon K.H.
        • Park J.J.
        • Han J.K.
        • Koh J.S.
        • Lee S.E.
        • Yang H.M.
        • Lee H.Y.
        • Kang H.J.
        • Koo B.K.
        • Oh B.H.
        • Park Y.B.
        • Kim H.S.
        Enhanced clopidogrel response in smokers is reversed after discontinuation as assessed by VerifyNow assay: additional evidence for the concept of 'smokers' paradox'.
        Heart. 2012; 98: 1000-1006https://doi.org/10.1136/heartjnl-2011-301565
        • Buonamici P.
        • Marcucci R.
        • Migliorini A.
        • Gensini G.F.
        • Santini A.
        • Paniccia R.
        • et al.
        Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis.
        J. Am. Coll. Cardiol. 2007; 49: 2312-2317https://doi.org/10.1016/j.jacc.2007.01.094
        • Bonello L.
        • Tantry U.S.
        • Marcucci R.
        • Blindt R.
        • Angiolillo D.J.
        • Becker R.
        • et al.
        Working group on high on treatment platelet reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.
        J. Am. Coll. Cardiol. 2010; 56: 919-933https://doi.org/10.1016/j.jacc.2010.04.047
        • Aradi D.
        • Kirtane A.
        • Bonello L.
        • Gurbel P.A.
        • Tantry U.S.
        • Huber K.
        • Freynhofer M.K.
        • et al.
        Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.
        Eur. Heart J. 2015; 36: 1762-1771https://doi.org/10.1093/eurheartj/ehv104
        • Frelinger 3rd, A.L.
        • Gachet C.
        • Mumford A.D.
        • Noris P.
        • Mezzano D.
        • Harrison P.
        • et al.
        Subcommittee on platelet physiology. Laboratory monitoring of P2Y12 inhibitors: communication from the SSC of the ISTH.
        J. Thromb. Haemost. 2018; 16: 2341-2346https://doi.org/10.1111/jth.14282
        • Sorkin G.C.
        • Dumont T.M.
        • Wach M.M.
        • Eller J.L.
        • Mokin M.
        • Natarajan S.K.
        • et al.
        Carotid artery stenting outcomes: do they correlate with antiplatelet response assays?.
        J. Neurointerv. Surg. 2014; 6: 373-378https://doi.org/10.1136/neurintsurg-2013-010771
        • Barnett H.J.M.
        • Taylor D.W.
        • Haynes R.B.
        • Sackett D.L.
        • Peerless S.J.
        • Ferguson G.G.
        • et al.
        North american symptomatic carotid endarterectomy trial collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
        N. Engl. J. Med. 1991; 325: 445-453https://doi.org/10.1056/NEJM199108153250701
        • Cronenwett J.L.
        • Johnston K.W.
        Rutherford’s Vascular Surgery.
        7th edition. Elsevier, Philadelphia2010https://doi.org/10.1308/003588411X561062
        • Bates E.R.
        • Babb J.D.
        • Casey Jr., D.E.
        • Cates C.U.
        • Duckwiler G.R.
        • Feldman T.E.
        • et al.
        ACCF/SCAI/SVMB/SIR/ASITN 2007 clinical expert consensus document on carotid stenting: a report of the American College of Cardiology Foundation task force on clinical expert consensus documents (ACCF/SCAI/SVMB/SIR/ASITN clinical expert consensus document committee on carotid Stenting).
        J. Am. Coll. Cardiol. 2007; 49: 126-170https://doi.org/10.1016/j.jacc.2006.10.021
        • Simonte G.
        • Fiorucci B.
        • Isernia G.
        • Parlani G.
        • Verzini F.
        • Cieri E.
        • et al.
        Long-term results of tapered stents in endovascular treatment of carotid stenosis.
        Ann. Vasc. Surg. 2017; 45: 79-84https://doi.org/10.1016/j.avsg.2017.06.052
        • Packham MA
        • Rand ML
        Historical perspective on ADP-induced platelet activation.
        Purinergic Signal. 2011; 7: 283-292https://doi.org/10.1007/s11302-011-9227-x
        • Ranucci M.
        • Baryshnikova E.
        • Soro G.
        • Ballotta A.
        • De Benedetti D.
        • Conti D.
        • Surgical and Clinical Outcome Research (SCORE) Group
        Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines.
        Ann. Thorac. Surg. 2011; 91: 123-129https://doi.org/10.1016/j.athoracsur.2010.09.022
        • Lee M.S.
        • Shlofmitz E.
        • Haag E.
        • Santiago L.
        • Pollack S.
        • Reichek N.
        • et al.
        Optimal same-day platelet inhibition in patients receiving drug-eluting stents with or without previous maintenance thienopyridine therapy: from the evaluation of platelet inhibition in patients having a VerifyNow assay (EPIPHANY) trial.
        Am. J. Cardiol. 2017; 119: 991-995https://doi.org/10.1016/j.amjcard.2016.11.057
        • Crescente M.
        • Mezzasoma A.M.
        • Del Pinto M.
        • Palmerini F.
        • Di Castelnuovo A.
        • Cerletti C.
        • et al.
        Incomplete inhibition of platelet function as assessed by the platelet function analyzer (PFA-100) identifies a subset of cardiovascular patients with high residual platelet response while on aspirin.
        Platelets. 2011; 22: 179-187https://doi.org/10.3109/09537104.2010.543710
        • Falcinelli E.
        • Francisci D.
        • Belfiori B.
        • Petito E.
        • Guglielmini G.
        • Malincarne L.
        • et al.
        In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients.
        Thromb. Haemost. 2013; 110: 349-357https://doi.org/10.1160/TH12-07-0504
        • Gresele P.
        • Pignatelli P.
        • Guglielmini G.
        • Carnevale R.
        • Mezzasoma A.M.
        • Ghiselli A.
        • et al.
        Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.
        J. Nutr. 2008; 138: 1602-1608https://doi.org/10.1093/jn/138.9.1602
        • Gresele P
        • Bury L
        • Mezzasoma AM
        • Falcinelli E
        Platelet function assays in diagnosis: an update.
        Expert Rev. Hematol. 2019; 12: 29-46https://doi.org/10.1080/17474086.2019.1562333
        • Koessler J.
        • Kobsar A.L.
        • Rajkovic M.S.
        • Schafer A.
        • Flierl U.
        • Pfoertsch S.
        • Bauersachs J.
        • Steigerwald U.
        • Rechner A.R.
        • Walter U.
        The new INNOVANCE® PFA P2Y cartridge is sensitive to the detection of the P2Y12 receptor inhibition.
        Platelets. 2011; 22: 20-27https://doi.org/10.3109/09537104.2010.514967
        • Breet N.J.
        • van Werkum J.W.
        • Bouman H.J.
        • Kelder J.C.
        • Ruven H.J.
        • Bal E.T.
        • et al.
        Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
        JAMA. 2010; 8: 754-762https://doi.org/10.1001/jama.2010.181
        • Aradi D.
        • Magyarlaki T.
        • Tokés-Füzesi M.
        • Rideg O.
        • Vorobcsuk A.
        • Komócsi A.
        Comparison of conventional aggregometry with VASP for monitoring P2Y12-specific platelet inhibition.
        Platelets. 2010; 21: 563-570https://doi.org/10.3109/09537104.2010.494742
        • Blindt R.
        • Stellbrink K.
        • de Taeye A.
        • Müller R.
        • Kiefer P.
        • Yagmur E.
        • et al.
        The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis.
        Thromb. Haemost. 2007; 98: 1329-1334https://doi.org/10.1160/TH07-05-0324
        • Mingant F.
        • Didier R.
        • Gilard M.
        • Martin F.
        • Nicol P.P.
        • Ugo V.
        • et al.
        Comparison of four methods to assess high-on platelet reactivity under P2Y12 receptor inhibitor.
        Platelets. 2018; 29: 257-264https://doi.org/10.1080/09537104.2018.1453058
        • Aleil B.
        • Ravanat C.
        • Cazenave J.P.
        • Rochoux G.
        • Heitz A.
        • Gachet C.
        Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases.
        J. Thromb. Haemost. 2005; 3: 85-92https://doi.org/10.1111/j.1538-7836.2004.01063.x
        • Danese E.
        • Fava C.
        • Beltrame F.
        • Tavella D.
        • Calabria S.
        • Benati M.
        • Gelati M.
        • Gottardo R.
        • Tagliaro F.
        • Guidi G.C.
        • Cattaneo M.
        • Minuz P.
        Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry.
        J. Thromb. Haemost. 2016; 14: 282-293https://doi.org/10.1111/jth.13197
        • van Werkum J.W.
        • van der Stelt C.A.
        • Seesing T.H.
        • ten Berg J.M.
        • Hackeng C.M.
        The flow cytometric VASP assay can be used to determine the effectiveness of clopidogrel in patients treated with abciximab.
        J. Thromb. Haemost. 2007; 5: 881-883https://doi.org/10.1111/j.1538-7836.2007.02421.x
        • Lordkipanidzé M.
        • Pharand C.
        • Nguyen T.A.
        • Schampaert E.
        • Palisaitis D.A.
        • Diodati J.G.
        Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients.
        Eur. Heart J. 2008; 29: 2877-2885https://doi.org/10.1093/eurheartj/ehn419
        • Parodi G.
        • Marcucci R.
        • Valenti R.
        • Gori A.M.
        • Migliorini A.
        • Giusti B.
        • et al.
        High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
        JAMA. 2011; 306: 1215-1223https://doi.org/10.1001/jama.2011.1332
        • Migliorini A.
        • Valenti R.
        • Marcucci R.
        • Parodi G.
        • Giuliani G.
        • Buonamici P.
        • et al.
        High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
        Circulation. 2009; 120: 2214-2221https://doi.org/10.1161/CIRCULATIONAHA.109.883454
        • Hochholzer W.
        • Valina C.M.
        • Bömicke T.
        • Amann M.
        • Stratz C.
        • Nührenberg T.
        • Trenk D.
        • Neumann F.J.
        Intrinsic platelet reactivity before start with clopidogrel as predictor for on-clopidogrel platelet function and long-term clinical outcome.
        Thromb. Haemost. 2015; 114: 109-114https://doi.org/10.1160/TH14-10-0900
        • Bömicke T.
        • Valina C.M.
        • Stratz C.
        • Amann M.
        • Neumann F.J.
        • Hochholzer W.
        On-clopidogrel platelet reactivity as predictor for long-term clinical outcome in patients after planned discontinuation of clopidogrel.
        Thromb. Haemost. 2017; 117: 1644-1650https://doi.org/10.1160/TH17-02-0122
        • Sibbing D.
        • Aradi D.
        • Alexopoulos D.
        • Ten Berg J.
        • Bhatt D.L.
        • Bonello L.
        • et al.
        Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention.
        JACC Cardiovasc Interv. 2019; 12: 1521-1537https://doi.org/10.1016/j.jcin.2019.03.034
        • Marcucci R.
        • Gori A.M.
        • Paniccia R.
        • Giusti B.
        • Valente S.
        • Giglioli C.
        • et al.
        Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.
        Circulation. 2009; 119: 237-242https://doi.org/10.1161/CirculationAHA.109. 883454
        • Freynhofer M.K.
        • Bruno V.
        • Brozovic I.
        • Jarai R.
        • Vogel B.
        • Farhan S.
        • et al.
        Variability of on-treatment platelet reactivity in patients on clopidogrel.
        Platelets. 2014; 25: 328-336https://doi.org/10.3109/09537104.2013.827781
        • Nührenberg T.G.
        • Stratz C.
        • Leggewie S.
        • Hochholzer W.
        • Valina C.M.
        • Gick M.
        • et al.
        Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation. An ADAPT-DES substudy.
        Thromb Haemost. 2015; 114: 1020-1027https://doi.org/10.1160/TH15-03-0257
        • Zwart B.
        • Godschalk T.C.
        • Zheng K.
        • Denteneer J.
        • Kelder J.C.
        • Ten Berg J.M.
        Measuring high on-treatment platelet reactivity in clinical practice; should we use a panel of platelet function tests?.
        Blood Coagul. Fibrinolysis. 2019; 30: 263-269https://doi.org/10.1097/MBC.0000000000000831
        • Claassens D.M.F.
        • GJA Vos
        • Bergmeijer T.O.
        • Hermanides R.S.
        • van der Harst P.
        • van 't Hof A.W.J.
        • et al.
        A Genotype-guided strategy for oral P2Y12 inhibitors in primary PCI.
        N. Engl. J. Med. 2019; 381: 1621-1623https://doi.org/10.1056/NEJMoa1907096
        • Cuisset T.
        • Grosdidier C.
        • Loundou A.D.
        • Quilici J.
        • Loosveld M.
        • Camoin L.
        • et al.
        Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs).
        JACC Cardiovasc Interv. 2013; 6: 854-863https://doi.org/10.1016/j.jcin.2013.04.009
        • Ghamraoui A.K.
        • Chang H.
        • Maldonado T.S.
        • Ricotta 2nd, J.J.
        Clopidogrel versus ticagrelor for antiplatelet therapy in transcarotid artery revascularization (TCAR) in the Society for Vascular Surgery Vascular Quality Initiative.
        J. Vasc. Surg. 2021; S0741–5214: 02596-02599https://doi.org/10.1016/j.jvs.2021.11.060