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 Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. 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 Effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study). Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
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 BACKGROUND Milrinone , a phosphodiesterase inhibitor , enhances cardiac contractility by increasing intracellular levels of cyclic AMP , but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined . METHODS We r and omly assigned 1,088 patients with severe chronic heart failure ( New York Heart Association class III or IV ) and advanced left ventricular dysfunction to double-blind treatment with  ( 40 mg of oral milrinone daily ( 561 patients ) or placebo ( 527 patients ) . In addition , all patients received conventional therapy with digoxin , diuretics , and a converting-enzyme inhibitor throughout the trial . The median period of follow-up was 6.1 months ( range , 1 day to 20 months ) . RESULTS As compared with placebo , milrinone therapy was associated with a 28 percent increase in mortality from all causes ( 95 percent confidence interval , 1 to 61 percent ; P = 0.038 ) and a 34 percent increase in cardiovascular mortality ( 95 percent confidence interval , 6 to 69 percent ; P = 0.016 ) . The adverse effect of milrinone was greatest in patients with the most severe symptoms ( New York Heart Association class IV ) , who had a 53 percent increase in mortality ( 95 percent confidence interval , 13 to 107 percent ; P = 0.006 ) . Milrinone did not have a beneficial effect on the survival of any subgroup . Patients treated with milrinone had more hospitalizations ( 44 vs. 39 percent , P = 0.041 ) , were withdrawn from double-blind therapy more frequently ( 12.7 vs. 8.7 percent , P = 0.041 ) , and had serious adverse cardiovascular reactions , including hypotension ( P = 0.006 ) and syncope ( P = 0.002 ) , more often than the patients given placebo . CONCLUSIONS Our findings indicate that despite its beneficial hemodynamic actions , long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure . The mechanism by which the drug exerts its deleterious effects is unknown 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 Data from epidemiologic , autopsy , Holter monitoring , and electrophysiologic studies support the hypothesis that acute myocardial ischemia , even in the absence of myocardial infa rct ion , is a critical component of the pathophysiology of sudden coronary death . Acute myocardial ischemia superimposed upon ventricles damaged from previous infa rct ions has been demonstrated to enhance the generation of lethal ventricular arrhythmias . This is a retrospective analysis of 6,797 participants in the Studies of Left Ventricular Dysfunction prevention and treatment trials . Both univariate and multivariate Cox proportional-hazards modeling were used to study the association of anticoagulant and antiplatelet therapy with the risk for sudden cardiac death . The following covariates were adjusted for in the analysis : age , ejection fraction , gender , atrial fibrillation , diabetes , a history of angina , prior infa rct ion , prior revascularization , and the regular use of beta blockers , diuretics , digoxin , antiarrhythmic agents , or enalapril . The overall incidence of sudden cardiac death per 100 patient-years of follow-up was 2.24 % . In multivariate analysis , antiplatelet and anticoagulant monotherapy each remained independently associated with a reduction in the risk of sudden cardiac death :  antiplatelet therapy with a 24 % reduction ( relative risk [ RR ] 0.76 ; 95 % confidence interval [ CI ] 0.61 - 0.95 ) and antiplatelet monotherapy with a 32 % reduction ( RR 0.68 ; 95 % CI 0.48 - 0.96 ) . Thus , in patients with moderate to severe left ventricular systolic dysfunction result ing from coronary artery disease , antiplatelet and anticoagulant therapy are each associated with a reduction in the risk of sudden cardiac death 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 It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity . We studied the effect of an angiotensin-converting -- enzyme inhibitor , enalapril , on total mortality and mortality from cardiovascular causes , the development of heart failure , and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure . METHODS Patients were r and omly assigned to receive either placebo ( n = 2117 ) or enalapril ( n = 2111 ) at doses of 2.5 to 20 mg per day in a double-blind trial . Follow-up averaged 37.4 months . RESULTS There were 334 deaths in the placebo group , as compared with 313 in the enalapril group ( reduction in risk , 8 percent by the log-rank test ; 95 percent confidence interval , -8 percent [ an increase of 8 percent ] to 21 percent ; P = 0.30 ) . The reduction in mortality from cardiovascular causes was larger but was not statistically significant ( 298 deaths in the placebo group vs. 265 in the enalapril group ; risk reduction , 12 percent ; 95 percent confidence interval , -3 to 26 percent ; P = 0.12 ) . When we combined patients in whom heart failure developed and those who died , the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group ( 630 vs. 818 ; risk reduction , 29 percent ; 95 percent confidence interval , 21 to 36 percent ; P less than 0.001 ) . In addition , fewer patients given enalapril  died or were hospitalized for heart failure ( 434 in the enalapril group ; vs. 518 in the placebo group ; risk reduction , 20 percent ; 95 percent confidence interval , 9 to 30 percent ; P less than 0.001 ) . CONCLUSIONS The angiotensin-converting -- enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations , as compared with the rates in the group given placebo , among patients with asymptomatic left ventricular dysfunction . There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril OBJECTIVES The aims of this study were to describe the incidence and spectrum of thromboembolic events experienced by patients with moderate to severe left ventricular systolic dysfunction in normal sinus rhythm and to study the association between ejection fraction and thromboembolic risk . BACKGROUND The annual incidence of thromboembolic events in patients with heart failure is estimated to range from 0.9 % to 5.5 % . Previous studies demonstrating a relation between worsening left ventricular systolic function and thromboembolic risk are difficult to interpret because of the prevalence of atrial fibrillation , an independent risk factor for thromboembolism , in the patients with a lower ejection fraction . METHODS This is a retrospective analysis of the Studies of Left Ventricular Dysfunction prevention and treatment trials data base . Patients with atrial fibrillation were excluded , result ing in 6,378 participants in sinus rhythm at the time of r and omization .  Thromboembolic events include strokes , pulmonary emboli and peripheral emboli . Separate analyses were conducted in each gender because there was evidence of a significant interaction between ejection fraction and gender on the risk of thromboembolic events ( p = 0.04 ) . RESULTS The overall annual incidence of thromboembolic events was 2.4 % in women and 1.8 % in men . On univariate analysis , a decline in ejection fraction was [ corrected ] associated with thromboembolic risk in women ( relative risk [ RR ] per 10 % decrease in ejection fraction 1.58 , 95 % confidence interval [ CI ] 1.10 to 2.26 , p = 0.01 ) , but not in men . On multivariate analysis , a decline in ejection fraction remained independently associated with thromboembolic risk in women ( RR per 10 % decrease 1.53 , 95 % CI 1.06 to 2.20 , p = 0.02 ) , but no relation was demonstrated in men . CONCLUSIONS In patients with left ventricular systolic dysfunction and sinus rhythm , the annual incidence of thromboembolic events is low . Ejection fraction appears to be independently associated with thromboembolic risk in women , but not in men OBJECTIVES This study sought to evaluate the relation between antiplatelet agent ( APA ) use and survival and morbidity from cardiac disease in patients with left ventricular ( LV ) systolic dysfunction . BACKGROUND APAs play an important role in the prevention and treatment of coronary disease . Their effects in patients with LV systolic dysfunction are unknown . METHODS We review ed data on  APA use in 6,797 patients enrolled in the Studies of Left Ventricular Dysfunction ( SOLVD ) trial and analyzed the relation between their use and all-cause mortality as well as the combined end point of death or hospital admission for heart failure ( HF ) . We used Cox regression to adjust for differences in baseline characteristics and to test for the interaction between APA use and selected patient variables in relation to outcome . RESULTS APA use ( 46.3 % of patients ) was associated with significantly reduced mortality from all causes ( adjusted hazard ratio [ HR ] 0.82 , 95 % confidence interval [ CI ] 0.73 to 0.92 , p = 0.0005 ) and reduced risk of death or hospital admission for HF ( adjusted HR 0.81 , 95 % CI 0.74 to 0.89 , p < 0.0001 ) but was not influenced by trial assignment , gender , LV ejection fraction , New York Heart Association class or etiology . A strong interaction was observed among  APA use , r and omization group and all-cause mortality . The association between APA use and survival was not observed in the enalapril group , nor was an enalapril benefit on survival detectable in patients receiving APAs at baseline . However , r and omization to enalapril therapy significantly reduced the combined end point of death or hospital admission for HF in APA users . CONCLUSIONS In patients with LV systolic dysfunction , use of APAs is associated with improved survival and reduced morbidity . This association is retained after adjustment for baseline characteristics . APA use is associated with retained but reduced benefit from enalapril In the Persantine-Aspirin Reinfa rct ion Study , Part II ( PARIS II ) , 3,128 persons who had recovered from myocardial infa rct ion , suffered from 4 weeks to 4 months previously , were r and omized into two groups : dipyridamole ( Persantine ) plus aspirin ( n = 1,563 ) and placebo ( n = 1,565 ) . The average length of follow-up was 23.4 months . Prespecified primary end points were coronary incidence ( definite nonfatal myocardial infa rct ion plus death due to recent or acute cardiac event ) , coronary mortality ( death due to recent or acute cardiac event ) and total mortality , each at 1 year of patient follow-up and at the end of the study . Coronary incidence in the Persantine plus aspirin group was significantly lower than in the placebo group , both at 1 year ( 30 % reduction ) and at the end of the study ( 24 % reduction ) . The statistically significant differences in coronary incidence , at 1 year and at the end of the study , in favor of the combination treatment remained after adjustment for multiple baseline variables and adjustment for multiple testing ( three end points for two time periods ) . Although there were reductions for other end points , these differences were not statistically significant . Coronary mortality was 20 % lower in the Persantine plus aspirin group compared with the placebo group at 1 year , and 6 % lower overall . Total mortality in the treated group compared with the placebo group was 11 % lower at 1 year and 3 % lower overall . The reduced rates of coronary incidence largely reflected lower rates of definite nonfatal myocardial infa rct ion in the Persantine plus aspirin group . Several subgroups were defined a priori and at the end of the study . The beneficial effect of Persantine plus aspirin compared with placebo for coronary incidence tended to be greater for the following groups of patients : those who had a non-Q wave infa rct ; those who were not taking digitalis ; those who were receiving beta-receptor blocking drugs at baseline ; those who were in New York Heart Association functional class I ; those who had had only one myocardial infa rct ion ; or those who were enrolled in the study early , that is within 85 days of the qualifying myocardial infa rct ion 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 BACKGROUND Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently . We studied the effect of an angiotensin-converting-enzyme inhibitor , enalapril , on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35 . METHODS Patients receiving conventional treatment for heart failure were r and omly assigned to receive either placebo ( n = 1284 ) or enalapril ( n = 1285 ) at doses of 2.5 to 20 mg per day in a double-bind trial . Approximately 90 percent of the patients were in New York Heart Association functional classes II and III . The follow-up averaged 41.4 months . RESULTS There were 510 deaths in the placebo group ( 39.7 percent ) , as compared with 452 in the enalapril group ( 35.2 percent ) ( reduction in risk , 16 percent ; 95 percent confidence interval , 5 to 26 percent ; P = 0.0036 ) . Although reductions in mortality were observed in several categories of cardiac deaths , the largest reduction occurred among the deaths attributed to progressive heart failure ( 251 in the placebo group vs. 209 in the enalapril group ; reduction in risk , 22 percent ; 95 percent confidence interval , 6 to 35 percent ) . There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure . Fewer patients died or were hospitalized for worsening heart failure ( 736 in the placebo group and 613 in the enalapril group ; risk reduction , 26 percent ; 95 percent confidence interval , 18 to 34 percent ; P less than 0.0001 ) . CONCLUSIONS The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions
target: At present , there are no data on the role of oral anticoagulation versus antiplatelet agents in heart failure with preserved ejection fraction with sinus rhythm .
  Also , there were no data from RCTs on the utility of non-vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm
background: BACKGROUND Morbidity in patients with chronic heart failure is high , and this predisposes them to thrombotic complications , including stroke and thromboembolism , which in turn contribute to high mortality .
  Oral anticoagulants ( e.g. warfarin ) and antiplatelet agents ( e.g. aspirin ) are the principle oral antithrombotic agents .
  Many heart failure patients with sinus rhythm take aspirin because coronary artery disease is the leading cause of heart failure .
  Oral anticoagulants have become a st and ard in the management of heart failure with atrial fibrillation .
  However , a question remains regarding the appropriateness of oral anticoagulants in heart failure with sinus rhythm .
  This up date of a review previously published in 2012 aims to address this question .
  OBJECTIVES To assess the effects of oral anticoagulant therapy versus antiplatelet agents for all-cause mortality , non-fatal cardiovascular events and risk of major bleeding in adults with heart failure ( either with reduced or preserved ejection fraction ) who are in sinus rhythm .