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: BACKGROUND Patients with transient ischaemic attack ( TIA ) or minor stroke are at high immediate risk of stroke . The optimum early treatment options for these patients are not known . METHODS Within 24 h of symptom onset , we r and omly assigned , in a factorial design , 392 patients with TIA or minor stroke to clopidogrel  ( 300 mg loading dose then 75 mg daily ; 198 patients ) or placebo ( 194 patients ) , and simvastatin ( 40 mg daily ; 199 patients ) or placebo ( 193 patients ) . All patients were also given aspirin and were followed for 90 days . Descriptive analyses were done by intention to treat . The primary outcome was total stroke ( ischaemic and haemorrhagic ) within 90 days . Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin . This study is registered as an International St and ard R and omised Controlled Trial ( number 35624812 ) and with Clinical Trials.gov ( NCT00109382 ) . FINDINGS The median time to stroke outcome was 1 day ( range 0 - 62 days ) . The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins . 14 ( 7.1 % ) patients on clopidogrel had a stroke within 90 days compared with 21 ( 10.8 % ) patients on placebo ( risk ratio 0.7 [ 95 % CI 0.3 - 1.2 ] ; absolute risk reduction -3.8 % [ 95 % CI -9.4 to 1.9 ] ; p=0.19 ) . 21 ( 10.6 % ) patients on simvastatin had a stroke within 90 days compared with 14 ( 7.3 % ) patients on placebo ( risk ratio 1.3 [ 0.7 - 2.4 ] ; absolute risk increase 3.3 % [ -2.3 to 8.9 ] ; p=0.25 ) . The interaction between clopidogrel and simvastatin was not significant ( p=0.64 ) . Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo ( absolute risk increase 1.0 % [ -0.4 to 2.4 ] ; p=0.5 ) . There was no difference between groups for the simvastatin safety outcomes . INTERPRETATION Immediately after TIA or minor stroke , patients are at high risk of stroke , which might be reduced by using clopidogrel in addition to aspirin . The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit . We were unable to provide evidence of benefit of simvastatin in this setting . This aggressive prevention approach merits further study BACKGROUND Clopidogrel therapy has recently been shown to reduce cardiovascular events in patients with stable vascular disease . This benefit may be due to effects not exclusively related to platelet aggregation . The aim of this study was to evaluate the effect of clopidogrel therapy on microvascular endothelial function in subjects with stable coronary artery disease ( CAD ) . METHODS AND RESULTS Forty subjects with stable CAD were r and omised to clopidogrel therapy ( 75mg/day ) or control . Blood and endothelial function testing occurred at baseline , one week and three months following r and omisation . Microvascular endothelial function was assessed via reactive hyperaemic index ( RHI ) . Platelet function was assessed by adenosine diphosphate (ADP)-induced whole blood aggregation and the VerifyNow ™ system . Plasma markers of endothelial function ( asymmetric dimethylarginine , ADMA ) and oxidative stress ( myeloperoxidase , MPO ) were also tested . The primary endpoint was endothelial function assessment ( RHI ) at three months . At one week RHI increased by 20±10 % in the clopidogrel group ; this effect was maintained at three months ( 21±9 % increase from baseline ; P<0.01 ) . A significant decrease in ADP-induced platelet aggregation and P2Y12 reaction units was observed in the clopidogrel therapy group ( P<0.01 ) . There was no correlation between endothelial function and platelet function testing in the clopidogrel therapy group . CONCLUSION Clopidogrel therapy is associated with improved microvascular endothelial function in patients with stable CAD . This effect is independent of its effects on ADP-induced platelet reactivity Background The aim of this study was to analyze the benefits and safety associated with the combination therapy of clopidogrel and aspirin among minor stroke or transient ischemic attack patients treated within 12 hours . Methods and Results This was a sub analysis of the CHANCE ( Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events ) trial , mainly limited to the prespecified group of patients r and omized within 12 hours to either the combination of clopidogrel plus aspirin or aspirin alone .  The primary outcome was ischemic stroke during 90‐day follow‐up . Recurrent ischemic stroke and progressive ischemic stroke were analyzed . Multivariable Cox modeling showed that r and omization within 12 hours was an independent predictor of ischemic stroke events ( hazard ratio [ 95 % CI ] 1.25 [ 1.04–1.49 ] , P=0.02 ) . Among 2573 patients r and omized within 12 hours , 282 ( 10.96 % ) patients had ischemic stroke events  . Among them , 158 ( 12.34 % ) of 1280 patients taking aspirin  experienced ischemic stroke compared with 124 ( 9.59 % ) of 1293 patients taking clopidogrel – aspirin ( P=0.02 ) . The dual antiplatelet was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke ( 6.57 % versus 8.91 % , P=0.03 ) but not progressive ischemic stroke ( 3.02 % versus 3.43 % , P=0.28 ) . There was no significant difference in hemorrhagic events ( P=0.39 ) . Conclusions Among patients treated within 12 hours , the combination of clopidogrel and aspirin was more effective  than aspirin alone in reducing the risk of recurrent ischemic stroke during the 90‐day follow‐up and did not increase the hemorrhagic risk . Clinical Trial Registration URL : https://www . clinical trials.gov/. Unique identifier : NCT00979589 OBJECTIVES We prospect ively assessed cardiac and pulmonary function in patients with stable coronary artery disease ( CAD ) treated with ticagrelor , clopidogrel , or placebo  in the ONSET/OFFSET ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease ) study . BACKGROUND Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes . Dyspnea develops in some patients treated with ticagrelor , and it is not known whether this is associated with changes in cardiac or pulmonary function . METHODS In all , 123 stable aspirin-treated CAD patients r and omly received either ticagrelor ( 180 mg load , then 90 mg twice daily ; n=57 ) , clopidogrel ( 600 mg load , then 75 mg daily ; n=54 ) , or placebo ( n=12 ) for 6 weeks in a double-blind , double-dummy design . Electrocardiography , echocardiography , serum N-terminal pro-brain natriuretic peptide , and pulmonary function tests were performed before ( baseline ) and 6 weeks after drug administration and /or after development of dyspnea . RESULTS After drug administration , dyspnea was reported by 38.6 % , 9.3 % , and 8.3 % of patients in the ticagrelor , clopidogrel , and placebo groups , respectively ( p<0.001 ) . Most instances were mild and /or lasted<24 h , although 3 patients discontinued ticagrelor because of dyspnea . Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week , respectively , after drug administration . In all treatment groups , and in ticagrelor-treated patients with dyspnea , there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters . CONCLUSIONS Dyspnea is commonly associated with ticagrelor therapy , but was not associated in this study with any adverse change in cardiac or pulmonary function . ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ ONSET/OFFSET ] ; NCT00528411 ) Background — The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events ( CHANCE ) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone , but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination . We report the 1-year follow-up outcomes of this trial . Methods and Results — The trial was 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 onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy ( loading dose of 300 mg of clopidogrel on day 1 , followed by 75 mg of clopidogrel per day for 90 days , plus 75 mg of aspirin per day for the first 21 days ) or to the aspirin-alone group ( 75 mg/d for 90 days ) . The primary outcome was stroke event ( ischemic or hemorrhagic ) during 1-year follow-up . Differences in outcomes between groups were assessed by using the Cox proportional hazards model . Stroke occurred in 275 ( 10.6 % ) patients in the clopidogrel-aspirin group , in comparison with 362 ( 14.0 % ) patients in the aspirin group ( hazard ratio , 0.78 ; 95 % confidence interval , 0.65–0.93 ; P=0.006 ) . Moderate or severe hemorrhage occurred in 7 ( 0.3 % ) patients in the clopidogrel-aspirin group and in 9 ( 0.4 % ) patients in the aspirin group ( P=0.44 ) . Conclusions — The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00979589 Background — The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown . Methods and Results — In the Clopidogrel After Surgery for Coronary Artery DiseasE ( CASCADE ) trial , a total of 113 patients were r and omized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting . In this secondary analysis , the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses grade d serially by using 6 thresholds ( grade 0 [ 0%–24 % ] , grade 1 [ 25%–37 % ] , grade 2 [ 38%–62 % ] , grade 3 [ 63%–82 % ] , grade 4 [ 83%–98 % ] , and grade 5 [ 99%–100 % ] ) . We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups . A total of 543 preoperative stenoses and occlusions were quantified and followed . At 1-year postoperatively , there were 103 evolving ( 94 worsened , 9 improved ) and 22 new lesions . The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease ( P⩽0.02 ) . There were no differences in clinical events between treatment groups , and the proportion of patients with evolving or new lesions was also similar ( 70 % versus 74 % , aspirin – clopidogrel versus aspirin – placebo , respectively ; P=0.8 ) . However , in evolving or new lesions , the mean grade change ( 1.1±1.0 versus 1.6±1.1 , respectively ; P=0.01 ) and the proportion of new occlusions ( 7 % versus 22 % ; P=0.02 ) were lower in the asp 
    Output:
    
agent
The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infa rct ion and ischaemic stroke , and an increased risk of major and minor bleeding compared with aspirin alone .
According to GRADE criteria , the quality of evidence was moderate for all outcomes except all-cause mortality ( low quality evidence ) and adverse events ( very low quality evidence )
***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 Patients with transient ischaemic attack ( TIA ) or minor stroke are at high immediate risk of stroke . The optimum early treatment options for these patients are not known . METHODS Within 24 h of symptom onset , we r and omly assigned , in a factorial design , 392 patients with TIA or minor stroke to clopidogrel  ( 300 mg loading dose then 75 mg daily ; 198 patients ) or placebo ( 194 patients ) , and simvastatin ( 40 mg daily ; 199 patients ) or placebo ( 193 patients ) . All patients were also given aspirin and were followed for 90 days . Descriptive analyses were done by intention to treat . The primary outcome was total stroke ( ischaemic and haemorrhagic ) within 90 days . Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin . This study is registered as an International St and ard R and omised Controlled Trial ( number 35624812 ) and with Clinical Trials.gov ( NCT00109382 ) . FINDINGS The median time to stroke outcome was 1 day ( range 0 - 62 days ) . The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins . 14 ( 7.1 % ) patients on clopidogrel had a stroke within 90 days compared with 21 ( 10.8 % ) patients on placebo ( risk ratio 0.7 [ 95 % CI 0.3 - 1.2 ] ; absolute risk reduction -3.8 % [ 95 % CI -9.4 to 1.9 ] ; p=0.19 ) . 21 ( 10.6 % ) patients on simvastatin had a stroke within 90 days compared with 14 ( 7.3 % ) patients on placebo ( risk ratio 1.3 [ 0.7 - 2.4 ] ; absolute risk increase 3.3 % [ -2.3 to 8.9 ] ; p=0.25 ) . The interaction between clopidogrel and simvastatin was not significant ( p=0.64 ) . Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo ( absolute risk increase 1.0 % [ -0.4 to 2.4 ] ; p=0.5 ) . There was no difference between groups for the simvastatin safety outcomes . INTERPRETATION Immediately after TIA or minor stroke , patients are at high risk of stroke , which might be reduced by using clopidogrel in addition to aspirin . The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit . We were unable to provide evidence of benefit of simvastatin in this setting . This aggressive prevention approach merits further study BACKGROUND Clopidogrel therapy has recently been shown to reduce cardiovascular events in patients with stable vascular disease . This benefit may be due to effects not exclusively related to platelet aggregation . The aim of this study was to evaluate the effect of clopidogrel therapy on microvascular endothelial function in subjects with stable coronary artery disease ( CAD ) . METHODS AND RESULTS Forty subjects with stable CAD were r and omised to clopidogrel therapy ( 75mg/day ) or control . Blood and endothelial function testing occurred at baseline , one week and three months following r and omisation . Microvascular endothelial function was assessed via reactive hyperaemic index ( RHI ) . Platelet function was assessed by adenosine diphosphate (ADP)-induced whole blood aggregation and the VerifyNow ™ system . Plasma markers of endothelial function ( asymmetric dimethylarginine , ADMA ) and oxidative stress ( myeloperoxidase , MPO ) were also tested . The primary endpoint was endothelial function assessment ( RHI ) at three months . At one week RHI increased by 20±10 % in the clopidogrel group ; this effect was maintained at three months ( 21±9 % increase from baseline ; P<0.01 ) . A significant decrease in ADP-induced platelet aggregation and P2Y12 reaction units was observed in the clopidogrel therapy group ( P<0.01 ) . There was no correlation between endothelial function and platelet function testing in the clopidogrel therapy group . CONCLUSION Clopidogrel therapy is associated with improved microvascular endothelial function in patients with stable CAD . This effect is independent of its effects on ADP-induced platelet reactivity Background The aim of this study was to analyze the benefits and safety associated with the combination therapy of clopidogrel and aspirin among minor stroke or transient ischemic attack patients treated within 12 hours . Methods and Results This was a sub analysis of the CHANCE ( Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events ) trial , mainly limited to the prespecified group of patients r and omized within 12 hours to either the combination of clopidogrel plus aspirin or aspirin alone .  The primary outcome was ischemic stroke during 90‐day follow‐up . Recurrent ischemic stroke and progressive ischemic stroke were analyzed . Multivariable Cox modeling showed that r and omization within 12 hours was an independent predictor of ischemic stroke events ( hazard ratio [ 95 % CI ] 1.25 [ 1.04–1.49 ] , P=0.02 ) . Among 2573 patients r and omized within 12 hours , 282 ( 10.96 % ) patients had ischemic stroke events  . Among them , 158 ( 12.34 % ) of 1280 patients taking aspirin  experienced ischemic stroke compared with 124 ( 9.59 % ) of 1293 patients taking clopidogrel – aspirin ( P=0.02 ) . The dual antiplatelet was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke ( 6.57 % versus 8.91 % , P=0.03 ) but not progressive ischemic stroke ( 3.02 % versus 3.43 % , P=0.28 ) . There was no significant difference in hemorrhagic events ( P=0.39 ) . Conclusions Among patients treated within 12 hours , the combination of clopidogrel and aspirin was more effective  than aspirin alone in reducing the risk of recurrent ischemic stroke during the 90‐day follow‐up and did not increase the hemorrhagic risk . Clinical Trial Registration URL : https://www . clinical trials.gov/. Unique identifier : NCT00979589 OBJECTIVES We prospect ively assessed cardiac and pulmonary function in patients with stable coronary artery disease ( CAD ) treated with ticagrelor , clopidogrel , or placebo  in the ONSET/OFFSET ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease ) study . BACKGROUND Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes . Dyspnea develops in some patients treated with ticagrelor , and it is not known whether this is associated with changes in cardiac or pulmonary function . METHODS In all , 123 stable aspirin-treated CAD patients r and omly received either ticagrelor ( 180 mg load , then 90 mg twice daily ; n=57 ) , clopidogrel ( 600 mg load , then 75 mg daily ; n=54 ) , or placebo ( n=12 ) for 6 weeks in a double-blind , double-dummy design . Electrocardiography , echocardiography , serum N-terminal pro-brain natriuretic peptide , and pulmonary function tests were performed before ( baseline ) and 6 weeks after drug administration and /or after development of dyspnea . RESULTS After drug administration , dyspnea was reported by 38.6 % , 9.3 % , and 8.3 % of patients in the ticagrelor , clopidogrel , and placebo groups , respectively ( p<0.001 ) . Most instances were mild and /or lasted<24 h , although 3 patients discontinued ticagrelor because of dyspnea . Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week , respectively , after drug administration . In all treatment groups , and in ticagrelor-treated patients with dyspnea , there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters . CONCLUSIONS Dyspnea is commonly associated with ticagrelor therapy , but was not associated in this study with any adverse change in cardiac or pulmonary function . ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ ONSET/OFFSET ] ; NCT00528411 ) Background — The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events ( CHANCE ) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone , but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination . We report the 1-year follow-up outcomes of this trial . Methods and Results — The trial was 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 onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy ( loading dose of 300 mg of clopidogrel on day 1 , followed by 75 mg of clopidogrel per day for 90 days , plus 75 mg of aspirin per day for the first 21 days ) or to the aspirin-alone group ( 75 mg/d for 90 days ) . The primary outcome was stroke event ( ischemic or hemorrhagic ) during 1-year follow-up . Differences in outcomes between groups were assessed by using the Cox proportional hazards model . Stroke occurred in 275 ( 10.6 % ) patients in the clopidogrel-aspirin group , in comparison with 362 ( 14.0 % ) patients in the aspirin group ( hazard ratio , 0.78 ; 95 % confidence interval , 0.65–0.93 ; P=0.006 ) . Moderate or severe hemorrhage occurred in 7 ( 0.3 % ) patients in the clopidogrel-aspirin group and in 9 ( 0.4 % ) patients in the aspirin group ( P=0.44 ) . Conclusions — The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00979589 Background — The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown . Methods and Results — In the Clopidogrel After Surgery for Coronary Artery DiseasE ( CASCADE ) trial , a total of 113 patients were r and omized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting . In this secondary analysis , the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses grade d serially by using 6 thresholds ( grade 0 [ 0%–24 % ] , grade 1 [ 25%–37 % ] , grade 2 [ 38%–62 % ] , grade 3 [ 63%–82 % ] , grade 4 [ 83%–98 % ] , and grade 5 [ 99%–100 % ] ) . We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups . A total of 543 preoperative stenoses and occlusions were quantified and followed . At 1-year postoperatively , there were 103 evolving ( 94 worsened , 9 improved ) and 22 new lesions . The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease ( P⩽0.02 ) . There were no differences in clinical events between treatment groups , and the proportion of patients with evolving or new lesions was also similar ( 70 % versus 74 % , aspirin – clopidogrel versus aspirin – placebo , respectively ; P=0.8 ) . However , in evolving or new lesions , the mean grade change ( 1.1±1.0 versus 1.6±1.1 , respectively ; P=0.01 ) and the proportion of new occlusions ( 7 % versus 22 % ; P=0.02 ) were lower in the asp 
    Output:
    