human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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 .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    