Download One Weapon, Two Blows in the War Against the Thrombus

Journal of the American College of Cardiology
Ó 2014 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
One Weapon,
Two Blows in the
War Against the Thrombus*
Srijita Sen-Chowdhry, MBBS, MD,yz
Richard J. Gordon, MDx
London, United Kingdom; and Munford, Tennessee
Old habits die hard, as do old clinical precepts. The war
against the thrombus in clinical practice has long been based
on the twin paradigms of white versus red thrombi and
Virchow’s triad. Platelet-predominant white thrombi form
in high-flow arterial streams. Red thrombi, rich in fibrin
and trapped erythrocytes, form in low-pressure environments in the venous circulation and atria (1). Virchow’s triad
offers a 3-way breakdown of the predisposition to thrombosis into abnormalities affecting the vessel wall, blood flow,
and/or blood constituents (2).
See page 2689
Originally described in venous thromboembolism (VTE),
the scope of Virchow’s triad has expanded with the recognition that it can be usefully applied to both atrial fibrillation
(AF) and arteriopathy. For arterial thrombi, the foremost
determinant is endothelial injury/dysfunction associated
with atherosclerosis, hypertension, inflammation, or trauma;
but turbulent blood flow at bifurcations or stenotic regions
and platelet hyperactivity also contribute. For venous
thrombi, cognate risk factors are vascular injury (trauma,
surgery, vasculitis, sepsis), venous stasis, and hypercoagulable
states, whether genetic (e.g., factor V Leiden mutation) or
acquired (e.g., supplemental estrogen). Susceptibility to
intracardiac thrombus is increased in AF by atrial endothelial dysfunction; stasis of blood, particularly in the
atrial appendages; and local inflammation coupled with
a systemic prothrombotic state (3). Stroke risk in AF
is widely estimated with the CHADS2 (Congestive heart
failure, Hypertension, Age 75 years, Diabetes, Stroke/
thromboembolism) or CHA2DS2-VASc (plus Vascular
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the yInstitute of Cardiovascular Science, University College London, London,
United Kingdom; zDepartment of Epidemiology, Imperial College, St Mary’s
Campus, London, United Kingdom; and xThe Stern Cardiovascular Foundation,
Munford, Tennessee. Dr. Sen-Chowdhry is supported by the British Heart Foundation. Dr. Gordon is a speaker for Boehringer Ingelheim on Pradaxa.
Vol. 63, No. 24, 2014
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.03.040
disease, Age 65 to 74 years, female Sex) scores; the clinical
modifiers represented therein likely operate, at a mechanistic level, via Virchow’s triad (2,4).
The white/red thrombus paradigm provides the rationale
for pharmacological management of thrombosis. Antiplatelet agents are the mainstay of therapy for coronary/
peripheral artery disease, whereas the coagulation pathway
is the target in VTE and AF. In AF, for example, aspirin
lowers the risk of ischemic stroke by 21%, whereas vitamin K
antagonist (VKA) therapy achieves a 67% reduction, unfortunately at the cost of doubling the intracranial hemorrhage rate (4). Among other drawbacks, dose requirements
for VKA therapy show substantial interindividual and intraindividual variation, influenced by age, genetic variants in
CYP2C9 and VKORC1, diet, gut flora, drug interactions,
and liver function (4). Despite regular monitoring, time
spent in the narrow therapeutic range is w60% (5). Dual
antiplatelet therapy predictably fails to alter plasma indices
of thrombogenesis, but was established by the ACTIVE
(Atrial fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events) trials as an acceptable middle
course. Stroke risk was 40% lower with VKAs than aspirin
plus clopidogrel, which in turn offered 27% reduction over
aspirin alone (1,6).
The question then arises: if the red/white thrombus dichotomy is so clear cut, why does aspirin confer even a
modest reduction in the stroke risk in AF and why should
addition of clopidogrel offer incremental benefit? One
plausible albeit orthodox response invokes the common association of AF with vascular disease and its risk factors,
such as hypertension. The reduction in vascular events
observed with aspirin use in known arteriopathy is in the
same range (20% to 30%) as that in AF. The implication is
that the recognized benefit of aspirin in vascular disease
accounts for much of its apparent benefit in AF (1).
By the same token, anticoagulation might be expected to
have limited role in vascular disease. Whether the remit of
VKA therapy can be extended becomes particularly relevant
in the common scenario of dual pathology: coexisting AF
and vascular disease. Diabetes and hypertension, key risk
factors for vascular disease, are also CHADS2 modifiers;
and vascular disease per sedincluding myocardial infarction (MI), peripheral artery disease, and complex aortic
plaquedincreases thromboembolic risk in AF, as reflected
in the upgrading of CHADS2 to the CHA2DS2-VASc score
(4). These patients often need anticoagulation and adding
antiplatelet agents augments their bleeding risk. Could VKAs
confer sufficient protection from vascular events to be used as
the sole therapy in this population?
In the setting of recent acute coronary syndrome (ACS)
and/or percutaneous coronary intervention, the answer is
probably no. VKA therapy is relatively effective in preventing secondary events unless stenting is involved, in which
case, even when combined with aspirin, it is inferior to
regimens incorporating a P2Y12 receptor inhibitor (clopidogrel, prasugrel, ticlopidine, ticagrelor) (4). The current
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Sen-Chowdhry and Gordon
Antithrombotics: Sometimes One Is Enough
recommendation is aspirin plus P2Y12 receptor inhibitor
for 12 months; adherence may be particularly important
after deployment of drug-eluting stents owing to delayed
re-endothelialization. Yet omission of anticoagulation
also appears suboptimal, increasing mortality (hazard ratio
[HR]: 3.43) and major cardiac events in a study of 426
patients with AF and recent stenting (7). An argument exists
for triple therapydaspirin, P2Y12 inhibitor, and VKAdbut
potential benefits may be offset by up to 16% annual incidence of hemorrhage (8). An alternative strategy involves
conjunctive use of VKA and P2Y12 receptor inhibitor,
which, in a trial of 573 patients, attenuated bleeding risk
versus triple therapy (HR: 0.36) without increasing major
cardiovascular events (9). Although the WOEST (What is
the Optimal antiplatElet and anticoagulant therapy in
patients with oral anticoagulation and coronary StenTing)
trial was underpowered to exclude excess stent thrombosis,
a subsequent registry study supported the noninferiority of
VKA plus clopidogrel versus triple therapy (10). Dropping
the aspirin appears, then, to hold promise after recent
ACS/revascularization.
Posing a distinct challenge are patients with AF and
stable coronary artery disease (in whom 12 months have
elapsed after ACS/revascularization or there is no history of
either). Anticoagulation remains optimal, but the risk/
benefit ratio of add-on antiplatelet therapy alters owing to
the now minimal threat of stent thrombosis and declining,
although persistent, concerns over plaque instability. The
2011 American Heart Association/American College of
Cardiology Foundation guidelines recommend VKA plus
aspirin (11). A recent study of 8,700 patients with AF and
stable coronary disease, however, found no difference in
myocardial infarction/coronary death or thromboembolic
risk between VKA therapy, VKA plus aspirin therapy, or
VKA plus clopidogrel therapy (12).
In this issue of the Journal, Lamberts et al. (13) investigate
the burden, impact, and optimal management of AF in
>37,000 registry patients with both vascular disease and
heart failure. The mean CHA2DS2-VASc score of 5 confirms a high-risk stratum; the mean HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding
history or predisposition, Labile international normalized
ratio, Elderly [age >65 years], Drugs/alcohol concomitantly)
score was 2.1, underscoring the need to achieve a delicate
balance.
Besides being observational and retrospective in design,
registry studies have limited available clinical details; we do
not know how AF was picked up in these patients. Given
real-world variations in practice, this may have ranged
from 12-lead electrocardiography prompted by symptomatic
deterioration to the more proactive approach of periodic
ambulatory rhythm monitoring. Although the 29,660 patients without an AF diagnosis had improved survival, undiagnosed silent AF is a concern in this population, leading
clinicians to seek surrogate markers such as left atrial dimensions. Even assuming, however, that some of these
JACC Vol. 63, No. 24, 2014
June 24, 2014:2699–701
patients had paroxysmal AF, VKA therapy afforded no
advantage over antiplatelet therapy in lowering thromboembolic risk (HR: 1.06; 95% confidence interval: 0.86 to
1.31). This is heartening because it implies that the burden
of silent AF in these patients may not be sufficient to
warrant anticoagulation. The WARCEF (Warfarin versus
Aspirin in Reduced Cardiac Ejection Fraction) trial also
found no difference in all-cause mortality between VKA
versus aspirin in 2,305 patients with left ventricular systolic
dysfunction and sinus rhythm, but this may have been
because the benefits of VKA therapy in reducing ischemic
stroke were offset by an increase in major hemorrhage
among older patients (14).
Lamberts et al. (13) subdivided their AF sample into
prevalent (pre-existing) and incident (new onset) categories
but found similar thromboembolic risk. VKA therapy was
more effective than antiplatelet therapy in attenuating this
risk; combining the 2 afforded no advantage but did increase
bleeding. This was no surprise; antiplatelet agents are included as additional protection against coronary events,
not thromboembolism. But then came the pivotal finding:
adding an antiplatelet agent to VKA therapy offered no
incremental benefit in reducing the risk of MI/coronary
death. Nor was there any significant difference between
VKA-only therapy and VKA plus antiplatelet therapy in
the combined outcome of thromboembolism and MI
(HR: 1.00; 95% confidence interval: 0.89 to 1.14) (13).
Despite the large sample in this study, some of the reported confidence intervals are wide, suggesting possible
underpowering. Nevertheless, it adds to accumulating evidence that an optimal risk/benefit balance in some patients
with AF and vascular disease may be achieved by VKA
therapy alone. In a clinical setting, decision making will be
mutual and individualized, taking into account not only
CHA2DS2-VASc and HAS-BLED scores but also coronary anatomy and, in heart failure patients, the extent of
viable at-risk myocardium.
Returning to the red/white clot paradigm, however, the
apparent efficacy of VKA therapy in preventing coronary
events requires some explaining. If we assume the distinction
in the thrombotic process is absolute, then the answer may
lie in the pleiotropic properties of many drugs. Statin therapy, for example, may effect the reported 22% reduction
in VTE risk by modulating endothelial function, inflammatory responses, and thrombogenesis (2). Similarly, VKAs
have beneficial effects on myocardial contractility, oxygen
consumption, platelet adhesiveness, and inflammatory reactions (15).
Yet it may also be time to replace our perception of a
white/red thrombus dichotomy with a continuous spectrum.
Carotid plaques and adverse cardiovascular events are more
prevalent among VTE patients with idiopathic disease than
those with transient acquired risk factors. At a mechanistic
level, cytokine release, leukocyte recruitment, platelet activation, and fibrin turnover are common to both arterial and
venous thrombosis. Antiplatelet therapy has been shown to
JACC Vol. 63, No. 24, 2014
June 24, 2014:2699–701
reduce the incidence of VTE, just as warfarin can forestall
coronary events (2,4).
One weapon can deal 2 blows in the war against the
thrombus, which is good news for reducing iatrogenic
bleeding. In patients with stable coronary disease, heart
failure, and AF, VKAs can sometimes be that weapon. The
impact of this finding may diminish in years to come as
VKA use in nonvalvular AF declines in favor of alternatives
that selectively inhibit factor Xa (rivaroxaban, apixaban and
edoxaban) and thrombin (dabigatran). As direct-acting oral
anticoagulants reduce the rate of intracranial hemorrhage
by 50%, the risk/benefit ratio will shift and demand revisiting of the issues (5). Still relevant will be the recognition
underpinning the current spate of antithrombotic studies:
that optimal management of patients with apparent dual
pathology is best guided by observational and empirical data
to complement the oversimplified precepts of old.
Sen-Chowdhry and Gordon
Antithrombotics: Sometimes One Is Enough
5.
6.
7.
8.
9.
10.
Acknowledgments
The authors are grateful to Prof. William McKenna and
Dr. Sripurna Das for constructive comments.
Reprint requests and correspondence: Dr. Srijita Sen-Chowdhry,
Institute of Cardiovascular Science, University College London,
Paul O’Gorman Building, 72 Huntley Street, London WC1E
6DD, United Kingdom. E-mail: [email protected].
11.
12.
13.
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Key Words: antithrombotic treatment - atrial fibrillation
coronary artery disease - heart failure - vascular disease.
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