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 — 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 PURPOSE To determine the incidence of major bleeding in out patients treated with warfarin  and to identify predictive factors known at the start of therapy . PATIENTS AND METHODS The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were review ed . Follow-up information was obtained for 562 patients ( 99.5 % ) .  Bleeding was classified as major or minor using explicit criteria . The cumulative incidence of bleeding was estimated by means of survival analysis . Independent risk factors for major bleeding were identified using Cox regression analysis in 375 r and omly chosen patients ; they were tested in the remaining 187 patients . RESULTS Major bleeding occurred in 65 patients ( 12 % ) and was fatal in 10 patients ( 2 % ) . The cumulative incidences of major bleeding at one , 12 , and 48 months were 3 % , 11 % , and 22 % , respectively . The monthly risk of major bleeding decreased over time , from 3 % during the first month of outpatient therapy to 0.3 % per month after the first year of therapy . Five independent risk factors for major bleeding -- age 65 years or greater , history of stroke , history of gastrointestinal bleeding , a serious comorbid condition ( recent myocardial infa rct ion , renal insufficiency , or severe anemia ) , atrial fibrillation -- predicted major bleeding in the testing group ; the cumulative incidence of major bleeding at 48 months was 2 % in 57 low-risk patients , 17 % in 110 middle-risk patients , and 63 % in 20 high-risk patients . CONCLUSION These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin . Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined OBJECTIVES We sought to evaluate the relation between warfarin anticoagulation and survival and morbidity from cardiac disease in patients with left ventricular ( LV ) dysfunction . BACKGROUND Warfarin anticoagulation plays a major role in the management of patients who have had a large myocardial infa rct ion and in those with atrial fibrillation . However , its use in patients with LV systolic dysfunction has been controversial . METHODS We review ed data on  warfarin use in 6,797 patients enrolled in the Studies of Left Ventricular Dysfunction ( SOLVD ) trial and analyzed the relation between warfarin use and all-cause mortality , as well as the combined end point of death or hospital admission for heart failure . We used Cox regression to adjust for differences in baseline characteristics and to test for the interaction between warfarin use and selected patient variables in relation to outcome . RESULTS On multivariate analysis , use of warfarin was associated with a significant reduction in all-cause mortality ( adjusted hazard ratio [ HR ] 0.76 , 95 % confidence interval [ CI ] 0.65 to 0.89 , p = 0.0006 ) and in the risk of death or hospital admission for heart failure ( HR 0.82 , 95 % CI 0.72 to 0.93 , p = 0.0002 ) . Risk reduction was observed when each trial or r and omization arm was analyzed separately , as well as in both genders . It was not significantly influenced by the presence of atrial fibrillation , age , ejection fraction , New York Heart Association functional class or etiology . CONCLUSIONS In patients with LV systolic dysfunction , warfarin use is associated with improved survival and reduced morbidity . This association is primarily due to a reduction in cardiac events and does not appear to be limited to any particular subgroup Background Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke . Methods and Main Results . The Stroke Prevention in Atrial Fibrillation Study , a multicenter , r and omized trial , compared 325 mg/day aspirin ( double-blind ) or warfarin with placebo for prevention of ischemic stroke and systemic embolism ( primary events ) , and included 1,330 in patients and out patients with constant or intermittent atrial fibrillation . During a mean follow-up of 1.3 years , the rate of primary events in patients assigned to placebo was 6.3 % per year and was reduced by 42 % in those assigned to aspirin ( 3.6 % per year , p = 0.02 ; 95 % confidence interval , 9–63 % ) . In the subgroup of  warfarin-eligible patients ( most less than 76 years old ) , warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67 % ( warfarin versus placebo , 2.3 % versus 7.4 % per year , p = 0.01 ; 95 % confidence interval , 27–85 % ) . Primary events or death were reduced 58 % ( p = 0.01 ) by warfarin and 32 % ( p = 0.02 ) by aspirin . The risk of significant bleeding was 1.5 % , 1.4 % , and 1.6%o per year in patients assigned to warfarin , aspirin , and placebo , respectively . Conclusions Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation . Because warfarin-eligible patients composed a subset of all aspirin-eligible patients , the magnitude of reduction in events by warfarin versus aspirin can not be compared . Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin , and the trial is continuing to address this issue . Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke To evaluate the influence of the angiotensin-converting enzyme inhibitor , enalapril ( 2.5 to 40 mg/day ) , on the prognosis of severe congestive heart failure , defined as New York Heart Association functional class IV , a double-blind study was undertaken in which 253 patients were r and omized to receive either placebo  ( n = 126 ) or enalapril ( n = 127 ) in addition to conventional treatment , including  vasodilators . Follow-up averaged 188 days ( range 1 day to 20 months ) . The reduction in crude mortality within 6 months ( primary objective ) was 40 % in the enalapril-treated group ( from 44 to 26 % , p = 0.002 ) and within 1 year 31 % ( p = 0.001 ) . By the end of the study , 68 subjects in the placebo group and 50 in the enalapril group had died -- a reduction of 27 % ( p = 0.003 ) . The entire reduction in total mortality ( 50 % ) was found in patients dying from progressive heart failure , whereas no difference was seen in the incidence of sudden cardiac death . There was a significant improvement in New York Heart Association classification in the enalapril group , together with a reduction in heart size and a reduced requirement for other heart failure medication . It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms . The effect seems to be due to a reduction in death from progression of heart failure BACKGROUND Heart failure is commonly associated with vascular disease and a high rate of athero-thrombotic events , but the risks and benefits of antithrombotic therapy are unknown . METHODS The current study was an open-label , r and omized , controlled trial comparing no antithrombotic therapy , aspirin ( 300 mg/day ) , and warfarin ( target international normalized ratio 2.5 ) in patients with heart failure and left ventricular systolic dysfunction requiring diuretic therapy . The primary objective was to demonstrate the feasibility and inform the design of a larger outcome study . The primary clinical outcome was death , nonfatal myocardial infa rct ion , or nonfatal stroke . RESULTS Two hundred seventy-nine patients were r and omized and 627 patient-years exposure were accumulated over a mean follow-up time of 27 + /- 1 months . Twenty-six ( 26 % ) , 29 ( 32 % ) , and 23 ( 26 % ) patients r and omized to no antithrombotic treatment , aspirin , and warfarin , respectively , reached the primary outcome ( ns ) . There were trends to a worse outcome among those r and omized to aspirin for a number of secondary outcomes . Significantly ( P = .044 ) more patients r and omized to aspirin were hospitalized for cardiovascular reasons , especially worsening heart failure . CONCLUSIONS The Warfarin/Aspirin Study in Heart failure ( WASH ) provides no evidence that aspirin is effective or safe in patients with heart failure . The benefits of warfarin for patients with heart failure in sinus rhythm have not been established . Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy BACKGROUND In patients who have had a myocardial infa rct ion , the long-term risk of stroke and its relation to the extent of left ventricular dysfunction have not been determined . We studied whether a reduced left ventricular ejection fraction is associated with an increased risk of stroke after myocardial infa rct ion and whether other factors such as older age and therapy with anticoagulants , thrombolytic agents , or captopril affect long-term rates of stroke . METHODS We performed an observational analysis of prospect ively collected data on 2231 patients who had left ventricular dysfunction after acute myocardial infa rct ion who were enrolled in the Survival and Ventricular Enlargement trial . The mean follow-up was 42 months . Risk factors for stroke were assessed by both univariate and multivariate Cox proportional-hazards analysis . RESULTS Among these patients , 103 ( 4.6 percent ) had fatal or nonfatal strokes during the study ( rate of stroke per year of follow-up , 1.5 percent ) . The estimated five-year rate of stroke in all the patients was 8.1 percent . As compared with patients without stroke , patients with stroke were older ( mean [ + /-SD ] age , 63+/-9 years vs. 59+/-11 years ; P<0.001 ) and had lower ejection fractions ( 29+/-7 percent vs. 31+/-7 percent , P=0.01 ) . Independent risk factors for stroke included a lower ejection fraction ( for every decrease of 5 percentage points in the ejection fraction there was an 18 percent increase in the risk of stroke ) , older age , and the absence of aspirin or anticoagulant therapy . Patients with ejection fractions of < or = 28 percent after myocardial infa rct ion had a relative risk of stroke of 1.86 , as compared with patients with ejection fractions of more than 35 percent ( P=0.01 ) . The use of thrombolytic agents and captopril had no significant effect on the risk of stroke . CONCLUSIONS During the five years after myocardial infa rct ion , patients have a substantial risk of stroke . A decreased ejection fraction and older age are both independent predictors of an increased risk of stroke .  Anticoagulant therapy appears to have a protective effect against stroke after myocardial infa rct ion Background The incidence of thromboembolism and the benefit 
    Output:
    
agent
Based on the two major r and omised trials ( HELAS 2006 ; WASH 2004 ) , there is no convincing evidence that oral anticoagulant therapy modifies mortality or vascular events in patients with heart failure and sinus rhythm .
Although oral anticoagulation is indicated in certain groups of patients with heart failure ( for example those with atrial fibrillation ) , the available data does not support the routine use of anticoagulation in heart failure patients who remain in sinus rhythm
***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 — 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 PURPOSE To determine the incidence of major bleeding in out patients treated with warfarin  and to identify predictive factors known at the start of therapy . PATIENTS AND METHODS The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were review ed . Follow-up information was obtained for 562 patients ( 99.5 % ) .  Bleeding was classified as major or minor using explicit criteria . The cumulative incidence of bleeding was estimated by means of survival analysis . Independent risk factors for major bleeding were identified using Cox regression analysis in 375 r and omly chosen patients ; they were tested in the remaining 187 patients . RESULTS Major bleeding occurred in 65 patients ( 12 % ) and was fatal in 10 patients ( 2 % ) . The cumulative incidences of major bleeding at one , 12 , and 48 months were 3 % , 11 % , and 22 % , respectively . The monthly risk of major bleeding decreased over time , from 3 % during the first month of outpatient therapy to 0.3 % per month after the first year of therapy . Five independent risk factors for major bleeding -- age 65 years or greater , history of stroke , history of gastrointestinal bleeding , a serious comorbid condition ( recent myocardial infa rct ion , renal insufficiency , or severe anemia ) , atrial fibrillation -- predicted major bleeding in the testing group ; the cumulative incidence of major bleeding at 48 months was 2 % in 57 low-risk patients , 17 % in 110 middle-risk patients , and 63 % in 20 high-risk patients . CONCLUSION These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin . Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined OBJECTIVES We sought to evaluate the relation between warfarin anticoagulation and survival and morbidity from cardiac disease in patients with left ventricular ( LV ) dysfunction . BACKGROUND Warfarin anticoagulation plays a major role in the management of patients who have had a large myocardial infa rct ion and in those with atrial fibrillation . However , its use in patients with LV systolic dysfunction has been controversial . METHODS We review ed data on  warfarin use in 6,797 patients enrolled in the Studies of Left Ventricular Dysfunction ( SOLVD ) trial and analyzed the relation between warfarin use and all-cause mortality , as well as the combined end point of death or hospital admission for heart failure . We used Cox regression to adjust for differences in baseline characteristics and to test for the interaction between warfarin use and selected patient variables in relation to outcome . RESULTS On multivariate analysis , use of warfarin was associated with a significant reduction in all-cause mortality ( adjusted hazard ratio [ HR ] 0.76 , 95 % confidence interval [ CI ] 0.65 to 0.89 , p = 0.0006 ) and in the risk of death or hospital admission for heart failure ( HR 0.82 , 95 % CI 0.72 to 0.93 , p = 0.0002 ) . Risk reduction was observed when each trial or r and omization arm was analyzed separately , as well as in both genders . It was not significantly influenced by the presence of atrial fibrillation , age , ejection fraction , New York Heart Association functional class or etiology . CONCLUSIONS In patients with LV systolic dysfunction , warfarin use is associated with improved survival and reduced morbidity . This association is primarily due to a reduction in cardiac events and does not appear to be limited to any particular subgroup Background Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke . Methods and Main Results . The Stroke Prevention in Atrial Fibrillation Study , a multicenter , r and omized trial , compared 325 mg/day aspirin ( double-blind ) or warfarin with placebo for prevention of ischemic stroke and systemic embolism ( primary events ) , and included 1,330 in patients and out patients with constant or intermittent atrial fibrillation . During a mean follow-up of 1.3 years , the rate of primary events in patients assigned to placebo was 6.3 % per year and was reduced by 42 % in those assigned to aspirin ( 3.6 % per year , p = 0.02 ; 95 % confidence interval , 9–63 % ) . In the subgroup of  warfarin-eligible patients ( most less than 76 years old ) , warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67 % ( warfarin versus placebo , 2.3 % versus 7.4 % per year , p = 0.01 ; 95 % confidence interval , 27–85 % ) . Primary events or death were reduced 58 % ( p = 0.01 ) by warfarin and 32 % ( p = 0.02 ) by aspirin . The risk of significant bleeding was 1.5 % , 1.4 % , and 1.6%o per year in patients assigned to warfarin , aspirin , and placebo , respectively . Conclusions Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation . Because warfarin-eligible patients composed a subset of all aspirin-eligible patients , the magnitude of reduction in events by warfarin versus aspirin can not be compared . Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin , and the trial is continuing to address this issue . Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke To evaluate the influence of the angiotensin-converting enzyme inhibitor , enalapril ( 2.5 to 40 mg/day ) , on the prognosis of severe congestive heart failure , defined as New York Heart Association functional class IV , a double-blind study was undertaken in which 253 patients were r and omized to receive either placebo  ( n = 126 ) or enalapril ( n = 127 ) in addition to conventional treatment , including  vasodilators . Follow-up averaged 188 days ( range 1 day to 20 months ) . The reduction in crude mortality within 6 months ( primary objective ) was 40 % in the enalapril-treated group ( from 44 to 26 % , p = 0.002 ) and within 1 year 31 % ( p = 0.001 ) . By the end of the study , 68 subjects in the placebo group and 50 in the enalapril group had died -- a reduction of 27 % ( p = 0.003 ) . The entire reduction in total mortality ( 50 % ) was found in patients dying from progressive heart failure , whereas no difference was seen in the incidence of sudden cardiac death . There was a significant improvement in New York Heart Association classification in the enalapril group , together with a reduction in heart size and a reduced requirement for other heart failure medication . It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms . The effect seems to be due to a reduction in death from progression of heart failure BACKGROUND Heart failure is commonly associated with vascular disease and a high rate of athero-thrombotic events , but the risks and benefits of antithrombotic therapy are unknown . METHODS The current study was an open-label , r and omized , controlled trial comparing no antithrombotic therapy , aspirin ( 300 mg/day ) , and warfarin ( target international normalized ratio 2.5 ) in patients with heart failure and left ventricular systolic dysfunction requiring diuretic therapy . The primary objective was to demonstrate the feasibility and inform the design of a larger outcome study . The primary clinical outcome was death , nonfatal myocardial infa rct ion , or nonfatal stroke . RESULTS Two hundred seventy-nine patients were r and omized and 627 patient-years exposure were accumulated over a mean follow-up time of 27 + /- 1 months . Twenty-six ( 26 % ) , 29 ( 32 % ) , and 23 ( 26 % ) patients r and omized to no antithrombotic treatment , aspirin , and warfarin , respectively , reached the primary outcome ( ns ) . There were trends to a worse outcome among those r and omized to aspirin for a number of secondary outcomes . Significantly ( P = .044 ) more patients r and omized to aspirin were hospitalized for cardiovascular reasons , especially worsening heart failure . CONCLUSIONS The Warfarin/Aspirin Study in Heart failure ( WASH ) provides no evidence that aspirin is effective or safe in patients with heart failure . The benefits of warfarin for patients with heart failure in sinus rhythm have not been established . Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy BACKGROUND In patients who have had a myocardial infa rct ion , the long-term risk of stroke and its relation to the extent of left ventricular dysfunction have not been determined . We studied whether a reduced left ventricular ejection fraction is associated with an increased risk of stroke after myocardial infa rct ion and whether other factors such as older age and therapy with anticoagulants , thrombolytic agents , or captopril affect long-term rates of stroke . METHODS We performed an observational analysis of prospect ively collected data on 2231 patients who had left ventricular dysfunction after acute myocardial infa rct ion who were enrolled in the Survival and Ventricular Enlargement trial . The mean follow-up was 42 months . Risk factors for stroke were assessed by both univariate and multivariate Cox proportional-hazards analysis . RESULTS Among these patients , 103 ( 4.6 percent ) had fatal or nonfatal strokes during the study ( rate of stroke per year of follow-up , 1.5 percent ) . The estimated five-year rate of stroke in all the patients was 8.1 percent . As compared with patients without stroke , patients with stroke were older ( mean [ + /-SD ] age , 63+/-9 years vs. 59+/-11 years ; P<0.001 ) and had lower ejection fractions ( 29+/-7 percent vs. 31+/-7 percent , P=0.01 ) . Independent risk factors for stroke included a lower ejection fraction ( for every decrease of 5 percentage points in the ejection fraction there was an 18 percent increase in the risk of stroke ) , older age , and the absence of aspirin or anticoagulant therapy . Patients with ejection fractions of < or = 28 percent after myocardial infa rct ion had a relative risk of stroke of 1.86 , as compared with patients with ejection fractions of more than 35 percent ( P=0.01 ) . The use of thrombolytic agents and captopril had no significant effect on the risk of stroke . CONCLUSIONS During the five years after myocardial infa rct ion , patients have a substantial risk of stroke . A decreased ejection fraction and older age are both independent predictors of an increased risk of stroke .  Anticoagulant therapy appears to have a protective effect against stroke after myocardial infa rct ion Background The incidence of thromboembolism and the benefit 
    Output:
    