***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: BACKGROUND The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute myocardial infa rct ion are unresolved questions . The current trial was design ed to compare new , aggressive thrombolytic strategies with st and ard thrombolytic regimens in the treatment of acute myocardial infa rct ion . Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained reperfusion would improve survival . METHODS In 15 countries and 1081 hospitals , 41,021 patients with evolving myocardial infa rct ion were r and omly assigned to four different thrombolytic strategies , consisting of the use of streptokinase and subcutaneous heparin , streptokinase and intravenous heparin , accelerated tissue plasminogen activator ( t-PA ) and intravenous heparin , or a combination of streptokinase plus t-PA with intravenous heparin . ( " Accelerated " refers to the administration of t-PA over a period of 1 1/2 hours -- with two thirds of the dose given in the first 30 minutes -- rather than the conventional period of 3 hours . ) The primary end point was 30-day mortality . RESULTS The mortality rates in the four treatment groups were as follows : streptokinase and subcutaneous heparin , 7.2 percent ; streptokinase and intravenous heparin , 7.4 percent ; accelerated t-PA and intravenous heparin , 6.3 percent , and the combination of both thrombolytic agents with intravenous heparin , 7.0 percent . This represented a 14 percent reduction ( 95 percent confidence interval , 5.9 to 21.3 percent ) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies ( P = 0.001 ) . The rates of hemorrhagic stroke were 0.49 percent , 0.54 percent , 0.72 percent , and 0.94 percent in the four groups , respectively , which represented a significant excess of hemorrhagic strokes for accelerated t-PA ( P = 0.03 ) and for the combination strategy ( P < 0.001 ) , as compared with streptokinase only . A combined end point of death or disabling stroke was significantly lower in the accelerated-tPA group than in the streptokinase-only groups ( 6.9 percent vs. 7.8 percent , P = 0.006 ) . CONCLUSIONS The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous st and ard thrombolytic regimens IMPORTANCE Data are limited regarding the association between CYP2C19 genetic variants and clinical outcomes of patients with minor stroke or transient ischemic attack treated with clopidogrel .  OBJECTIVE To estimate the association between CYP2C19 genetic variants and clinical outcomes of  clopidogrel-treated patients with minor stroke or transient ischemic attack . DESIGN , SETTING , AND PARTICIPANTS Three CYP2C19 major alleles ( * 2 , * 3 , * 17 ) were genotyped among 2933 Chinese patients from 73 sites who were enrolled in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events ( CHANCE ) r and omized trial conducted from January 2 , 2010 , to March 20 , 2012 . INTERVENTIONS Patients with acute minor ischemic stroke or transient ischemic attack in the trial were r and omized to treatment with clopidogrel combined with aspirin or to aspirin alone . MAIN OUTCOMES AND MEASURES The primary efficacy outcome was new stroke . The secondary efficacy outcome was a composite of new composite vascular events ( ischemic stroke , hemorrhagic stroke , myocardial infa rct ion , or vascular death ) . Bleeding was the safety outcome . RESULTS Among 2933 patients , 1948 ( 66.4 % ) were men , with a mean age of 62.4 years . Overall , 1207 patients ( 41.2 % ) were noncarriers and 1726 patients ( 58.8 % ) were carriers of loss-of-function alleles ( * 2 , * 3 ) . After day 90 follow-up , clopidogrel-aspirin reduced the rate of new stroke in the noncarriers but not in the carriers of the loss-of-function alleles ( P = .02 for interaction ; events among noncarriers , 41 [ 6.7 % ] with clopidogrel-aspirin vs 74 [ 12.4 % ] with aspirin ; hazard ratio [ HR ] , 0.51 [ 95 % CI , 0.35 - 0.75 ] ; events among carriers , 80 [ 9.4 % ] with clopidogrel-aspirin vs 94 [ 10.8 % ] with aspirin ; HR , 0.93 [ 95 % CI , 0.69 to 1.26 ] ) . Similar results were observed for the secondary composite efficacy outcome ( noncarriers : 41 [ 6.7 % ] with clopidogrel-aspirin vs 75 [ 12.5 % ] with aspirin ; HR , 0.50 [ 95 % CI , 0.34 - 0.74 ] ; carriers : 80 [ 9.4 % ] with clopidogrel-aspirin vs 95 [ 10.9 % ] with aspirin ; HR , 0.92 [ 95 % CI , 0.68 - 1.24 ] ; P = .02 for interaction ) . The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles ( 2.3 % for carriers and 2.5 % for noncarriers in the clopidogrel-aspirin group vs 1.4 % for carriers and 1.7 % for noncarriers in the aspirin only group ; P = .78 for interaction ) . CONCLUSIONS AND RELEVANCE Among patients with minor ischemic stroke or transient ischemic attack , the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles . These findings support a role of CYP2C19 genotype in the efficacy of this treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00979589 OBJECT Symptomatic intracranial atherosclerotic disease ( ICAD ) has a high risk of recurrent stroke . Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients , but have not been studied in ICAD . The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms ( SNPs ) in symptomatic ICAD patients . METHODS Genotype testing for CYP2C19 * 2 , (*)3 , (*)8 , (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin .  Testing was performed prospect ively at 1 center , and retrospectively from a DNA sample biorepository at 2 centers . Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint , which was a composite of transient ischemic attack ( TIA ) , stroke , myocardial infa rct ion , or death within 12 months . RESULTS The primary endpoint occurred in 14.9 % of the 188 cases . In multiple logistic regression analysis , the presence of the CYP2C19 loss of function ( LOF ) alleles * 2 , * 3 , and * 8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes ( odds ratio [ OR ] 0.13 , 95 % CI 0.03 - 0.62 , p = 0.0101 ) . Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint , with hazard ratio ( HR ) of 0.27 ( 95 % CI 0.08 - 0.95 ) , p = 0.041 . A sensitivity analysis of a secondary composite endpoint of TIA , stroke , or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants , with lower odds of secondary endpoint in patients carrying at least 1 LOF allele ( * 2 , * 3 , * 8) than in wild-type homozygotes ( OR 0.27 , 95 % CI 0.06 - 1.16 , p = 0.078 ) . Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint ( HR 0.22 , 95 % CI 0.05 - 1.04 , p = 0.056 ) . CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD . Variant alleles of CYP2C19 ( * 2 , * 3 , * 8) were associated with lower odds of the primary and secondary composite endpoints . However , the direction of the association was opposite of what is expected based on this SNP . This may reflect an incomplete underst and ing of this genetic variation and its effect in symptomatic ICAD and warrants further investigations BACKGROUND Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events .  Aspirin and ticlopidine have been shown to be effective , but both have potentially serious adverse effects .  Clopidogrel , a new thienopyridine derivative similar to ticlopidine , is an inhibitor of platelet aggregation induced by adenosine diphosphate . METHODS CAPRIE was a r and omised , blinded , international trial design ed to assess the relative efficacy of clopidogrel ( 75 mg once daily ) and aspirin ( 325 mg once daily ) in reducing the risk of a composite outcome cluster of ischaemic stroke , myocardial infa rct ion , or vascular death ; their relative safety was also assessed . The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke , recent myocardial infa rct ion , or symptomatic peripheral arterial disease . Patients were followed for 1 to 3 years . FINDINGS 19,185 patients , with more than 6300 in each of the clinical subgroups , were recruited over 3 years , with a mean follow-up of 1.91 years . There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32 % risk of ischaemic stroke , myocardial infa rct ion , or vascular death compared with 5.83 % with aspirin . These rates reflect a statistically significant ( p = 0.043 ) relative-risk reduction of 8.7 % in favour of clopidogrel ( 95 % Cl 0.3 - 16.5 ) . Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4 % . There were no major differences in terms of safety . Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash ( 0.26 % vs 0.10 % ) , diarrhoea ( 0.23 % vs 0.11 % ) , upper gastrointestinal discomfort ( 0.97 % vs 1.22 % ) , intracranial haemorrhage ( 0.33 % vs 0.47 % ) , and gastrointestinal haemorrhage ( 0.52 % vs 0.72 % ) , respectively . There were ten ( 0.10 % ) patients in the clopidogrel group with significant reductions in neutrophils ( < 1.2 x 10(9)/L ) and 16 ( 0.17 % ) in the aspirin group . INTERPRETATION Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke , myocardial infa rct ion , or vascular death . The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin BACKGROUND Stroke is common during the first few weeks after a transient ischemic attack ( TIA ) or minor ischemic stroke .  Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone . METHODS In a r and omized , double-blind , placebo-controlled trial conducted at 114 centers in China , we r and omly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin ( clopidogrel at an initial dose of 300 mg , followed by 75 mg per day for 90 days , plus aspirin at a dose of 75 mg per day for the first 21 days ) or to placebo plus aspirin ( 75 mg per day for 90 days ) . All participants received open 
    Output:
    
Conclusions : Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel