antiplatelet and anticoagulant agents in heart...

JACC: Heart Failure Vol. 2, No. 1, 2014� 2014 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.07.007

STATE-OF-THE-ART PAPER

Antiplatelet and Anticoagulant Agentsin Heart Failure
Current Status and Future Perspectives
Paul A. Gurbel, MD, Udaya S. Tantry, PHD

Baltimore, Maryland

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Merck, Medtronic

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Sanofi-Aventis, M

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here has been a 3-fold increase in hospital discharges for heart failure (HF) and also significantly increasedmortality rate in HF patients in recent years. A major focus of HF research has been in the area of neurohormonalcontrol and resynchronization therapy. There is a great urgency in better understanding the pathophysiologyunderlying the exceedingly high mortality and a need for exploration of therapeutic strategies beyond those thatinfluence neurohormonal pathways. The decision to treat patients with HF with antiplatelet therapy remains largelyinfluenced by the presence or absence of concomitant arterial disease. Antithrombotic therapy has been shown tobe effective in many forms of cardiac disease, including patients with HF and atrial fibrillation. Although it is clearthat platelet activation and hypercoagulability are present in HF, and there is evidence that stroke is reduced bywarfarin therapy in the HF patient, the available data suggest that the risk of major bleeding overshadows theantithromboembolic benefit in HF patients in sinus rhythm. The utility of oral anticoagulant and/or antiplatelettherapy has never been evaluated in an adequately powered dedicated clinical trial of HF patients in sinus rhythm.In this state-of-the art paper we explore the evidence for targeting the inhibition of platelet function and coagulationto improve outcomes in the HF patient. (J Am Coll Cardiol HF 2014;2:1–14) ª 2014 by the American College ofCardiology Foundation

On the basis of data from National Health and NutritionExamination Survey 2007 to 2010, an estimated 5.1 millionAmericans�20 years of age have heart failure (HF) (NationalHeart, Lung and Blood Institute tabulation). One in 9 deathcertificates (274,601 deaths) in the United States mentionedHF in 2009. There has been a 3-fold increase in hospitaldischarges for HF since 1979 in the United States (1).

A major focus of HF research has been in the area ofneurohormonal control and resynchronization therapy (2).However, venous thromboembolism (VTE), cardioembolicstroke, and sudden death occur in 30% of HF patients andcontribute to the observed high overall mortality andmorbidity (3). After atrial fibrillation (AF), which accountsfor 15% of strokes, HF is the next most frequent associated

enter for Thrombosis Research, Baltimore, Maryland. Dr. Gurbel

sultant for Daiichi Sankyo, Sankyo, Lilly, Pozen, Novartis, Bayer,

umetrics, Nanosphere, Sanofi-Aventis, Boehringer Ingelheim,

, Iverson Genetics, CSL, and Haemonetics; has received grants

Institutes of Health, Daiichi Sankyo, Lilly, Pozen, CSL, Astra-

ventis, Haemoscope, Medtronic, Harvard Clinical Research

e Clinical Research Institute; has received payment for lectures,

on speakers’ bureaus from Lilly, Daiichi Sankyo, Nanosphere,

erck, and Iverson Genetics; has received payment for development

entations from Merck, the Discovery Channel, and Pri-Med; owns

ons in Merck, Medtronic, and Pfizer; and holds patents in the area

tiplatelet therapy and interventional cardiology. Dr. Tantry has

as no relationships relevant to the contents of this paper.

ived May 22, 2013; revised manuscript received July 25, 2013,

013.

cardiac condition accounting for 9% of all strokes (4).Although AF significantly increases the risk of stroke, theheightened risk of thromboembolism in HF patients is in-dependent of AF. These observations serve as evidence fora potential “heart failure research paradox” where compara-tively less information has been gained from adequately sizedprospective investigations of thrombogenicity and antith-rombotic therapy in the HF patient. Despite the fact thattreatment with angiotensin-converting enzyme (ACE) in-hibitors, angiotensin receptor blockers, beta adrenergic an-tagonists, and mineralocorticoid receptor antagonists in HFpatients has improved outcomes, morbidity or mortality re-mains particularly high in patients with acute decompensatedHF (2). In patients hospitalized for HF, the mortality rateis 4% at 1 month, 18% at 6months,w30% at 12 months, andw40% at 38 months (2). These dismal statistics suggest ur-gency in better understanding the pathophysiology underly-ing the exceedingly high mortality and a need for explorationof therapeutic strategies beyond those that influence neuro-hormonal pathways. In this state-of-the art paper we explorethe evidence for targeting the inhibition of platelet functionand coagulation to improve outcomes in the HF patient.

Pathophysiology of Arterial Thrombosis in HF

Approximately 70% of patients with HF and left ventricularsystolic dysfunction will have ischemic heart disease (5).Nonischemic etiologies will be responsible for the remainder

http://dx.doi.org/10.1016/j.jchf.2013.07.007

Abbreviationsand Acronyms

ACE = angiotensin-

converting enzyme

ACS = acute coronary

syndromes

ADP = adenosine

diphoshpate

AF = atrial fibrillation

CAD = coronary artery

disease

CI = confidence interval

F = circulating coagulation

factor

GP = glycoprotein

HF = heart failure

HR = hazard ratio

INR = international

normalization ratio

LVEF = left ventricular

ejection fraction

MI = myocardial infarction

OAC = oral anticoagulant

OR = odds ratio

RR = relative risk

TF = tissue factor

VTE = venous

thromboembolism

Gurbel and Tantry JACC: Heart Failure Vol. 2, No. 1, 2014Antiplatelet and Anticoagulant Agents in Heart Failure February 2014:1–14

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of HF with systolic dysfunction.Platelets play a central role in thegenesis of thrombosis at the siteof arterial wall injury (Fig. 1).Ruptured plaque or denudedarterial endothelium results in theexposure of various prothrom-botic factors thereby promotingplatelet adhesion, activation, andfinally generation of a platelet-rich thrombus generation. Expo-sure of the subendothelial matrixfollowing atherosclerotic plaquerupture and the subsequent releaseof various factors facilitate plateletadhesion and activation. Plateletactivation leads to the releaseof important secondary agonists,thromboxane A2 and adenosinediphosphate (ADP). Throm-boxane A2 is produced frommembrane phospholipids, andADP is released from densegranules. Through autocrine andparacrine mechanisms, these 2locally generated secondary ago-nists play a critical role in thesustained activation of aIIbb3 re-ceptors and stable platelet aggre-gation. Plaque rupture results in

tissue factor (TF) exposure at the site of vascular injury and thegeneration of femtomolar amounts of thrombin, the mostpotent primary platelet agonist. Tissue factor bearing cellscome in contact with circulating coagulation factor (F) VIIresulting in the autoactivation of FVII to form the TF-FVIIacomplex, which in turn activates FX to FXa and FIX to FIXa.FXa initially activates small amounts of thrombin, which inturn activates platelets and also FV and FVIII. Subsequently,the intrinsic FXase (FVIIIa-FIXa) and prothrombinase (FVa-FXa) are formed on the activated platelet surface where largeamounts of thrombin are generated by the conversion ofprothrombin to thrombin. Plasminogen activator inhibitor-1,released from platelets, depresses fibrinolysis. Thrombinfinally catalyzes the conversion of soluble fibrinogen to insol-uble strands of fibrin, thereby initiating clot formation (Fig. 1).Thrombin also activates FXIII to inducefibrin polymerization.The final result is a platelet-fibrin clot that mediates normalhemostasis and pathologic thrombosis at the site of athero-sclerotic plaque rupture or endothelial denudation. Thrombigenerated on ruptured plaques may embolize downstreamand occlude the microvasculature resulting in microinfarction.The latter mechanism may participate in the progression ofleft ventricular dysfunction in the HF patient. At present, itremains unknown whether there is interindividual variabilityand time dependence in the importance of thromboxane A2,ADP, and thrombin in thrombus generation (6,7).

Occlusive thrombus generation at the site of plaque ruptureis dependent on vulnerable blood (hypercoagulability, en-hanced platelet function, inflammation) and vulnerable vessel(endothelial dysfunction, and ruptured plaque/denudedendothelium/abnormal anatomy) (Fig. 2). Reduced plateletsurvival time, increased mean platelet volume, and greaterplatelet activation and reactivity have been observed inpatients with HF (8,9). In addition, elevated levels of b-thromboglobulin, p-selectin, platelet/endothelial cell adhe-sion molecule-1, and osteonectin as well as increased plateletsurface p-selectin and CD40L all serve as further evidence ofheightened platelet activation in patients with HF (10–12).High levels of circulating fibrinogen, fibrinopeptide A, andD-dimer have also been demonstrated in patients with HF.In addition, high levels of fibrinogen and D-dimer observedin patients with HF have correlated with disease severity (13).Decreased circulating levels ofADAMTS-13and increased vonWillebrand factor (vWF)were found to be significant predictorsof clinical events in patients with HF (14). In addition, a pro-thrombotic environment in the setting of HF is indicated byincreased inflammatory cytokines such as tumor necrosis factor-a and interleukin-1. These factors in turn are associated withincreased expression of tissue factor and thrombin generationand decreased thrombomodulin and protein C pathway acti-vation (anticoagulant factors) (15–17). Vulnerable vessel ischaracterized by decreased antithrombotic factor expressionsuch as nitric oxide, thrombomodulin and increased expressionof TF, vWF, and elevated inflammation at the site of plaquerupture. Moreover, a bifurcated and stenotic vessel affectsarterial shear and promotes platelet activation (18,19).

Pathophysiology of Venous Thrombosis in HF

Heart failure has been recognized as a prothrombotic or hy-percoagulable state. Themajor components of Virchow’s triadare present in venous thrombosis-vessel wall abnormalities,vulnerable blood, and blood flow abnormalities (Fig. 3) (2).

Venous stasis induced by high pressure, a low-flow state,and immobility result in distention of the vessel wall local andlocal hypoxia, causing ischemia and oxidative stress(18,20,21). The latter mechanisms in addition to neurohor-monal activation result in endothelial cell activation. Endo-thelial activation is characterized by increased expression ofadhesion molecules-selectins and decreased production ofantithrombotic factor-nitric oxide. These mechanisms pro-mote platelet/monocyte adhesion and activation. Impor-tantly, TF-rich microparticles released from activatedendothelial cells and monocytes attach to the expressedadhesion molecules on the endothelium at the site of injuredvessel wall (20,22,23). TF initiates the coagulation cascadeand, ultimately, fibrin-rich thrombus generation. In this line,increased circulating endothelial adhesion molecules,increased microparticles of endothelial origin, and leukocyteactivation have been demonstrated in patients with VTE andHF (22–24). Finally, venous stasis promotes thrombosis bydecreased clearance of activated coagulation factors (23).

Figure 1 Antithtrombotic Therapy Targets in Heart Failure

During arterial thrombosis, at the site of “altered” vessel wall, exposure of the subendothelial matrix leads to adhesion and activation of platelets and subsequent release of

secondary agonists, thromboxane A2 (TxA2) and adenosine diphosphate (ADP). These 2 locally-generated secondary agonists play a critical role in the sustained activation of

glycoprotein (GP) IIb/IIIa receptors and stable platelet aggregation. During venous thrombosis, tissue factor (TF) delivered by microparticles to the site of vessel wall injury binds

to autoactivated factor (F) VII (VIIa) to form TF-FVIIa complex, which in turn activates factor X to Xa. Initial formation of small amounts of Xa initiates the coagulation process on

the surface of activated platelets and leukocytes, where large amounts of thrombin are generated. During arterial thrombosis, TF is exposed at the site of plaque rupture and

initiates the coagulation process. Xa along with Va converts FII to FIIa. Simultaneously, trace amounts of thrombin activate FVIII and FV, which dramatically enhances catalytic

activity of FIX and FX, respectively. Thrombin-activated FXIIIa catalyzes the formation of covalent cross-links between adjacent fibrin chains to form polymerized fibrin. Finally,

together with aggregated platelets, the polymerized fibrin network leads to the formation of a stable, occlusive, platelet-fibrin clot and subsequent ischemic events. In venous

thrombosis, the coagulation pathway plays a major role resulting in fibrin-rich clot formation, whereas in arterial thrombosis, platelet activation and aggregation play a major role

resulting in platelet-rich thrombus formation. Therefore, the management of venous thrombosis is mainly centered around anticoagulation strategies whereas management of

arterial thrombosis is focused on antiplatelet strategies. Vitamin K is a cofactor that promotes the biosynthesis of g-carboxyglutamic acid residues in coagulation factor proteins

that are essential for biological activity. Anticoagulation strategies include warfarin that acts by inhibiting the synthesis of vitamin K-dependent clotting factors, II, VII, IX, and X,

and the anticoagulant proteins C and S. Warfarin inhibits clotting factor synthesis by inhibition of vitamin K epoxide reductase (VKORC1), thereby reducing the regeneration of

vitamin K1 epoxide. Other anticoagulants include direct thrombin inhibitors such as bivalirudin and dabigatran; direct Xa inhibitors such as rivaroxaban and apixaban; LMWH,

heparin, and fondaparinux bind to antithrombin (AT), facilitating its inhibition of coagulation factors. Fondaparinux and LMWH preferentially inhibit Xa as compared to heparin,

which more greatly inhibits IIa. Antiplatelet strategies include inhibition of platelet cyclooxygenase-1 enzyme by aspirin resulting in the inhibition of generation of TxA2 and TxA2-

induced platelet aggregation; inhibition of ADP receptor, P2Y12, by clopidogrel, prasugrel, ticagrelor, and cangrelor; inhibition of activated GPIIb/IIIa receptor by abciximab,

eptifibatide, and tirofiban; and vorapaxar that inhibits thrombin receptor protease activated receptor (PAR)-1. Factor II ¼ prothrombin; Factor IIa ¼ thrombin; LMWH ¼ low

molecular weight heparin; TP ¼ thromboxane A2 receptor; vWF ¼ von Willebrand factor.

JACC: Heart Failure Vol. 2, No. 1, 2014 Gurbel and TantryFebruary 2014:1–14 Antiplatelet and Anticoagulant Agents in Heart Failure

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Myocardial Infarction and Stroke Risk in HF

In patients with HF secondary to coronary artery disease(CAD), ongoing silent or symptomatic ischemia has beingassociated with HF progression (25). The elderly, women,and those with prior myocardial infarction (MI) are atgreatest risk for developing HF. However, a relatively lowrate (2% to 4%) of fatal or non-fatal MI has been reported inpatients with HF (26,27). In contrast, compared with a 0.1%to 0.5% annual rate of stroke in patients 80 years of age,

HF patients have a 1.0% to 3.5% annual rate of stroke, witha possible relationship between low ventricular ejectionfraction (LVEF) and stroke risk (28).

Strokes associated with HF have been attributed to mul-tiple etiologies. Concomitant AF is associated with loss ofatrial contraction. In the setting of stasis, thrombosis is pro-moted in the left appendage, and embolization may ensue. Inaddition, AF is associated with atherosclerosis. Therefore,atheroembolism from nonatrial sources may also explain aheightened risk for stroke. In HF patients in sinus rhythm,

Figure 2 Mechanisms of Coronary Arterial Thrombosis

Plaque rupture and endothelial erosion are the primary events associated with arterial thrombosis. The occlusive thrombus generation at the site of vessel injury is dependent on

the presence of vulnerable blood and vulnerable vessel. Platelet activation and aggregation play major roles in arterial thrombosis, leading to the formation of a platelet-rich

thrombus. NO ¼ nitric oxide; other abbreviations as in Figure 1.


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underlying atherosclerosis may play a dominant mechanisticrole in stroke occurrence. Among HF patients with stroke,about one-half have been reported to have AF (29). Thesignificant impact of HF on stroke risk in AF patients wassuggested in the Stroke Prevention in Atrial Fibrillation In-vestigators studies (30). The risk may also depend on howHFis defined and whether it is decompensated versus stable (31).Significantly more circulating platelet aggregates weredemonstrated in patients with HF compared with normalvolunteers by Mehta et al. (32). In the same study, thenumber of circulating platelet aggregates declined to normallevels following sodium nitroprusside infusion, and there wassignificantly lower ex vivo epinephrine- and ADP-inducedplatelet aggregation, which was associated with a 30%decrease in systemic vascular resistance and a 28% increase incardiac output. The authors suggested that an increase invascular resistance in certain HF patients may cause an in-crease in circulating platelet aggregates and that antiplatelettherapy may be beneficial in these patients.

Insight into the heightened risk of stroke and death in HFwas gained in the Diet, Cancer and Health study. Amongthe 51,553 patients without prior HF, 1,239 were identifiedwith incident HF. There was a markedly increased risk ofdeath, and death or stroke (ischemic or hemorrhagic orboth) in the first 30 days after presentation with first HFrelative to non-HF exposed patients (hazard ratios [HR]:42.8 and 38.4, respectively). There was attenuation of risk

at 30 days to 6 months (HRs: 12.7 and 9.3, respectively) and>6 months (HRs: 4.9 and 4.0, respectively) (33). Warfarinuse was associated with a lower risk for death and thecomposite of death or stroke compared with no warfarintherapy and this effect was more prominent in the first 30days. Finally, independent predictors for death, stroke, andthe composite of death or stroke were previous stroke/transient ischemic attack/transient ischemia (33).

In the Rotterdam study, 7,546 participants �55 years old(female ¼ 61%) without a history of stroke were continu-ously monitored for major events including stroke and HF.At baseline, 233 (3.1%) patients had HF, whereas 1,014patients developed HF and 827 patients developed strokeduring an average follow-up time of 9.7 years. There was amore than 5-fold increase in the risk of ischemic stroke inthe first month after HF diagnosis (age- and sex-adjustedHR: 5.79, 95% confidence interval [CI]: 2.15 to 15.62),but the risk decreased over time after 1 to 6 months (age-and sex-adjusted HR: 3.50, 95% CI: 1.96 to 6.25) and after0.5 to 6 years (HR: 0.83, 95% CI: 0.53 to 1.29) (34).

In the SAVE (Survival and Ventricular Enlargement)trial, 2,231 patients who had LV dysfunction after acute MIwere followed for an average of 42 months. The annual rateof fatal and nonfatal stroke was 1.5%, and the 5-year rate ofstroke was 8.1%. There was a 2-fold increased risk forstroke in patients with left ventricular ejection fraction(LVEF) �28% compared with patients with LVEF of

Figure 3 Mechanisms of Venous Thrombosis in Heart Failure

Venous thrombosis is dependent on vulnerable blood and vessel wall and blood flow abnormalities. Endothelial dysfunction results from hypoxia/distension/neurohormonal

activation, setting up a cascade of downstream prothrombotic events. CO ¼ cardiac output; IL ¼ interleukin; RBC ¼ red blood cell; TNF ¼ tumor necrosis factor; tPA ¼ tissue

plasminogen activator; other abbreviations as in Figures 1 and 2.


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>35% (p ¼ 0.01). In this study, lower ejection fraction (forevery decrease of 5 percentage points in the ejection fractionthere was an 18% increase in the risk of stroke), older age,and the absence of aspirin or anticoagulant therapy werefound to be independent risk factors for stroke (35).

Venous Thromboembolism

It has been reported that patients with HF have an increasedrisk for developing deep vein thrombosis versus those withoutHF, with adjusted odds ratios (ORs) of 1.47 (95% CI: 1.47 to1.48) to 2.93 (95% CI: 1.55 to 5.56) (36). Moreover, there is a10% to 22% risk of venographically-proven VTE in HF pa-tients in the absence of pharmacologic treatment (36,37). Inseveral case-cohort studies,HF patients were found to have a 2-to 3-fold increased risk for VTE compared with patients withother medical conditions. The rate of VTEwas 2.7 and 2.1 per100 patient-years in the V-HeFT (Veterans AffairsVasodilator-Congestive Heart Failure) I and II trials, respec-tively, that included both patients in sinus rhythm and withAF(38). In ananalysis of theSCD-HeFT(SuddenCardiacDeath-Heart Failure Trial), which excluded all patients with AF atthe time of randomization, the rate of thromboembolism was3.4% over a median follow-up of 45.5 months. A trend towardan increased 4-year Kaplan-Meier rate of thromboembolismwith lower LVEF was observed (3.5%, 3.6%, and 4.6% withLVEF30% to35%, 20% to30%, and<20%, respectively) (28).

Antithrombotic Therapy in Patients With HF

The previous evidence suggests that antithrombotic therapytargeting the platelet and/or coagulation may providebeneficial effects in patients with HF, particularly early afterpresentation. Long-term oral anticoagulant (OAC) therapyis an established major preventive treatment strategy againststroke in patients with AF (5). However, unlike AF, the roleof antithrombotic agents in the prevention of stroke in pa-tients with HF and sinus rhythm has been much lessinvestigated. Personalized antithrombotic therapy has beenstudied in patients treated with coronary stents with the goalof determining a therapeutic window for on-treatmentplatelet reactivity that optimally prevents ischemic eventswhile avoiding medically-important bleeding (39). Labora-tory tests are available that identify high intrinsic throm-bogenicity that have been associated with clinical thromboticevents after stenting (40). Similar investigations have neverbeen undertaken to identify the prothrombotic HF patient.Despite the extensive research in the PCI population, thegoal of optimal antithrombotic therapy that balancesreduction in ischemia and avoidance of bleeding remainselusive in HF patients. Moreover, platelet activation andaggregation, and thrombin formation, are highly interlinked.Optimal target(s) for the inhibition of the effects ofthrombin remain unclear; proposed strategies include directthrombin inhibition, inhibition of the coagulation factors


6

upstream from thrombin formation including FXa, FIXa,FVIIa, or FVa, or the platelet thrombin receptor-proteaseactivated receptor-1.

Antiplatelet Therapy

Aspirin is chosen in HF based on its role in secondaryprevention in patients with atherosclerotic vascular disease.To this date there has been no dedicated randomized trial ofantiplatelet therapy in the HF patient. All of the random-ized trials have included an anticoagulant arm (see subse-quent discussion). In patients with high-risk coronary arterydisease, it is well established that simultaneous inhibition ofcyclooxygenase-1 with aspirin and the adenosine diphos-phate-P2Y12 receptor with clopidogrel is associated with asignificant reduction in MI (41). However, the efficacy ofdual antiplatelet therapy on stroke reduction is uncertain.Adding aspirin to clopidogrel in patients with recentischemic stroke or transient ischemic attack in the large-scale MATCH trial (Management of atherothrombosiswith clopidogrel in high-risk patients with recent transientischaemic attack or ischaemic stroke) was not associatedwith a benefit in reducing major vascular events (RRR[relative risk reduction]: 6.4%, 95% CI: –4.6 to 16.3, p ¼0.244). However, the risk of life-threatening or majorbleeding was increased by the addition of aspirin to clopi-dogrel (42). In the ESPRIT (European/Australasian StrokePrevention in Reversible Ischaemia Trial), treatment ofaspirin (30 to 325 mg/day) with dipyridamole (200 mg twicedaily) was associated with a 20% relative risk (RR) reductionin the composite end point of composite of death from allvascular causes, nonfatal stroke, nonfatal MI, or majorbleeding complication in patients with transient ischemicattack or minor stroke of presumed arterial origin comparedto aspirin alone (43). Similarly, aspirin plus extended releasedipyridamole versus clopidogrel was associated with similarincidences of primary endpoint of first recurrence of stroke(HR: 1.01, 95% CI: 0.92 to 1.11) in patients with a recentischemic stroke in the PRoFESS (Prevention Regimen forEffectively Avoiding Second Strokes) trial (44).

A meta-analysis performed by Antithrombotic Trialists’collaboration of secondary prevention trials demonstratedthat aspirin therapy was associated with an 1.5% absolutereduction in serious vascular events (6.7% vs. 8.2% per year,p < 0.0001) and a 20% reduction in total stroke (2.08% vs.2.54% per year, p ¼ 0.002) and coronary events (4.3% vs.5.3% per year, p < 0.0001) but a nonsignificant increase inhemorrhagic stroke (45). Treatment failure and pharmaco-logic limitations associated with clopidogrel therapy fosteredthe development of more potent P2Y12 receptor blockerssuch as, prasugrel, an irreversible agent, and ticagrelor, areversibly binding agent. Treatment of patients with acutecoronary syndromes (ACS) with the latter agents was moreeffective than clopidogrel; however, the observed degree ofadverse event reduction (w20% relative and w2% absolute),and significantly greater bleeding remain major concerns

(39). Moreover, it is also interesting to note that althoughmore potent P2Y12 receptor blockers are more effective thanclopidogrel in the overall patient population, in “very high-risk patients” (diabetes mellitus, elderly patients, and thosewith renal failure, history of MI, stroke, and stent throm-bosis), the overall rate of ischemic event occurrence remainsvery high. In addition, some of these “very high risk” groupsare also associated with an increased bleeding risk. Theprevious limitations highlight the ceiling effect of currentdual antiplatelet therapy targeting COX-1 and the P2Y12

receptor in high-risk CAD patients and suggest that theresidual ischemic event occurrences are mediated by otherpathways that are unblocked by current antiplatelet therapy.There is no information available on the outcomes ofHF patients treated with either prasugrel or ticagrelor.Thus, the indication for antiplatelet therapy in theHFpatientsdepends upon the presence of concomitant vascular disease.

Warfarin

Warfarin (vitamin K antagonist) blocks multiple steps ofcoagulation by reducing the synthesis of vitamin K depen-dent coagulation factors. In a meta-analysis of trialsinvolving patients with AF, warfarin therapy was found to beassociated with a 64% reduction in stroke and a 26%reduction in all-cause mortality when compared with pla-cebo/control (46). As warfarin is metabolized by the cyto-chrome P450 isoenzymes, interactions with other drugs thatare metabolized by the same cytochrome P450 isoenzymesinfluence the pharmacokinetics and pharmacodynamics ofwarfarin. The metabolism and efficacy of warfarin areinfluenced by liver function, genetic polymorphisms, andalcohol and food consumption (47). The major concern ofgenetic variability lies within the CYP2C9 and VKORC1genes that encode proteins involved in the metabolism ofwarfarin (48,49). Warfarin therapy is associated with arelatively narrow therapeutic window of internationalnormalization ratio (INR) values between 2.0 and 3.0.Insufficient anticoagulation and a subsequent rise in the riskof ischemic strokes are associated with INR values below2.0, and a higher risk of intracranial bleeding is associatedwith an INR >4.0 (49,50).

New Oral Anticoagulants

Currently known anticoagulants can be classified asparenteral or oral (based on their administration route)or direct or indirect inhibitors (based on their target ofaction). New OACs have been developed to overcomesome of the limitations of warfarin therapy. The directthrombin inhibitors (“gatrans,” e.g., dabigatran) directlybind to thrombin and block thrombin-induced conversionof fibrinogen to fibrin and the activation of FV, FVII, FIX,and platelets. The latter functions are responsible for theamplification of thrombin generation. Moreover, directthrombin inhibitors inhibit the activity of fibrin-boundthrombin (51,52).


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The inhibition of coagulation protease enzymes respon-sible for the propagation phase attenuates the generation ofthrombin. Anticoagulants have been developed to inhibitFIXa (e.g., the DNA aptamer pegnivacogin), FVIIIa (TB-402), and FVa/FVIIIa (drotrecogin, a recombinant form ofhuman activated protein C). Recomodulin and solulin aresoluble recombinant derivatives of human thrombomodulin.The most widely investigated FXa inhibitors have beenrivaroxaban and apixaban. Other FXa inhibitors includeedoxaban, otamixaban, darexaban, betrixaban, and TAK-442. Among the new OACs, dabigatran and apixiban havebeen shown to be more effective in preventing stroke thanwarfarin in patients with nonvalvular AF. In addition, lowerrates of intracranial bleeding have been reported with apix-iban, rivaroxaban, and dabigatran in the latter group of pa-tients. Additional advantages of these new OACs overwarfarin include the absence of any reported interactions withfood, fewer interactions with other medications, and absenceof frequent laboratory monitoring and dose adjustments (51).

Evidence for Antithrombotic Efficacy in HF

In a post hoc analysis of major HF trials associated withreduced ejection fraction and anticoagulant therapy, theannual rate of stroke was between 1.1% and 4.6%. Most ofthe trials included in the analysis had some patients with AF(53). Clinical trials conducted in the 1940s and 1950 havefirst assessed the utility of OAC in patients with HF. Manyof the patients in these studies also had accompanying AFand valvular disease. Dicumarol therapy, the primary OACused was associated with reduced thromboembolic eventoccurrence and death (54–56). However, the relevance ofthese trials in patients with sinus rhythm, which is moreprevalent in current practice, is limited.

In the SOLVD (Studies of Left Ventricular Dysfunction)trial (n ¼ 6,797), antiplatelet therapy was used in 46.3% ofpatients and was associated with significantly reduced allcause death (adjusted HR: 0.82, 95% CI: 0.73 to 0.92, p ¼0.0005) and reduced risk of death or hospital admission forHF (adjusted HR: 0.81, 95% CI: 0.74 to 0.89, p < 0.0001)compared to patients not treated with antiplatelet therapy(57). Interestingly, the observation that the addition of ena-lapril did not decrease the mortality rate in patients receivingantiplatelet agents, and conversely neither did the addition ofaspirin in patients receiving enalapril fueled great controversyabout an aspirin–ACE inhibitor interaction (58). Furthersupport for an aspirin-ACE inhibitor interaction arose fromthe CONSENSUS II (Co-operative New ScandinavianEnalapril Survival Study II) Study. Differential effects of theACE inhibitor enalapril in subgroups defined by use of aspirinat baseline were analyzed. Logistic regression demonstratedthat the enalapril–aspirin interaction term was a significantpredictor of mortality and was a borderline significant pre-dictor of mortality 30 days after randomization (59).

The ACTIVE (Atrial fibrillation Clopidogrel Trial withIrbesartan for the prevention of Vascular Events) program

added support for the use of aspirin in HF patients on ACEinhibitor therapy. In over 2,000 patients with a history ofHF and AF, there was no evidence of aspirin-relatedattenuation of ACE inhibitor benefit (60).

In a multivariate analysis of the SOLVD trial, warfarintherapy (n ¼ 861) was associated with a significant reductionin all-cause mortality (adjusted HR: 0.76, 95% CI: 0.65 to0.89, p ¼ 0.0006) and in the risk of death or hospitaladmission for HF (HR: 0.82, 95% CI: 0.72 to 0.93,p ¼ 0.0002) compared to warfarin nonuse. The benefit ofwarfarin therapy was not influenced by the presence of AF,age, ejection fraction, New York Heart Association func-tional class, or etiology (57).

Randomized Trials of Antithrombotic Therapy in HF

In the WASH (Warfarin/Aspirin Study in Heart Failure)pilot study, 279 patients were randomized to receive noantithrombotic treatment (26%), 300 mg/day aspirin (32%)or warfarin (26%, target INR 2.5) for w27 months. In thisstudy, w75% of patients were male, w60% of patients hadischemic heart disease, and only 4% to 7% of patients hadAF. No difference in the primary endpoint of first occur-rence of death, nonfatal MI, or nonfatal stroke was observedbetween the treatment groups. However, compared towarfarin, aspirin treated patients were twice as likely to havea cardiovascular hospitalization or death during the first 12months follow-up. Aspirin treatment was also associatedwith significantly more hospitalizations for cardiovascularreasons, especially worsening HF (p ¼ 0.044). Therapy withwarfarin and aspirin therapy was associated with a higherrate of minor bleeding, although few overall major hemor-rhagic events were reported. The overall study results arguedagainst the benefit of antiplatelet therapy in HF patients toprevent thromboembolic events (Table 1) (61).

The subsequent HELAS (HEart failure Long-termAntithrombotic Study) trial was prematurely terminated af-ter enrolling 197 of an intended 6,500 patients due to slowenrollment. In this trial, 115 patients with ischemic cardio-myopathywere randomized to 325mgdaily aspirin orwarfarin(INR 2.0 to 3.0), whereas 82 patients with nonischemic car-diomyopathy were randomized to placebo or warfarin (INR2.5 to 3.0) for 18.5 to 21.9 months. Similar to the WASHstudy, there was no difference in the occurrence of the primarycomposite endpoint between the groups and only warfarintherapy was associated with 7 major hemorrhagic events thatwere predominantly due to high anticoagulation (62).

In the WATCH (Warfarin and Antiplatelet Therapy inChronic Heart Failure) trial, 1,587 of 4,500 planned patientswith symptomatic HF (New York Heart Association func-tional class II to IV) for at least 3 months were studied. Thetrial was terminated prematurely due to slow enrollment.These patients were in sinus rhythm with documentedLVEF �35% and received 162 mg daily aspirin, 75 mg dailyclopidogrel (in a double-blind, double dummy fashion), oropen label warfarin (target INR 2.5 to 3.0) for a mean


8

duration of 1.9 years (63). There was no placebo arm in thisstudy. Similar to previous studies, there was no difference inthe rate of the primary composite endpoint of first occur-rence of death, nonfatal stroke, or nonfatal MI with warfarinversus aspirin therapy (HR: 0.98, 95% CI: 0.86 to 1.12,p ¼ 0.77); with clopidogrel versus aspirin therapy (HR:1.08, 95% CI: 0.83 to 1.40, p ¼ 0.57); and with warfarinversus clopidogrel therapy (HR: 0.89, 95% CI: 0.68 to 1.16,p ¼ 0.39). There was no difference in mortality betweentherapies. Warfarin therapy was associated with a reductionin the incidence of stroke (both fatal and disabling) comparedto aspirin and clopidogrel (p < 0.02 for both). But, there wassignificantly increased bleeding in the warfarin groupcompared to clopidogrel group (n¼ 30 vs. n¼ 12, p< 0.01)but not compared to the aspirin group (n ¼ 30 vs. n ¼ 19,p ¼ 0.22). A significant reduction in stroke was observed inpatients with ischemic HF (73% of population) where thestroke rates were 0% in warfarin group versus 2.7% in clo-pidogrel group (p ¼ 0.009) and 1.6% in aspirin group (p ¼0.01). Furthermore, significantly increased incidences ofhospitalization were observed in patients receiving aspirincompared to warfarin (p< 0.001). The overall evidence fromthe primary endpoint occurrences and mortality did notsupport that warfarin is superior to aspirin and that clopi-dogrel is superior to aspirin in HF patients with ejectionfraction �35% who are in sinus rhythm (63).

In the largest study to date, theWARCEF (Warfarin versusAspirin in patients with Reduced Cardiac Ejection Fraction)study, the efficacy of 325 mg daily aspirin versus warfarintherapy (target INR 2.5 to 3.0) was evaluated in a double-blind, double-dummy study design with sham INRs in2,305 patients in sinus rhythm with LVEF� 35% (64). Thistrial included a relatively young population (mean age ¼ 61years) with HF and a mean LVEF of 25%. In this trial, 48%of patients had MI, 43% had ischemic cardiomyopathy, 4%had AF, w80% of patients were male, and 75% were a non-Hispanic white population. The mean duration of follow-upwas 3.5 years. In 34% and 32% of the total follow-up time,patients did not receive the randomized warfarin and aspirintherapy, respectively. There was no control arm in this trial.Similar to slow recruitment problems observed in previoustrials, in theWARCEF trial, the enrollment was stopped after2,305 patients from 11 countries instead of a planned 2,860patients, reducing the power to test the primary hypothesisfrom 89% to 69%.Themaximum follow-up was extended to 6years instead of 5 years. There was no significant differencebetween treatment groups for the occurrence of the primaryendpoint of death, ischemic stroke or intracerebral hemorrhage(7.47% vs. 7.93% events per 100 patient-years, respectively;HR: 0.93, 95% CI: 0.79 to 1.10, p¼ 0.40). In a time-varyinganalysis using a Cox model, there was a marginal trend in theprimary endpoint favoring a benefit with warfarin therapyversus aspirin therapy over time with an HR of 0.89 peryear (95% CI: 0.80 to 0.998, p ¼ 0.046) and HR of 0.76 fa-voring warfarin by year 4 (p¼ 0.04) (64). As in theWATCHtrial, there was a significant reduction in ischemic stroke, 1

of the secondary endpoints, throughout the follow-up periodwith warfarin therapy compared to aspirin therapy (0.72% vs.1.36%/year; HR: 0.52, 95% CI: 0.33 to 0.82, p ¼ 0.005) butwith significantly greater major hemorrhagic events (5.8% vs.2.7%; OR: 2.2, 95%CI: 1.42 to 2.47, p< 0.001) (63,64). Thereduction in stroke associated with warfarin therapy in pa-tients with HF appeared similar to the reduction in strokeobserved in patients treated with warfarin for AF (53).However, the overall stroke rate was lower in the HF popu-lation in sinus rhythm. Furthermore, there was no differencein the combined rate of intracranial and intracerebral hem-orrhage between warfarin and aspirin therapy (0.8% vs. 0.8%)but the rate of major gastrointestinal hemorrhage was 3 timeshigher with warfarin therapy compared to aspirin therapy(3.2% vs. 1.4%; HR: 3.0, 95% CI: 1.30 to 4.38, p ¼ 0.008).In contrast to the WATCH and WASH trials, aspirintherapy was not associated with an increased rate of hospi-talization (61,63). The lack of an effect of warfarin therapyon death in this HF population in sinus rhythm suggests thatthe mechanism of death in these patients is not due tothromboembolism but may be mostly due to pump failure orventricular arrhythmias (65).

In a recently reported subgroup analysis of the WARCEFtrial, it was demonstrated that among 32 variables exploredfor an interaction with treatment, patients <60 years of agehad a 37% reduction in the occurrence of the primaryendpoint (HR: 0.63, 95% CI: 0.48 to 0.84, p ¼ 0.001) ascompared with no benefit observed in patients the �60 yearsof age group. Again, this benefit in patients <60 years of agewas mainly driven by a significantly lower mortality rate thatwas not observed in patients �60 years of age. In addition,there was less major bleeding risk with warfarin therapy inthe younger cohort (66).

The previous 4 randomized trials have important limita-tions. Enrollment was largely incomplete and all studies wereunderpowered to test the proposed hypothesis. Second,heterogeneous drug administration, a variable degree of un-derlying HF etiology, and varying definitions of the primarycomposite endpoint were observed. Finally, the WATCHand WARCEF trials did not have a placebo arm to evaluatethe actual efficacy of antithrombotic therapy (63,64).

Meta-Analyses of Randomized Trialsand Registry Data

In a meta-analysis that included 4,378 patients from the 4randomized trials of chronic HF and reduced ejectionfraction in SR, there was no difference in all-cause mortality(RR: 1.00, 95% CI: 0.88 to 1.13, p ¼ 0.94), HF-relatedhospitalizations (RR: 1.16, 95% CI: 0.79 to 1.71, p ¼ 0.45),and nonfatal MI (RR: 0.87, 95% CI: 0.63 to 1.21, p ¼ 0.40)between warfarin and aspirin treatments. However, warfarintherapy compared to aspirin therapy was associated witha 41% reduction in all strokes (RR: 0.59, 95% CI: 0.41to 0.85, p ¼ 0.004) and 52% reduction in fatal andnonfatal ischemic strokes (RR: 0.48, 95% CI: 0.32 to 0.73,

Table 1 Randomized Antithrombotic Trials in Patients With Heart Failure

Patients Treatment and Follow-Up Primary Outcome Outcome Comments

WASH (Warfarin/AspirinStudy in Heart Failure)

HF: �35% LVEFn ¼ 279

Randomized to noantithrombotictherapy, 300 mgaspirin, or warfarin(INR 2.5)

Mean follow-up:27 � 1 month

Death, nonfatal MI,nonfatal stroke

26% no antithrombotic32% aspirin26% warfarin

More HF hospitalizationwith aspirin

More hemorrhage withwarfarin

HELAS (HEart failureLong-termAntithromboticStudy)

HF: <35% LVEF andNYHA functional classII to IV

n ¼ 197

HF pts were randomizedto 325 mg aspirin orwarfarin (INR 2–3)n ¼ 115

DCM pts wererandomized towarfarin (INR 2.5)or placebo

Mean followup:19 to 21 months

Nonfatal stroke,peripheral or PE, MI,re-hospitalization,exacerbation of HFor death

No significant differencebetween groups

Low n

WATCH (Warfarin andAntiplatelet Therapy inChronic Heart Failure)

HF >3 months, in sinusrhythm + �35% LVEF

n ¼ 1,587

Randomized to open-label warfarin (INR2.5–3.0) + double-blind treatment to162 mg aspirin or75 mg clopidogrel

Mean follow-up:>12 months

First occurrence of death,nonfatal MI, ornonfatal stroke

Warfarin vs. aspirin:HR: 0.98,95% CI: 0.86–1.12;p ¼ 0.77

Clopidogrel vs. aspirin:HR: 1.08,95% CI: 0.83–1.40;p ¼ 0.57

Warfarin vs. clopidogrel:HR: 0.89,95% CI: 0.68–1.16,p ¼ 0.39

Lower stroke rate withwarfarin

More HF hospitalizationwith aspirin

WARCEF (Warfarinversus Aspirin inpatients with ReducedCardiac EjectionFraction)

HF: normal sinus rhythm,�35% LVEF

n ¼ 2,305

Randomized to warfarin(INR 2–3.5) or 325 mgaspirin

Mean follow-up:42 � 18 months

First occurrence ofischemic stroke,intracerebralhemorrhage, or deathfor any cause

26.4% vs. 27.5%.HR: 0.93,95% CI: 0.79–1.10;p ¼ 0.40

Ischemic stroke2.5% vs. 4.7%,HR: 0.52, 95% CI:0.33–0.82;p ¼ 0.005

Major hemorrhage5.8% vs. 2.7%,HR: 2.21,95% CI: 1.42–3.47,p < 0.001

Hospitalization for HF20.9% vs. 17.5%,HR: 1.12,95% CI: 0.998–1.47;p ¼ 0.053

No significant differencebetween groups.

Lower ischemic strokewith warfarin offset byhigher majorhemorrhage.

CI ¼ confidence interval; DCM ¼ dilated cardiomyopathy; HF ¼ heart failure, HR ¼ hazard ratio, INR ¼ international normalization ratio; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction;NYHA ¼ New York Heart Association; PE ¼ pulmonary embolism.


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p ¼ 0.0006), and a 2-fold increased risk of major hemor-rhage (RR: 2.02, 95% CI: 1.45 to 2.80, p ¼ 0.0001). Thus,the overall benefit from warfarin in this population appearscounterbalanced by the increased risk of bleeding (67).

Another meta-analysis including the same patient popu-lation from the previous 4 randomized trials specificallyaddressed stroke prevention. The number needed to reduce1 stroke was 61 and that needed to harm (major hemor-rhage) was 34 for warfarin therapy (68). Warfarin did notincrease mortality or confer an increased risk of intracerebralhemorrhage compared with aspirin.

The REDINSCOR (Red de investigación clínica y básicaen insuficiencia cardiaca) registry included 2,263 patientswith ejection fraction �35% and sinus rhythm without other

anticoagulation indications and 26% of patients werereceiving anticoagulation therapy. Anticoagulation therapywas associated with no significant differences in total mor-tality (14% vs. 12.5%) or stroke (0.8% vs. 0.9%), but wasassociated with a reduction in the combined endpointoccurrence of cardiac death, heart transplantation, coronaryrevascularization, and cardiovascular hospitalization in apropensity score–adjusted multivariate analysis (HR: 0.74,95% CI: 0.56 to 0.97, p ¼ 0.03) (69).

Potential Role of New Anticoagulants

The new oral anticoagulants have been studied in compar-ison to warfarin mainly in AF patients and for treatment

Table 2 Trials of New Oral Anticoagulants in the Subgroups of Patients With Heart Failure

Patients Treatment and Primary Outcome Results Comments

Dabigatran

RE-LY (Randomized Evaluation ofLong-term anticoagulanttherapY)

Patients with AFNo sHF ¼ 13,203, sHF ¼ 4,904

Warfarin vs. dabigatran110 mg vs. dabigatran150 mg 2-yr stroke orsystemic embolism

Overall ¼ 1.69% vs.1.53% vs. 1.11%

No sHF ¼ 1.63% vs.1.40% vs. 1.00%

sHF ¼ 1.85% vs.1.90% vs. 1.44%

No significant treatmentinteraction (p ¼ 0.42and 0.33)

Apixaban

ARISTOTLE (Apixaban forReduction In STroke and OtherThromboemboLic Events inatrial fibrillation)

Patients with AF and 1 additionalrisk for stroke

With HF ¼ 5,541No HF ¼ 12,660

Warfarin vs. apixaban5 mg bid

1.8 yr ischemic orhemorrhagic orsystemic embolism

Overall ¼ 1.6% vs. 1.27%No HF ¼ 1.6% vs. 1.2%HF ¼ 1.6% vs. 1.4%

No significant treatmentinteraction (p ¼ 0.45)

APPRAISE-2 (Apixaban forPrevention of Acute IschemicEvents 2)

Patients with a recent ACS and atleast 2 additional risk factors forrecurrent ischemic events

No HF ¼ 5,362HF ¼ 2,028

Placebo vs. apixaban5 mg bid + standardantiplatelet therapy

241 days CV death, MI, orischemic stroke

Overall ¼ 7.9% vs. 7.5%No HF, HR: 1.05(95% CI: 0.86–1.29)

HF, HR: 0.77(95% CI: 058–1.02)


Rivaroxaban

ROCKET AF (Rivaroxaban OnceDaily Oral Direct Factor XaInhibition Compared withVitamin K Antagonism forPrevention of Stroke andEmbolism Trial in AtrialFibrillation)

Patients with nonvalvular AFcHF ¼ 8,851No cHF ¼ 5,318

Dose-adjusted warfarin vs.20 mg rivaroxaban

1.7 yr stroke or systemicembolism

Overall ¼ 2.2% vs. 1.7%cHF ¼ 3.9% vs. 3.6%no cHF ¼ 5.01% vs. 4.13%


ATLAS ACS TIMI 51 (Anti-XaTherapy to Lower CardiovascularEvents in Addition to StandardTherapy in Subjects with AcuteCoronary Syndrome–Thrombolysis In MyocardialInfarction 51)

Recent ACSNo cHF¼ 4,282cHF ¼ 483

Placebo vs. 2.5 mgrivaroxaban bid vs. 5 mgrivaroxaban

13 months CV death, MI,or stroke

Overall ¼ 10.7% vs.9.1% vs. 8.8%

No cHF¼ 6.0% vs. 5.5%(2.5 mg rivaroxaban)

HF ¼ 16.8% vs. 10.1%(2.5 mg rivaroxaban)

ACS ¼ acute coronary syndromes; bid ¼ twice daily dose; cHF ¼ congestive heart failure; CV death ¼ cardiovascular death; sHF ¼ symptomatic heart failure; other abbreviations as in Table 1.


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of and prophylaxis against VTE. In a recent meta-analysisof trials in patients with AF, new oral anticoagulants were22% more effective in the prevention of stroke comparedto warfarin (RR: 0.78, 95% CI: 0.67 to 0.92) and there wasa significantly reduced risk of intracranial hemorrhage(RR: 0.49, 95% CI: 0.36 to 0.66) (70). Based on the datafrom the Danish National Patient Registry, the new anti-coagulants were superior to warfarin for net clinical benefitregardless of the risk of bleeding in patients at high risk ofstrokedCHADS(2) score �1 or CHA(2)DS(2)-VASc �2.The benefit was more prevalent when stroke risk andbleeding risk were high (71).Bivalirudin. In a pooled analysis of randomized trials ofbivalirudin therapy that included 14,258 ACS patientstreated with dual antiplatelet therapy, bivalirudin therapycompared with heparin plus glycoprotein (GP) IIb/IIIa in-hibitor therapy was significantly associated with lowermortality risk in patients with <35% LVEF (random RR:0.47, 95% CI: 0.30 to 0.72, p ¼ 0.0004), which wasconsistent across studies. However, the benefit of bivalirudintherapy was attenuated in patients with �35% LVEF(pooled analysis RR: 0.92, 95% CI: 0.72 to 1.17, p ¼ 0.50)(72). Similarly, in the PREMIER (Prospective RegistryEvaluating Outcomes After Myocardial Infarctions: Eventsand Recovery) registry, a 37% RR reduction in in-hospital

mortality (p < 0.0001) was reported in patients with HFwho were treated with bivalirudin compared to heparin plusa GPII/IIIa inhibitor (73). These hypothesis-generatingdata suggest a potential benefit of direct thrombin inhibi-tion in HF patients in the setting of ACS.Dabigatran. In the RE-LY trial (Randomized Evaluationof Long-term anticoagulant therapY), a fixed dose(110 mg or 150 mg twice daily) of dabigatran wascompared for noninferiorty for the prevention of stroke orsystemic embolism versus adjusted-dose warfarin in pa-tients with AF. This trial demonstrated that 110 mg twicedaily dose of dabigatran was associated with similar ratesof stroke and systemic embolism and lower rates of majorhemorrhage compared with warfarin whereas 150 mgtwice daily dose of dabigatran was associated with lowerrates of stroke and systemic embolism but similar rates ofmajor hemorrhage compared to warfarin. Among 4,904patients enrolled with symptomatic HF, there was nosignificant interaction with treatment effect with both 100and 150 mg doses of dabigatran (p for interaction ¼ 0.42and 0.33, respectively) (74).Apixaban. In the ARISTOTLE trial (Apixaban forReduction In STroke and Other ThromboemboLic Eventsin atrial fibrillation), 5 mg twice daily apixaban was superiorto warfarin in the prevention of stroke or systemic embolism

Table 3 Trials of Antiplatelet Agents and New Oral Anticoagulants in Patients With Heart Failure

Name of the Study Patients Treatment Arms and Duration Primary Endpoints

COMMANDER HFNCT01877915 (A Study toAssess the Effectivenessand Safety of Rivaroxabanin Reducing the Risk ofDeath, Myocardial Infarctionor Stroke in Patients WithHeart Failure and CoronaryArtery Disease FollowingHospitalization for Heart Failure)

HF (EF �40%) þCADn ¼ 5,000

Rivaroxaban 2.5 mg bid vs.placebo for 6 to 30 months

Time to the first occurrence of any of thefollowing: death from any cause, MI, or stroke

Time to the first occurrence of either fatalbleeding or bleeding into a critical spacewith potential for permanent disability

Platelet Inhibition in PatientsWith Systolic Heart Failure

NCT01765400

New York Heart Associationfunctional class III to IV (EF�35%)

n ¼ 50

Prasugrel 10 mg qd vs.clopidogrel 75 mg qd for 2 weeks

The change in platelet aggregation measuredby the VerifyNow P2Y12 assay betweenbaseline and each antiplatelet medication

CAD ¼ coronary artery disease; EF ¼ ejection fraction; qd ¼ once daily; other abbreviations as in Tables 1 and 2.


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and was associated with less major bleeding and lowermortality compared to warfarin (target INR 2.0 to 3.0) inpatients with AF. One-third of patients had HF or reducedLVEF in this trial and similar to the RE-LY trial, there wasno significant interaction with treatment effect (p forinteraction ¼ 0.50) (75).

In the APPRAISE-2 trial (Apixaban for Prevention ofAcute Ischemic Events 2), a 5 mg twice daily dose ofapixaban in addition to standard antiplatelet therapy wasassociated with no significant reduction in recurrentischemic events but an increased incidence of major bleedingevents in patients with a recent ACS and at least 2 additionalrisk factors for recurrent ischemic events. The trial wasterminated prematurely for the high bleeding rate in theapixaban arm. In this trial, 28% of patients had HF. Therewas a 23% reduction in the occurrence of the primaryendpoint with apixaban versus placebo (HR: 0.77, 95% CI:0.58 to 1.02) in patients with HF compared to 5% increasein the occurrence of the primary endpoint in patientswithout HF (HR: 1.05, 95% CI: 0.86 to 1.29, p forinteraction ¼ 0.08) (76).Rivaroxaban. In the ROCKET AF (Rivaroxaban OnceDaily Oral Direct Factor Xa Inhibition Compared withVitamin K Antagonism for Prevention of Stroke and Em-bolism Trial in Atrial Fibrillation), rivaroxaban wascompared to warfarin for the prevention of ischemic strokein AF patients; w60% of the population had HF. Rivar-oxaban therapy was noninferior to warfarin for the preven-tion of stroke or systemic embolism. Major bleeding wassimilar between the groups and rivaroxaban was associatedwith less frequent intracranial and fatal bleeding. In a sub-group analysis, there was no significant interaction betweentreatment with rivaroxaban and the presence of HF (p forinteraction ¼ 0.419) (77).

In the ATLAS ACS–TIMI 51 trial (Anti-Xa Therapyto Lower Cardiovascular Events in Addition to StandardTherapy in Subjects with Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 51), 2 dose regimensof rivaroxaban (2.5 mg twice daily and 5.0 mg twice daily)were compared with placebo in patients with ACS. Nearly10% of patients had HF and in this subgroup, rivaroxaban

2.5 mg twice daily dose was associated with a lower rate ofoccurrence of the primary endpoint compared with placebo(10.1% vs. 16.8%). Although the confidence intervals werewide in the HF group, there was no difference in the firstoccurrence of treatment-emergent non–coronary arterybypass graft related TIMI major bleeding events. However,in patients without HF, there was no apparent difference inthe primary endpoint occurrence between the rivaroxabangroup and placebo (5.5% vs. 6.0%). There was higher non–coronary artery bypass graft related TIMI major bleeding(1.4% vs. 0.4%) in the rivaroxaban group (78).

In a small study of patients with acute decompensatedHF and patients withNewYorkHeart Association functionalclass III/IV HF, the pharmacodynamics and pharmacoki-netics of rivaroxaban were similar. In patients with functionalclass III/IV HF treated with placebo, prothrombin fragment1.2 increased over 7 days whereas rivaroxaban therapy (10 mgonce daily) was associated with a reduction in prothrombinfragment 1.2. A nonsignificant reduction in the rate ofD-dimer and thrombin-antithrombin complex increase overtime was also associated with rivaroxaban therapy (79).

There are only 2 trials undergoing involving treatmentwith antiplatelet and new oral anticoagulants as given inTable 3.

Meta-Analysis of New Oral Anticoagulants

In a recent semisystematic review and meta-analysis of phaseIII trials (ARISTOTLE, RE-LY, and ROCKET-AF)including 44,563 patients with AF, new OAC treatmentwas not associated with a significant reduction in stroke andsystemic embolism compared with warfarin among patientswith HF (n ¼ 21,095, OR: 0.91, 95% CI: 0.78 to 1.06, p ¼0.22) but was associated with 24% reduction in patientswithout HF (OR: 0.76, 95% CI: 0.67 to 0.87, p < 0.0001).The definitions of HF in the 3 trials were not uniform. Inthe RE-LY trial, HF was defined as ejection fraction <40%by echocardiogram, radionuclide, or contrast angiogramwithin 6 months, or symptoms of New York Heart Asso-ciation functional class >II HF within 6 months. In theROCKET AF trial, the definition included symptoms of

http://www.clinicaltrials.gov/ct2/show/NCT01877915?term=NCT01877915%26rank=1

http://www.clinicaltrials.gov/ct2/show/NCT01765400?term=NCT01765400%26rank=1

Table 4 Guidelines

A. Heart Failure Society of America (81)

� Treatment with warfarin (goal international normalized ratio [INR] 2.0–3.0) is recommended for all patients with HF and chronic or documented paroxysmal, persistent, or long-standing atrial fibrillation (Strength of Evidence 5 A) or a history of systemic or pulmonary emboli, including stroke or transient ischemic attack (Strength of Evidence 5 C), unlesscontraindicated.

� It is recommended that patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documentedLV thrombus be treated with warfarin (goal INR 2.0–3.0) for the initial 3 months post-MI (Strength of Evidence 5 B) unless contraindicated.

� Other patients with ischemic or nonischemic cardiomyopathy and LV thrombus should be considered for chronic anticoagulation, depending on the characteristics of thethrombus, such as its size, mobility, and degree of calcification. (Strength of Evidence 5 C).

� Long-term treatment with an antiplatelet agent, generally aspirin in doses of 75 to 81 mg, is recommended for patients with HF due to ischemic cardiomyopathy, whether ornot they are receiving ACE inhibitors. (Strength of Evidence 5 B)

� Warfarin (goal INR 2.0–3.0) and clopidogrel (75 mg) also have prevented vascular events in post- MI patients and may be considered as alternatives to aspirin.(Strength of Evidence 5 B)

� Routine use of aspirin is not recommended in patients with HF without atherosclerotic vascular disease. (Strength of Evidence 5 C)

B. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 (80)

� Other than in patients with AF (both HF-REF and HF-PEF), there is no evidence that an oral anticoagulant reduces mortality–morbidity compared with placebo or aspirin.

C. 2012 Consensus Document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis (53)

� In the absence of a specific indication, such as documented coronary artery disease, aspirin should not be initiated.� Given no overall benefit of warfarin on rates of death and stroke, with an increase in major bleedingddespite the potential for a reduction in ischemic stroked

there is currently no compelling reason to use warfarin routinely for all HF patients in sinus rhythm.� Until more evidence becomes available, clinical decisions to treat patients with HF in sinus rhythm with anticoagulants must be made on a patient-by-patient basis, balancing

the individual benefits against the risks of treatment, especially amongst high risk patients.� Clinical trials are needed to see if the new oral anticoagulants (oral direct thrombin inhibitors, oral Factor Xa inhibitors) that may offer a different risk–benefit profile compared

with warfarin could offer the reduction in ischemic stroke with less risk of major bleeding.� Anticoagulation may potentially be considered by some clinicians in the following HF patient groups: HFrEF with previous thrombo-embolism (stroke, transient ischemic

attack, VTE), newly diagnosed intracardiac thrombus, and right heart failure with pulmonary hypertension, but evidence is limited and more research is needed toascertain the long-term risk–benefit ratio.

ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ESC ¼ European Society of Cardiology; HF-PEF ¼ heart failure with preserved ejection fraction; HF-REF ¼ heart failure with reduced ejectionfraction; LV ¼ left ventricular; VTE ¼ venous thromboembolism; other abbreviations as in Table 1.


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HF or an ejection fraction of �35%. The definition in theARISTOTLE trial was symptomatic HF �3 months orejection fraction �40%. The analysis was uncorrected forconfounding variables (31).

Guidelines

The European and American guidelines for the treatment ofpatients with AF are presented in Table 4 (80–82). Ac-cording to the 2012 European Society of Cardiologyguidelines, “other than in patients with AF (both HF withreduced and preserved ejection fraction), there is no evi-dence that an OAC reduces mortality and morbiditycompared with placebo or aspirin” (80). A similar view alsohas been provided by the recent consensus document fromthe European Society of Cardiology Heart Failure Associ-ation and the European Society of Cardiology WorkingGroup on Thrombosis as follows: “Given no overall benefitof warfarin on rates of death and stroke, with an increase inmajor bleedingddespite the potential for a reduction inischemic strokedthere is currently no compelling reason toroutinely use warfarin for all HF patients in sinus rhythm”

(53). The 2009 updated American College of Cardiology/American Heart Association guidelines acknowledged theavailability of limited data for the recommendation of OACuse in patients with HF, but it recommends OAC in HFpatients with a previous thromboembolic event (82).

Finally, the 2010 Heart Failure Society of Americaguidelines for HF or systolic dysfunction recommend that“Treatment with warfarin (goal INR 2.0 to 3.0) is recom-mended for all patients with HF and chronic or documented

paroxysmal, persistent, or long-standing AF or a history ofsystemic or pulmonary emboli, including stroke or transientischemic attack, unless contraindicated,” and “Antiplatelettherapy is recommended to reduce vascular events in patientswith HF and CAD unless contraindicated” (81).

Conclusions

Heart failure is a common clinical problem with a prevalenceof 1% to 2% in the general population that is increasing dueto the aging population. Despite the heightened risk forstroke and thromboembolism in patients with HF and AF,in patients with systolic HF in sinus rhythm, the level ofincreased thromboembolic risk is less clear. The decision totreat patients with HF with antiplatelet therapy remainslargely influenced by the presence or absence of concomitantarterial disease. Antithrombotic therapy has been shown tobe effective in many forms of cardiac disease, includingpatients with HF and AF. However, the utility of oralanticoagulant and/or antiplatelet therapy has never beenevaluated in an adequately powered dedicated clinical trial ofHF patients in sinus rhythm. Although it is clear thatplatelet activation and hypercoagulability are present in HF,and there is evidence that stroke is reduced by warfarintherapy in the HF patient, the available data suggest that therisk of major bleeding overshadows the antithromboembolicbenefit in HF patients in sinus rhythm. These findings havebeen reflected in the guidelines.

The CHADS2 and HAS-BLED risk scores may behelpful to select patients for future studies of antithrombotictherapy in the setting of HF and sinus rhythm. The window


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of greatest advantage for antithrombotic therapy may beearly after initial presentation, when a markedly increasedrisk of death, and death or stroke, has been reported.Selecting patients for enrollment may also be facilitated byobjective assessments of thrombogenicity using laboratorytesting. Thromboelastography is a potential method thatdetermines platelet function in addition to thrombin gen-eration and the viscoelastic characteristics of the platelet-fibrin clot. Large-scale, adequately, powered trials thathave refined selection criteria, possible including laboratorytesting, will be needed to establish the role of antithrombotictherapy in the HF patient in sinus rhythm.

Reprint requests and correspondence: Dr. Paul A. Gurbel, SinaiCenter for Thrombosis Research, Cardiac Catheterization Labo-ratory, 2401 West Belvedere Avenue, Baltimore, Maryland 21215.E-mail: [email protected].

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