Therapy for Reduction of Myocardial Damage During Angioplasty. Bleeding Study)

Transcription

1 Usefulness of Platelet Response to Clopidogrel by Point-of-Care Testing to Predict Bleeding Outcomes in Patients Undergoing Percutaneous Coronary Intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty- Bleeding Study) Giuseppe Patti, MD a, Vincenzo Pasceri, MD b, Vincenzo Vizzi, MD a, Elisabetta Ricottini, MD a, and Germano Di Sciascio, MD a, * Platelet reactivity predicts ischemic outcomes in patients who undergo percutaneous coronary intervention (PCI), but the correlation of heightened platelet response with bleeding has not been characterized. The aim of this study was to evaluate whether low platelet reactivity by point-of-care measurement after clopidogrel administration correlates with bleeding complications of PCI. A total of 310 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured with the VerifyNow P2Y12 assay. The primary end point was the 30-day incidence of major bleeding or entry-site complications according to quartile distribution of P2Y12 reaction units (PRU). The primary end point occurred more frequently in patients with preprocedural PRU levels in the lowest quartile compared to those in the highest quartile (10.1% vs 1.3%, p 0.043), due mainly to entry-site hemorrhages. Absolute PRU levels were lower in patients with major bleeding ( vs in patients without, p 0.002). On multivariate analysis, pre-pci PRU levels in the first quartile were associated with a 4.5-fold increased risk for major bleeding (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p 0.01). By receiver-operating characteristic curve analysis, the optimal cutoff for the primary end point was a pre-pci PRU value <189 (area under the curve 0.76, 95% confidence interval 0.66 to 0.87, p 0.001). In conclusion, this study suggests that an enhanced response to clopidogrel may be associated with higher risk for early major bleeding or entry-site complications in patients who undergo PCI. Point-of-care monitoring of platelet reactivity after clopidogrel administration may help identify patients in whom individualized strategies are indicated to limit bleeding complications after coronary intervention Elsevier Inc. All rights reserved. (Am J Cardiol 2011;xx:xxx) Methods ARMYDA-BLEEDS is a prospective study of 310 consecutive clopidogrel-treated patients who underwent PCI at Campus Bio-Medico University of Rome from April 1 to December 31, This population represents 69% of patients (310 of 449) who underwent PCI at our institution during the enrollment period. Inclusion criteria were (1) indication for percutaneous coronary revascularization for angina with inducible myocardial ischemia or non ST-segment elevation acute coronary syndromes (ACS) and (2) clopidogrel therapy initiated before PCI, as a 600-mg load 7 given 6 hours before intervention (n 104) or long-term clopidogrel therapy 75 mg/day for 5 days (n 206). Exclusion criteria were indication for long-term therapy with vitamin K antagonists, intervention for ST-segment elevation acute myocardial infarction 24 hours (representing most patients excluded from the study from the whole cohort of PCI patients during the enrollment period), platea Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome; and b Interventional Cardiology Unit, San Filippo Neri Hospital, Rome, Italy. Manuscript received September 19, 2010; revised manuscript received and accepted November 16, *Corresponding author: Tel: ; fax: address: g.disciascio@unicampus.it (G. Di Sciascio); g.patti@ unicampus.it (G. Patti). Significant interindividual variability in clopidogrel response has been demonstrated, 1,2 and various investigations correlated low clopidogrel responsiveness with enhanced risk for early and late adverse cardiac events in the setting of percutaneous coronary intervention (PCI). 3 5 Conversely, there is a gap of knowledge on the possible relation between higher clopidogrel responsiveness and increased bleeding risk. Because periprocedural bleeding complications strongly impair prognosis after PCI, 6 assays measuring residual platelet reactivity after clopidogrel administration might help rapidly stratify patients according to their bleeding risk. The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA) study group 3,7 11 has designed the ARMYDA Bleeding Study (ARMYDA-BLEEDS) to prospectively evaluate levels of platelet reactivity by a pointof-care assay that may correlate with bleeding complications in patients who undergo coronary stent implantation /11/$ see front matter 2011 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 2 The American Journal of Cardiology ( Table 1 Main clinical and procedural features Characteristic First Quartile Second Quartile Third Quartile Fourth Quartile p Value (n 77) (n 77) (n 77) (n 79) Age (years) Women 16 (21%) 12 (16%) 19 (25%) 20 (25%) 0.59 Diabetes mellitus 30 (39%) 26 (34%) 25 (32%) 34 (43%) 0.68 Hypercholesterolemia ( 200 mg/dl) 55 (71%) 51 (66%) 52 (68%) 62 (79%) 0.44 Body mass index (kg/m 2 ) Previous myocardial infarction 20 (26%) 26 (34%) 24 (31%) 21 (27%) 0.92 Previous transient ischemic attack/stroke 2 (3%) 2 (3%) 4 (5%) 2 (3%) 1 Previous PCI 34 (44%) 33 (43%) 25 (32%) 31 (39%) 0.61 Previous major bleeding 2 (3%) 1 (1%) 2 (3%) 0.73 Clinical presentation Unstable angina/non ST-segment elevation myocardial infarction 19 (25%) 26 (34%) 29 (38%) 26 (33%) 0.50 Stable angina 58 (75%) 51 (66%) 48 (62%) 53 (67%) 0.50 Left ventricular ejection fraction (%) Serum creatinine (mg/dl) Hemoglobin (g/l) Vessel treated Left anterior descending coronary artery 41 (47%) 47 (51%) 44 (50%) 45 (45%) 1 Left circumflex coronary artery 18 (20%) 25 (27%) 21 (24%) 25 (25%) 1 Right coronary artery 28 (32%) 20 (22%) 23 (26%) 29 (29%) 0.64 Left main coronary artery 1 (1%) 1 (1%) 0.80 Lesion type B2/C 48 (62%) 56 (73%) 50 (65%) 55 (70%) 0.70 Multivessel intervention 14 (18%) 15 (19%) 14 (18%) 15 (19%) 1 Use of drug-eluting stents 19 (25%) 23 (30%) 29 (38%) 24 (30%) 0.51 Statin therapy 64 (83%) 72 (94%) 70 (91%) 74 (94%) 0.12 Sheath size 6Fr 72 (94) 72 (94) 71 (92) 73 (92) 1 7Fr 5 (6) 5 (6) 6 (8) 6 (8) 1 Antithrombotic therapy Unfractionated heparin 64 (83%) 68 (88%) 66 (86%) 74 (94%) 0.29 Bivalirudin 13 (17%) 9 (12%) 11 (14%) 5 (6%) 0.29 Glycoprotein IIb/IIIa inhibitors 9 (12%) 8 (10%) 11 (14%) 6 (8%) 0.83 Data are expressed as mean SD or as number (percentage). let count /L, coronary bypass surgery in the previous 3 months, and severe chronic renal failure with baseline serum creatinine 2 mg/dl. All interventions were performed using the femoral approach, with weight-adjusted intravenous unfractionated heparin (70 IU/kg body weight). During PCI, bivalirudin was used instead of unfractionated heparin in patients considered at high bleeding risk (age 75 years, history of previous bleeding, renal failure, low body weight); periprocedural use of glycoprotein IIb/IIIa inhibitors was left to the operator s discretion according to the presence of thrombus at the site of the index stenosis, occurrence of no-reflow, or vessel closure. The sheath size was 6Fr (7Fr in case of bifurcating lesions). The arterial sheath was removed when the activated clotting time was 180 seconds. The femoral arteries were closed by manual compression in all cases; manual compression was performed until the achievement of full hemostasis plus an additional 5 minutes. By protocol, patients receiving long-term clopidogrel therapy were not reloaded in the catheterization laboratory. Clopidogrel was continued (75 mg/day) for 1 month after PCI, except in patients receiving drug-eluting stents or treated for ACS, in whom the drug was discontinued 1 year after intervention. Aspirin was given to all patients and continued indefinitely. Platelet reactivity was evaluated in the catheterization laboratory immediately before PCI and at 8 and 24 hours after intervention using the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California), a rapid cartridgebased assay specifically measuring the direct effects of clopidogrel on the platelet P2Y12 receptor. Technical details have been described elsewhere. 12 Results are expressed as P2Y12 reaction units (PRU), which inversely correlate with the degree of P2Y12 receptor inhibition by clopidogrel. Twenty-five randomly selected patients were analyzed to assess intra-assay variability, which was % (coefficient of variation 6%). Blood samples were also drawn before and at 8 and 24 hours in all patients to measure hemoglobin levels; further hemoglobin determinations were performed if clinically indicated. Patients were clinically evaluated after PCI for the detection of bleeding events and entry-site complications (hematoma, pseudoaneurysm, or arteriovenous fistula). One-month clinical follow-up was then obtained by office visit in all patients. Each patient gave informed consent to the study. The primary end point of ARMYDA-BLEEDS was the 30-day incidence of major bleeding or significant entry-site complications in relation to periprocedural quartile distribution of platelet reactivity measured by PRU assay. Major

3 Coronary Artery Disease/High Clopidogrel Response Predicts PCI Bleeding 3 Figure 2. Periprocedural PRU values in patients with or without major bleeding complications. Figure 1. Incidence of the primary end point (major bleeding or entry-site complications at 30 days) according to quartile distribution of preintervention PRU values. bleeding was defined according to the Thrombolysis In Myocardial Infarction criteria. 13 Significant entry-site complications were defined as hematoma 10 cm in diameter, pseudoaneurysm, or arteriovenous fistula. Secondary end points were (1) evaluation of absolute PRU values in patients with or without major bleeding and (2) correlation of PRU values with minor bleeding 13 or post-pci hematoma 10 cm in diameter. Continuous variables were compared using Student s t tests for normally distributed values; otherwise, Mann- Whitney U tests were used. Proportions were compared using Fisher s exact test when the expected frequency was 5; otherwise, chi-square tests were applied. Odds ratios and 95% confidence intervals investigating the independent predictive role of PRU quartiles on the occurrence of the primary end point were assessed by logistic regression. The following parameters were first evaluated in a univariate model: PRU quartile, age, gender, body mass index, diabetes mellitus, clinical presentation (stable angina vs ACS), chronic renal failure, hemoglobin levels, previous transient ischemic attack or stroke, previous major bleeding, use of bivalirudin versus unfractionated heparin, and use of glycoprotein IIb/IIIa inhibitors. Variables with p values 0.15 were then entered into the final model of multivariate logistic regression analysis. The ability of the assay to discriminate between patients with and without major bleeding at 30 days was evaluated using receiver-operating characteristic curve analysis. The optimal cut-off value was calculated by determining the PRU value providing the greatest sum of sensitivity and specificity. Results are expressed as mean SD. Two-tailed p values 0.05 were considered significant. Analysis was performed using SPSS version 12.0 (SPSS, Inc., Chicago, Illinois). Results Clinical and procedural characteristics according to preintervention PRU quartiles are listed in Table 1. Procedural success was achieved in 98% of patients, without need for repeat PCI or coronary artery bypass grafting at 30 days. The overall incidence of major bleeding or entry-site complications was 4.8% (15 of 310 patients): 3 patients had gastrointestinal bleeding, 2 had bladder or urethral bleeding, and the remaining had entry-site hematomas 10 cm. Patients in the lowest PRU quartile before PCI had a higher incidence of major bleeding at 1 month (10.1%) compared to those in the highest quartile (1.3%, p 0.043) and the third quartile (1.4%, p 0.05) (Figure 1). Absolute PRU values before PCI were lower in patients with compared to those without major bleeding at 30 days ( vs , p 0.002). Periprocedural PRU values in patients with or without major bleeding are reported in Figure 2; PRU increased at 8 hours after PCI and decreased over 24 hours. Multivariate analysis identified pre-pci PRU level in the lowest quartile as an independent predictor of increased major bleeding risk at 30 days (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p 0.01; Figure 3). Age 70 years and periprocedural use of glycoprotein IIb/IIIa inhibitors were also associated with a significantly higher risk for major bleeding. On multivariate analysis, there was a trend toward increased major bleeding in patients with body mass indexes 22 kg/m 2. Moreover, PRU values in patients in the lowest body mass index quartile tended to be lower than those of patients in the highest quartile ( vs , p 0.09). Receiver-operating characteristic curve analysis showed that PRU levels significantly discriminated between patients with and without 30-day major bleeding, with an area under the curve of 0.76 (95% confidence interval 0.66 to 0.87, p 0.001). A PRU value 189 was identified as the optimal cut-off point to predict 30-day bleeding outcome, with sensitivity of 87% and specificity of 70%. The incidence of major bleeding at 1 month was 11.6% in patients with pre-pci PRU values 189 and 1.9% in those with PRU values 189 (p 0.001). The occurrence of 30-day minor bleeding was significantly higher in patients with pre-pci PRU values 189 (13.7%) compared to those with PRU values 189 (5.1%) (p 0.001). No relation was found between bleeding com-

4 4 The American Journal of Cardiology ( Figure 3. Results of multivariate analysis showing that patients with preintervention PRU levels in the lowest quartile had a significantly higher risk for 30-day major bleeding or entry-site complications (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p 0.01). BMI body mass index. plications and PRU levels measured at 8 and 24 hours after intervention (p 0.39), probably because entry-site bleeding complications occurred earlier, while in the hours after PCI, there was an increase of platelet reactivity due to the procedure in the groups of patients with and without major bleeding. Discussion This prospective study indicates that low residual platelet reactivity after clopidogrel, as measured by a point-of-care assay at the time of intervention, is associated with a significantly higher incidence of 30-day major bleeding or entry-site complications after PCI. Residual platelet reactivity after clopidogrel administration in an index population follows a Gaussian distribution, 14 reflecting the interindividual variability of drug response 15,16 ; of note, CYP2C19*17 carrier status 17 and some drugs 18 may promote the cytochrome activity and accelerate the rate of clopidogrel activation in the liver, thus causing an enhanced degree of platelet inhibition in response to the drug and a possible increase in bleeding risk. Various studies have focused on PCI patients with low response to clopidogrel, demonstrating a significantly higher incidence of periprocedural myocardial infarction 3 and adverse cardiac events during follow-up. 19,20 Accordingly, more aggressive antiplatelet strategies in patients with ACS, particularly those who undergo PCI, increase the degree of platelet inhibition and significantly reduce ischemic events, but at the price of higher bleeding complications (aspirin plus clopidogrel vs aspirin alone, prasugrel vs clopidogrel, ticagrelor vs clopidogrel) The prognostic role of bleeding is now largely recognized in interventional cardiology; in particular, a fourfold increase in the risk for death at 30 days was observed in patients with ACS with major bleeding 24,25 and threefold higher mortality at 1 year in patients with early bleeding complications after PCI. 6 Although ARMYDA Platelet Reactivity Predicts Outcome (ARMYDA-PRO) 3 and other studies 19,20,26 have established an efficacy threshold of platelet inhibition (i.e., 240 PRU by the VerifyNow assay), the optimal safety threshold for bleeding complications has not been identified. In our study, the relation between low PRU values and bleeding complications in the multiple logistic regression model was independent of various predictors of bleeding (i.e., older age, presentation with ACS, low body mass index, renal failure, previous bleeding events, and concomitant antithrombotic therapies). In particular, a pre-pci PRU value in the lowest quartile was associated with a 4.5-fold increased risk for postintervention major bleeding or entry-site complications compared to the highest quartile. More pronounced platelet inhibition was also associated with higher incidence of minor bleeding at 30 days. In a prospective study, 27 the in-hospital incidence of major bleeding was 3.5-fold higher in PCI patients with enhanced clopidogrel responsiveness (defined as 188 aggregation units) measured before the procedure by the multiple electrode aggregometry. In contrast, in a recent investigation on patients who underwent elective PCI, 28 several platelet function tests failed to predict postdischarge bleeding events up to 1 year. Receiver-operating characteristic analysis in our study indicated that the VerifyNow assay can predict periprocedural bleeding outcomes, with an optimal cut-off point to discriminate patients at higher risk for 30-day major bleeding of 189 PRU and sensitivity of 87%. Thus, ARMYDA- BLEEDS confirms the usefulness of a rapid point-of-care assay for monitoring residual platelet reactivity after clopidogrel administration, to identify a clinically driven threshold of platelet reactivity defining patients at increased risk for bleeding complications, in whom individualized therapeutic strategies (i.e., limited use of glycoprotein IIb/IIIa inhibitors, more extensive utilization of bivalirudin, restricted use of drug-eluting stents, and more liberal use of gastroprotective agents) may be indicated. In our study, most bleeding events were large entry-site hematomas; thus, a radial approach, which has been associated with a lower incidence of vascular complications, 29 might be also indicated in patients with higher degrees of platelet inhibition in

5 Coronary Artery Disease/High Clopidogrel Response Predicts PCI Bleeding 5 Figure 4. Incidence of major adverse cardiac events in the ARMYDA-PRO study and of major bleeding or entry-site complications in ARMYDA- BLEEDS according to preintervention PRU values. The flat portion of the curves may represent the therapeutic window for clopidogrel therapy. response to clopidogrel. ARMYDA-BLEEDS, by defining the lower threshold for bleeding in clopidogrel-treated patients (189 PRU) represents the pendant of the ARMYDA-PRO study, 3 in which a cut-off point of PRU 240 was identified as a threshold associated with increased risk for major ischemic cardiac events at 30 days (odds ratio 6.1); therefore, the therapeutic range of 190 to 239 PRU could be the most favorable in the clinical setting. On the basis of the results of ARMYDA-BLEEDS and the previous ARMYDA-PRO study, the incidence of ischemic and bleeding events according to PRU values follows a curvilinear distribution (Figure 4) in which, below a certain safety threshold of PRU, ischemic events are not further reduced, to the expense of increased bleeding, and above an efficacy threshold, bleeding is not reduced, but ischemic events may be significantly increased. This curvilinear distribution was also described in a recent research correspondence by Sibbing et al 30 in a population of 2,533 patients in whom multiple electrode aggregometry was used to evaluate platelet aggregation: the incidence of bleeding was highest in enhanced responders, and the incidence of stent thrombosis was highest in low responders; a threshold phenomenon was observed, and a therapeutic window of P2Y12 receptor inhibition was identified with that technique. We believe that ARMYDA-BLEEDS may represent a further contribution to the quest for the optimal therapeutic window in platelet inhibition after clopidogrel, in which the risk for both bleeding and ischemic events would be low; accordingly, modulated antithrombotic therapies should be applied in patients in relation to indexes of platelet reactivity, to prevent bleeding as well as thrombosis. 1. Gurbel PA, Bliden KP, Hiatt BL, O Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107: Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45: Patti G, Nusca A, Mangiacapra F, Gatto L, D Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention. Results of the ARMYDA-PRO (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008;52: Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Büttner HJ, Neumann FJ. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. JAm Coll Cardiol 2006;48: Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. 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: Ndrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ, Schömig A, Kastrati A. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51: Patti G, Colonna G, Pasceri V, Lassandro Pepe L, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) study. Circulation 2005;111: Patti G, Chello M, Pasceri V, Colonna D, Nusca A, Miglionico M, D Ambrosio A, Covino E, Di Sciascio G. Protection from procedural myocardial injury by atorvastatin is associated with lower levels of adhesion molecules after percutaneous coronary intervention: results from the ARMYDA-CAMs substudy. J Am Coll Cardiol 2006;48: Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, Montinaro A, Di Sciascio G. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007;49: Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 2009;54: Di Sciascio G, Patti G, Pasceri V, Colonna G, Mangiacapra F, Montinaro A. Clopidogrel reloading in patients undergoing percutaneous coronary intervention on chronic clopidogrel therapy. Results of the ARMYDA-4 RELOAD (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) randomized trial. Eur Heart J 2010;31: Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol 2006;28: Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR, Knatterud G, Robertson TL, Terrin ML. Thrombolysis In Myocardial Infarction (TIMI) Trial Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11: Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study. J Am Coll Cardiol 2005;46: Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003;107: Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Cavallari U, Trabetti E, Sabaté M, Hernández R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Contri-

6 6 The American Journal of Cardiology ( bution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006;26: Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010;121: Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004;109: Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-ofcare assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29: Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF. 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: Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345: Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON- TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357: Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP. Bleeding and blood transfusion issues in patients with non-st-segment elevation acute coronary syndromes. Eur Heart J 2007;28: Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114: Mangiacapra F, Barbato E, Patti G, Gatto L, Vizzi V, Ricottini E, D Ambrosio A, Wijns W, Di Sciascio G. Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010;3: Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Schömig A, von Beckerath N, Kastrati A. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010;8: Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, Deneer VH, Harmsze AM, van der Heyden JA, Rensing BJ, Suttorp MJ, Hackeng CM, ten Berg JM. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303: Agostoni P, Biondi-Zoccai GG, de Benedictis ML, Rigattieri S, Turri M, Anselmi M, Vassanelli C, Zardini P, Louvard Y, Hamon M. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44: Sibbing D, Steinhubl SR, Schulz S, Schomig A, Kastrati A. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol 2010;56: