511058

research-article2013

AOPXXX10.1177/1060028013511058Annals of PharmacotherapyProm et al

Research Article

Antithrombotics in Heart Failure With Reduced Ejection Fraction and Normal Sinus Rhythm: An Evidence Appraisal

Annals of Pharmacotherapy XX(X) 1­–12 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013511058 aop.sagepub.com

Rathasen Prom, PharmD1, James E. Usedom, MD, FACC1, and Ryan B. Dull, PharmD, BCPS2

Abstract Objective: To review the thromboembolic risk, pathophysiology associated with the risk, and literature investigating the use of antithrombotics in patients with heart failure with reduced ejection fraction and normal sinus rhythm (HFrEFNSR). Data Sources: An English language literature search was performed with MEDLINE/PubMed and Embase from January 1950 to October 2013 using the search terms heart failure, HFrEF, systolic heart failure, cardiomyopathy, left ventricular dysfunction, sinus rhythm, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, acute coronary syndrome, acute coronary events, coronary artery disease, stroke, and cerebrovascular events to identify relevant articles. References in the retrieved articles were also assessed to identify other important articles. Study Selection and Data Abstraction: All pertinent original studies, reviews, consensus documents, and guidelines were evaluated for inclusion. Data Synthesis: Patients with HFrEF-NSR may be predisposed to developing thromboembolic events. Studies that have examined the role of antithrombotics (warfarin and/or antiplatelet therapy) for reducing thromboembolic risk have been inconclusive. The WASH and HELAS pilot trials—the only studies with a no-antithrombotics or placebo comparator group—did not find a benefit with antithrombotic therapy but found an increased risk of bleeding with warfarin and of hospitalizations with aspirin. Although the clinical outcome studies (WATCH and WARCEF) suggested that warfarin may reduce stroke risk compared with antiplatelet therapy, the lack of a placebo group and lower-thanprojected enrollment prevents definitive conclusions from being made. Conclusions: Current evidence does not support the routine use of antithrombotics for preventing thromboembolic events in patients with HFrEF-NSR without compelling indications. Keywords heart failure, cardiomyopathy, sinus rhythm, thromboembolism, anticoagulation, antithrombotics, warfarin, antiplatelets, aspirin, clopidogrel

Introduction Heart failure with reduced ejection fraction (HFrEF) is a complex cardiac condition associated with high rates of morbidity and mortality. In the past 3 decades, the adoption and routine utilization of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists based on evidence from landmark clinical trials have led to improved outcomes, which is reflected by significant reductions in hospitalizations and mortalities as well as improvements in heart failure symptoms and cardiac function.1,2 Even with these advances, there remains an unmet need in the treatment of HFrEF because rates of adverse clinical outcomes are still unacceptably high. Given that many of these clinical events may have thromboembolic origins, questions have arisen

regarding the potential role of antithrombotics in HFrEF therapy.3 Evidence suggests that patients with HFrEF who are in normal sinus rhythm (HFrEF-NSR) may be predisposed to developing arterial and venous thromboembolic events, including stroke, myocardial infarction (MI), deep-vein thrombosis (DVT), and pulmonary embolism (PE).4-11 Antithrombotics have demonstrated efficacy in the primary and/or secondary prophylaxis of these events in patients 1

Mission Hospitals, Asheville, NC, USA Creighton University, Omaha, NE, USA

2

Corresponding Author: Rathasen Prom, PharmD, Department of Pharmacy, Mission Hospitals, 509 Biltmore Avenue, Asheville, NC 28806, USA. Email: [email protected]

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Annals of Pharmacotherapy XX(X)

with specific indications such as atrial fibrillation (AF), prosthetic heart valves, acute coronary syndrome, coronary artery disease, and venous thromboembolism (VTE).12-17 It would seem reasonable to believe that prophylaxis of arterial and venous thromboembolic events with antithrombotics may be especially beneficial to patients with HFrEF-NSR, even without the aforementioned indications. However, because of low-quality data, there is considerable debate surrounding this topic.4-6 European and North American expert societies recognize the uncertainty surrounding the role of antithrombotic therapy in patients with HFrEF-NSR.1,3 A 2012 European Society of Cardiology consensus statement does not recommend the routine use of aspirin in patients with heart failure unless a specific indication, such as coronary artery disease, is present.3 It additionally points out that heart failure by itself is not an indication for anticoagulation and that anticoagulation can be considered in patients with AF, prolonged immobility or rest, intracardiac thrombus, previous ischemic stroke or systemic embolism, right-heart failure, and pulmonary hypertension. The American College of Cardiology/American Heart Association acknowledges that there is no clear benefit from the use of aspirin in those with heart failure and describes its use in patients with comorbid coronary artery disease as controversial.1 They further indicate that it is unclear how to prescribe anticoagulants in heart failure patients but suggest that their use may be justified in those with AF or a previous embolic event. This article reviews the evidence of thromboembolic risk, pathophysiology associated with the risk, and randomized clinical evidence surrounding the use of antithrombotics in patients with HFrEF-NSR.

Data Sources and Selection An English language literature search was performed with MEDLINE/PubMed and Embase from January 1950 to October 2013 using the search terms heart failure, HFrEF, systolic heart failure, cardiomyopathy, left ventricular dysfunction, sinus rhythm, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, acute coronary syndrome, acute coronary events, coronary artery disease, stroke, and cerebrovascular events to identify relevant articles. The references in the retrieved articles were also reviewed to identify other pertinent articles.

Evidence of Thromboembolic Risk Stroke.  The perceived stroke risk in patients with HFrEFNSR stems from case-control studies, post hoc analyses of randomized clinical trials, and epidemiological studies. Case-control studies have suggested that stroke risk ranges from 1.4% to 12.5%, whereas estimates from post hoc analyses of randomized trials have the annual risk ranging from

1.0% to 4.6%.18-27 Epidemiological data have further shown that about 15% to 20% of patients who developed a stroke had a history of heart failure or asymptomatic left-ventricular dysfunction.28 The risk of stroke appears to correlate with the time since heart failure diagnosis and also the degree of left-ventricular dysfunction.24,29 In the Rotterdam Study, as compared with patients without heart failure, the first month since heart failure diagnosis was associated with the highest risk (5-fold increased risk) and was followed by a decline in risk (3.5-fold increased risk) in the subsequent 5 months.29 After 6 months, however, the risk did not appear to be elevated. In a study involving post-MI patients, each 5-percentage point decrease in left-ventricular ejection fraction (LVEF) resulted in an 18% increase in the risk of stroke.24 It is important to note that many patients in these studies had concomitant AF or prosthetic heart valves, and some trials did not differentiate between HFrEF and heart failure with preserved ejection fraction. Therefore, the event rates would need to be interpreted with caution. Acute coronary events. The frequency of acute coronary events as a contributor to adverse clinical outcomes may be underestimated and underappreciated in both the literature and in clinical practice. Mortalities in HFrEF patients are largely diagnosed clinically as being a result of sudden cardiac death (SCD) or progressive myocardial failure.10,11 Although SCD and deaths caused by myocardial failure were previously attributed to ventricular arrhythmias and intractable heart failure, respectively, evidence from postmortem autopsies indicate that acute coronary events are the underlying causes of many of these deaths.10,11,30,31 In the Assessment of Treatment With Lisinopril and Survival (ATLAS) and Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) studies, autopsies performed in patients classified as dying from SCD or arrhythmias revealed acute coronary findings (plaque rupture, coronary thrombus, and recent or acute MI) in 47% and 55%, respectively; in patients listed as dying from myocardial failure, acute coronary findings were present in 25% and 81%.10,11 When all autopsies irrespective of the clinical diagnosis of death were analyzed, the rate of acute coronary findings ranged from 33% to 57%, and 79% to 83% of these events were unrecognized during life.10,11 Venous thromboembolism.  Heart failure is considered to be an independent risk factor for VTE in both ambulatory and hospitalized medical patients.7,9,32-34 Case-control studies involving outpatients showed that the presence of heart failure was associated with a 1.8- to 2.9-fold increased risk of VTE.7,32,33 The severity of systolic dysfunction appeared to contribute to the risk, with an LVEF between 20% and 44% and less than 20% resulting in a 2.8- and 38.3-fold increased risk of VTE, respectively.33 In hospitalized patients, an

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Prom et al analysis of the National Hospital Discharge Survey showed that those with heart failure had a 1.2-fold increased risk of DVT and 2.1-fold increased risk of PE when compared with patients without heart failure.9

levels of β-thromboglobulin, fibrinopeptide A, thrombinantithrombin III complexes, d-dimer, and circulating fibrinogen have been reported in patients with heart failure and are indicative of increased platelet activation, thrombin activity, and fibrinolysis.54,55

Pathophysiology of Thromboembolism The prothrombotic and hypercoagulable states seen in patients with HFrEF-NSR may be attributed to irregularities in blood flow, endothelial dysfunction, and abnormalities in blood constituents, which are the 3 components of Virchow’s triad.3 The presence of left-ventricular dysfunction and low cardiac output in patients with HFrEF-NSR can lead to dilation of and static blood flow within the left chambers of the heart. As a result, there is a substrate for intracardiac thrombus formation and a subsequent risk of systemic embolization. Echocardiographic studies involving patients with dilated cardiomyopathy have shown that left-ventricular thrombi and systemic embolic events are frequently observed at rates ranging from 11% to 44% and 0% to 33%, respectively.18-21 It is interesting to note that these studies, which looked specifically for the occurrence of thrombus in the left ventricle, showed that the absence of a left-ventricular thrombus on echocardiography does not preclude an embolic event from occurring.18-21 Although a nonvisualized left-ventricular thrombus may explain some of these events, an alternative source may be the left-atrial appendage, a location that has also been associated with clot formation.35,36 Endothelial dysfunction or injury may contribute to the prothrombotic state in patients with HFrEF-NSR because of the associated reduction in endothelium-derived nitric oxide release and elevation in plasma levels of von Willebrand factor (vWF) and soluble P-selectin.37-44 Nitric oxide, in addition to being a potent vasodilatory agent, prevents monocyte adhesion to the vessel wall and possesses antiinflammatory, antithrombotic, and antiplatelet activity.45 vWF, in contrast, promotes the adhesion of platelets to the vascular endothelium and also serves as a carrier protein for coagulation factor VIII.45 A marker of platelet function, soluble P-selectin may have a role in atherogenesis, and increased levels may result in increased platelet and leukocyte adhesion to the endothelium.42,46-48 In light of the various hemostatic functions and properties possessed by nitric oxide, vWF, and soluble P-selectin, the observed imbalances of these endothelial biomarkers in patients with HFrEF-NSR may suggest or confer an increased risk of thrombosis. Indeed, reduced nitric oxide release or availability and high vWF and soluble P-selectin levels have been associated with thrombotic events in patients with MI, AF, and VTE.46,49-53 Abnormalities in blood constituents may also contribute to thrombogenesis in patients with HFrEF-NSR. Elevated

Clinical Trials of Antithrombotics in Heart Failure with Reduced Ejection Fraction and Normal Sinus Rhythm The study designs and results of randomized clinical trials that investigated the role of antithrombotics in patients with HFrEF-NSR are presented in Table 1. WASH trial. The Warfarin/Aspirin Study of Heart Failure (WASH) trial was the first clinical study since the 1950s seeking to evaluate the role of antithrombotics in HFrEFNSR and randomized 279 patients to open-label treatments with warfarin (target international normalized ratio [INR] = 2-3), aspirin 300 mg orally daily, or no-antithrombotics.56 There were few patients (6%) who had AF; for those who did have AF, it was recommended that they receive anticoagulation regardless of treatment allocation. Study recruitment began in November 1995 and terminated in November 1997, and follow-up continued until September 1998. At 1 year, there was a high rate of crossover, with only 79%, 88%, and 75% of patients in the no-antithrombotics, aspirin, and warfarin groups still receiving treatment according to their original study allocation. The time in therapeutic range (TTR) for warfarin was not provided; however, the mean INR was 2.3. The mean age of patients was 64 years, and the majority of them were male (74%). MI and ischemic heart disease were the etiologies of HFrEF in 59% and 50%, respectively, whereas dilated cardiomyopathy was the etiology in 15% and hypertension in 4%. In all, 27% were in New York Heart Association (NYHA) class III and 2% in NYHA class IV; 20% had a history of diabetes mellitus, and the mean serum creatinine (SCr) was 1.27 mg/dL. Although ACE inhibitors (91%) and loop diuretics (96%) were widely prescribed, use of β-blockers was low (11%). After a mean follow-up of 2.25 years, there were no differences between the 3 groups in the primary composite outcome of nonfatal MI, nonfatal stroke, and all-cause death; an analysis including only patients in NSR revealed similar results. However, aspirin led to significantly higher rates of all-cause hospitalizations (P < .05) compared with both the warfarin and no-antithrombotics groups, which was mainly driven by higher rates of heart failure hospitalizations (P = .032). Further exploratory analyses into the reasons for heart failure hospitalizations with aspirin revealed that acute breathlessness rather than heart failure deterioration was the cause in most cases. In the safety analyses, there were only 5 major hemorrhages (all gastrointestinal) in the study, with 4

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Participants

Design

Interventions Primary Death Stroke MI All-cause hospitalization HF hospitalization

a

ICM n = 197; Inclusion  HELAS MC (>40 •  ICM: ASA, 57 criteria: 20-75 years (2006) centers 325 mg/d old, LVEF ≤35%, from Bulgaria, (n = 61; mean NYHA II-IV, NSR; Cyprus, follow-up of Primaryb key exclusion criteria: Georgia, 18.5 months); Death contraindication to Greece, warfarin, target Stroke warfarin or ASA, Poland, INR 2-3 (n = 54; MI mitral valve disease, Romania, mean follow-up HF hospitalization intracardiac thrombus, Yugoslavia), of 18.7 months) hypertrophic DB, DD, •  DCM: Placebo cardiomyopathy, RCT (n = 44; mean reversible ischemia follow-up of 18.9 months); warfarin, target INR 2-3 (n = 38; mean follow-up of 21.9 months)

n = 279; Inclusion WASH MC (17 centers Warfarin, target criteria: LVEF ≤35% (2004)56 in the United INR 2-3 (n = 89); (or LVEDP ≥56 mm or Kingdom and ASA, 300 mg/d 30 mm/m2 + fractional 3 centers in (n = 91); noshortening ≤28%), the United antithrombotics NSR; key exclusion States), OL, (n = 99); mean criteria: mitral stenosis, PS follow-up of 2.25 MHV, contraindication years to warfarin or ASA, MI within previous 4 weeks

Study

ASA 14.9% 9.6% 2.1% None 3.2%

15.7% 13.3% 2.4% 1.2% 2.4%

26% 24.7% None 3.4% 47% 20%

Warfarin

Warfarin

26% 21% 2% 7.1% 48% 19%

None

Efficacy

32% 29.7% 2.2% 8.8% 64% 34%

ASA

N/A N/A N/A N/A N/A

Statistics

No difference N/A N/A N/A p = 0.044 p = 0.032

Statistics

Major hemorrhage

4.8%

Warfarin

None

ASA

N/A

(continued)

.033 13% 17% 5%

Minor hemorrhage

ICM

.014 14.3% 6.7%

3.0%

GI events

Statistics

P Value .028

ASA 1.1%

Warfarin 4.5%

None

Safety

None

Major hemorrhage

Table 1.  Clinical Trials of Antithrombotics in Heart Failure with Reduced Ejection Fraction and Normal Sinus Rhythm.

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Primary Death Stroke MI HF hospitalization

b

Warfarin

Warfarin, target INR Primaryj 2-3.5 (n = 1142); Death ASA, 325 mg/d Ischemic stroke (n = 1163); mean ICH hemorrhage follow-up of 3.5 MI years (minimum 1 HF hospitalization year, maximum 6 years)

Warfarin, target Primary INR 2-3.5 (n = Death 540); ASA, 162 All strokef mg/d (n = 523); MI clopidogrel, 75 HF hospitalizationi mg/d (n = 524); mean follow-up of 1.9 years

c

14.8% 8.9% 1.5% None 5.9%

7.47% 6.63% 0.72% 0.12% 0.80% 6.79%

Warfarin

21.6% 18.3% 2.3% 2.5% 18.5%

7.93% 6.52% 1.36% 0.05% 0.87% 5.67%

ASA

19.6% 17% 0.6% 3.9% 16.5%

Clopidogrel Warfarin

8.9% 3% None 1.5% 4.4%

Major hemorrhage

0.93 (0.79-1.10) 1.01 (0.85-1.20) 0.52 (0.33-0.82) 2.22 (0.43-11.66) 0.98 (0.58-1.64) 1.21 (1.0-1.47)

d

Major hemorrhage Intracranial GI All other Minor hemorrhage Thrombocytopenia/ Anemia/Leukopenia

No difference Major hemorrhage No difference CNS bleedse Differences exist Minor bleedsg No difference Diarrheah Differences exist

Statistics

N/A N/A N/A N/A N/A

Statistics

Statistics

HR (95% CI)

20.7% 18% 2.3% 2.7% 22.2%

ASA

ASA

1.78% 0.15% 0.94% 0.57% 11.6% 0.3%

Warfarin

2.1% 0.2% 22.7% 43.9%

Clopidogrel

4.4%

Warfarin

None

None

Placebo

0.87% 0.17% 0.45% 0.2% 7.34% 0.0%

ASA

5.2% 1.1% 28.7% 44.4%

Warfarin

DCM

Warfarin

Safety

       

Difference exists Difference exists Difference exists Difference exists

Statistics

N/A

Statistics

P Value

2.05 (1.36-3.12) 0.86 (0.29-2.85) 2.10 (1.19-3.70) 2.88 (1.3-6.94) 1.56 (1.34-1.81) N/A

HR (95% CI)

3.6% 0.6% 23.5% 35.4%

ASA

ASA

Abbreviations: AF, atrial fibrillation; ASA, aspirin; AST, aspartate transaminase; CNS, central nervous system; DB, double-blinded; DCM, dilated cardiomyopathy; DD, double dummy; GI, gastrointestinal; HELAS, Heart Failure Long-Term Anti-Thrombotic; HF, heart failure; HR, hazard rate; INR, international normalized ratio; ICH, intracerebral hemorrhage; ICM, ischemic cardiomyopathy; LVEDP, left-ventricular end diastolic pressure; LVEF, left-ventricular ejection fraction; MC, multicenter; MHV, mechanical heart valve; MI, myocardial infarction; NSR, normal sinus rhythm; NYHA, New York Heart Association; OL, open-label; PE, pulmonary embolism; PS, pilot study; RCT, randomized controlled trial; SCr, serum creatinine; ULN, upper limit of normal; WARCEF, Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction; WASH, Warfarin/Aspirin Study of Heart Failure; WATCH, Warfarin and Anti-platelet Therapy in Chronic Heart Failure. a Nonfatal MI, nonfatal stroke, all-cause death. b Nonfatal MI, nonfatal stroke, all-cause death, peripheral or pulmonary embolism, rehospitalization, heart failure exacerbation. c Nonfatal MI, nonfatal stroke, all-cause death. d Warfarin vs aspirin, P = .2184; warfarin vs clopidogrel, P = .0074; clopidogrel vs aspirin, P = .1369. e Warfarin vs aspirin, P = .3390; warfarin vs clopidogrel, P = .0634; clopidogrel vs aspirin, P = .3155. f Warfarin vs aspirin, P = .0163; warfarin vs clopidogrel, P = .0164; clopidogrel vs aspirin, P = .9962. g Warfarin vs aspirin, P = .0544; warfarin vs clopidogrel, P = .0254; clopidogrel vs aspirin, P = .7564. h Warfarin vs aspirin, P = .0025; clopidogrel vs aspirin, P = .0048. i Warfarin vs aspirin, P = .0186; warfarin vs clopidogrel, P = .3834; clopidogrel vs aspirin, P = .1404. j Ischemic stroke, intracerebral hemorrhage, all-cause death.

WARCEF n = 2305; Inclusion MC, DB, DD, (2012)59 criteria: age ≥18 years RCT old, LVEF ≤35% (or wall-motion index ≤1.2), NYHA I-IV, NSR; key exclusion criteria: AF, MHV, mobile or pedunculate intracardiac thrombus, endocarditis, valve vegetation, contraindication to warfarin or ASA, AST >3 times ULN or cirrhosis, SCr >3.0 mg/ dL, cardiac surgery or angioplasty or MI within previous 3 months, decompensated HF

 

WATCH n = 1587; Inclusion criteria: MC (142 age ≥18 years old, LVEF centers in (2009)58 ≤35%, symptomatic Canada, HF >3 months, NYHA the United II-IV, NSR; key exclusion States, and criteria: anticipated the United procedures requiring Kingdom), withdrawal of or RCT treatment with study medications, HF from reversible causes, condition warranting treatment with or being a contraindication to study medications

 

         

Warfarin

None

Placebo

Interventions

 

Design DCM

Participants

Efficacy

 

Study

Table 1. (continued)

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of the cases occurring in the warfarin group. However, 1 of the 4 cases in the warfarin group occurred after warfarin was discontinued for 2 weeks, whereas another occurred after it was discontinued for 2 years; therefore, on-treatment major hemorrhage with warfarin only occurred in 2 patients. The rates of minor hemorrhages were more common in the warfarin and aspirin groups (P = .033), and gastrointestinal adverse effects (mainly dyspepsia) were more frequent with aspirin (P = .014). Finally, there was a nonsignificant trend toward increased blood pressure with aspirin. Of note, results according to HFrEF etiology (ischemic vs nonischemic) were not reported. WASH suggested that the use of aspirin or warfarin in HFrEF-NSR patients may not have a favorable benefit-torisk profile because of their failure in reducing thromboembolic events, increased risk of major and minor bleeding, and the increased risk of hospitalizations caused by heart failure exacerbation or acute breathlessness with aspirin. However, definitive conclusions cannot be made regarding either benefits or risks because of the small sample size and the high rate of crossover between treatment groups. In addition to evaluating the benefits and risks of giving aspirin or warfarin in patients with HFrEF-NSR, WASH looked to determine the feasibility of conducting a large clinical outcomes study with a placebo or no-antithrombotics treatment arm. During the course of the study, it was determined that this was unlikely because of slow enrollment and reluctance of funding agencies to support a trial that included a no-antithrombotics group. Considering that a substantial proportion of patients in WASH had heart failure of an ischemic origin, this is reasonable given that those patients would warrant therapy with at least an antiplatelet agent (ie, aspirin) according to clinical practice guidelines. HELAS trial.  The Heart Failure Long-Term Anti-Thrombotic (HELAS) trial was conducted after WASH (study enrollment began in January 1998 and ended in August 1999) and was initially intended to be a large, placebo-controlled, clinical outcomes study with a projected enrollment of 6000 patients. However, recruitment was slow and subsequently resulted in the decision to change it to a pilot study, with a final enrollment of 197 patients.57 This trial, unlike WASH, performed treatment randomization according to heart failure etiology, with ischemic cardiomyopathy patients randomized to receive either warfarin (target INR = 2-3) or aspirin 325 mg orally per day and dilated cardiomyopathy patients to warfarin (target INR = 2-3) or placebo. Of note, in patients who had ischemic cardiomyopathy caused by an MI, the MI had to have occurred >2 months from the date of enrollment. Patients with AF at baseline were excluded; those patients who did not have AF at baseline and then developed AF during the course of the study were withdrawn from the trial. Patients were followed for a mean of 18.5 to 21.9 months for the occurrence of the

primary composite end point of nonfatal MI, stroke, death, peripheral embolism or PE, rehospitalization, or heart failure exacerbation. The TTR and mean INR for warfarin were not disclosed. In patients who had cardiomyopathy of an ischemic origin, the mean age was 62 years; 89% of them were male, 29% had a history of diabetes mellitus, and the mean LVEF was 29%. The use of optimal medical therapy was low, with only 57% using ACE inhibitors or ARBs, 15% β-blockers, and 56% diuretics. Among the patients with dilated cardiomyopathy, the mean age was 55 years; 78% of them were male, 10% had a history of diabetes mellitus, and the mean LVEF was 27%. The use of ACE inhibitors or ARBs (66%), β-blockers (7%), and diuretics (63%) was also low. HELAS was not able to provide any additional answers regarding the role of antithrombotics in HFrEF-NSR patients. The sample size was too small to detect any differences between any of the treatment groups relative to the primary composite outcome and to the individual components of the primary composite outcome. This is unfortunate given that this was the only trial that performed treatment randomization according to HFrEF etiology and, therefore, could have reasonably and ethically included a placebo arm. Of note, although treatment benefits could not be confirmed, this trial did reveal the potential bleeding risk associated with warfarin, which caused all the major hemorrhages (7 cases) in the study. WATCH trial. The Warfarin and Anti-platelet Therapy in Chronic Heart Failure (WATCH) trial compared aspirin 162 mg orally daily, clopidogrel 75 mg orally daily, and warfarin (target INR = 2-3.5) in patients with HFrEF-NSR.58 Aspirin and clopidogrel were administered blinded, whereas warfarin was given open-label. Study inclusion required patients to have received treatment with diuretics and ACE inhibitors (or hydralazine plus isosorbide or ARBs in the case of ACE inhibitor intolerance) for at least 60 days prior to enrollment, and β-blocker use was highly recommended. At the end of the study, the TTR for warfarin was 70.4%, and the mean INR was 2.6. Patient recruitment started in October 1999 and ended in June 2002. Like HELAS, WATCH was ambitious and looked to enroll 4500 patients over a time period of 3 years, with a mean follow-up of 3.5 years to provide 90% power to detect a 20% difference in the primary end point among the 3 treatment groups. However, slow recruitment resulted in the study’s early termination after only 1587 patients were enrolled, thereby shortening the enrollment and mean followup periods to 2.6 years and 1.9 years, respectively; additionally, the power was reduced significantly to 41%. At the end of the study, about 4.8% of patients were lost to follow-up. The mean age of patients was 63 years, and 85% of them were male, 77% were white, and 13% were black. Among them, 73% of patients had ischemic cardiomyopathy,

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Prom et al whereas 21% had primary cardiomyopathy. The majority of patients had NYHA class II to III (98%) heart failure, and the mean LVEF was 25%. Heart failure was present for >1 year in 89%, with 70% having heart failure for ≥2 years. A history of MI was documented in 58%, diabetes mellitus in 34%, and stroke in 5%. The mean SCr was 1.3 mg/dL. Most patients were on optimal medical therapy, with 99% receiving a loop diuretic, 87% an ACE inhibitor, 10% an ARB, 70% a β-blocker, and 28% an aldosterone antagonist. In the overall analysis, there were no differences between the treatment groups with respect to the primary composite outcome of all-cause mortality, nonfatal MI, and nonfatal stroke and the secondary outcomes of nonfatal MI or allcause mortality. However, warfarin significantly lowered the risk of nonfatal strokes (warfarin vs aspirin: P = .0095; warfarin vs clopidogrel: P = .0031) and all strokes (warfarin vs aspirin: P = .0163; warfarin vs clopidogrel: P = .0164) compared with both aspirin and clopidogrel. There were no differences in the rates of nonfatal or total strokes between aspirin and clopidogrel. Aspirin use resulted in significantly higher rates of hospitalization for heart failure decompensation compared with warfarin (P = .0186), whereas it was nonsignificantly higher compared with clopidogrel (P = .1404). In the safety analyses, major hemorrhage was significantly higher with warfarin compared with clopidogrel (P = .0074), whereas it was similar between warfarin and aspirin (P = .2184) and clopidogrel and aspirin (P = .1369). The rates of central nervous system bleeds were low among the 3 treatment groups, with a trend toward higher rates with warfarin compared with clopidogrel (P = .0634) but not with warfarin compared with aspirin (P = .3390) or clopidogrel compared with aspirin (P = .3155). Minor bleeding was significantly higher with warfarin compared with clopidogrel (P = .0254), but it was only nonsignificantly higher with warfarin compared with aspirin (P = .0544) and similar between clopidogrel and aspirin (P = .7564). An analysis was performed to determine treatment benefits according to HFrEF etiology (ischemic vs nonischemic). In patients with ischemic heart failure, the only difference between treatment groups was in the rate of strokes, with warfarin leading to lower rates compared with both aspirin (0% vs 1.6%; P = .01) and clopidogrel (0% vs 2.7%; P = .0009). In nonischemic patients, major hemorrhage was the only significant finding, with clopidogrel yielding lower rates compared with warfarin (0.7% vs 6.3%; P = .0093). WATCH was the first clinical outcomes study and the first trial to signal a possible superiority of warfarin over antiplatelet therapy in reducing the risk of strokes. Yet, although larger than WASH and HELAS, it is unclear if this is a true benefit because of the considerably lowerthan-projected enrollment. Given the findings of the WASH trial, WATCH also led to further questions regarding the

potential increased risk of heart failure hospitalization with aspirin compared with warfarin. WARCEF trial. The Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, the largest study to date, examined the use of warfarin (target INR = 2-3.5) compared with aspirin 325 mg orally per day in HFrEF-NSR patients.59 The use of optimal medical therapy with β -blockers, ACE inhibitors or ARBs, or hydralazine combined with nitrates was a requirement, and patients could only be on either warfarin or aspirin. Patients could not be on both antithrombotics. The TTR for warfarin was 63%. Patients were followed for up to 6 years for the occurrence of the primary composite end point of ischemic stroke, intracerebral hemorrhage, and all-cause death. Study enrollment commenced in October 2002 with the intention of recruiting 2860 patients for 89% power to test the primary composite end point, with the assumption of a hazard rate reduction of 17.82% in either group as compared with the other. However, as with HELAS and WATCH, study recruitment was slow and resulted in the projected sample size being adjusted to 2303 patients, with an associated power reduction to 69%. When study enrollment ended in January 2010, 2305 patients were included. About 1.5% of patients were lost to follow-up in both groups, and survival status was known for 97% of patients. The mean age was 61 years, and 80% were male. Most patients (50%) were from North America, followed by Europe (46%) and Argentina (4%). About 43% had ischemic cardiomyopathy; the majority of patients were NYHA class II to III (84.4%); and the mean LVEF was 25%. MI was a comorbid condition in 48%, diabetes mellitus in 31%, transient ischemic attack or stroke in 12.8%, AF in 3.7%, and PE in 2.3%. β-Blockers were used by 89.9%, ACE inhibitors or ARBs by 98.8%, aldosterone antagonists by 60.4%, and diuretics by 80.9%. After a mean follow-up of 3.5 years, the rates of the primary composite outcome were similar between both groups (P = .40). However, a time-varying analysis discovered decreasing hazard ratios with warfarin compared with aspirin and suggested a significant benefit with warfarin over aspirin by the fourth year of follow-up (P = .046). The rates of the individual components of the primary end point of all-cause death (P = .91) and intracerebral hemorrhage (P = .35) were also similar between warfarin and aspirin. However, warfarin led to a 48% lower rate of ischemic stroke compared with aspirin (P = .005). In the secondary outcome analyses, more patients in the warfarin group were hospitalized for heart failure (P = .053), and the MI rates were similar between both groups. In the safety analyses, warfarin use resulted in a 2.2-fold increase rate of total major hemorrhage (P < .001), 2.1-fold increase in gastrointestinal hemorrhage (P = .010), 2.9-fold increase in all other major hemorrhages (P = .01), and

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1.56-fold increase in minor hemorrhages (P < .001). Although the rate of intracerebral hemorrhage was also increased by 2.5-fold with warfarin (P = .45), this was not statistically significant because of the small number of events in both study groups. There was no difference in the rate of intracranial hemorrhage (P = 1.00), which included intracranial, spinal, subarachnoid, subdural, epidural, and retinal hemorrhages. WARCEF demonstrated that warfarin may have a potential advantage over aspirin but also showed that warfarin should not be routinely recommended over aspirin. The first evidence of benefit involved the time-varying analysis, which suggested that warfarin may significantly lower the rate of the primary outcome at the fourth year of follow-up. However, the clinical relevance of this finding is unclear. The second evidence of benefit was the significantly lower rate of ischemic stroke with warfarin. Yet because the rates of ischemic strokes were low in both groups, the significantly higher rate of major and minor hemorrhages with warfarin offsets this potential benefit. Interestingly, in direct contrast to results from the WASH and WATCH trials, warfarin increased the risk for hospitalization when compared with aspirin.

Discussion The role of antithrombotic therapy in reducing thromboembolic events in patients with HFrEF-NSR is controversial. Patients with HFrEF have been believed to be at greater risk for developing thromboembolic events, a conclusion that was largely based on case-control, post hoc analyses of randomized clinical trials and epidemiological and survey data.7,9-11,18-25,28,32,33 While early studies evaluating antithrombotic therapy in heart failure demonstrated a substantial reduction in mortality and thromboembolic events, this benefit was likely driven by effects in subsets with AF and valvular disease.5,6,60 More recent randomized, controlled trials evaluating antithrombotic therapy in HFrEF-NSR yielded inconclusive results. The clinical significance of these studies is limited by a substantial crossover rate among treatment groups, lack of a placebo group, inadequate or lack of treatment blinding, failure to randomize treatments according to HFrEF etiology, low incidences of embolic events, and slow recruitment rates leading to a diminished power to detect a difference in primary outcome. Future clinical trials need to address these limitations for definitive conclusions to be made. Aspirin reduces the risk of atherothrombotic events in patients with coronary artery disease, a common comorbidity in those with HFrEF. Clinical practice guidelines recommend its use in the presence of ischemic heart disease, but this is based primarily on findings from those without heart failure.61 A retrospective cohort analysis of the Studies of Left Ventricular Dysfunction (SOLVD) examined the relationship between

antiplatelet use—primarily aspirin—and survival. The results from this study suggested an association between antiplatelet therapy and improved clinical outcomes.62 In contrast, results from the only randomized, controlled trial comparing aspirin with no-antithrombotic therapy in heart failure patients did not demonstrate a reduction in the composite of death, nonfatal MI, and nonfatal stroke.56 Although this study was underpowered and not definitive, it casts doubt on the efficacy of antithrombotics in this setting. Despite the lack of proven benefit of aspirin over no-antithrombotic therapy, aspirin is the most widely used antithrombotic agent in this population.3,63 In addition to the uncertainty regarding the efficacy of aspirin in HFrEF-NSR, there are concerns about its safety. Patients with heart failure are nearly 6 times more likely to experience a gastrointestinal bleed while receiving aspirin when compared with those without heart failure.64 A similar finding was reported in a randomized clinical trial of HFrEF-NSR. In the WASH trial, a significantly greater number of patients randomized to aspirin had serious adverse gastrointestinal events and a higher incidence of minor hemorrhages when compared with patients with noantithrombotic therapy.56 A potential interaction between ACE inhibitors and aspirin, particularly in heart failure patients, may mitigate the benefits of ACE inhibitors and increase the rate of hospitalization for heart failure.65 The exact reason for this interaction is unclear but may reflect a reduction in the prostaglandin-mediated effect of ACE inhibitors. A metaanalysis of 3 large randomized trials of ACE inhibitors suggests the reduction in fatal and nonfatal vascular events with ACE inhibitors is lessened with concomitant aspirin use.66 Additionally, a post hoc analysis of the SOLVD study suggests that patients receiving aspirin may gain less benefit from ACE inhibitors in terms of survival or hospitalization for worsening of heart failure.67 In the WASH and WATCH trials, aspirin use was associated with an increased risk of hospitalization for worsening heart failure. However, this finding contrasts with results from the larger WARCEF trial, which did not find a higher rate of hospitalization for heart failure with aspirin use, even though a large proportion of patients in the aspirin group were treated with ACE inhibitors.59 A concern for diminished outcomes and hospitalization for worsening heart failure as a result of a possible prostaglandin-mediated drug-drug interaction between aspirin and ACE inhibitors prompted investigators to evaluate the use of clopidogrel in patients with chronic HFrEF-NSR. The WATCH trial was designed to determine whether warfarin is superior to antiplatelet therapy with aspirin and if clopidogrel is superior to aspirin in preventing major cardiovascular outcomes in this population. There were no differences between warfarin, aspirin, or clopidogrel in the time to first occurrence in the composite of death, nonfatal MI, or nonfatal stroke. Although the frequency of

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Prom et al hospitalizations for worsening heart failure was higher in the aspirin group than the warfarin group, there was no difference between aspirin and clopidogrel.58 The Clopidogrel Versus Aspirin in Chronic Heart Failure (CACHE) trial is an open-label, randomized study designed to compare the effects of aspirin and clopidogrel on outcomes in patients with symptomatic HFrEF-NSR.68 This trial is currently enrolling patients and may provide greater insight into aspirin’s effect on cardiovascular outcomes in this population. Oral vitamin K antagonists such as warfarin reduce morbidity in patients with AF and heart failure, but the net clinical benefit in patients who are in sinus rhythm is less evident. A cohort analysis from the SOLVD study examined the relation between warfarin use and long-term survival.67 The results of this analysis suggest that baseline warfarin use in HFrEF patients is associated with a significant reduction in all-cause mortality and in the combined end point of death or hospital admission for heart failure or acute coronary syndrome. This association was not influenced by age, gender, etiology, functional class, or presence of AF. Although the studies included in this review did not demonstrate any differences between treatment groups relative to the primary composite end points, death, or non-fatal MI, a consistent and significant reduction in ischemic strokes with warfarin use as compared with aspirin was reported in the WATCH and WARCEF trials.58,59 However, the effectiveness of warfarin in reducing ischemic strokes remains uncertain because this was a secondary outcome and warfarin was not compared with placebo. The comorbidities and medications associated with HFrEF complicate the management of vitamin K antagonists and may increase the risk of clinically significant bleeding. The rates of major bleeding episodes in those with HFrEF-NSR assigned to warfarin are greater than with aspirin or clopidogrel.56-59 Major hemorrhage, primarily caused by overanticoagulation, in the HELAS trial was limited to those assigned to warfarin at a rate of 4.6 per 100 patient-years. The WATCH investigators reported a significantly greater number of major bleeding episodes in patients on warfarin compared with clopidogrel but not in those on aspirin.58 The nearly 50% reduction in ischemic strokes in the WARCEF trial was associated with a 2-fold increase in the rates of major bleeding when compared with aspirin.59 This finding suggests that the net clinical benefit associated with antithrombotics in HFrEF-NSR may be offset by major bleeding episodes. European and North American consensus statements and clinical guidelines recommend oral anticoagulation for patients with heart failure and AF.1,3 These groups recognize the lack of proven benefit and highlight the possibility of adverse outcomes associated with antithrombotic therapy in HFrEF-NSR. The European Society of Cardiology guidelines state that there is no evidence that antiplatelet agents reduce atherosclerotic risk in patients with heart failure and

that there is no proven role for anticoagulation in patients with heart failure without AF, a prosthetic valve, intracardiac thrombus, or evidence of systemic embolism.69 Similarly, the American College of Cardiology/American Heart Association acknowledges that there is no clear benefit from the use of aspirin in those with heart failure and coronary artery disease and describe its use as controversial.1 However, they do recommend antiplatelet agents for the prevention of MI and death in patients with heart failure and underlying coronary artery disease. In the absence of definitive clinical data, the decision to use antithrombotics in HFrEF-NSR should be made based on each patient’s clinical features. Oral direct thrombin inhibitors and factor Xa inhibitors offer alternatives to some of the limitations with warfarin because of a more consistent therapeutic response and lack of requirement for routine coagulation monitoring. In clinical trials of nonvalvular AF with warfarin as a comparator, dabigatran and rivaroxaban (safety, as-treated analysis) led to significantly lower rates of the composite of stroke and systemic embolism, with similar rates of bleeding, whereas apixaban resulted in lower rates of both bleeding and the composite of stroke and systemic embolism.70-72 In 1 study that compared apixaban to aspirin, apixaban produced similar rates of bleeding but significantly lowered the risk of stroke and systemic embolism.73 If these agents prove to be more efficacious with lower rates of bleeding than traditional antithrombotic treatments, a net clinical benefit in HFrEF-NSR seems conceivable. However, these novel anticoagulants have not been evaluated in patients with HFrEF-NSR.

Conclusion Heart failure is a complex cardiac condition associated with an increased risk of thromboembolism. However, the role of antithrombotic therapy in reducing thromboembolic events in patients with HFrEF-NSR without compelling indications is controversial. The available clinical data evaluating antithrombotics in HFrEF-NSR patientsdo not establish a clinical benefit but have several limitations that preclude definitive conclusions; antithrombotic therapy also increases the risk of major hemorrhage, which may diminish outcomes. Future clinical trials need to address these limitations to allow better insight. Until more evidence is available, the decision to use antithrombotics in those with HFrEF-NSR should be based on each patient’s clinical features. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Usedom has received speaker fees from Boehringer Ingelheim in 2011.

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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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