Advertisement

Risk of Stroke in Patients With High On-Clopidogrel Platelet Reactivity to Adenosine Diphosphate After Percutaneous Coronary Intervention

      Several prospective studies have shown that high on-clopidogrel platelet reactivity (HPR) in patients undergoing percutaneous coronary intervention (PCI) is a risk factor for ischemic events. All studies were insufficiently powered to detect differences in stroke between patients with HPR and those without. Therefore, we performed a systematic review and meta-analysis of available publications aimed at determining whether patients undergoing PCI with HPR are also at increased risk of stroke. We searched for prospective studies enrolling patients undergoing PCI and treated with aspirin and clopidogrel that reported on clinical relevance of HPR to adenosine diphosphate. Study end point was the rate of stroke. We also investigated whether there was an interaction on the relative risk of stroke between HPR, clinical presentation, duration of follow-up, or laboratory methods. Fourteen studies including 11,959 patients were deemed eligible. On pooled analysis, the risk of stroke was higher in patients with HPR compared with patients with no HPR (1.2% vs 0.7%, relative risk on fixed effect 1.84, 95% confidence interval 1.21 to 2.80). There was no heterogeneity among the studies (I2 = 0%, p = 0.5). Clinical presentation (p = 0.39 for interaction), duration of follow-up (p = 0.87 for interaction), and laboratory method for detection of HPR (p = 0.99 for interaction) did not affect the relative increase in the risk of stroke in patients with HPR compared with patients with no HPR. In conclusion, in patients with coronary artery disease undergoing PCI, the presence of HPR to adenosine diphosphate is a risk factor for stroke.
      Dual antiplatelet therapy with aspirin and the adenosine diphosphate (ADP) receptor inhibitor clopidogrel is the most widely used treatment to inhibit platelet reactivity and prevent ischemic events after percutaneous coronary intervention (PCI).
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • Bailey S.R.
      • Bittl J.A.
      • Cercek B.
      • Chambers C.E.
      • Ellis S.G.
      • Guyton R.A.
      • Hollenberg S.M.
      • Khot U.N.
      • Lange R.A.
      • Mauri L.
      • Mehran R.
      • Moussa I.D.
      • Mukherjee D.
      • Nallamothu B.K.
      • Ting H.H.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      However, a significant individual variability in platelet reactivity after clopidogrel administration exists related to nongenetic and genetic factors.
      • Sibbing D.
      • Byrne R.A.
      • Bernlochner I.
      • Kastrati A.
      High platelet reactivity and clinical outcome—fact and fiction.
      A large amount of evidence derived from longitudinal prospective studies
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Hochholzer W.
      • Trenk D.
      • Bestehorn H.P.
      • Fischer B.
      • Valina C.M.
      • Ferenc M.
      • Gick M.
      • Caputo A.
      • Buttner H.J.
      • Neumann F.J.
      Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Cuisset T.
      • Frere C.
      • Quilici J.
      • Gaborit B.
      • Castelli C.
      • Poyet R.
      • Bali L.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.
      • Marcucci R.
      • Gori A.M.
      • Paniccia R.
      • Giusti B.
      • Valente S.
      • Giglioli C.
      • Buonamici P.
      • Antoniucci D.
      • Abbate R.
      • Gensini G.F.
      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.
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Price M.J.
      • Berger P.B.
      • Teirstein P.S.
      • Tanguay J.F.
      • Angiolillo D.J.
      • Spriggs D.
      • Puri S.
      • Robbins M.
      • Garratt K.N.
      • Bertrand O.F.
      • Stillabower M.E.
      • Aragon J.R.
      • Kandzari D.E.
      • Stinis C.T.
      • Lee M.S.
      • Manoukian S.V.
      • Cannon C.P.
      • Schork N.J.
      • Topol E.J.
      Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.
      • Park K.W.
      • Jeon K.H.
      • Kang S.H.
      • Oh I.Y.
      • Cho H.J.
      • Lee H.Y.
      • Kang H.J.
      • Park S.K.
      • Koo B.K.
      • Oh B.H.
      • Park Y.B.
      • Kim H.S.
      Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study).
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      • Stone G.W.
      • Witzenbichler B.
      • Weisz G.
      • Rinaldi M.J.
      • Neumann F.J.
      • Metzger D.C.
      • Henry T.D.
      • Cox D.A.
      • Duffy P.L.
      • Mazzaferri E.
      • Gurbel P.A.
      • Xu K.
      • Parise H.
      • Kirtane A.J.
      • Brodie B.R.
      • Mehran R.
      • Stuckey T.D.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.
      and meta-analyses
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      have shown that patients undergoing PCI and disclosing a high on-clopidogrel platelet reactivity (HPR) are at increased risk of ischemic events, including cardiovascular death
      • Marcucci R.
      • Gori A.M.
      • Paniccia R.
      • Giusti B.
      • Valente S.
      • Giglioli C.
      • Buonamici P.
      • Antoniucci D.
      • Abbate R.
      • Gensini G.F.
      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.
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      and stent thrombosis.
      • Cuisset T.
      • Frere C.
      • Quilici J.
      • Gaborit B.
      • Castelli C.
      • Poyet R.
      • Bali L.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Stone G.W.
      • Witzenbichler B.
      • Weisz G.
      • Rinaldi M.J.
      • Neumann F.J.
      • Metzger D.C.
      • Henry T.D.
      • Cox D.A.
      • Duffy P.L.
      • Mazzaferri E.
      • Gurbel P.A.
      • Xu K.
      • Parise H.
      • Kirtane A.J.
      • Brodie B.R.
      • Mehran R.
      • Stuckey T.D.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      However, the relative risk (RR) of stroke of patients with HPR and those without has not been investigated in depth, because all studies were insufficiently powered for this purpose. Therefore, we performed a systematic review and meta-analysis of available publications aimed at determining whether patients undergoing PCI with HPR are also at increased risk of stroke.

      Methods

      We carried out a systematic review of the available publications according to the current Meta-analysis Of Observational Studies in Epidemiology guidelines to perform meta-analyses of observational studies.
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D.
      • Moher D.
      • Becker B.J.
      • Sipe T.A.
      • Thacker S.B.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      We searched for relevant reports published from January 1, 2002 to September 30, 2013 in the MEDLINE database and the Cochrane Library using the following keywords that were variously combined: “clopidogrel,” “clopidogrel resistance,” “platelet reactivity,” “high on-treatment platelet reactivity,” “outcome,” and “stroke.” No language restriction was used. We also checked the reference lists of reviews and relevant reports.
      Inclusion criteria were as follows: (1) prospective longitudinal design, (2) studies that enrolled patients receiving aspirin and clopidogrel, (3) patients divided into patients with HPR or not on the basis of absolute measure of on-treatment platelet reactivity by current accepted ADP-specific platelet function assays
      • Sibbing D.
      • Byrne R.A.
      • Bernlochner I.
      • Kastrati A.
      High platelet reactivity and clinical outcome—fact and fiction.
      (ADP-stimulated light transmission aggregometry [LTAADP], VerifyNow P2Y12, [Accumetrics, San Diego, California], flow cytometric assessment of vasodilator-stimulated phosphoprotein phosphorylation [BioCytex, Marseille, France], and multiple electrode aggregometry with ADP stimuli [Dynabyte, Munich, Germany]), (4) availability of numbers of cases in both HPR and no HPR groups, and (5) data on stroke prospectively collected. Two investigators (NT and TP) independently reviewed the titles, abstracts, and studies to determine whether they met the inclusion criteria. Conflicts between reviewers were resolved by consensus.
      RRs and 95% confidence intervals were used as the summary statistic. The pooled RR was calculated using both fixed-effects (inverse variance weighted) and random-effects (DerSimonian and Laird) models. Between-study heterogeneity of effects was analyzed using the chi-square and inconsistency across study results quantified by I2 statistics, with I2 <25%, 25% ≤ I2 ≤ 50%, and I2 >50%, respectively, representing mild, moderate, and severe inconsistency.
      Sensitivity analysis was performed by evaluating the influence of removing individual studies on the pooled RR. Sensitivity analysis was also performed with reference to the following study characteristics: clinical presentation, duration of follow-up, and laboratory methods used to measure platelet reactivity. The possibility of publication bias was assessed by Harbord's test.
      Statistical analyses were performed using Stata/SE 11.2 (StataCorp LP, College Station, Texas).

      Results

      Figure 1 shows the flow chart for the study analysis. Of 1,322 potentially relevant reports initially screened, 14 met the inclusion criteria and were included in the meta-analysis,
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      with a total of 11,959 patients. Table 1 lists the main characteristics of the studies included. Of these, 4 included patients with acute coronary syndrome (ACS),
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      6 all comers,
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      and 4 patients with stable coronary artery disease
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      or low risk ACS.
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      Mean age of patients was 66 ± 3 years ranging from 61 to 71. All studies enrolled predominantly male patients (prevalence ranging from 59% to 83%). The prevalence of smokers and of patients with diabetes ranged from 11% to 56% and from 19% to 44%, respectively. HPR was measured by LTAADP in 7 studies,
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      by VerifyNow in 5,
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      and by multiple electrode aggregometry with ADP stimuli in 1 study.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      In 1 study,
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      HPR was measured by both LTAADP and VerifyNow. The mean prevalence of HPR was 30 ± 15% ranging from 6% to 67% and was greater in studies using the VerifyNow compared with those using the LTAADP (42 ± 13% vs 22 ± 10%, p = 0.006).
      Table 1Characteristics of studies included in the meta-analysis
      AuthorYear of PublicationDesignPatient ProfilePatientsLaboratory MethodSelected Cutoff for HPRHPR (%)Clopidogrel (LD/MD, mg)Aspirin (LD/MD, mg)Platelet Function Test TimingDuration of DAPT (Mo)Follow-Up (Mo)
      Geisler et al
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      2006Single centerSymptomatic CAD363LTA, ADP 20 μmol/LMax AGG >70% (a priori)6600/75; LD before PCI0/100; MD daily before enrollment>6 h after LD33
      Bliden et al
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      2007Single centerNonemergent PCI100LTA, ADP 5 μmol/LAGG >50% (a priori)220/75; MD ≥1 month0/≥81; MD ≥7 days before PCIBefore PCI in the cath lab612
      Gurbel et al
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      2008Single centerNonemergent PCI297LTA, ADP 5 μmol/L>46% (ROC curve defined)30600/75, 300/75, 0/75; LD on day of PCI0/81–325; MD ≥7 days before PCI plus 325 on the day of PCIAt dischargeNot specified24
      LTA, ADP 20 μmol/L>59% (ROC curve defined)34
      Migliorini et al
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      2009Single centerStable CAD/ACS LM PCI, DES215LTA, ADP 10 μmol/LAGG ≥70% (a priori)19600/75, LD at least 12 h before PCI325/325; LD ≥12 h before PCI12–18 h after LD126
      Sibbing et al
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      20092 Participating centersStable CAD/ACS DES1,608MEAHighest quintile >416 AU20600/75, LD before PCI500 IV/100 twice daily; LD after angiography and before PCI>2 h after LD encouragedNot specified1
      Geisler et al
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      2010Single centerStable CAD/ACS1,019LTA, ADP 20 μmol/LLate AGG >42.5 (border of upper tertile)32600/75, LD before PCI500 IV/100; LD before PCI>6 h after 600-mg LD, >24 h for those on long-term MD + plus 300-mg LD33
      Breet et al
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      2010Single centerStable CAD1,052VerifyNow≥236 PRU (ROC curve defined)39300/75 (LD ≥24 h), 600/75 (LD ≥4 h), 0/75 (MD for at least 5 days) before PCI0/80–100; MD ≥10 days before PCIBefore PCI in the cath lab1212
      1,049LTA, ADP 5 μmol/LMax AGG ≥42.9% (ROC curve defined)42
      606PlateletworksAGG ≥80.5% (ROC curve defined)43
      Campo et al
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      2010Multicenter RCT substudyStable CAD/UA468VerifyNowPlatelet inhibition <40% (a priori)39300/75 (LD ≥6 h), 600/75 (LD ≥2 h), 0/75 (MD for at least 7 days) before PCI0/≥80; MD ≥5 days before PCI>6 h after 300-mg LD; >2 h after 600-mg LD, >7 days of MD1212
      Parodi et al
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      2011Single centerACS1,772LTA, ADP 10 μmol/LMax AGG >70% (a priori)14600/75 or 600/150–300 in patients with HPR, LD before PCI325/325; LD before PCI12–18 h after LD624
      Park et al
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      2011Single centerStable CAD/NSTE-ACS DES, Asian population2,849VerifyNowPRU >235 (a priori)67600/75, 300/75 (LD ≥12 h), 0/75 (MD >5 days), before PCI200/100, 200/200; LD before PCI24–48 h after PCI1224
      Yu et al
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      2012Single centerStable CAD/NSTE-ACS STEMI >12 h186VerifyNowPRU ≥240 (a priori)41300/75; LD >6 h300/100; LD >6 h12–24 h after PCI1212
      Saia et al
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      2013MulticenterNSTE-ACS833VerifyNowPRU ≥208 (a priori)39600/75 (LD >2 h), 300/75 (LD >6 h) before PCINot reported30 Days after the procedure1212
      Liang et al
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      2013Single centerACS, DES, Chinese patients1,016LTA, ADP 20 μmol/LMax AGG >60.7% (ROC curve defined)28600/75, LD before PCI300/100; LD before PCI12 h after PCI1212
      Jin et al
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      20133 CentersSTEMI, DES181VerifyNowPRU ≥282 (ROC curve defined)30600/75, LD at admission300/100, LD after hospital admissionAt discharge1212
      AGG = aggregation; AU = arbitrary unit; CAD = coronary artery disease; cath lab = catheterization laboratory; DES = drug-eluting stent; LD = loading dose; LM = left main artery; Max = maximal; MD = maintenance dose; MEA = multiple electrode aggregometry; NSTE-ACS = non–ST elevation acute coronary syndrome; PRU = platelet reaction unit; RCT = randomized controlled trial; ROC = receiver operating characteristic; STEMI = ST elevation myocardial infarction; UA = unstable angina.
      In the 11,959 patients included, the rate of stroke was 0.9%. On pooled analysis, the risk of stroke was higher in patients with HPR compared with patients with no HPR (1.2% vs 0.7%, RR on fixed effect 1.84, 95% confidence interval 1.21 to 2.80). There was no heterogeneity among the studies (I2 = 0%, p = 0.5; Figure 2). One study
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      including 100 patients in which no strokes occurred was excluded from the main analyses.
      Figure thumbnail gr2
      Figure 2Risk of stroke in patients with HPR versus patients with no HPR. The square, line and diamonds are classical icons for study weight, confidence intervals and summary effect. CI = confidence interval; D+L = DerSimonian and Laird; I−V = inverse variance weighted.
      By reestimating the summary RR in the absence of each study, we found that no individual study significantly influenced the summary effect estimate; indeed, even after removing the study with the greatest effect estimate,
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      patients with HPR were still at increased risk of stroke (RR 1.66, 95% confidence interval 1.07 to 2.58).
      On further sensitivity analyses, clinical profile (p for interaction = 0.39), duration of follow-up (p for interaction = 0.87), and laboratory method for detection of HPR (p for interaction = 0.99) did not affect the relative increase in the risk of stroke in patients with HPR compared with patients with no HPR (Figure 3). There was no small-study effect according to Harbord's test (p = 0.49).
      Figure thumbnail gr3a
      Figure 3Sensitivity analysis. Studies are grouped by (A) clinical presentation, (B) duration of follow-up, and (C) laboratory methods to detect HPR to ADP (The only study using multiple electrode aggregometry with ADP stimuli is not included.). The square, line and diamonds are classical icons for study weight, confidence intervals and summary effect. CAD = coronary artery disease; CI = confidence interval; D+L = DerSimonian and Laird; I−V = inverse variance weighted.
      Figure thumbnail gr3bc
      Figure 3Sensitivity analysis. Studies are grouped by (A) clinical presentation, (B) duration of follow-up, and (C) laboratory methods to detect HPR to ADP (The only study using multiple electrode aggregometry with ADP stimuli is not included.). The square, line and diamonds are classical icons for study weight, confidence intervals and summary effect. CAD = coronary artery disease; CI = confidence interval; D+L = DerSimonian and Laird; I−V = inverse variance weighted.

      Discussion

      The main results of the present study, drawn from 14 prospective observational studies including 11,959 patients are as follows: (1) after PCI, patients with HPR are at increased risk of stroke compared with patients without and (2) although stroke rates were higher in patients with ACS and in those with longer follow-up, the relative increase in stroke was not affected by either clinical presentation or duration of follow-up.
      During the last decade, several longitudinal prospective studies
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Hochholzer W.
      • Trenk D.
      • Bestehorn H.P.
      • Fischer B.
      • Valina C.M.
      • Ferenc M.
      • Gick M.
      • Caputo A.
      • Buttner H.J.
      • Neumann F.J.
      Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Cuisset T.
      • Frere C.
      • Quilici J.
      • Gaborit B.
      • Castelli C.
      • Poyet R.
      • Bali L.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.
      • Marcucci R.
      • Gori A.M.
      • Paniccia R.
      • Giusti B.
      • Valente S.
      • Giglioli C.
      • Buonamici P.
      • Antoniucci D.
      • Abbate R.
      • Gensini G.F.
      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.
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Price M.J.
      • Berger P.B.
      • Teirstein P.S.
      • Tanguay J.F.
      • Angiolillo D.J.
      • Spriggs D.
      • Puri S.
      • Robbins M.
      • Garratt K.N.
      • Bertrand O.F.
      • Stillabower M.E.
      • Aragon J.R.
      • Kandzari D.E.
      • Stinis C.T.
      • Lee M.S.
      • Manoukian S.V.
      • Cannon C.P.
      • Schork N.J.
      • Topol E.J.
      Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.
      • Park K.W.
      • Jeon K.H.
      • Kang S.H.
      • Oh I.Y.
      • Cho H.J.
      • Lee H.Y.
      • Kang H.J.
      • Park S.K.
      • Koo B.K.
      • Oh B.H.
      • Park Y.B.
      • Kim H.S.
      Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study).
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      • Stone G.W.
      • Witzenbichler B.
      • Weisz G.
      • Rinaldi M.J.
      • Neumann F.J.
      • Metzger D.C.
      • Henry T.D.
      • Cox D.A.
      • Duffy P.L.
      • Mazzaferri E.
      • Gurbel P.A.
      • Xu K.
      • Parise H.
      • Kirtane A.J.
      • Brodie B.R.
      • Mehran R.
      • Stuckey T.D.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.
      and meta-analyses
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      have shown that patients with coronary artery disease undergoing PCI, and treated with aspirin and clopidogrel but disclosing an HPR status, are at increased risk of ischemic events, including cardiovascular death
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      and stent thrombosis.
      • Cuisset T.
      • Frere C.
      • Quilici J.
      • Gaborit B.
      • Castelli C.
      • Poyet R.
      • Bali L.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Stone G.W.
      • Witzenbichler B.
      • Weisz G.
      • Rinaldi M.J.
      • Neumann F.J.
      • Metzger D.C.
      • Henry T.D.
      • Cox D.A.
      • Duffy P.L.
      • Mazzaferri E.
      • Gurbel P.A.
      • Xu K.
      • Parise H.
      • Kirtane A.J.
      • Brodie B.R.
      • Mehran R.
      • Stuckey T.D.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.
      • Aradi D.
      • Komocsi A.
      • Vorobcsuk A.
      • Rideg O.
      • Tokes-Fuzesi M.
      • Magyarlaki T.
      • Horvath I.G.
      • Serebruany V.L.
      Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
      • Brar S.S.
      • ten Berg J.
      • Marcucci R.
      • Price M.J.
      • Valgimigli M.
      • Kim H.S.
      • Patti G.
      • Breet N.J.
      • DiSciascio G.
      • Cuisset T.
      • Dangas G.
      Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
      However, all studies to date were insufficiently powered to detect differences in stroke between patients with HPR and those without.
      The risk of stroke in patients undergoing PCI has been historically associated with procedural factors with an incidence during hospitalization of <0.4%.
      • Fuchs S.
      • Stabile E.
      • Kinnaird T.D.
      • Mintz G.S.
      • Gruberg L.
      • Canos D.A.
      • Pinnow E.E.
      • Kornowski R.
      • Suddath W.O.
      • Satler L.F.
      • Pichard A.D.
      • Kent K.M.
      • Weissman N.J.
      Stroke complicating percutaneous coronary interventions: incidence, predictors, and prognostic implications.
      • Aggarwal A.
      • Dai D.
      • Rumsfeld J.S.
      • Klein L.W.
      • Roe M.T.
      Incidence and predictors of stroke associated with percutaneous coronary intervention.
      However, recent data show that most events occur during follow-up,
      • Mack M.J.
      • Head S.J.
      • Holmes Jr., D.R.
      • Stahle E.
      • Feldman T.E.
      • Colombo A.
      • Morice M.C.
      • Unger F.
      • Erglis A.
      • Stoler R.
      • Dawkins K.D.
      • Serruys P.W.
      • Mohr F.W.
      • Kappetein A.P.
      Analysis of stroke occurring in the SYNTAX trial comparing coronary artery bypass surgery and percutaneous coronary intervention in the treatment of complex coronary artery disease.
      mainly related to risk factors such as diabetes, advanced age, left ventricular dysfunction, atrial fibrillation, ACS at presentation, or previous transient ischemic attack or stroke, probably because of a greater extent of cardiovascular disease, increased susceptibility to atherothrombosis, or thromboembolism.
      Our meta-analysis, which included 11,959 patients, shows that HPR may be considered as an adjunctive risk factor for stroke in patients with coronary artery disease undergoing PCI. The strength of this finding relies on the satisfaction of all requirements for meta-analysis in terms of low heterogeneity, no publication bias, and sensitivity analyses. Yet, it is noteworthy to mention that no events were referred as PCI complications.
      Mechanisms of stroke are heterogeneous, and the present study was not designed to elucidate the mechanisms linking HPR and the risk of stroke. However, our findings support the theory that platelet reactivity may play a crucial role in determining this risk. Indeed, recent meta-analyses
      • Gouya G.
      • Arrich J.
      • Wolzt M.
      • Huber K.
      • Verheugt F.W.
      • Gurbel P.A.
      • Pirker-Kees A.
      • Siller-Matula J.M.
      Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis.
      • Helton T.J.
      • Bavry A.A.
      • Kumbhani D.J.
      • Duggal S.
      • Roukoz H.
      • Bhatt D.L.
      Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials.
      including >70,000 subjects with different clinical presentation have shown that dual antiplatelet therapy with clopidogrel and aspirin significantly reduces the risk of stroke compared with aspirin alone.
      The results of the present study should be interpreted with caution given some limitations.
      This meta-analysis was based on aggregate data, and we were prevented from evaluating the role of possible confounders, because all studies lacked adjusted risk of stroke, probably because of the low incidence of stroke in patients undergoing PCI. This is particularly relevant, because HPR is associated with traditional risk factors for stroke such as age, diabetes mellitus, and left ventricular dysfunction
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      that could partly account for its prognostic significance. However, to date no studies are available describing the direct association between HPR and stroke. Further investigations should address whether this association is independent or mediated by other clinical factors. The type of stroke was not equally described in the 14 studies included. Most studies reported data on ischemic stroke,
      • Geisler T.
      • Langer H.
      • Wydymus M.
      • Gohring K.
      • Zurn C.
      • Bigalke B.
      • Stellos K.
      • May A.E.
      • Gawaz M.
      Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
      • Bliden K.P.
      • DiChiara J.
      • Tantry U.S.
      • Bassi A.K.
      • Chaganti S.K.
      • Gurbel P.A.
      Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
      • Gurbel P.A.
      • Antonino M.J.
      • Bliden K.P.
      • Dichiara J.
      • Suarez T.A.
      • Singla A.
      • Tantry U.S.
      Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
      • Sibbing D.
      • Braun S.
      • Morath T.
      • Mehilli J.
      • Vogt W.
      • Schomig A.
      • Kastrati A.
      • von Beckerath N.
      Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
      • Geisler T.
      • Zurn C.
      • Simonenko R.
      • Rapin M.
      • Kraibooj H.
      • Kilias A.
      • Bigalke B.
      • Stellos K.
      • Schwab M.
      • May A.E.
      • Herdeg C.
      • Gawaz M.
      Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ruven H.J.
      • Bal E.T.
      • Deneer V.H.
      • Harmsze A.M.
      • van der Heyden J.A.
      • Rensing B.J.
      • Suttorp M.J.
      • Hackeng C.M.
      • ten Berg J.M.
      Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      • Liang Z.Y.
      • Han Y.L.
      • Zhang X.L.
      • Li Y.
      • Yan C.H.
      • Kang J.
      The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
      • Jin H.Y.
      • Yang T.H.
      • Kim D.I.
      • Chung S.R.
      • Seo J.S.
      • Jang J.S.
      • Kim D.K.
      • Kim D.K.
      • Kim K.H.
      • Seol S.H.
      • Nam C.W.
      • Hur S.H.
      • Kim W.
      • Park J.S.
      • Kim Y.J.
      • Kim D.S.
      High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
      1 study on hemorrhagic stroke (n = 1),
      • Migliorini A.
      • Valenti R.
      • Marcucci R.
      • Parodi G.
      • Giuliani G.
      • Buonamici P.
      • Cerisano G.
      • Carrabba N.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.
      and in 4 studies
      • Campo G.
      • Fileti L.
      • de Cesare N.
      • Meliga E.
      • Furgieri A.
      • Russo F.
      • Colangelo S.
      • Brugaletta S.
      • Ferrari R.
      • Valgimigli M.
      Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
      • Park D.W.
      • Lee S.W.
      • Yun S.C.
      • Song H.G.
      • Ahn J.M.
      • Lee J.Y.
      • Kim W.J.
      • Kang S.J.
      • Kim Y.H.
      • Lee C.W.
      • Park S.W.
      • Park S.J.
      A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
      • Yu L.H.
      • Kim M.H.
      • Zhang H.Z.
      • Park J.S.
      • Park T.H.
      • Kim Y.D.
      • Cha K.S.
      • Han J.Y.
      Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
      • Saia F.
      • Marino M.
      • Campo G.
      • Valgimigli M.
      • Guastaroba P.
      • Taglieri N.
      • Tondi S.
      • Manari A.
      • Guiducci V.
      • Sangiorgio P.
      • Varani E.
      • Magnavacchi P.
      • De Palma R.
      • Marzocchi A.
      Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
      the type of stroke was not specified. For this reason, we were prevented from distinguishing the effect of HPR on both ischemic and hemorrhagic stroke; indeed, our results should refer to the risk of stroke as a whole. However, it is plausible to believe that the effect of HPR on the risk of ischemic stroke was not outfitted by the risk of hemorrhagic stroke that theoretically may be associated with low on-treatment platelet reactivity.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Levine G.N.
        • Bates E.R.
        • Blankenship J.C.
        • Bailey S.R.
        • Bittl J.A.
        • Cercek B.
        • Chambers C.E.
        • Ellis S.G.
        • Guyton R.A.
        • Hollenberg S.M.
        • Khot U.N.
        • Lange R.A.
        • Mauri L.
        • Mehran R.
        • Moussa I.D.
        • Mukherjee D.
        • Nallamothu B.K.
        • Ting H.H.
        2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
        J Am Coll Cardiol. 2011; 58: e44-e122
        • Sibbing D.
        • Byrne R.A.
        • Bernlochner I.
        • Kastrati A.
        High platelet reactivity and clinical outcome—fact and fiction.
        Thromb Haemost. 2011; 106: 191-202
        • Geisler T.
        • Langer H.
        • Wydymus M.
        • Gohring K.
        • Zurn C.
        • Bigalke B.
        • Stellos K.
        • May A.E.
        • Gawaz M.
        Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.
        Eur Heart J. 2006; 27: 2420-2425
        • Hochholzer W.
        • Trenk D.
        • Bestehorn H.P.
        • Fischer B.
        • Valina C.M.
        • Ferenc M.
        • Gick M.
        • Caputo A.
        • Buttner H.J.
        • Neumann F.J.
        Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.
        J Am Coll Cardiol. 2006; 48: 1742-1750
        • Bliden K.P.
        • DiChiara J.
        • Tantry U.S.
        • Bassi A.K.
        • Chaganti S.K.
        • Gurbel P.A.
        Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
        J Am Coll Cardiol. 2007; 49: 657-666
        • Gurbel P.A.
        • Antonino M.J.
        • Bliden K.P.
        • Dichiara J.
        • Suarez T.A.
        • Singla A.
        • Tantry U.S.
        Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
        Platelets. 2008; 19: 595-604
        • Cuisset T.
        • Frere C.
        • Quilici J.
        • Gaborit B.
        • Castelli C.
        • Poyet R.
        • Bali L.
        • Morange P.E.
        • Alessi M.C.
        • Bonnet J.L.
        Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.
        Am J Cardiol. 2009; 104: 1078-1082
        • Marcucci R.
        • Gori A.M.
        • Paniccia R.
        • Giusti B.
        • Valente S.
        • Giglioli C.
        • Buonamici P.
        • Antoniucci D.
        • Abbate R.
        • Gensini G.F.
        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: 237-242
        • Migliorini A.
        • Valenti R.
        • Marcucci R.
        • Parodi G.
        • Giuliani G.
        • Buonamici P.
        • Cerisano G.
        • Carrabba N.
        • Gensini G.F.
        • Abbate R.
        • Antoniucci D.
        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: 2214-2221
        • Sibbing D.
        • Braun S.
        • Morath T.
        • Mehilli J.
        • Vogt W.
        • Schomig A.
        • Kastrati A.
        • von Beckerath N.
        Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.
        J Am Coll Cardiol. 2009; 53: 849-856
        • Geisler T.
        • Zurn C.
        • Simonenko R.
        • Rapin M.
        • Kraibooj H.
        • Kilias A.
        • Bigalke B.
        • Stellos K.
        • Schwab M.
        • May A.E.
        • Herdeg C.
        • Gawaz M.
        Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions.
        Eur Heart J. 2010; 31: 59-66
        • Breet N.J.
        • van Werkum J.W.
        • Bouman H.J.
        • Kelder J.C.
        • Ruven H.J.
        • Bal E.T.
        • Deneer V.H.
        • Harmsze A.M.
        • van der Heyden J.A.
        • Rensing B.J.
        • Suttorp M.J.
        • Hackeng C.M.
        • ten Berg J.M.
        Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.
        JAMA. 2010; 303: 754-762
        • Campo G.
        • Fileti L.
        • de Cesare N.
        • Meliga E.
        • Furgieri A.
        • Russo F.
        • Colangelo S.
        • Brugaletta S.
        • Ferrari R.
        • Valgimigli M.
        Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.
        J Am Coll Cardiol. 2010; 56: 1447-1455
        • Parodi G.
        • Marcucci R.
        • Valenti R.
        • Gori A.M.
        • Migliorini A.
        • Giusti B.
        • Buonamici P.
        • Gensini G.F.
        • Abbate R.
        • Antoniucci D.
        High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
        JAMA. 2011; 306: 1215-1223
        • Price M.J.
        • Berger P.B.
        • Teirstein P.S.
        • Tanguay J.F.
        • Angiolillo D.J.
        • Spriggs D.
        • Puri S.
        • Robbins M.
        • Garratt K.N.
        • Bertrand O.F.
        • Stillabower M.E.
        • Aragon J.R.
        • Kandzari D.E.
        • Stinis C.T.
        • Lee M.S.
        • Manoukian S.V.
        • Cannon C.P.
        • Schork N.J.
        • Topol E.J.
        Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.
        JAMA. 2011; 305: 1097-1105
        • Park K.W.
        • Jeon K.H.
        • Kang S.H.
        • Oh I.Y.
        • Cho H.J.
        • Lee H.Y.
        • Kang H.J.
        • Park S.K.
        • Koo B.K.
        • Oh B.H.
        • Park Y.B.
        • Kim H.S.
        Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study).
        Am J Cardiol. 2011; 108: 1556-1563
        • Park D.W.
        • Lee S.W.
        • Yun S.C.
        • Song H.G.
        • Ahn J.M.
        • Lee J.Y.
        • Kim W.J.
        • Kang S.J.
        • Kim Y.H.
        • Lee C.W.
        • Park S.W.
        • Park S.J.
        A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation.
        J Am Coll Cardiol. 2011; 58: 2630-2639
        • Yu L.H.
        • Kim M.H.
        • Zhang H.Z.
        • Park J.S.
        • Park T.H.
        • Kim Y.D.
        • Cha K.S.
        • Han J.Y.
        Impact of platelet function test on platelet responsiveness and clinical outcome after coronary stent implantation: platelet responsiveness and clinical outcome.
        Korean Circ J. 2012; 42: 382-389
        • Saia F.
        • Marino M.
        • Campo G.
        • Valgimigli M.
        • Guastaroba P.
        • Taglieri N.
        • Tondi S.
        • Manari A.
        • Guiducci V.
        • Sangiorgio P.
        • Varani E.
        • Magnavacchi P.
        • De Palma R.
        • Marzocchi A.
        Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study).
        Am J Cardiol. 2013; 112: 792-798
        • Liang Z.Y.
        • Han Y.L.
        • Zhang X.L.
        • Li Y.
        • Yan C.H.
        • Kang J.
        The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up: outcomes in patients with acute coronary syndrome after drug-eluting stent implantation.
        EuroIntervention. 2013; 9: 316-327
        • Jin H.Y.
        • Yang T.H.
        • Kim D.I.
        • Chung S.R.
        • Seo J.S.
        • Jang J.S.
        • Kim D.K.
        • Kim D.K.
        • Kim K.H.
        • Seol S.H.
        • Nam C.W.
        • Hur S.H.
        • Kim W.
        • Park J.S.
        • Kim Y.J.
        • Kim D.S.
        High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting.
        Int J Cardiol. 2013; 167: 1877-1881
        • Stone G.W.
        • Witzenbichler B.
        • Weisz G.
        • Rinaldi M.J.
        • Neumann F.J.
        • Metzger D.C.
        • Henry T.D.
        • Cox D.A.
        • Duffy P.L.
        • Mazzaferri E.
        • Gurbel P.A.
        • Xu K.
        • Parise H.
        • Kirtane A.J.
        • Brodie B.R.
        • Mehran R.
        • Stuckey T.D.
        Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.
        Lancet. 2013; 382: 614-623
        • Aradi D.
        • Komocsi A.
        • Vorobcsuk A.
        • Rideg O.
        • Tokes-Fuzesi M.
        • Magyarlaki T.
        • Horvath I.G.
        • Serebruany V.L.
        Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.
        Am Heart J. 2010; 160: 543-551
        • Brar S.S.
        • ten Berg J.
        • Marcucci R.
        • Price M.J.
        • Valgimigli M.
        • Kim H.S.
        • Patti G.
        • Breet N.J.
        • DiSciascio G.
        • Cuisset T.
        • Dangas G.
        Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
        J Am Coll Cardiol. 2011; 58: 1945-1954
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • Olkin I.
        • Williamson G.D.
        • Rennie D.
        • Moher D.
        • Becker B.J.
        • Sipe T.A.
        • Thacker S.B.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
        JAMA. 2000; 283: 2008-2012
        • Fuchs S.
        • Stabile E.
        • Kinnaird T.D.
        • Mintz G.S.
        • Gruberg L.
        • Canos D.A.
        • Pinnow E.E.
        • Kornowski R.
        • Suddath W.O.
        • Satler L.F.
        • Pichard A.D.
        • Kent K.M.
        • Weissman N.J.
        Stroke complicating percutaneous coronary interventions: incidence, predictors, and prognostic implications.
        Circulation. 2002; 106: 86-91
        • Aggarwal A.
        • Dai D.
        • Rumsfeld J.S.
        • Klein L.W.
        • Roe M.T.
        Incidence and predictors of stroke associated with percutaneous coronary intervention.
        Am J Cardiol. 2009; 104: 349-353
        • Mack M.J.
        • Head S.J.
        • Holmes Jr., D.R.
        • Stahle E.
        • Feldman T.E.
        • Colombo A.
        • Morice M.C.
        • Unger F.
        • Erglis A.
        • Stoler R.
        • Dawkins K.D.
        • Serruys P.W.
        • Mohr F.W.
        • Kappetein A.P.
        Analysis of stroke occurring in the SYNTAX trial comparing coronary artery bypass surgery and percutaneous coronary intervention in the treatment of complex coronary artery disease.
        JACC Cardiovasc Interv. 2013; 6: 344-354
        • Gouya G.
        • Arrich J.
        • Wolzt M.
        • Huber K.
        • Verheugt F.W.
        • Gurbel P.A.
        • Pirker-Kees A.
        • Siller-Matula J.M.
        Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis.
        Stroke. 2014; 45: 492-503
        • Helton T.J.
        • Bavry A.A.
        • Kumbhani D.J.
        • Duggal S.
        • Roukoz H.
        • Bhatt D.L.
        Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials.
        Am J Cardiovasc Drugs. 2007; 7: 289-297