title: Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. Paraoxonase-1 is a major determinant of clopidogrel efficacy Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study Increased risk of minor bleeding and antiplatelet therapy cessation in patients with acute coronary syndromes and low on-aspirin platelet reactivity. A prospective cohort study Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI  Prasugrel versus clopidogrel in patients with acute coronary syndromes. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. Simple risk algorithm to predict serious bleeding in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: RISK-PCI bleeding score. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding Academic Research Consortium Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. 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).
abstract: Recent guidelines have recommended the use of aspirin and prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention . However , prasugrel use has been evaluated only in r and omized trials . This study sought to evaluate bleeding rates and adherence to treatment in " real-world " patients treated with prasugrel .  In total 298 consecutive patients 68 ± 10 years old ( 31 % > 75 years old ) underwent stent implantation and received prasugrel therapy .  Indications to prasugrel therapy were ( 1 ) ST-elevation acute myocardial infa rct ion ( 41 % ) , ( 2 ) drug-eluting stent implantation in diabetics ( 24 % ) , ( 3 ) stent thrombosis ( 3 % ) , ( 4 ) left main coronary artery drug-eluting stent implantation ( 6 % ) , and ( 5 ) percutaneous coronary intervention in patients with high residual platelet reactivity on clopidogrel therapy ( 26 % ) . All patients received a loading of prasugrel 60 mg . Patients ≥75 years old and with body weight ≤60 kg received a maintenance dose of 5 mg/day ( 10 mg/day for all the other patients ) . Follow-up data including adherence to prasugrel therapy were collected by telephone interviews or outpatient visits . Minimal follow-up length was 6 months ( mean 9 ± 3 ) . Major , minor , and minimal bleedings ( Thrombolysis In Myocardial Infa rct ion criteria ) occurred in 2.7 % , 4.7 % , and 15.1 % of enrolled patients . Low residual platelet reactivity ( p = 0.001 ) and female gender ( p = 0.29 ) were independent predictors of bleeding events . The most frequent minimal bleeding event was epistaxis . Only 8 patients ( 2.7 % ) permanently discontinued prasugrel therapy because of bleeding events ( n = 4 ) , possible side effects ( n = 2 ) , or medical decisions not associated with bleeding or side effects ( n = 2 ) . Fourteen patients ( 4.7 % ) temporarily discontinued prasugrel ( average 6.5 days ) mainly because of surgical procedures . No definite or probable stent thrombosis occurred , although 3 patients develop de novo myocardial infa rct ion and 1 an ischemic stroke . There were 11 deaths because of heart failure or refractory cardiogenic shock in 9 , pulmonary embolism in 1 , and cancer in 1 . In conclusion , in clinical practice , major and minor bleeding event rates associated with prasugrel therapy are comparable to those reported in controlled r and omized trials . The minimal bleeding event rate is higher than reported but does not seem to affect adherence to treatment BACKGROUND It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite . METHODS We genotyped patients from two large , r and omized trials that showed that clopidogrel , as compared with placebo , reduced the rate of cardiovascular events ( the primary efficacy outcome ) among patients with acute coronary syndromes and among patients with atrial fibrillation . Patients were genotyped for three single-nucleotide polymorphisms ( * 2 , * 3 , * 17 ) that define the major CYP2C19 alleles . RESULTS Among 5059 genotyped patients with acute coronary syndromes , clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome , irrespective of the genetically determined metabolizer phenotype ( P=0.12 for heterogeneity ) . The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles ( rate among carriers , 8.0 % with clopidogrel vs. 11.6 % with placebo ; hazard ratio with clopidogrel , 0.69 ; 95 % confidence interval [ CI ] , 0.49 to 0.98 ; rate among noncarriers , 9.5 % vs. 13.0 % ; hazard ratio , 0.72 ; 95 % CI , 0.59 to 0.87 ) . In contrast , gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers ( rate of primary outcome among carriers , 7.7 % vs. 13.0 % ; hazard ratio , 0.55 ; 95 % CI , 0.42 to 0.73 ; rate among noncarriers , 10.0 % vs. 12.2 % ; hazard ratio , 0.85 ; 95 % CI , 0.68 to 1.05 ; P=0.02 for interaction ) . The effect of clopidogrel on bleeding did not vary according to genotypic subgroups . Among 1156 genotyped patients with atrial fibrillation , there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype , loss-of-function carrier status , or gain-of-function carrier status . CONCLUSIONS Among patients with acute coronary syndromes or atrial fibrillation , the effect of clopidogrel as compared with placebo is consistent , irrespective of CYP2C19 loss-of-function carrier status . ( Funded by Sanofi-Aventis and Bristol-Myers Squibb ; Clinical Trials.gov number , NCT00249873 . ) Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite . The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors , but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear . Using in vitro metabolomic profiling techniques , we identified paraoxonase-1 ( PON1 ) as the crucial enzyme for clopidogrel bioactivation , with its common Q192R polymorphism determining the rate of active metabolite formation . We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy .  PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis , lower PON1 plasma activity , lower plasma concentrations of active metabolite and lower platelet inhibition . Thus , we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel . These findings have therapeutic implication s and may be exploited to prospect ively assess the clinical efficacy of clopidogrel BACKGROUND The relation between platelet reactivity and  stent thrombosis , major bleeding , and other adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterised . We aim ed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation . METHODS ADAPT-DES was a prospect i ve , multicentre registry of patients successfully treated with one or more drug-eluting stents and given aspirin and clopidogrel at 10 - 15 US and European hospitals . We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays  , and assigned different cutoffs to define high platelet reactivity . The primary endpoint was definite or probable stent thrombosis ; other endpoints were all-cause mortality , myocardial infa rct ion , and clinical ly relevant bleeding . We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events . This study is registered with Clinical Trials.gov , number NCT00638794 . FINDINGS Between Jan 7 , 2008 , and Sept 16 , 2010 , 8665 patients were prospect ively enrolled at 11 sites , of which 8583 were eligible . At 1-year follow-up , stent thrombosis had occurred in 70 ( 0·8 % ) patients , myocardial infa rct ion in 269 ( 3·1 % ) , clinical ly relevant bleeding in 531 ( 6·2 % ) , and death in 161 ( 1·9 % ) patients . High platelet reactivity on  clopidogrel  was strongly related to stent thrombosis ( adjusted HR 2·49 [ 95 % CI 1·43 - 4·31 ] , p=0·001 ) and myocardial infa rct ion ( adjusted HR 1·42 [ 1·09 - 1·86 ] , p=0·01 ) , was inversely related to bleeding ( adjusted HR 0·73 [ 0·61 - 0·89 ] , p=0·002 ) , but was not related to mortality ( adjusted HR 1·20 [ 0·85 - 1·70 ] , p=0·30 ) . High platelet reactivity on aspirin was not significantly associated with stent thrombosis ( adjusted HR 1·46 [ 0·58 - 3·64 ] , p=0·42 ) , myocardial infa rct ion , or death , but was inversely related to bleeding ( adjusted HR 0·65 [ 0·43 - 0·99 ] , p=0·04 ) . INTERPRETATION The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation , and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised . FUNDING Boston Scientific , Abbott Vascular , Medtronic , Cordis , Biosensors , The Medicines Company , Daiichi-Sankyo , Eli Lilly , Volcano , and Accumetrics Bleeding negatively affects prognosis and adherence to antiplatelet therapy  after acute coronary syndromes ( ACSs ) . The potential association of on-aspirin platelet reactivity and bleeding is not established . We sought to determine whether low on-aspirin platelet reactivity ( LAPR ) is associated with bleeding events and antiplatelet therapy compliance in patients with ACSs receiving coronary stenting . On-aspirin platelet reactivity was measured by the VerifyNow ™ Aspirin assay ( Accumetrics Inc. , San Diego , CA , USA ) in 531 patients with ACS . Cut-offs for LAPR were calculated by receiver-operating characteristic curve ( ROC ) analysis . Bleeding was reported according to Bleeding Academic Research Consortium ( BARC ) definition . The endpoints were minor bleeding ( BARC types 1 or 2 ) , major bleeding ( BARC types 3 or 5 ) and antiplatelet therapy cessation during 6-months follow-up . By ROC analysis the VerifyNow ™ Aspirin assay was able to distinguish between patients with and without minor bleeding ( area under the curve [ AUC ] 0.66 , 95 % confidence interval [ CI ] 0.62–0.70 , P < 0.0001 ) whereas major bleeding could not be predicted by the assay ( AUC 0.54 , 95 % CI 0.49–0.58 , P = 0.473 ) . By logistic regression , LAPR was associated with increased risk of minor bleeding ( odds ratio [ OR ] 4.32 , 95 % CI 2.78–6.71 , P < 0.0001 ) but not major bleeding ( OR 2.05 , 95 % CI 0.83–5.06 , P = 0.117 ) . Antiplatelet therapy discontinuation was more frequent in patients with LAPR as compared to those with no LAPR ( 21.6 vs. 9.1 % , P = 0.0008 ) . In conclusion , early point-of-care on-aspirin platelet reactivity testing in ACS may identify patients with increased risk of minor bleeding events and subsequent discontinuation of antiplatelet therapy . The possible impact of LAPR on major bleeding needs to be determined in larger trials AIMS To evaluate the associations of myocardial infa rct ion ( MI ) and major bleeding with  1-year mortality .  Both MI and major bleeding predict 1-year mortality in patients presenting with acute coronary syndrome ( ACS ) . However , the risk of each of these events on the magnitude and timing of mortality has not been well studied . METHODS AND RESULTS A multivariable Cox regression model was developed relating 13 independent baseline predictors to 1-year mortality for 13 819 patients with moderate and high-risk ACS enrolled in the Acute Catheterization and Urgent Intervention Triage strategy trial . After adjustment for baseline predictors , Cox models with  major bleeding  and recurrent MI as time-up date d covariates estimated the effect of these events on mortality hazard over time . Within 30 days of r and omization , 705 patients ( 5.1 % ) had an MI , 645 ( 4.7 % ) had a major bleed ; 524 ( 3.8 % ) died within a year . The occurrence of an MI was associated with a hazard ratio of 3.1 compared with patients not yet having an MI , after adjustment for baseline predictors . However , MI within 30 days markedly increased the mortality risk for the first 2 days after the event ( adjusted hazard ratio of 17.6 ) , but this risk declined rapidly post-infa rct ( hazard ratio of 1.4 beyond 1 month after the MI event ) . In contrast , major bleeding had a prolonged association with mortality risk ( hazard ratio of 3.5 ) which remained fairly steady over time throughout 1 year . CONCLUSION After accounting for baseline predictors of mortality , major bleeds and MI have similar overall strength of association with mortality in the first year after ACS . MI is correlated with a dramatic increase in short-term risk , whereas major bleeding correlates with a more prolonged mortality risk Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation . Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome . Design , Setting , and Patients Prospect i ve , observational , single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007 . On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry , Verify Now P2Y12 and Platelet works assays , and the IMPACT-R and the platelet function analysis system ( PFA-100 ) ( with the Dade PFA collagen/adenosine diphosphate ( ADP ) cartridge and Innovance PFA P2Y ) . Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve ( ROC ) analysis . Main Outcome Measurement The primary end point was defined as a composite of all-cause death , nonfatal acute myocardial infa rct ion , stent thrombosis , and ischemic stroke . The primary safety end point included TIMI ( Thrombolysis In Myocardial Infa rct ion ) criteria major and minor bleeding . Results Kaplan-Meier analysis demonstrated that at 1-year follow-up , the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry ( 52 [ 11.7 % ; 95 % confidence interval { CI } , 8.9%-15.0 % ] vs 36 [ 6.0%;95%CI , 4.2%-8.2 % ] P.001 ; n=1049),Verify Now ( 54 [ 13.3 % ; 95 % CI , 10.2%-17.0 % ] vs 37 [ 5.7 % ; 95 % CI , 4.1%-7.8%]P.001 ; n=1052 ) , Platelet works ( 33 [ 12.6 % ; 95 % CI , 8.8%-17.2 % ] vs 21 [ 6.1%;95 % CI , 3.8%-9.2 % ] P=.005 ; n=606 ) , and Innovance PFA P2Y ( 18 [ 12.2 % ; 95%CI ; 7.4%-18.6 % ] vs 28 [ 6.3 % ; 95 % CI , 4.3%-8.9 % ] P=.02 ; n=588 ) . ROC-curve analysis demonstrated that light transmittance aggregometry ( area under the curve[AUC ] , 0.63 ; 95 % CI , 0.58 - 0.68 ) , Verify Now ( AUC , 0.62 ; 95 % CI , 0.57 - 0.67 ) , and Platelet works ( AUC , 0.61 ; 95 % CI , 0.53 - 0.69 ) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up . The IMPACT-R(n=905 ) and the Siemens PFA Collagen/ADP ( n=812 ) were unable to discriminate between patients with and without the primary end point at 1-year follow-up ( all AUCs included 0.50 in the CI ) . None of the tests identified patients at risk for bleeding . Conclusions Of the platelet function tests assessed , light transmittance aggregometry , Verify Now , Platelet works , and Innovance PFA P2Y were significantly associated with the primary end point . However , the predictive accuracy of these 4 tests was only modest . None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation . Trial Registration clinical trials.gov Identifier : NCT00352014 [ corrected ] OBJECTIVES This study sought to develop a risk score predictive of bleeding in patients undergoing percutaneous coronary intervention ( PCI )  and to investigate the impact of bleeding on subsequent mortality . BACKGROUND Bleeding complications after PCI have been independently associated with early and late mortality . METHODS This study represents a patient-level pooled analysis including 17,034 patients undergoing PCI from 3 large , r and omized trials of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors , including the REPLACE-2 ( R and omized Evaluation of PCI Linking Angiomax to Reduced Clinical Events ) , ACUITY ( Acute Catheterization and Urgent Intervention Triage Strategy ) , and HORIZONS-AMI ( Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infa rct ion ) trials . We developed a risk score to predict noncoronary artery bypass graft (CABG)-related TIMI ( Thrombolysis In Myocardial Infa rct ion ) major bleeding and evaluated the impact of various types of bleeding on 1-year mortality . RESULTS A non-CABG-related TIMI major bleed occurred within 30 days in 267 patients ( 1.6 % ) , and death occurred in 497 patients ( 2.9 % ) within 1 year . A risk score was developed to predict the bleeding risk of patients undergoing PCI  , consisting of 7 variables ( serum creatinine , age , sex , presentation , white blood cell count , cigarette smoking , and r and omized treatment ) . The TIMI major bleeding rates increased by bleeding risk score groups : from 0.4 % for those in the lowest to 5.8 % for those in the highest risk group . Non-CABG-related TIMI major bleeding and the occurrence of myocardial infa rct ion within 30 days were independent predictors of subsequent mortality , with respective hazard ratios of 4.2 and 2.9 , each p < 0.001 . Ranked in order of severity , TIMI major bleeding , blood transfusion without TIMI bleed , TIMI minor bleeding requiring blood transfusion , and TIMI minor bleeding not requiring blood transfusion were independent predictors of subsequent mortality with hazard ratios of 4.89 , 2.91 , 2.73 , and 1.66 , respectively . Isolated hematomas were not predictive of subsequent mortality . CONCLUSIONS Non-CABG-related bleeding within 30 days is strongly associated with an increased risk of subsequent mortality at 1 year in patients undergoing PCI  for all indications . A risk score was established to calculate the bleeding risk for patients undergoing PCI  , allowing therapeutic decision making to minimize the incidence of bleeding BACKGROUND Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention . METHODS To compare prasugrel , a new thienopyridine , with clopidogrel , we r and omly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel ( a 60-mg loading dose and a 10-mg daily maintenance dose ) or clopidogrel ( a 300-mg loading dose and a 75-mg daily maintenance dose ) , for 6 to 15 months . The primary efficacy end point was death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . The key safety end point was major bleeding . RESULTS The primary efficacy end point occurred in 12.1 % of patients receiving clopidogrel and 9.9 % of patients receiving prasugrel ( hazard ratio for prasugrel vs. clopidogrel , 0.81 ; 95 % confidence interval [ CI ] , 0.73 to 0.90 ; P<0.001 ) . We also found significant reductions in the prasugrel group in the rates of myocardial infa rct ion ( 9.7 % for clopidogrel vs. 7.4 % for prasugrel ; P<0.001 ) , urgent target-vessel revascularization ( 3.7 % vs. 2.5 % ; P<0.001 ) , and stent thrombosis ( 2.4 % vs. 1.1 % ; P<0.001 ) . Major bleeding was observed in 2.4 % of patients receiving prasugrel and in 1.8 % of patients receiving clopidogrel ( hazard ratio , 1.32 ; 95 % CI , 1.03 to 1.68 ; P=0.03 ) . Also greater in the prasugrel group was the rate of life-threatening bleeding ( 1.4 % vs. 0.9 % ; P=0.01 ) , including nonfatal bleeding ( 1.1 % vs. 0.9 % ; hazard ratio , 1.25 ; P=0.23 ) and fatal bleeding ( 0.4 % vs. 0.1 % ; P=0.002 ) . CONCLUSIONS In patients with acute coronary syndromes with scheduled percutaneous coronary intervention , prasugrel therapy was associated with significantly reduced rates of ischemic events , including stent thrombosis , but with an increased risk of major bleeding , including fatal bleeding . Overall mortality did not differ significantly between treatment groups . ( Clinical Trials.gov number , NCT00097591 [ Clinical Trials.gov ] . BACKGROUND Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies . OBJECTIVES To compare different assays for prediction of events during long-term follow-up . METHODS In this prospect i ve cohort study polymorphisms of CYP2C19 * 2 and CYP2C19 * 17 alleles , vasodilator-stimulated phosphoprotein phosphorylation ( VASP ) assay , multiple electrode aggregometry ( MEA ) , cone and platelet analyser ( CPA ) and platelet function analyser ( PFA-100 ) were performed in 416 patients undergoing percutaneous coronary intervention .  The rates of events were recorded during a 12-month follow-up . RESULTS Platelet aggregation by MEA predicted stent thrombosis ( 2.4 % ) better ( c-index = 0.90 ; P < 0.001 ; sensitivity = 90 % ; specificity = 83 % ) than the VASP assay , CPA or PFA-100 ( c-index < 0.70 ; P > 0.05 ; sensitivity < 70 % ; specificity < 70 % for all ) or even the CYP2C19 * 2 polymorphism ( c-index < 0.56 ; P > 0.05 ; sensitivity = 30 % ; specificity = 71 % ) . Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders ( 12.5 % vs. 0.3 % , P < 0.001 , and 18.5 % vs. 11.3 % , P = 0.022 , respectively ) , whereas poor metabolizers ( CYP2C19 * 1/*2 or * 2/*2 carriers ) were not at increased risks ( stent thrombosis , 2.7 % vs. 2.5 % , P > 0.05 ; MACE , 13.5 % vs. 12.1 % , P = 0.556 ) . The incidence of major bleedings ( 2.6 % ) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA ( 4 % vs. 0 % ) or in ultra-metabolizers vs. regular metabolizers ( CYP2C19 * 17/*17 vs. CYP2C19 * 1/*1 ; 9.5 % vs. 2 % ) . The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status . CONCLUSIONS Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping BACKGROUND Bleeding is a potentially catastrophic complication after primary percutaneous coronary intervention ( PPCI ) . It occurs most frequently within the first 30 days following the intervention . The aim of this study was to generate a simple and accurate risk model for the prediction of bleeding after PPCI . METHODS AND RESULTS The training set included 2,096 patients enrolled in the RISK-PCI trial . The model was vali date d using a data base of 961 patients enrolled in the ART-PCI trial .  Bleeding was defined as type ≥3a bleeding according to the Bleeding Academic Research Consortium definition . Multivariate logistic regression was used to evaluate the predictors of outcome . A sum of weighted points for specific predictors was calculated to determine the final score . The model included 5 independent predictors of 30-day bleeding : gender ( female ) ; history of peptic ulcer ; creatinine clearance at admission ( < 60 ml/min ) ; hemoglobin at presentation ( < 125 g/dl ) ; and Killip class > 1 heart failure at admission . The model showed good discrimination and calibration for the prediction of bleeding in the derivation set ( C-statistic , 0.79 ; goodness of fit , P=0.12 ) and in the validation set ( C-statistic , 0.76 ; goodness of fit , P=0.37 ) . Patients were classified into 3 risk classes and the observed incidence of 30-day bleeding of 1.0 % , 3.5 % and 10.7 % corresponded to the low- , intermediate- and high-risk classes , respectively . CONCLUSIONS A simple risk model was developed that has a reasonably good capacity for the prediction of 30-day bleeding after PPCI AIMS We assessed prospect ively the association between occurrence of post-discharge non-CABG-related TIMI major and minor bleeding  and post-treatment platelet reactivity in patients with non-ST elevation acute coronary syndrome ( NSTE ACS ) . METHODS AND RESULTS Five hundred and ninety-seven consecutive patients admitted with NSTE ACS were prospect ively included . Between hospital discharge and one month follow-up , we observed 16 ( 2.7 % ) non-CABG-related TIMI haemorrhagic complications including five ( 0.84 % ) major and 11 ( 1.8 % ) minor bleeds . Patients with bleeding had significantly lower post-treatment values of ADP-induced aggregation ( 43+/-14 % versus . 56+/-19 % , p=0.002 ) and platelet reactivity index VASP ( 43+/-14 % versus 54+/-23 % ; p=0.04 ) and a trend for lower values of arachidonic acid-induced aggregation ( 2.4+/-5.4 versus 13+/-21 ; p=0.27 ) . After stratification by quartiles based on post-treatment ADP-induced platelet aggregation , we identified patients in the first quartile as hyper-responders with very low post-treatment platelet reactivity , below < 40 % . The risk of TIMI major and minor bleeding was significantly higher in the first quartile of hyper-responders than in the others quartiles : 10 ( 6.6 % ) versus six ( 1.4 % ) , p=0.001 . CONCLUSIONS Our results suggest that assessment of post-treatment platelet reactivity might be used to detect hyper-responders to antiplatelet therapy with higher risk of non-CABG related bleeding and tailor antiplatelet therapy according to both ischaemic and bleeding risk Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention . In an earlier consensus document , we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate ( ADP ) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests ( PFTs ) . Up date d American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention , although routine testing is not recommended ( Class III ) . Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor . Recent prospect i ve r and omized trials of PFT did not demonstrate clinical benefit , thus question ing whether treatment modification based on the results of current PFT platforms can actually influence outcomes . However , there are major limitations associated with these r and omized trials . In addition , recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding . Therefore , a therapeutic window concept has been proposed for P2Y12 inhibitor therapy . In this up date d consensus document , we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events . In addition , we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy Bleeding is a complication of current therapies for acute coronary syndrome ( ACS ) . No studies have examined the effect of bleeding events on clinical outcomes . We analyzed pooled data from 4 multicenter , r and omized clinical trials of patients who had ACS ( n = 26,452 ) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate . The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting .  Of all the patients included , 27.6 % had > or = 1 bleeding episode .  Patients who bled were older and sicker at presentation than were those who did not bleed . Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased . There were stepwise increases in the adjusted hazards of 30-day mortality ( mild bleeding , hazard ratio [ HR ] 1.6 , 95 % confidence interval [ CI ] 1.3 to 1.9 ; moderate bleeding , HR 2.7 , 95 % CI l 2.3 to 3.4 ; severe bleeding , HR 10.6 , 95 % CI 8.3 to 13.6 ) and 6-month mortality ( mild bleeding , HR 1.4 , 95 % CI 1.2 to 1.6 ; moderate bleeding , HR 2.1 , 95 % CI 1.8 to 2.4 ; severe bleeding , HR 7.5 , 95 % CI 6.1 to 9.3 ) as bleeding severity increased . Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds . In conclusion , the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events . Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS Advances in antithrombotic therapy , along with an early invasive strategy , have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes ( ACS ; unstable angina , non – ST-segment – elevation myocardial infa rct ion [ MI ] , and ST-segment – elevation MI).1,–,4 However , the combination of multiple pharmacotherapies , including aspirin , platelet P2Y12 inhibitors , heparin plus glycoprotein IIb/IIIa inhibitors , direct thrombin inhibitors , and the increasing use of invasive procedures , has also been associated with an increased risk of bleeding . Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes , including MI , stroke , stent thrombosis , and death , in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting .11,12 Thus , balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients . Prior r and omized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS , bleeding events have been systematic ally identified as a crucial end point for the assessment of the safety of drugs during the course of r and omized clinical trials , and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events ( eg , cardiac death , MI , stent thrombosis ) , for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use . Lack of st and ardization makes it difficult to optimally organize key clinical trial processes such as adjudication , and even more difficult to interpret relative BACKGROUND Post-treatment platelet reactivity ( PR ) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists . OBJECTIVES We aim ed to study the relationship between post-treatment PR after a 60-mg loading dose ( LD ) of prasugrel and 1-year thrombotic and bleeding events . METHOD Patients were prospect ively included in this multicenter study if they had a successful percutaneous coronary intervention ( PCI ) for acute coronary syndrome ( ACS ) and received prasugrel .  The platelet reactivity index ( PRI ) was measured using the Vasodilator-Stimulated Phosphoprotein index ( VASP ) after a prasugrel LD . Endpoints included the rate of thrombotic events and bleeding events at 1 year . RESULTS Among the 301 patients enrolled , 9 ( 3 % ) were lost to follow-up at 1 year . The rates of thrombotic and bleeding events at 1 year were of 7.5 % and 6.8 % , respectively . Receiver-operating curve ( ROC ) analysis demonstrated an optimal cut-off value of 53.5 % of PRI to predict thrombotic events at 1 year . Using this cut-off value we observed that patients exhibiting high on-treatment platelet reactivity ( HTPR ) had a higher rate of thrombotic events ( 22.4 % vs. 2.9 % ; P < 0.001 ) . In parallel the optimal cut-off value of PRI to predict bleeding was 16 % . Patients with a PRI ≤ 16 % had a higher rate of bleeding events compared with those with a PRI > 16 % ( 15.6 % vs. 3.3 % ; P < 0.001 ) . In multivariate analysis , the PRI predicted both thrombotic and bleeding events ( OR : 1.44 , 95 % confidence interval [ CI ] : 1.2 - 1.72 ; P < 0.001 and OR : 0.75 , 95 % CI : 0.59 - 0.96 ; P = 0.024 [ respectively , per 10 % increase ] ) . CONCLUSION Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow-up for ACS patients undergoing PCI AIMS This double-blind , parallel-group study was conducted to assess the pharmacodynamics , pharmacokinetics , and safety of AZD6140 , the first oral , reversible adenosine diphosphate ( ADP ) receptor antagonist . METHODS AND RESULTS Patients ( n = 200 ) with atherosclerosis were r and omized to receive AZD6140 50 , 100 , or 200 mg twice daily ( bid ) or 400 mg daily ( qd ) or clopidogrel 75 mg qd for 28 days . All groups received aspirin 75 - 100 mg qd . AZD6140 ( 100 and 200 mg bid , 400 mg qd ) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing ( day 1 ) and at day 28 . On day 1 , peak final-extent inhibition of platelet aggregation ( IPA ) was observed 2 - 4 h post-dose with AZD6140 , whereas clopidogrel minimally inhibited platelet aggregation ( mean percentage IPA < 20 % , all time points ) . Four hour post-dose at steady state , the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA ( approximately 90 - 95 % ) , which exceeded that with AZD6140 50 mg bid or clopidogrel ( approximately 60 % ) . AZD6140 was generally well tolerated . All bleeding events , except one in a patient receiving 400 mg qd , were minor and of mild-to-moderate severity . CONCLUSION AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy 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 prospect ively 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 ( 171 ± 49 vs 227 ± 68 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
target: Most studies indicated that low on-treatment platelet reactivity ( LTPR ) , as measured by several platelet function tests , and the carriage of CYP2C19 * 17 allele were independent risk factors for bleeding .
  A bleeding score also proved to be helpful in identifying patients at risk .
  Several patient characteristics were also identified as independent predictors of bleeding , such as older age , female sex and renal failure .
background: Patients with coronary artery disease are usually treated with dual antiplatelet therapy ( DAPT ) after percutaneous coronary intervention .
  Patients on DAPT are at risk of both ischaemic and bleeding events .
  Although side-lined for a long time , real-life studies have shown that both the incidence and the associated morbidity and mortality of out-of-hospital bleeding are high .
  This indicates that prevention of ( post-interventional ) bleeding is as important as prevention of ischaemia .
  For this purpose it is crucial to reliably identify patients with a high bleeding risk .
  In order to postulate an algorithm , which could help identifying these patients , we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding .