JACC: Heart Failure Vol. 2, No.

1, 2014
 2014 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.07.007

STATE-OF-THE-ART PAPER

Antiplatelet and Anticoagulant Agents

in Heart Failure
Current Status and Future Perspectives
Paul A. Gurbel, MD, Udaya S. Tantry, PHD
Baltimore, Maryland

There has been a 3-fold increase in hospital discharges for heart failure (HF) and also significantly increased
mortality rate in HF patients in recent years. A major focus of HF research has been in the area of neurohormonal
control and resynchronization therapy. There is a great urgency in better understanding the pathophysiology
underlying the exceedingly high mortality and a need for exploration of therapeutic strategies beyond those that
influence neurohormonal pathways. The decision to treat patients with HF with antiplatelet therapy remains largely
influenced by the presence or absence of concomitant arterial disease. Antithrombotic therapy has been shown to
be effective in many forms of cardiac disease, including patients with HF and atrial fibrillation. Although it is clear
that platelet activation and hypercoagulability are present in HF, and there is evidence that stroke is reduced by
warfarin therapy in the HF patient, the available data suggest that the risk of major bleeding overshadows the
antithromboembolic benefit in HF patients in sinus rhythm. The utility of oral anticoagulant and/or antiplatelet
therapy 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 coagulation
to improve outcomes in the HF patient. (J Am Coll Cardiol HF 2014;2:1–14) ª 2014 by the American College of
Cardiology Foundation

On the basis of data from National Health and Nutrition
Examination Survey 2007 to 2010, an estimated 5.1 million
Americans
20 years of age have heart failure (HF) (National
Heart, Lung and Blood Institute tabulation). One in 9 death
certificates (274,601 deaths) in the United States mentioned
HF in 2009. There has been a 3-fold increase in hospital
discharges for HF since 1979 in the United States (1).
A major focus of HF research has been in the area of
neurohormonal control and resynchronization therapy (2).
However, venous thromboembolism (VTE), cardioembolic
stroke, and sudden death occur in 30% of HF patients and
contribute to the observed high overall mortality and
morbidity (3). After atrial fibrillation (AF), which accounts
for 15% of strokes, HF is the next most frequent associated
From the Sinai Center for Thrombosis Research, Baltimore, Maryland. Dr. Gurbel
has served as a consultant for Daiichi Sankyo, Sankyo, Lilly, Pozen, Novartis, Bayer,
AstraZeneca, Accumetrics, Nanosphere, Sanofi-Aventis, Boehringer Ingelheim,
Merck, Medtronic, Iverson Genetics, CSL, and Haemonetics; has received grants
from the National Institutes of Health, Daiichi Sankyo, Lilly, Pozen, CSL, Astra-
Zeneca, Sanofi-Aventis, Haemoscope, Medtronic, Harvard Clinical Research
Institute, and Duke Clinical Research Institute; has received payment for lectures,
including service on speakers’ bureaus from Lilly, Daiichi Sankyo, Nanosphere,
Sanofi-Aventis, Merck, and Iverson Genetics; has received payment for development
of educational presentations from Merck, the Discovery Channel, and Pri-Med; owns
stock or stock options in Merck, Medtronic, and Pfizer; and holds patents in the area
of personalized antiplatelet therapy and interventional cardiology. Dr. Tantry has
reported that he has no relationships relevant to the contents of this paper.
Manuscript received May 22, 2013; revised manuscript received July 25, 2013,
accepted July 25, 2013.
cardiac condition accounting for 9% of all strokes (4).
Although AF significantly increases the risk of stroke, the
heightened risk of thromboembolism in HF patients is in-
dependent of AF. These observations serve as evidence for
a potential “heart failure research paradox” where compara-
tively less information has been gained from adequately sized
prospective investigations of thrombogenicity and antith-
rombotic therapy in the HF patient. Despite the fact that
treatment with angiotensin-converting enzyme (ACE) in-
hibitors, angiotensin receptor blockers, beta adrenergic an-
tagonists, and mineralocorticoid receptor antagonists in HF
patients has improved outcomes, morbidity or mortality re-
mains particularly high in patients with acute decompensated
HF (2). In patients hospitalized for HF, the mortality rate
is 4% at 1 month, 18% at 6 months, w30% at 12 months, and
w40% 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 exploration
of therapeutic strategies beyond those that influence neuro-
hormonal pathways. In this state-of-the art paper we explore
the evidence for targeting the inhibition of platelet function
and coagulation to improve outcomes in the HF patient.
Pathophysiology of Arterial Thrombosis in HF
Approximately 70% of patients with HF and left ventricular
systolic dysfunction will have ischemic heart disease (5).
Nonischemic etiologies will be responsible for the remainder
2 Gurbel and Tantry JACC: Heart Failure Vol. 2, No. 1, 2014
Antiplatelet and Anticoagulant Agents in Heart Failure February 2014:1–14

Abbreviations of HF with systolic dysfunction. Occlusive thrombus generation at the site of plaque rupture
and Acronyms Platelets play a central role in the is dependent on vulnerable blood (hypercoagulability, en-
genesis of thrombosis at the site hanced platelet function, inflammation) and vulnerable vessel
ACE = angiotensin-
converting enzyme
of arterial wall injury (Fig. 1). (endothelial dysfunction, and ruptured plaque/denuded
Ruptured plaque or denuded endothelium/abnormal anatomy) (Fig. 2). Reduced platelet
ACS = acute coronary
syndromes arterial endothelium results in the survival time, increased mean platelet volume, and greater
ADP = adenosine
exposure of various prothrom- platelet activation and reactivity have been observed in
diphoshpate botic factors thereby promoting patients with HF (8,9). In addition, elevated levels of b-
AF = atrial fibrillation
platelet adhesion, activation, and thromboglobulin, p-selectin, platelet/endothelial cell adhe-
CAD = coronary artery
finally generation of a platelet- sion molecule-1, and osteonectin as well as increased platelet
disease rich thrombus generation. Expo- surface p-selectin and CD40L all serve as further evidence of
CI = confidence interval
sure of the subendothelial matrix heightened platelet activation in patients with HF (10–12).
following atherosclerotic plaque High levels of circulating fibrinogen, fibrinopeptide A, and
F = circulating coagulation
factor rupture and the subsequent release D-dimer have also been demonstrated in patients with HF.
GP = glycoprotein
of various factors facilitate platelet In addition, high levels of fibrinogen and D-dimer observed
adhesion and activation. Platelet in patients with HF have correlated with disease severity (13).
HF = heart failure
activation leads to the release Decreased circulating levels of ADAMTS-13 and increased von
HR = hazard ratio
of important secondary agonists, Willebrand factor (vWF) were found to be significant predictors
INR = international thromboxane A2 and adenosine of clinical events in patients with HF (14). In addition, a pro-
normalization ratio
diphosphate (ADP). Throm- thrombotic environment in the setting of HF is indicated by
LVEF = left ventricular
boxane A2 is produced from increased inflammatory cytokines such as tumor necrosis factor-
ejection fraction
membrane phospholipids, and a and interleukin-1. These factors in turn are associated with
MI = myocardial infarction
ADP is released from dense increased expression of tissue factor and thrombin generation
OAC = oral anticoagulant
granules. Through autocrine and and decreased thrombomodulin and protein C pathway acti-
OR = odds ratio paracrine mechanisms, these 2 vation (anticoagulant factors) (15–17). Vulnerable vessel is
RR = relative risk locally generated secondary ago- characterized by decreased antithrombotic factor expression
TF = tissue factor nists play a critical role in the such as nitric oxide, thrombomodulin and increased expression
VTE = venous sustained activation of aIIbb3 re- of TF, vWF, and elevated inflammation at the site of plaque
thromboembolism ceptors and stable platelet aggre- rupture. Moreover, a bifurcated and stenotic vessel affects
gation. Plaque rupture results in arterial shear and promotes platelet activation (18,19).
tissue factor (TF) exposure at the site of vascular injury and the
generation of femtomolar amounts of thrombin, the most Pathophysiology of Venous Thrombosis in HF
potent primary platelet agonist. Tissue factor bearing cells
come in contact with circulating coagulation factor (F) VII Heart failure has been recognized as a prothrombotic or hy-
resulting in the autoactivation of FVII to form the TF-FVIIa percoagulable state. The major components of Virchow’s triad
complex, which in turn activates FX to FXa and FIX to FIXa. are present in venous thrombosis-vessel wall abnormalities,
FXa initially activates small amounts of thrombin, which in vulnerable blood, and blood flow abnormalities (Fig. 3) (2).
turn activates platelets and also FV and FVIII. Subsequently, Venous stasis induced by high pressure, a low-flow state,
the intrinsic FXase (FVIIIa-FIXa) and prothrombinase (FVa- and immobility result in distention of the vessel wall local and
FXa) are formed on the activated platelet surface where large local hypoxia, causing ischemia and oxidative stress
amounts of thrombin are generated by the conversion of (18,20,21). The latter mechanisms in addition to neurohor-
prothrombin to thrombin. Plasminogen activator inhibitor-1, monal activation result in endothelial cell activation. Endo-
released from platelets, depresses fibrinolysis. Thrombin thelial activation is characterized by increased expression of
finally catalyzes the conversion of soluble fibrinogen to insol- adhesion molecules-selectins and decreased production of
uble strands of fibrin, thereby initiating clot formation (Fig. 1). antithrombotic factor-nitric oxide. These mechanisms pro-
Thrombin also activates FXIII to induce fibrin polymerization. mote platelet/monocyte adhesion and activation. Impor-
The final result is a platelet-fibrin clot that mediates normal tantly, TF-rich microparticles released from activated
hemostasis and pathologic thrombosis at the site of athero- endothelial cells and monocytes attach to the expressed
sclerotic plaque rupture or endothelial denudation. Thrombi adhesion molecules on the endothelium at the site of injured
generated on ruptured plaques may embolize downstream vessel wall (20,22,23). TF initiates the coagulation cascade
and occlude the microvasculature resulting in microinfarction. and, ultimately, fibrin-rich thrombus generation. In this line,
The latter mechanism may participate in the progression of increased circulating endothelial adhesion molecules,
left ventricular dysfunction in the HF patient. At present, it increased microparticles of endothelial origin, and leukocyte
remains unknown whether there is interindividual variability activation have been demonstrated in patients with VTE and
and time dependence in the importance of thromboxane A2, HF (22–24). Finally, venous stasis promotes thrombosis by
ADP, and thrombin in thrombus generation (6,7). decreased clearance of activated coagulation factors (23).
JACC: Heart Failure Vol. 2, No. 1, 2014 Gurbel and Tantry 3
February 2014:1–14 Antiplatelet and Anticoagulant Agents in Heart Failure

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.

Myocardial Infarction and Stroke Risk in HF
In patients with HF secondary to coronary artery disease
(CAD), ongoing silent or symptomatic ischemia has being
associated with HF progression (25). The elderly, women,
and those with prior myocardial infarction (MI) are at
greatest risk for developing HF. However, a relatively low
rate (2% to 4%) of fatal or non-fatal MI has been reported in
patients 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, with
a possible relationship between low ventricular ejection
fraction (LVEF) and stroke risk (28).
Strokes associated with HF have been attributed to mul-
tiple etiologies. Concomitant AF is associated with loss of
atrial contraction. In the setting of stasis, thrombosis is pro-
moted in the left appendage, and embolization may ensue. In
addition, AF is associated with atherosclerosis. Therefore,
atheroembolism from nonatrial sources may also explain a
heightened risk for stroke. In HF patients in sinus rhythm,
4 Gurbel and Tantry
Antiplatelet and Anticoagulant Agents in Heart Failure
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.
underlying atherosclerosis may play a dominant mechanistic
role in stroke occurrence. Among HF patients with stroke,
about one-half have been reported to have AF (29). The
significant impact of HF on stroke risk in AF patients was
suggested in the Stroke Prevention in Atrial Fibrillation In-
vestigators studies (30). The risk may also depend on how HF
is defined and whether it is decompensated versus stable (31).
Significantly more circulating platelet aggregates were
demonstrated in patients with HF compared with normal
volunteers by Mehta et al. (32). In the same study, the
number of circulating platelet aggregates declined to normal
levels following sodium nitroprusside infusion, and there was
significantly lower ex vivo epinephrine- and ADP-induced
platelet aggregation, which was associated with a 30%
decrease in systemic vascular resistance and a 28% increase in
cardiac output. The authors suggested that an increase in
vascular resistance in certain HF patients may cause an in-
crease in circulating platelet aggregates and that antiplatelet
therapy may be beneficial in these patients.
Insight into the heightened risk of stroke and death in HF
was gained in the Diet, Cancer and Health study. Among
the 51,553 patients without prior HF, 1,239 were identified
with incident HF. There was a markedly increased risk of
death, and death or stroke (ischemic or hemorrhagic or
both) in the first 30 days after presentation with first HF
relative to non-HF exposed patients (hazard ratios [HR]:
42.8 and 38.4, respectively). There was attenuation of risk
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
at 30 days to 6 months (HRs: 12.7 and 9.3, respectively) and
>6 months (HRs: 4.9 and 4.0, respectively) (33). Warfarin
use was associated with a lower risk for death and the
composite of death or stroke compared with no warfarin
therapy and this effect was more prominent in the first 30
days. Finally, independent predictors for death, stroke, and
the 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 1,014
patients developed HF and 827 patients developed stroke
during an average follow-up time of 9.7 years. There was a
more than 5-fold increase in the risk of ischemic stroke in
the first month after HF diagnosis (age- and sex-adjusted
HR: 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 after
0.5 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 MI
were followed for an average of 42 months. The annual rate
of fatal and nonfatal stroke was 1.5%, and the 5-year rate of
stroke was 8.1%. There was a 2-fold increased risk for
stroke in patients with left ventricular ejection fraction
(LVEF) 28% compared with patients with LVEF of
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
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.
>35% (p ¼ 0.01). In this study, lower ejection fraction (for
every decrease of 5 percentage points in the ejection fraction
there was an 18% increase in the risk of stroke), older age,
and the absence of aspirin or anticoagulant therapy were
found to be independent risk factors for stroke (35).
Venous Thromboembolism
It has been reported that patients with HF have an increased
risk for developing deep vein thrombosis versus those without
HF, with adjusted odds ratios (ORs) of 1.47 (95% CI: 1.47 to
1.48) to 2.93 (95% CI: 1.55 to 5.56) (36). Moreover, there is a
10% to 22% risk of venographically-proven VTE in HF pa-
tients in the absence of pharmacologic treatment (36,37). In
several case-cohort studies, HF patients were found to have a 2-
to 3-fold increased risk for VTE compared with patients with
other medical conditions. The rate of VTE was 2.7 and 2.1 per
100 patient-years in the V-HeFT (Veterans Affairs
Vasodilator-Congestive Heart Failure) I and II trials, respec-
tively, that included both patients in sinus rhythm and with AF
(38). In an analysis of the SCD-HeFT (Sudden Cardiac Death-
Heart Failure Trial), which excluded all patients with AF at
the time of randomization, the rate of thromboembolism was
3.4% over a median follow-up of 45.5 months. A trend toward
an increased 4-year Kaplan-Meier rate of thromboembolism
with lower LVEF was observed (3.5%, 3.6%, and 4.6% with
LVEF 30% to 35%, 20% to 30%, and <20%, respectively) (28).
Gurbel and Tantry 5
Antiplatelet and Anticoagulant Agents in Heart Failure
Antithrombotic Therapy in Patients With HF
The previous evidence suggests that antithrombotic therapy
targeting the platelet and/or coagulation may provide
beneficial effects in patients with HF, particularly early after
presentation. Long-term oral anticoagulant (OAC) therapy
is an established major preventive treatment strategy against
stroke in patients with AF (5). However, unlike AF, the role
of antithrombotic agents in the prevention of stroke in pa-
tients with HF and sinus rhythm has been much less
investigated. Personalized antithrombotic therapy has been
studied in patients treated with coronary stents with the goal
of determining a therapeutic window for on-treatment
platelet reactivity that optimally prevents ischemic events
while avoiding medically-important bleeding (39). Labora-
tory tests are available that identify high intrinsic throm-
bogenicity that have been associated with clinical thrombotic
events after stenting (40). Similar investigations have never
been undertaken to identify the prothrombotic HF patient.
Despite the extensive research in the PCI population, the
goal of optimal antithrombotic therapy that balances
reduction in ischemia and avoidance of bleeding remains
elusive in HF patients. Moreover, platelet activation and
aggregation, and thrombin formation, are highly interlinked.
Optimal target(s) for the inhibition of the effects of
thrombin remain unclear; proposed strategies include direct
thrombin inhibition, inhibition of the coagulation factors
6 Gurbel and Tantry
Antiplatelet and Anticoagulant Agents in Heart Failure
upstream from thrombin formation including FXa, FIXa,
FVIIa, or FVa, or the platelet thrombin receptor-protease
activated receptor-1.
Antiplatelet Therapy
Aspirin is chosen in HF based on its role in secondary
prevention in patients with atherosclerotic vascular disease.
To this date there has been no dedicated randomized trial of
antiplatelet 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 artery
disease, it is well established that simultaneous inhibition of
cyclooxygenase-1 with aspirin and the adenosine diphos-
phate-P2Y12 receptor with clopidogrel is associated with a
significant reduction in MI (41). However, the efficacy of
dual antiplatelet therapy on stroke reduction is uncertain.
Adding aspirin to clopidogrel in patients with recent
ischemic stroke or transient ischemic attack in the large-
scale MATCH trial (Management of atherothrombosis
with clopidogrel in high-risk patients with recent transient
ischaemic attack or ischaemic stroke) was not associated
with a benefit in reducing major vascular events (RRR
[relative risk reduction]: 6.4%, 95% CI: –4.6 to 16.3, p ¼
0.244). However, the risk of life-threatening or major
bleeding was increased by the addition of aspirin to clopi-
dogrel (42). In the ESPRIT (European/Australasian Stroke
Prevention in Reversible Ischaemia Trial), treatment of
aspirin (30 to 325 mg/day) with dipyridamole (200 mg twice
daily) was associated with a 20% relative risk (RR) reduction
in the composite end point of composite of death from all
vascular causes, nonfatal stroke, nonfatal MI, or major
bleeding complication in patients with transient ischemic
attack or minor stroke of presumed arterial origin compared
to aspirin alone (43). Similarly, aspirin plus extended release
dipyridamole versus clopidogrel was associated with similar
incidences of primary endpoint of first recurrence of stroke
(HR: 1.01, 95% CI: 0.92 to 1.11) in patients with a recent
ischemic stroke in the PRoFESS (Prevention Regimen for
Effectively Avoiding Second Strokes) trial (44).
A meta-analysis performed by Antithrombotic Trialists’
collaboration of secondary prevention trials demonstrated
that aspirin therapy was associated with an 1.5% absolute
reduction 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 in
hemorrhagic stroke (45). Treatment failure and pharmaco-
logic limitations associated with clopidogrel therapy fostered
the development of more potent P2Y12 receptor blockers
such as, prasugrel, an irreversible agent, and ticagrelor, a
reversibly binding agent. Treatment of patients with acute
coronary syndromes (ACS) with the latter agents was more
effective than clopidogrel; however, the observed degree of
adverse event reduction (w20% relative and w2% absolute),
and significantly greater bleeding remain major concerns
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
(39). Moreover, it is also interesting to note that although
more potent P2Y12 receptor blockers are more effective than
clopidogrel in the overall patient population, in “very high-
risk patients” (diabetes mellitus, elderly patients, and those
with renal failure, history of MI, stroke, and stent throm-
bosis), the overall rate of ischemic event occurrence remains
very high. In addition, some of these “very high risk” groups
are also associated with an increased bleeding risk. The
previous limitations highlight the ceiling effect of current
dual antiplatelet therapy targeting COX-1 and the P2Y12
receptor in high-risk CAD patients and suggest that the
residual ischemic event occurrences are mediated by other
pathways that are unblocked by current antiplatelet therapy.
There is no information available on the outcomes of
HF patients treated with either prasugrel or ticagrelor.
Thus, the indication for antiplatelet therapy in the HF patients
depends upon the presence of concomitant vascular disease.
Warfarin
Warfarin (vitamin K antagonist) blocks multiple steps of
coagulation by reducing the synthesis of vitamin K depen-
dent coagulation factors. In a meta-analysis of trials
involving patients with AF, warfarin therapy was found to be
associated 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 that
are metabolized by the same cytochrome P450 isoenzymes
influence the pharmacokinetics and pharmacodynamics of
warfarin. The metabolism and efficacy of warfarin are
influenced by liver function, genetic polymorphisms, and
alcohol and food consumption (47). The major concern of
genetic variability lies within the CYP2C9 and VKORC1
genes that encode proteins involved in the metabolism of
warfarin (48,49). Warfarin therapy is associated with a
relatively narrow therapeutic window of international
normalization ratio (INR) values between 2.0 and 3.0.
Insufficient anticoagulation and a subsequent rise in the risk
of ischemic strokes are associated with INR values below
2.0, and a higher risk of intracranial bleeding is associated
with an INR >4.0 (49,50).
New Oral Anticoagulants
Currently known anticoagulants can be classified as
parenteral or oral (based on their administration route)
or direct or indirect inhibitors (based on their target of
action). New OACs have been developed to overcome
some of the limitations of warfarin therapy. The direct
thrombin inhibitors (“gatrans,” e.g., dabigatran) directly
bind to thrombin and block thrombin-induced conversion
of fibrinogen to fibrin and the activation of FV, FVII, FIX,
and platelets. The latter functions are responsible for the
amplification of thrombin generation. Moreover, direct
thrombin inhibitors inhibit the activity of fibrin-bound
thrombin (51,52).
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
The inhibition of coagulation protease enzymes respon-
sible for the propagation phase attenuates the generation of
thrombin. Anticoagulants have been developed to inhibit
FIXa (e.g., the DNA aptamer pegnivacogin), FVIIIa (TB-
402), and FVa/FVIIIa (drotrecogin, a recombinant form of
human activated protein C). Recomodulin and solulin are
soluble recombinant derivatives of human thrombomodulin.
The most widely investigated FXa inhibitors have been
rivaroxaban and apixaban. Other FXa inhibitors include
edoxaban, otamixaban, darexaban, betrixaban, and TAK-
442. Among the new OACs, dabigatran and apixiban have
been shown to be more effective in preventing stroke than
warfarin in patients with nonvalvular AF. In addition, lower
rates 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 over
warfarin include the absence of any reported interactions with
food, fewer interactions with other medications, and absence
of frequent laboratory monitoring and dose adjustments (51).
Evidence for Antithrombotic Efficacy in HF
In a post hoc analysis of major HF trials associated with
reduced ejection fraction and anticoagulant therapy, the
annual rate of stroke was between 1.1% and 4.6%. Most of
the trials included in the analysis had some patients with AF
(53). Clinical trials conducted in the 1940s and 1950 have
first assessed the utility of OAC in patients with HF. Many
of the patients in these studies also had accompanying AF
and valvular disease. Dicumarol therapy, the primary OAC
used was associated with reduced thromboembolic event
occurrence and death (54–56). However, the relevance of
these trials in patients with sinus rhythm, which is more
prevalent 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% of
patients and was associated with significantly reduced all
cause death (adjusted HR: 0.82, 95% CI: 0.73 to 0.92, p ¼
0.0005) and reduced risk of death or hospital admission for
HF (adjusted HR: 0.81, 95% CI: 0.74 to 0.89, p < 0.0001)
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 receiving
antiplatelet agents, and conversely neither did the addition of
aspirin in patients receiving enalapril fueled great controversy
about an aspirin–ACE inhibitor interaction (58). Further
support for an aspirin-ACE inhibitor interaction arose from
the CONSENSUS II (Co-operative New Scandinavian
Enalapril Survival Study II) Study. Differential effects of the
ACE inhibitor enalapril in subgroups defined by use of aspirin
at baseline were analyzed. Logistic regression demonstrated
that the enalapril–aspirin interaction term was a significant
predictor of mortality and was a borderline significant pre-
dictor of mortality 30 days after randomization (59).
The ACTIVE (Atrial fibrillation Clopidogrel Trial with
Irbesartan for the prevention of Vascular Events) program
Gurbel and Tantry 7
Antiplatelet and Anticoagulant Agents in Heart Failure
added support for the use of aspirin in HF patients on ACE
inhibitor therapy. In over 2,000 patients with a history of
HF and AF, there was no evidence of aspirin-related
attenuation of ACE inhibitor benefit (60).
In a multivariate analysis of the SOLVD trial, warfarin
therapy (n ¼ 861) was associated with a significant reduction
in all-cause mortality (adjusted HR: 0.76, 95% CI: 0.65 to
0.89, p ¼ 0.0006) and in the risk of death or hospital
admission for HF (HR: 0.82, 95% CI: 0.72 to 0.93,
p ¼ 0.0002) compared to warfarin nonuse. The benefit of
warfarin 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 no
antithrombotic treatment (26%), 300 mg/day aspirin (32%)
or warfarin (26%, target INR 2.5) for w27 months. In this
study, w75% of patients were male, w60% of patients had
ischemic heart disease, and only 4% to 7% of patients had
AF. No difference in the primary endpoint of first occur-
rence of death, nonfatal MI, or nonfatal stroke was observed
between the treatment groups. However, compared to
warfarin, aspirin treated patients were twice as likely to have
a cardiovascular hospitalization or death during the first 12
months follow-up. Aspirin treatment was also associated
with significantly more hospitalizations for cardiovascular
reasons, especially worsening HF (p ¼ 0.044). Therapy with
warfarin and aspirin therapy was associated with a higher
rate of minor bleeding, although few overall major hemor-
rhagic events were reported. The overall study results argued
against the benefit of antiplatelet therapy in HF patients to
prevent thromboembolic events (Table 1) (61).
The subsequent HELAS (HEart failure Long-term
Antithrombotic Study) trial was prematurely terminated af-
ter enrolling 197 of an intended 6,500 patients due to slow
enrollment. In this trial, 115 patients with ischemic cardio-
myopathy were randomized to 325 mg daily aspirin or warfarin
(INR 2.0 to 3.0), whereas 82 patients with nonischemic car-
diomyopathy were randomized to placebo or warfarin (INR
2.5 to 3.0) for 18.5 to 21.9 months. Similar to the WASH
study, there was no difference in the occurrence of the primary
composite endpoint between the groups and only warfarin
therapy was associated with 7 major hemorrhagic events that
were predominantly due to high anticoagulation (62).
In the WATCH (Warfarin and Antiplatelet Therapy in
Chronic Heart Failure) trial, 1,587 of 4,500 planned patients
with symptomatic HF (New York Heart Association func-
tional class II to IV) for at least 3 months were studied. The
trial was terminated prematurely due to slow enrollment.
These patients were in sinus rhythm with documented
LVEF 35% and received 162 mg daily aspirin, 75 mg daily
clopidogrel (in a double-blind, double dummy fashion), or
open label warfarin (target INR 2.5 to 3.0) for a mean
8 Gurbel and Tantry
Antiplatelet and Anticoagulant Agents in Heart Failure
duration of 1.9 years (63). There was no placebo arm in this
study. Similar to previous studies, there was no difference in
the rate of the primary composite endpoint of first occur-
rence of death, nonfatal stroke, or nonfatal MI with warfarin
versus 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 warfarin
versus clopidogrel therapy (HR: 0.89, 95% CI: 0.68 to 1.16,
p ¼ 0.39). There was no difference in mortality between
therapies. Warfarin therapy was associated with a reduction
in the incidence of stroke (both fatal and disabling) compared
to aspirin and clopidogrel (p < 0.02 for both). But, there was
significantly increased bleeding in the warfarin group
compared to clopidogrel group (n ¼ 30 vs. n ¼ 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 in
patients with ischemic HF (73% of population) where the
stroke rates were 0% in warfarin group versus 2.7% in clo-
pidogrel group (p ¼ 0.009) and 1.6% in aspirin group (p ¼
0.01). Furthermore, significantly increased incidences of
hospitalization were observed in patients receiving aspirin
compared to warfarin (p < 0.001). The overall evidence from
the primary endpoint occurrences and mortality did not
support that warfarin is superior to aspirin and that clopi-
dogrel is superior to aspirin in HF patients with ejection
fraction 35% who are in sinus rhythm (63).
In the largest study to date, the WARCEF (Warfarin versus
Aspirin in patients with Reduced Cardiac Ejection Fraction)
study, the efficacy of 325 mg daily aspirin versus warfarin
therapy (target INR 2.5 to 3.0) was evaluated in a double-
blind, double-dummy study design with sham INRs in
2,305 patients in sinus rhythm with LVEF  35% (64). This
trial included a relatively young population (mean age ¼ 61
years) 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-up
was 3.5 years. In 34% and 32% of the total follow-up time,
patients did not receive the randomized warfarin and aspirin
therapy, respectively. There was no control arm in this trial.
Similar to slow recruitment problems observed in previous
trials, in the WARCEF trial, the enrollment was stopped after
2,305 patients from 11 countries instead of a planned 2,860
patients, reducing the power to test the primary hypothesis
from 89% to 69%. The maximum follow-up was extended to 6
years instead of 5 years. There was no significant difference
between treatment groups for the occurrence of the primary
endpoint 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, p ¼ 0.40). In a time-varying
analysis using a Cox model, there was a marginal trend in the
primary endpoint favoring a benefit with warfarin therapy
versus aspirin therapy over time with an HR of 0.89 per
year (95% CI: 0.80 to 0.998, p ¼ 0.046) and HR of 0.76 fa-
voring warfarin by year 4 (p ¼ 0.04) (64). As in the WATCH
trial, there was a significant reduction in ischemic stroke, 1
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
of the secondary endpoints, throughout the follow-up period
with 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) but
with 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). The
reduction in stroke associated with warfarin therapy in pa-
tients with HF appeared similar to the reduction in stroke
observed 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 difference
in 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 times
higher 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, aspirin
therapy was not associated with an increased rate of hospi-
talization (61,63). The lack of an effect of warfarin therapy
on death in this HF population in sinus rhythm suggests that
the mechanism of death in these patients is not due to
thromboembolism but may be mostly due to pump failure or
ventricular arrhythmias (65).
In a recently reported subgroup analysis of the WARCEF
trial, it was demonstrated that among 32 variables explored
for an interaction with treatment, patients <60 years of age
had a 37% reduction in the occurrence of the primary
endpoint (HR: 0.63, 95% CI: 0.48 to 0.84, p ¼ 0.001) as
compared with no benefit observed in patients the
60 years
of age group. Again, this benefit in patients <60 years of age
was mainly driven by a significantly lower mortality rate that
was not observed in patients
60 years of age. In addition,
there was less major bleeding risk with warfarin therapy in
the younger cohort (66).
The previous 4 randomized trials have important limita-
tions. Enrollment was largely incomplete and all studies were
underpowered to test the proposed hypothesis. Second,
heterogeneous drug administration, a variable degree of un-
derlying HF etiology, and varying definitions of the primary
composite endpoint were observed. Finally, the WATCH
and WARCEF trials did not have a placebo arm to evaluate
the actual efficacy of antithrombotic therapy (63,64).
Meta-Analyses of Randomized Trials
and Registry Data
In a meta-analysis that included 4,378 patients from the 4
randomized trials of chronic HF and reduced ejection
fraction 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-related
hospitalizations (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, warfarin
therapy compared to aspirin therapy was associated with
a 41% reduction in all strokes (RR: 0.59, 95% CI: 0.41
to 0.85, p ¼ 0.004) and 52% reduction in fatal and
nonfatal ischemic strokes (RR: 0.48, 95% CI: 0.32 to 0.73,
JACC: Heart Failure Vol. 2, No. 1, 2014 Gurbel and Tantry 9
February 2014:1–14 Antiplatelet and Anticoagulant Agents in Heart Failure

Table 1 Randomized Antithrombotic Trials in Patients With Heart Failure

Patients Treatment and Follow-Up Primary Outcome Outcome Comments

WASH (Warfarin/Aspirin HF: 35% LVEF Randomized to no Death, nonfatal MI, 26% no antithrombotic More HF hospitalization
Study in Heart Failure) n ¼ 279 antithrombotic nonfatal stroke 32% aspirin with aspirin
therapy, 300 mg 26% warfarin More hemorrhage with
aspirin, or warfarin warfarin
(INR 2.5)
Mean follow-up:
27  1 month
HELAS (HEart failure HF: <35% LVEF and HF pts were randomized Nonfatal stroke, No significant difference Low n
Long-term NYHA functional class to 325 mg aspirin or peripheral or PE, MI, between groups
Antithrombotic II to IV warfarin (INR 2–3) re-hospitalization,
Study) n ¼ 197 n ¼ 115 exacerbation of HF
DCM pts were or death
randomized to
warfarin (INR 2.5)
or placebo
Mean followup:
19 to 21 months
WATCH (Warfarin and HF >3 months, in sinus Randomized to open- First occurrence of death, Warfarin vs. aspirin: Lower stroke rate with
Antiplatelet Therapy in rhythm + 35% LVEF label warfarin (INR nonfatal MI, or HR: 0.98, warfarin
Chronic Heart Failure) n ¼ 1,587 2.5–3.0) + double- nonfatal stroke 95% CI: 0.86–1.12; More HF hospitalization
blind treatment to p ¼ 0.77 with aspirin
162 mg aspirin or Clopidogrel vs. aspirin:
75 mg clopidogrel HR: 1.08,
Mean follow-up: 95% CI: 0.83–1.40;
>12 months p ¼ 0.57
Warfarin vs. clopidogrel:
HR: 0.89,
95% CI: 0.68–1.16,
p ¼ 0.39
WARCEF (Warfarin HF: normal sinus rhythm, Randomized to warfarin First occurrence of 26.4% vs. 27.5%. No significant difference
versus Aspirin in 35% LVEF (INR 2–3.5) or 325 mg ischemic stroke, HR: 0.93, between groups.
patients with Reduced n ¼ 2,305 aspirin intracerebral 95% CI: 0.79–1.10; Lower ischemic stroke
Cardiac Ejection Mean follow-up: hemorrhage, or death p ¼ 0.40 with warfarin offset by
Fraction) 42  18 months for any cause Ischemic stroke higher major
2.5% vs. 4.7%, hemorrhage.
HR: 0.52, 95% CI:
0.33–0.82;
p ¼ 0.005
Major hemorrhage
5.8% vs. 2.7%,
HR: 2.21,
95% CI: 1.42–3.47,
p < 0.001
Hospitalization for HF
20.9% vs. 17.5%,
HR: 1.12,
95% CI: 0.998–1.47;
p ¼ 0.053

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.

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 appears
counterbalanced by the increased risk of bleeding (67).
Another meta-analysis including the same patient popu-
lation from the previous 4 randomized trials specifically
addressed stroke prevention. The number needed to reduce
1 stroke was 61 and that needed to harm (major hemor-
rhage) was 34 for warfarin therapy (68). Warfarin did not
increase mortality or confer an increased risk of intracerebral
hemorrhage compared with aspirin.
The REDINSCOR (Red de investigación clínica y básica
en insuficiencia cardiaca) registry included 2,263 patients
with ejection fraction 35% and sinus rhythm without other
anticoagulation indications and 26% of patients were
receiving anticoagulation therapy. Anticoagulation therapy
was associated with no significant differences in total mor-
tality (14% vs. 12.5%) or stroke (0.8% vs. 0.9%), but was
associated with a reduction in the combined endpoint
occurrence of cardiac death, heart transplantation, coronary
revascularization, and cardiovascular hospitalization in a
propensity 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
10 Gurbel and Tantry JACC: Heart Failure Vol. 2, No. 1, 2014
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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 of Patients with AF Warfarin vs. dabigatran Overall ¼ 1.69% vs. No significant treatment
Long-term anticoagulant No sHF ¼ 13,203, sHF ¼ 4,904 110 mg vs. dabigatran 1.53% vs. 1.11% interaction (p ¼ 0.42
therapY) 150 mg 2-yr stroke or No sHF ¼ 1.63% vs. and 0.33)
systemic embolism 1.40% vs. 1.00%
sHF ¼ 1.85% vs.
1.90% vs. 1.44%
Apixaban
ARISTOTLE (Apixaban for Patients with AF and 1 additional Warfarin vs. apixaban Overall ¼ 1.6% vs. 1.27% No significant treatment
Reduction In STroke and Other risk for stroke 5 mg bid No HF ¼ 1.6% vs. 1.2% interaction (p ¼ 0.45)
ThromboemboLic Events in With HF ¼ 5,541 1.8 yr ischemic or HF ¼ 1.6% vs. 1.4%
atrial fibrillation) No HF ¼ 12,660 hemorrhagic or
systemic embolism
APPRAISE-2 (Apixaban for Patients with a recent ACS and at Placebo vs. apixaban Overall ¼ 7.9% vs. 7.5% No significant treatment
Prevention of Acute Ischemic least 2 additional risk factors for 5 mg bid + standard No HF, HR: 1.05 interaction (p ¼ 0.08)
Events 2) recurrent ischemic events antiplatelet therapy (95% CI: 0.86–1.29)
No HF ¼ 5,362 241 days CV death, MI, or HF, HR: 0.77
HF ¼ 2,028 ischemic stroke (95% CI: 058–1.02)
Rivaroxaban
ROCKET AF (Rivaroxaban Once Patients with nonvalvular AF Dose-adjusted warfarin vs. Overall ¼ 2.2% vs. 1.7% No significant treatment
Daily Oral Direct Factor Xa cHF ¼ 8,851 20 mg rivaroxaban cHF ¼ 3.9% vs. 3.6% interaction (p ¼ 0.419)
Inhibition Compared with No cHF ¼ 5,318 1.7 yr stroke or systemic no cHF ¼ 5.01% vs. 4.13%
Vitamin K Antagonism for embolism
Prevention of Stroke and
Embolism Trial in Atrial
Fibrillation)
ATLAS ACS TIMI 51 (Anti-Xa Recent ACS Placebo vs. 2.5 mg Overall ¼ 10.7% vs.
Therapy to Lower Cardiovascular No cHF¼ 4,282 rivaroxaban bid vs. 5 mg 9.1% vs. 8.8%
Events in Addition to Standard cHF ¼ 483 rivaroxaban No cHF¼ 6.0% vs. 5.5%
Therapy in Subjects with Acute 13 months CV death, MI, (2.5 mg rivaroxaban)
Coronary Syndrome– or stroke HF ¼ 16.8% vs. 10.1%
Thrombolysis In Myocardial (2.5 mg rivaroxaban)
Infarction 51)

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.

of and prophylaxis against VTE. In a recent meta-analysis
of trials in patients with AF, new oral anticoagulants were
22% more effective in the prevention of stroke compared
to warfarin (RR: 0.78, 95% CI: 0.67 to 0.92) and there was
a significantly reduced risk of intracranial hemorrhage
(RR: 0.49, 95% CI: 0.36 to 0.66) (70). Based on the data
from the Danish National Patient Registry, the new anti-
coagulants were superior to warfarin for net clinical benefit
regardless of the risk of bleeding in patients at high risk of
strokedCHADS(2) score
1 or CHA(2)DS(2)-VASc
2.
The benefit was more prevalent when stroke risk and
bleeding risk were high (71).
Bivalirudin. In a pooled analysis of randomized trials of
bivalirudin therapy that included 14,258 ACS patients
treated with dual antiplatelet therapy, bivalirudin therapy
compared with heparin plus glycoprotein (GP) IIb/IIIa in-
hibitor therapy was significantly associated with lower
mortality risk in patients with <35% LVEF (random RR:
0.47, 95% CI: 0.30 to 0.72, p ¼ 0.0004), which was
consistent across studies. However, the benefit of bivalirudin
therapy 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 Registry
Evaluating Outcomes After Myocardial Infarctions: Events
and Recovery) registry, a 37% RR reduction in in-hospital
mortality (p < 0.0001) was reported in patients with HF
who were treated with bivalirudin compared to heparin plus
a GPII/IIIa inhibitor (73). These hypothesis-generating
data suggest a potential benefit of direct thrombin inhibi-
tion in HF patients in the setting of ACS.
Dabigatran. In the RE-LY trial (Randomized Evaluation
of Long-term anticoagulant therapY), a fixed dose
(110 mg or 150 mg twice daily) of dabigatran was
compared for noninferiorty for the prevention of stroke or
systemic embolism versus adjusted-dose warfarin in pa-
tients with AF. This trial demonstrated that 110 mg twice
daily dose of dabigatran was associated with similar rates
of stroke and systemic embolism and lower rates of major
hemorrhage compared with warfarin whereas 150 mg
twice daily dose of dabigatran was associated with lower
rates of stroke and systemic embolism but similar rates of
major hemorrhage compared to warfarin. Among 4,904
patients enrolled with symptomatic HF, there was no
significant interaction with treatment effect with both 100
and 150 mg doses of dabigatran (p for interaction ¼ 0.42
and 0.33, respectively) (74).
Apixaban. In the ARISTOTLE trial (Apixaban for
Reduction In STroke and Other ThromboemboLic Events
in atrial fibrillation), 5 mg twice daily apixaban was superior
to warfarin in the prevention of stroke or systemic embolism
JACC: Heart Failure Vol. 2, No. 1, 2014
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Table 3 Trials of Antiplatelet Agents and New Oral Anticoagulants in Patients With Heart Failure
Name of the Study Patients
COMMANDER HF HF (EF 40%) þCAD
NCT01877915 (A Study to n ¼ 5,000
Assess the Effectiveness
and Safety of Rivaroxaban
in Reducing the Risk of
Death, Myocardial Infarction
or Stroke in Patients With
Heart Failure and Coronary
Artery Disease Following
Hospitalization for Heart Failure)
Platelet Inhibition in Patients New York Heart Association
With Systolic Heart Failure functional class III to IV (EF35%)
NCT01765400 n ¼ 50
CAD ¼ coronary artery disease; EF ¼ ejection fraction; qd ¼ once daily; other abbreviations as in Tables 1 and 2.
and was associated with less major bleeding and lower
mortality compared to warfarin (target INR 2.0 to 3.0) in
patients with AF. One-third of patients had HF or reduced
LVEF in this trial and similar to the RE-LY trial, there was
no significant interaction with treatment effect (p for
interaction ¼ 0.50) (75).
In the APPRAISE-2 trial (Apixaban for Prevention of
Acute Ischemic Events 2), a 5 mg twice daily dose of
apixaban in addition to standard antiplatelet therapy was
associated with no significant reduction in recurrent
ischemic events but an increased incidence of major bleeding
events in patients with a recent ACS and at least 2 additional
risk factors for recurrent ischemic events. The trial was
terminated prematurely for the high bleeding rate in the
apixaban arm. In this trial, 28% of patients had HF. There
was a 23% reduction in the occurrence of the primary
endpoint with apixaban versus placebo (HR: 0.77, 95% CI:
0.58 to 1.02) in patients with HF compared to 5% increase
in the occurrence of the primary endpoint in patients
without HF (HR: 1.05, 95% CI: 0.86 to 1.29, p for
interaction ¼ 0.08) (76).
Rivaroxaban. In the ROCKET AF (Rivaroxaban Once
Daily Oral Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Em-
bolism Trial in Atrial Fibrillation), rivaroxaban was
compared to warfarin for the prevention of ischemic stroke
in 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 was
similar between the groups and rivaroxaban was associated
with less frequent intracranial and fatal bleeding. In a sub-
group analysis, there was no significant interaction between
treatment with rivaroxaban and the presence of HF (p for
interaction ¼ 0.419) (77).
In the ATLAS ACS–TIMI 51 trial (Anti-Xa Therapy
to Lower Cardiovascular Events in Addition to Standard
Therapy in Subjects with Acute Coronary Syndrome–
Thrombolysis In Myocardial Infarction 51), 2 dose regimens
of rivaroxaban (2.5 mg twice daily and 5.0 mg twice daily)
were compared with placebo in patients with ACS. Nearly
10% of patients had HF and in this subgroup, rivaroxaban
Gurbel and Tantry 11
Antiplatelet and Anticoagulant Agents in Heart Failure
Treatment Arms and Duration Primary Endpoints
Rivaroxaban 2.5 mg bid vs. Time to the first occurrence of any of the
placebo for 6 to 30 months following: death from any cause, MI, or stroke
Time to the first occurrence of either fatal
bleeding or bleeding into a critical space
with potential for permanent disability
Prasugrel 10 mg qd vs. The change in platelet aggregation measured
clopidogrel 75 mg qd for 2 weeks by the VerifyNow P2Y12 assay between
baseline and each antiplatelet medication
2.5 mg twice daily dose was associated with a lower rate of
occurrence of the primary endpoint compared with placebo
(10.1% vs. 16.8%). Although the confidence intervals were
wide in the HF group, there was no difference in the first
occurrence of treatment-emergent non–coronary artery
bypass graft related TIMI major bleeding events. However,
in patients without HF, there was no apparent difference in
the primary endpoint occurrence between the rivaroxaban
group 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 decompensated
HF and patients with New York Heart Association functional
class III/IV HF, the pharmacodynamics and pharmacoki-
netics of rivaroxaban were similar. In patients with functional
class III/IV HF treated with placebo, prothrombin fragment
1.2 increased over 7 days whereas rivaroxaban therapy (10 mg
once daily) was associated with a reduction in prothrombin
fragment 1.2. A nonsignificant reduction in the rate of
D-dimer and thrombin-antithrombin complex increase over
time was also associated with rivaroxaban therapy (79).
There are only 2 trials undergoing involving treatment
with antiplatelet and new oral anticoagulants as given in
Table 3.
Meta-Analysis of New Oral Anticoagulants
In a recent semisystematic review and meta-analysis of phase
III trials (ARISTOTLE, RE-LY, and ROCKET-AF)
including 44,563 patients with AF, new OAC treatment
was not associated with a significant reduction in stroke and
systemic embolism compared with warfarin among patients
with HF (n ¼ 21,095, OR: 0.91, 95% CI: 0.78 to 1.06, p ¼
0.22) but was associated with 24% reduction in patients
without 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. In
the RE-LY trial, HF was defined as ejection fraction <40%
by echocardiogram, radionuclide, or contrast angiogram
within 6 months, or symptoms of New York Heart Asso-
ciation functional class >II HF within 6 months. In the
ROCKET AF trial, the definition included symptoms of
12 Gurbel and Tantry JACC: Heart Failure Vol. 2, No. 1, 2014
Antiplatelet and Anticoagulant Agents in Heart Failure February 2014:1–14

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), unless
contraindicated.
 It is recommended that patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documented
LV 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 the
thrombus, 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 or
not 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 to
ascertain 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 ejection
fraction; LV ¼ left ventricular; VTE ¼ venous thromboembolism; other abbreviations as in Table 1.

HF or an ejection fraction of 35%. The definition in the
ARISTOTLE trial was symptomatic HF 3 months or
ejection fraction 40%. The analysis was uncorrected for
confounding variables (31).
Guidelines
The European and American guidelines for the treatment of
patients with AF are presented in Table 4 (80–82). Ac-
cording to the 2012 European Society of Cardiology
guidelines, “other than in patients with AF (both HF with
reduced and preserved ejection fraction), there is no evi-
dence that an OAC reduces mortality and morbidity
compared with placebo or aspirin” (80). A similar view also
has been provided by the recent consensus document from
the European Society of Cardiology Heart Failure Associ-
ation and the European Society of Cardiology Working
Group on Thrombosis as follows: “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 strokedthere is currently no compelling reason to
routinely use warfarin for all HF patients in sinus rhythm”
(53). The 2009 updated American College of Cardiology/
American Heart Association guidelines acknowledged the
availability of limited data for the recommendation of OAC
use in patients with HF, but it recommends OAC in HF
patients with a previous thromboembolic event (82).
Finally, the 2010 Heart Failure Society of America
guidelines 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 of
systemic or pulmonary emboli, including stroke or transient
ischemic attack, unless contraindicated,” and “Antiplatelet
therapy is recommended to reduce vascular events in patients
with HF and CAD unless contraindicated” (81).
Conclusions
Heart failure is a common clinical problem with a prevalence
of 1% to 2% in the general population that is increasing due
to the aging population. Despite the heightened risk for
stroke and thromboembolism in patients with HF and AF,
in patients with systolic HF in sinus rhythm, the level of
increased thromboembolic risk is less clear. The decision to
treat patients with HF with antiplatelet therapy remains
largely influenced by the presence or absence of concomitant
arterial disease. Antithrombotic therapy has been shown to
be effective in many forms of cardiac disease, including
patients with HF and AF. However, the utility of oral
anticoagulant and/or antiplatelet therapy has never been
evaluated in an adequately powered dedicated clinical trial of
HF patients in sinus rhythm. Although it is clear that
platelet activation and hypercoagulability are present in HF,
and there is evidence that stroke is reduced by warfarin
therapy in the HF patient, the available data suggest that the
risk of major bleeding overshadows the antithromboembolic
benefit in HF patients in sinus rhythm. These findings have
been reflected in the guidelines.
The CHADS2 and HAS-BLED risk scores may be
helpful to select patients for future studies of antithrombotic
therapy in the setting of HF and sinus rhythm. The window
JACC: Heart Failure Vol. 2, No. 1, 2014
February 2014:1–14
of greatest advantage for antithrombotic therapy may be
early after initial presentation, when a markedly increased
risk of death, and death or stroke, has been reported.
Selecting patients for enrollment may also be facilitated by
objective assessments of thrombogenicity using laboratory
testing. Thromboelastography is a potential method that
determines platelet function in addition to thrombin gen-
eration and the viscoelastic characteristics of the platelet-
fibrin clot. Large-scale, adequately, powered trials that
have refined selection criteria, possible including laboratory
testing, will be needed to establish the role of antithrombotic
therapy in the HF patient in sinus rhythm.
Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai
Center for Thrombosis Research, Cardiac Catheterization Labo-
ratory, 2401 West Belvedere Avenue, Baltimore, Maryland 21215.
E-mail: pgurbel@lifebridgelealth.org.
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Key Words: anticoagulant - antiplatelet - heart failure.