title: Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. Stroke Prevention in Atrial Fibrillation Study: Final Results Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Ventricular dysfunction and the risk of stroke after myocardial infarction. Incidence of Thromboembolic Events in Congestive Heart Failure Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study). The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. PLACEBO-CONTROLLED, RANDOMISED TRIAL OF WARFARIN AND ASPIRIN FOR PREVENTION OF THROMBOEMBOLIC COMPLICATIONS IN CHRONIC ATRIAL FIBRILLATION: The Copenhagen AFASAK Study Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study.
abstract: 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 of anticoagulation in congestive heart failure are controversial . Methods and Results The data base provided by the Veterans Affairs Vasodilator-Heart Failure Trials ( V-HeFT I and II ) was examined retrospectively to address these issues . In V-HeFT I , 642 men with heart failure were followed an average of 2.28 years , providing 1,464 patient-years of follow-up . In V-HeFT II , 804 men were followed an average of 2.56 years , with 2,061 patient-years of follow-up . Mean left ventricular ejection fraction was 30%o in V-HeFT I and 29 % in V-HeFT II . Functional capacity was at the interface of classes II and III with a peak exercise oxygen consumption of 14.7 mL. kg -1 . min-1 in V-HeFT I and 13.7 mL- kg-1 min-1 in V-HeFT II . Warfarin and antiplatelet agents were administered at the discretion of individual investigators . The incidence of all thromboembolic events during 1,068 patient-years without warfarin in V-HeFIT I was 2.7/100 patient-years and during 1,188 patient-years in V-HeFT II was 2.1/100 patient-years and was not reduced in patients treated with warfarin . Patients experiencing events had a lower peak exercise oxygen consumption ( P<0.03 in V-HeFT I and P<0.001 in V-HeFT II ) and a lower mean ejection fraction ( P=0.10 in V-HeFT I and P=0.07 in V-HeFT II ) . Atrial fibrillation was not associated with an increased risk of thromboembolic events . Conclusions The incidence of thromboembolism and stroke in class II or III congestive heart failure is not high and may not be significantly reduced with warfarin treatment . Routine use of anticoagulants in patients with heart failure may not be justified BACKGROUND In patients with congestive heart failure ( CHF ) , clinical trials have demonstrated the benefit of a number of drugs on morbidity and mortality . Nevertheless so far , there is no published controlled study of long-term antithrombotic therapy in patients with CHF . The aim of this work was to identify the relationship between cardiovascular drug use , especially antithrombotic therapy , and survival of CHF patients in current clinical practice , using an observational , population -based data base . METHODS The EPICAL study ( Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine ) has identified prospect ively all patients with severe CHF in the community of Lorraine . Inclusion criteria were age 20 - 80 years in 1994 , at least one hospitalisation for cardiac decompensation , NYHA III/IV HF , ventricular ejection fraction < or = 30 % or cardiothoracic index > or = 60 % and arterial hypotension or peripheral and /or pulmonary oedema . A total of 417 consecutive patients surviving at hospital discharge were included in the data base . The average follow-up period was 5 years . Univariate Cox models were used to test the relationship of baseline biological and clinical factors to survival .  Cardiovascular drug prescriptions were tested in a multivariate Cox model adjusted by other known predictive factors . RESULTS Duration of disease > 1 year , renal failure , serum sodium > or = 138 mmol/l , old age , serious comorbidity , previous decompensation , high doses of furosemide and vasodilators use were independently associated with poor prognosis at 1 and 5 years . Oral anticoagulants , aspirin , lipid lowering drugs and beta-blockers use were associated with better survival . There was no interaction between aspirin and angiotensin converting enzyme inhibitor use on survival . CONCLUSION Antithrombotic therapy was associated with a better long-term survival in our study population of severe CHF . These results together with other previously published circumstantial evidence urge for a prospect i ve , controlled and r and omised trial specifically design ed to evaluate optimal oral anticoagulants and aspirin in patients with congestive heart failure BACKGROUND Nonrheumatic atrial fibrillation increases the risk of stroke , presumably from atrial thromboemboli . There is uncertainty about the efficacy and risks of long-term warfarin therapy to prevent stroke . METHODS We conducted an unblinded , r and omized , controlled trial of long-term , low-dose warfarin therapy ( target prothrombin-time ratio , 1.2 to 1.5 ) in patients with nonrheumatic atrial fibrillation . The control group was not given warfarin but could choose to take aspirin . RESULTS A total of 420 patients entered the trial ( 212 in the warfarin group and 208 in the control group ) and were followed for an average of 2.2 years .  Prothrombin times in the warfarin group were in the target range 83 percent of the time . Only 10 percent of the patients assigned to receive warfarin discontinued the drug permanently . There were 2 strokes in the warfarin group ( incidence , 0.41 percent per year ) as compared with 13 strokes in the control group ( incidence , 2.98 percent per year ) , for a reduction of 86 percent in the risk of stroke ( warfarin : control incidence ratio = 0.14 ; 95 percent confidence interval , 0.04 to 0.49 ; P = 0.0022 ) . There were 37 deaths altogether . The death rate was markedly lower in the warfarin group than in the control group : 2.25 percent as compared with 5.97 percent per year , for an incidence ratio of 0.38 ( 95 percent confidence interval , 0.17 to 0.82 ; P = 0.005 ) . There was one fatal hemorrhage in each group . The frequency of bleeding events that led to hospitalization or transfusion was essentially the same in both groups . The warfarin group had a higher rate of minor hemorrhage than the control group ( 38 vs. 21 patients ) . CONCLUSIONS Long-term low-dose warfarin therapy is highly effective in preventing stroke in patients with non-rheumatic atrial fibrillation , and can be quite safe with careful monitoring From November , 1985 , to June , 1988 , 1007 out patients with chronic non-rheumatic atrial fibrillation ( AF ) entered a r and omised trial ; 335 received anticoagulation with warfarin openly , and in a double-blind study 336 received aspirin 75 mg once daily and 336 placebo . Each patient was followed up for 2 years or until termination of the trial . The primary endpoint was a thromboembolic complication ( stroke , transient cerebral ischaemic attack , or embolic complications to the viscera and extremities ) . The secondary endpoint was death . The incidence of thromboembolic complications and vascular mortality were significantly lower in the warfarin group than in the aspirin and placebo groups , which did not differ significantly . 5 patients on warfarin had thromboembolic complications compared with 20 patients on aspirin and 21 on placebo . 21 patients on warfarin were withdrawn because of non-fatal bleeding complications compared with 2 on aspirin and none on placebo . Thus , anticoagulation therapy with warfarin can be recommended to prevent thromboembolic complications in patients with chronic non-rheumatic AF BACKGROUND It is not clear if long-term antithrombotic treatment has a beneficial effect on the incidence of thromboembolism in chronic heart failure ( CHF ) . The HELAS study ( Heart failure Long-term Antithrombotic Study ) is a multicentre , r and omised , double-blind , placebo-controlled trial to evaluate antithrombotic treatment in patients with CHF . METHODS 197HF patients ( EF < 35 % ) were enrolled . Patients with Ischaemic Heart Disease were r and omised to receive either aspirin 325 mg or warfarin .  Patients with Dilated Cardiomyopathy ( DCM ) were r and omised to receive either warfarin or placebo . RESULTS Analysis of the data from 312 patient years showed an incidence of 2.2 embolic events per 100 patient years , with no significant difference between groups . The incidence of myocardial infa rct ion , hospitalisation , exacerbation of heart failure , death and haemorrhage were not different between the groups . No peripheral or pulmonary emboli were reported . Echocardiographic follow-up for 2years showed an overall increase in left ventricular ejection fraction from 28.2+/-6 to 30.3+/-7 p<0.05 , which was most obvious in patients with DCM taking warfarin ( EF 26.8+/-5.3 at baseline , 30.7+/-10 at 2 years , p<0.05 ) . CONCLUSIONS ( 1 ) Overall embolic events are rare in heart failure regardless of treatment . ( 2 ) Treatment does not seem to affect outcome
target: 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
background: BACKGROUND Patients with chronic heart failure ( heart failure ) are at risk of thromboembolic events , including stroke , pulmonary embolism and peripheral arterial embolism , whilst coronary ischaemic events also contribute to the progression of heart failure .
  Long-term oral anticoagulation is established in certain patient groups , including patients with heart failure and atrial fibrillation , but there is wide variation in the indications and use of oral anticoagulation in the broader heart failure population .
  OBJECTIVES To determine whether long-term oral anticoagulation reduces total deaths , cardiovascular deaths and major thromboembolic events in patients with heart failure .