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 We investigated the effects of aspirin ( 300 mg/d ) , ticlopidine ( 500 mg/d ) and their low‐dose combination ( aspirin 100 mg/d plus ticlopidine 250 mg/d ) on the platelet aggregability using the Wu and Hoak method . Each treatment group consisted of 25 patients with acute ischemic stroke .  Platelet aggregation ratios ( PAR ) were measured on the 1st ( before treatment ) , 10th and 90th days in the treatment groups and compared with those of 25 control cases . On the first day , comparison of PAR in each treatment group with the control was significant , while the differences between treatment groups were not significant . On the 90th day , differences of PAR between aspirin and control were significant , but differences between the other treatment groups and the control group were not significant , indicating a lower anti‐aggregant efficacy of aspirin BACKGROUND Concurrent therapy with a proton-pump inhibitor is a st and ard treatment for patients receiving aspirin who are at risk for ulcer . Current U.S. guidelines also recommend clopidrogel for patients who have major gastrointestinal intolerance of aspirin . We compared clopidogrel with aspirin plus esomeprazole for the prevention of recurrent bleeding from ulcers in high-risk patients . METHODS We studied patients who took aspirin to prevent vascular diseases and who presented with ulcer bleeding . After the ulcers had healed , we r and omly assigned patients who were negative for Helicobacter pylori to receive either 75 mg of clopidogrel daily plus esomeprazole placebo twice daily or 80 mg of aspirin daily plus 20 mg of esomeprazole twice daily for 12 months . The end point was recurrent ulcer bleeding . RESULTS We enrolled 320 patients ( 161 patients assigned to receive clopidogrel and 159 to receive aspirin plus esomeprazole ) .  Recurrent ulcer bleeding occurred in 13 patients receiving clopidogrel and 1 receiving aspirin plus esomeprazole . The cumulative incidence of recurrent bleeding during the 12-month period was 8.6 percent ( 95 percent confidence interval , 4.1 to 13.1 percent ) among patients who received clopidogrel and 0.7 percent ( 95 percent confidence interval , 0 to 2.0 percent ) among those who received aspirin plus esomeprazole ( difference , 7.9 percentage points ; 95 percent confidence interval for the difference , 3.4 to 12.4 ; P=0.001 ) . CONCLUSIONS Among patients with a history of aspirin-induced ulcer bleeding whose ulcers had healed before they received the study treatment , aspirin plus esomeprazole was superior to clopidogrel in the prevention of recurrent ulcer bleeding . Our finding does not support the current recommendation that patients with major gastrointestinal intolerance of aspirin be given clopidogrel Background — Chronic heart failure remains a major cause of mortality and morbidity . The role of antithrombotic therapy in patients with chronic heart failure has long been debated . The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm . Methods and Results — This prospect i ve , r and omized clinical trial of open-label warfarin ( target international normalized ratio of 2.5 to 3.0 ) and double-blind treatment with either aspirin ( 162 mg once daily ) or clopidogrel ( 75 mg once daily ) had a 30-month enrollment period and a minimum of 12 months of treatment . We enrolled 1587 men and women ≥18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of ≤35 % . The primary outcome was the time to first occurrence of death , nonfatal myocardial infa rct ion , or nonfatal stroke . For the primary composite end point , the hazard ratios were as follows : for warfarin versus aspirin , 0.98 ( 95 % CI , 0.86 to 1.12 ; P=0.77 ) ; for clopidogrel versus aspirin , 1.08 ( 95 % CI , 0.83 to 1.40 ; P=0.57 ) ; and for warfarin versus clopidogrel , 0.89 ( 95 % CI , 0.68 to 1.16 ; P=0.39 ) . Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel  . Hospitalization for worsening heart failure occurred in 116 ( 22.2 % ) , 97 ( 18.5 % ) , and 89 ( 16.5 % ) patients treated with aspirin , clopidogrel , and warfarin , respectively ( P=0.02 for warfarin versus aspirin ) . Conclusion — The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin OBJECTIVES We studied the modifier effect of platelet antigen polymorphism ( PlA2 ) on platelet inhibition by acetylsalicylic acid ( ASA , i.e. , aspirin ) , clopidogrel , or their combination in patients with coronary heart disease . BACKGROUND Clopidogrel , when administered with ASA , was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA . We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2 . Hence , an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or , like acetylsalicylic acid , more selective . METHODS Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned r and omly to ASA 325 mg/day , clopidogrel 75 mg/day , or both . After 10 days , platelet function was studied . RESULTS Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist , and combination therapy result ed in greater inhibition than either inhibitor used alone ( p < 0.0001 ) . The use of ASA result ed in greater inhibition compared with clopidogrel with epinephrine ( p < 0.0001 ) and collagen as agonists ( p < 0.0001 ) . With collagen as the agonist , platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA ( p = 0.005 ) . In contrast , with clopidogrel , no significant difference could be detected between inhibition of Pl(A1/A1 ) and Pl(A1/A2 ) platelets . CONCLUSIONS The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function . Pl(A2 ) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel . These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease OBJECTIVES The aim of the present study was to compare clopidogrel and ticlopidine after coronary stenting with regard to cardiovascular death during long-term follow-up . BACKGROUND R and omized trials comparing clopidogrel and ticlopidine with a restricted use of intravenous glycoprotein IIb/IIIa inhibition have reported a trend toward a higher incidence of thrombotic stent occlusion with clopidogrel at 30 days . METHODS After successful coronary stent implantation , 700 patients with 899 lesions were r and omly assigned to receive a four-week course of either 500 mg ticlopidine ( n = 345 ) or 75 mg clopidogrel ( n = 355 ) in addition to 100 mg aspirin .  Cardiovascular death was the primary end point and was recorded during a median follow-up period of 28 months . RESULTS Cardiovascular death occurred in eight patients with ticlopidine versus 26 patients with clopidogrel ( hazard ratio with ticlopidine compared with clopidogrel , 0.30 ; 95 % confidence interval [ CI ] , 0.14 to 0.66 ; p = 0.003 ) . After adjustment for co-variables , ticlopidine reduced the risk of cardiovascular death by 63 % compared with clopidogrel . The combined end point of cardiovascular death or nonfatal myocardial infa rct ion was present in 19 patients assigned ticlopidine , compared with 40 patients assigned clopidogrel ( hazard ratio , 0.45 ; p = 0.005 ) . The hazard ratio for all-cause mortality with ticlopidine as compared with clopidogrel was 0.30 ( 95 % CI , 0.14 to 0.64 ; p = 0.002 ) . CONCLUSIONS After the placement of coronary artery stents in unselected patients , ticlopidine was associated with a significantly lower mortality than clopidogrel . This raises concern about the current practice of substituting clopidogrel for ticlopidine after stenting and highlights the need for further long-term studies This study aim ed to compare the effects of clopidogrel , acetylsalicylic acid ( ASA ) , and the combination of both substances on platelet aggregation and expression of platelet membrane glycoproteins in patients with chronic coronary artery disease . We investigated platelet activation by flow cytometry and by platelet aggregation and disaggregation in 60 patients r and omly assigned to 3 treatment groups : ASA , clopidogrel , combination of clopidogrel and ASA , treated for 14 days . Adenosine diphosphate (ADP)–induced expression of P-selectin and of PAC-1 was significantly reduced after 2 wk of clopidogrel but not of ASA treatment . Treatment with clopidogrel reduced the ADP-induced platelet aggregation . The combination of clopidogrel and ASA did not increase the inhibition of platelet activation compared with clopidogrel alone . A significant increase in platelet disaggregation was observed with clopidogrel alone and was more pronounced with the combination of clopidogrel and ASA . ADP-induced platelet degranulation , activation of GPIIb/IIIa receptor , and aggregation in vivo are effectively inhibited by clopidogrel . The significantly increased disaggregation under clopidogrel and ASA suggests that the combined therapy may be superior to the monotherapy in patients with coron 
    Output:
    
agent
Compared with aspirin , thienopyridines significantly reduced gastrointestinal adverse effects .
However , thienopyridines increased the odds of skin rash and diarrhoea , ticlopidine more than clopidogrel .
Allocation to ticlopidine , but not clopidogrel , significantly increased the odds of neutropenia .
The thienopyridine derivatives are at least as effective as aspirin in preventing serious vascular events in patients at high risk , and possibly somewhat more so .
However , the size of any additional benefit is uncertain and could be negligible .
Clopidogrel has a more favourable adverse effects profile than ticlopidine and so is the thienopyridine of choice .
***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 We investigated the effects of aspirin ( 300 mg/d ) , ticlopidine ( 500 mg/d ) and their low‐dose combination ( aspirin 100 mg/d plus ticlopidine 250 mg/d ) on the platelet aggregability using the Wu and Hoak method . Each treatment group consisted of 25 patients with acute ischemic stroke .  Platelet aggregation ratios ( PAR ) were measured on the 1st ( before treatment ) , 10th and 90th days in the treatment groups and compared with those of 25 control cases . On the first day , comparison of PAR in each treatment group with the control was significant , while the differences between treatment groups were not significant . On the 90th day , differences of PAR between aspirin and control were significant , but differences between the other treatment groups and the control group were not significant , indicating a lower anti‐aggregant efficacy of aspirin BACKGROUND Concurrent therapy with a proton-pump inhibitor is a st and ard treatment for patients receiving aspirin who are at risk for ulcer . Current U.S. guidelines also recommend clopidrogel for patients who have major gastrointestinal intolerance of aspirin . We compared clopidogrel with aspirin plus esomeprazole for the prevention of recurrent bleeding from ulcers in high-risk patients . METHODS We studied patients who took aspirin to prevent vascular diseases and who presented with ulcer bleeding . After the ulcers had healed , we r and omly assigned patients who were negative for Helicobacter pylori to receive either 75 mg of clopidogrel daily plus esomeprazole placebo twice daily or 80 mg of aspirin daily plus 20 mg of esomeprazole twice daily for 12 months . The end point was recurrent ulcer bleeding . RESULTS We enrolled 320 patients ( 161 patients assigned to receive clopidogrel and 159 to receive aspirin plus esomeprazole ) .  Recurrent ulcer bleeding occurred in 13 patients receiving clopidogrel and 1 receiving aspirin plus esomeprazole . The cumulative incidence of recurrent bleeding during the 12-month period was 8.6 percent ( 95 percent confidence interval , 4.1 to 13.1 percent ) among patients who received clopidogrel and 0.7 percent ( 95 percent confidence interval , 0 to 2.0 percent ) among those who received aspirin plus esomeprazole ( difference , 7.9 percentage points ; 95 percent confidence interval for the difference , 3.4 to 12.4 ; P=0.001 ) . CONCLUSIONS Among patients with a history of aspirin-induced ulcer bleeding whose ulcers had healed before they received the study treatment , aspirin plus esomeprazole was superior to clopidogrel in the prevention of recurrent ulcer bleeding . Our finding does not support the current recommendation that patients with major gastrointestinal intolerance of aspirin be given clopidogrel Background — Chronic heart failure remains a major cause of mortality and morbidity . The role of antithrombotic therapy in patients with chronic heart failure has long been debated . The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm . Methods and Results — This prospect i ve , r and omized clinical trial of open-label warfarin ( target international normalized ratio of 2.5 to 3.0 ) and double-blind treatment with either aspirin ( 162 mg once daily ) or clopidogrel ( 75 mg once daily ) had a 30-month enrollment period and a minimum of 12 months of treatment . We enrolled 1587 men and women ≥18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of ≤35 % . The primary outcome was the time to first occurrence of death , nonfatal myocardial infa rct ion , or nonfatal stroke . For the primary composite end point , the hazard ratios were as follows : for warfarin versus aspirin , 0.98 ( 95 % CI , 0.86 to 1.12 ; P=0.77 ) ; for clopidogrel versus aspirin , 1.08 ( 95 % CI , 0.83 to 1.40 ; P=0.57 ) ; and for warfarin versus clopidogrel , 0.89 ( 95 % CI , 0.68 to 1.16 ; P=0.39 ) . Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel  . Hospitalization for worsening heart failure occurred in 116 ( 22.2 % ) , 97 ( 18.5 % ) , and 89 ( 16.5 % ) patients treated with aspirin , clopidogrel , and warfarin , respectively ( P=0.02 for warfarin versus aspirin ) . Conclusion — The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin OBJECTIVES We studied the modifier effect of platelet antigen polymorphism ( PlA2 ) on platelet inhibition by acetylsalicylic acid ( ASA , i.e. , aspirin ) , clopidogrel , or their combination in patients with coronary heart disease . BACKGROUND Clopidogrel , when administered with ASA , was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA . We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2 . Hence , an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or , like acetylsalicylic acid , more selective . METHODS Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned r and omly to ASA 325 mg/day , clopidogrel 75 mg/day , or both . After 10 days , platelet function was studied . RESULTS Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist , and combination therapy result ed in greater inhibition than either inhibitor used alone ( p < 0.0001 ) . The use of ASA result ed in greater inhibition compared with clopidogrel with epinephrine ( p < 0.0001 ) and collagen as agonists ( p < 0.0001 ) . With collagen as the agonist , platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA ( p = 0.005 ) . In contrast , with clopidogrel , no significant difference could be detected between inhibition of Pl(A1/A1 ) and Pl(A1/A2 ) platelets . CONCLUSIONS The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function . Pl(A2 ) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel . These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease OBJECTIVES The aim of the present study was to compare clopidogrel and ticlopidine after coronary stenting with regard to cardiovascular death during long-term follow-up . BACKGROUND R and omized trials comparing clopidogrel and ticlopidine with a restricted use of intravenous glycoprotein IIb/IIIa inhibition have reported a trend toward a higher incidence of thrombotic stent occlusion with clopidogrel at 30 days . METHODS After successful coronary stent implantation , 700 patients with 899 lesions were r and omly assigned to receive a four-week course of either 500 mg ticlopidine ( n = 345 ) or 75 mg clopidogrel ( n = 355 ) in addition to 100 mg aspirin .  Cardiovascular death was the primary end point and was recorded during a median follow-up period of 28 months . RESULTS Cardiovascular death occurred in eight patients with ticlopidine versus 26 patients with clopidogrel ( hazard ratio with ticlopidine compared with clopidogrel , 0.30 ; 95 % confidence interval [ CI ] , 0.14 to 0.66 ; p = 0.003 ) . After adjustment for co-variables , ticlopidine reduced the risk of cardiovascular death by 63 % compared with clopidogrel . The combined end point of cardiovascular death or nonfatal myocardial infa rct ion was present in 19 patients assigned ticlopidine , compared with 40 patients assigned clopidogrel ( hazard ratio , 0.45 ; p = 0.005 ) . The hazard ratio for all-cause mortality with ticlopidine as compared with clopidogrel was 0.30 ( 95 % CI , 0.14 to 0.64 ; p = 0.002 ) . CONCLUSIONS After the placement of coronary artery stents in unselected patients , ticlopidine was associated with a significantly lower mortality than clopidogrel . This raises concern about the current practice of substituting clopidogrel for ticlopidine after stenting and highlights the need for further long-term studies This study aim ed to compare the effects of clopidogrel , acetylsalicylic acid ( ASA ) , and the combination of both substances on platelet aggregation and expression of platelet membrane glycoproteins in patients with chronic coronary artery disease . We investigated platelet activation by flow cytometry and by platelet aggregation and disaggregation in 60 patients r and omly assigned to 3 treatment groups : ASA , clopidogrel , combination of clopidogrel and ASA , treated for 14 days . Adenosine diphosphate (ADP)–induced expression of P-selectin and of PAC-1 was significantly reduced after 2 wk of clopidogrel but not of ASA treatment . Treatment with clopidogrel reduced the ADP-induced platelet aggregation . The combination of clopidogrel and ASA did not increase the inhibition of platelet activation compared with clopidogrel alone . A significant increase in platelet disaggregation was observed with clopidogrel alone and was more pronounced with the combination of clopidogrel and ASA . ADP-induced platelet degranulation , activation of GPIIb/IIIa receptor , and aggregation in vivo are effectively inhibited by clopidogrel . The significantly increased disaggregation under clopidogrel and ASA suggests that the combined therapy may be superior to the monotherapy in patients with coron 
    Output:
    