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Antithrombotic Therapy for Atrial Fibrillation and Cardioversion
p = 0.5) but there was a significant difference in the composite end-point of major and minor bleeding
(2.9% vs. 5.5%, p
= 0.02) (74). These results helped to establish a TEE-guided strategy to cardiover-
sion as a safe and clinically-effective alternative to conventional management. The ACUTE II trial
established that enoxaparin as a bridging therapy for patients with AF undergoing TEE-guided cardio-
version is a safe and efficacious alternative to UFH and is more cost-effective
(65,66).
Anticoagulation and Catheter Ablation
There are two main interventional approaches for the management and potential cure of AF –
percutaneous catheter-based ablation and surgical approaches (Maze procedure with associated left
atrial appendage ligation or removal). Radiofrequency catheter ablation of AF with pulmonary vein
isolation, although not a first-line therapy for AF, is continuing to grow as a common procedure in
major hospitals throughout the world (75). Thromboembolism is recognized as one of the potential
major complications of this procedure. In addition to the inherent risk of the patient population in AF,
the procedure itself involves catheter manipulation in the left atrium and ablation of the left atrial
endothelium can be a potential nidus for thrombus. In patients who are in AF at the time of the
procedure, AF termination may be achieved at the time of the procedure by either catheter ablation or
cardioversion. It is important to remember that guidelines regarding anticoagulation at the time of
cardioversion apply in this circumstance. On the other hand, peri-procedural anticoagulation can
contribute to complications such as hemopericardium, cardiac tamponade and vascular complications
(76). Therefore, as emphasized by the recent HRS/EHRA/ECAS expert Consensus Statement, careful
attention must be paid to peri-procedural anticoagulation
(75).
It is recommended that in patients with persistent AF, who are in AF at the time of the procedure,
a TEE be performed to screen for thrombus whether or not they have been anticoagulated prior to the
procedure
(75). Most operators discontinue warfarin prior to the procedure with some advocating the
use of LWMH until the evening prior to the procedure. A small number of operators chose to continue
anticoagulation with warfarin in a therapeutic range before, during and after the procedure. The main
concern with this approach is the difficulty of managing potential bleeding complications, although it
has been reported as a safe strategy (77). After the procedure if warfarin has been discontinued,
anticoagulation with intravenous heparin or LWMH should be started until therapeutic anticoagulation
with warfarin has been re-established. The HRS/EHRA/ECAS expert Consensus Statement advises
that warfarin be continued in all patients for at least 2 months post procedure. Decisions about
continuing use after 2 months should be made on the basis of risk factors for stroke and not on the
presence of AF. Discontinuation of warfarin therapy is not advised in patients who have a CHADS2
score ³2 (Table 1).
Anticoagulation and Percutaneous Coronary Intervention
For the majority of patients with stable coronary artery disease and AF, warfarin therapy alone
should be a sufficient antithrombotic therapy (1). A common clinical scenario is the management of
patients with AF undergoing percutaneous intervention or presenting with an acute coronary syn-
drome where aspirin and clopidogrel have become standard antiplatelet therapy. The combination of
these therapies with warfarin increases the risk of intracranial bleeding, especially in the elderly.
There have been no clinical trials to date specifically addressing this issue. The recent ACC/AHA/
ESC guidelines advise that the use of dual antiplatelet therapy with 81 mg of aspirin daily and clopi-
dogrel is pivotal in maintaining stent and coronary patency, and that these agents should be used in
combination with ongoing warfarin therapy (78,79). While warfarin may need to be temporarily
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Antithrombotic Drug Therapy in Cardiovascular Disease
discontinued around the time of any percutaneous procedure, it should be recommenced as soon as it
is safe to do so. The intensity of anticoagulation should be carefully monitored when these agents are
combined with warfarin.
Anticoagulation and Acute Stroke
There have been limited trials involving anticoagulation in patients with AF presenting with acute
ischemic stroke. The presence of intracranial hemorrhage on computed tomography or magnetic reso-
nance imaging is a contraindication to the immediate and possibly the long-term use of warfarin. If a
large infarct is revealed, the initiation of anticoagulation should be delayed for 2–4 weeks because of
the potential risk of hemorrhagic transformation. Randomized trials comparing aspirin with heparin
during the first 2 weeks of acute ischemic stroke among patients in AF show no benefit from early
anticoagulation because any net gains from reduction in ischemic strokes are offset by the excess
hazards of hemorrhagic stroke (80,81).
Anticoagulation and Elective Diagnostic and Therapeutic Procedures
When a need to stop anticoagulant therapy in patients with AF undergoing elective procedures
arises, there is a need to balance the risk of stroke against the risk of bleeding complications if bridg-
ing short-acting anticoagulant therapy is used. In high risk patients (prosthetic heart valves, prior
stroke or embolic event), it is appropriate to substitute unfractionated or LMWH once INR falls below
2.0 (1,60). In patients with low risk of thromboembolism, it is reasonable to stop warfarin for a period
up to 1 week for procedures that carry a risk of bleeding without substituting heparin
(1,60). This is
based on extrapolation from the annual rate of thromboembolism in patients with non-valvular AF.
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21 Antithrombotic Therapy
for Valvular Heart Disease
Noah Rosenthal and Brian D. Hoit
Co n t e n t s
Native Valve Disease
Prosthetic Heart Valves
Pregnancy and Anticoagulation
Prosthetic Valve Thrombosis
Miscellaneous Topics: Witholding Anticoagulation, Bridging Therapy,
Over-Anticoagulation, Bleeding Emergencies
References
Ab s t r A c t Certain native valvular diseases and prosthetic valves require anticoagulation in order to prevent
catastrophic thrombotic consequences. Anticoagulation strategies and the treatment of complications are
areas under constant reevaluation and study. There are multiple sources of recommendations, and three
major societies have produced guidelines (ACCP, AHA/ACC, ESC) which make up the bulk of commonly
accepted practice. This is a review and evaluation of the guidelines and a counterpoint of current study and
opinions.
Key words:
Anticoagulation; Antithrombotic therapy; Atrial fibrillation; Mitral annular calcification; Mitral
stenosis; Mitral valve prolapse; Pregnancy; Prosthetic valve; Prosthetic valve thrombosis; Fibrinolysis
Although the elegant design of cardiac valves provides reduced shear surfaces for linear flow and
efficient function, the interruption of this blueprint by aging, disease, or prosthesis and the resulting
imbalance of anti- and pro-coagulant forces that comprise Virchow’s triad (injury, turbulent flow, and
stasis) create the milieu for thromboembolism (TE). Because of the potentially devastating effects that
may follow, optimization of anti-thrombotic regimens has been an intense area of refinement and
exploration. The present chapter summarizes the most recent publications and recommendations from
the three major guideline documents from the 7th American College of Chest Physicians conference
on antithrombotic and thrombolytic therapy (ACCP, 2004), the American Heart Association/American
College of Cardiology (AHA/ACC, 2006), and the European Society of Cardiology which published
their guidelines in 2005 and 2007 (1–4). This body of work comprises the contemporary foundation
for the management of antithrombotic therapy in valvular heart disease.
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_21
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
NATIVE VALVE DISEASE
Risk Factors
In accordance with all currently published guidelines for patients in normal sinus rhythm with
native valvular disease, primary prophylaxis against thromboembolic events is indicated only for
mitral stenosis, and then, only when additional risk factors are present (antithrombotic therapy is
recommended for mitral valve prolapse and mitral annular calcification after an embolic episode, see
below). Mitral stenosis creates a milieu of stasis in the left atrium upon which additional risk factors
greatly increase the risk of a subsequent thrombotic event. Factors currently recognized as imparting
the greatest risk are atrial fibrillation (AF), left ventricular dysfunction, prior thromboembolic events,
and perturbations of the coagulation cascade.
From a pathophysiological perspective, hypertension and its cardiovascular complications – AF, heart
failure, and left ventricular hypertrophy – produce a prothrombotic state (5). Although heart failure and
left ventricular dysfunction are known prothrombotic states imparting an increased risk of thromboem-
bolic events, prophylactic anticoagulation with warfarin has not been shown to improve outcomes (6,7).
The risk factor of thrombophilias (e.g., antiphospholipid antibodies, resistance to activated protein
C, factor V Leiden, prothrombin gene polymorphisms, protein C deficiency, protein S deficiency,
Antithrombin III deficiency) are themselves sufficient grounds for anticoagulation.
Atrial fibrillation is increasingly common as the population ages. It conveys an increased risk of
thromboembolism with advancing age, hypertension, heart failure, diabetes, and prior thrombotic
event, in turn elevating the relative risk of an embolic event in men by 2.4 and in women by 3 com-
pared to matched controls (8,9). While the rate of stroke is higher in selected patient populations with
an increasing number of risk factors (greater than 10 strokes per 100 patient-years in those most at
risk) (10), the use of warfarin in an unselected group of individuals with atrial fibrillation will reduce
the incidence of stroke by approximately 65%
(9). As alluded to earlier, atrial fibrillation may itself
impart a prothrombotic state beyond simple flow-related effects. Investigators found increased levels
of plasma von Willebrand factor, vascular endothelial growth factor, and angiopoietin-2 in 59 chronic
AF patients compared to healthy controls and postulated that these changes altered tissue factor
expression and endothelial integrity, consistent with earlier, preliminary observations (11,12).
It is no surprise that patients with the highest incidence of stroke are those with previous throm-
boembolic events, having already demonstrated a substrate prone to generating thrombi. A recent
meta-analysis showed that in the absence of antithrombotic therapy among patients with prior strokes,
the yearly average stroke rate is approximately 13% compared to 4.1% in those without a prior stroke
(13). This trend holds true in patients with mitral stenosis as well.
Mitral Stenosis
The presumptive mechanism of increased thrombogenicity in mitral stenosis (MS) is the remodeling
of the left atrium and appendage that occurs due to pressure and volume overload. Slow and non-
linear flow in the enlarged atrium leads to further atrial dysfunction and increased spontaneous echo
contrast associated with an increased risk of atrial thrombus (14). In addition, the expression of immu-
noreactive von Willebrand factor is increased in the endothelium of the left atrial appendage in
patients with mitral valve disease (with and without atrial fibrillation) and may be a predisposing factor
for atrial thrombus (15). Compounding the risk of thrombus is the common presence of superimposed
atrial fibrillation which imparts a sevenfold increase in the risk of TE events (16).
While non-anticoagulated mitral stenosis is uncommon in countries with intensive health care sur-
veillance, older studies cited in the 7th ACCP review reported an associated incidence of TE events in
up to 27% in these patients, with a future risk of detectable TE event in a patient with unrepaired rheumatic
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mitral valve disease of approximately one in five (1), making MS the highest risk valvular lesion for TE.
Guidelines support anticoagulation with vitamin K antagonists (VKA) for mitral stenosis patients in
normal sinus rhythm only when additional risk factors are present. These risk factors are: prior throm-
boembolism, dense spontaneous echocardiographic contrast on TEE, and a moderately enlarged left
atrial size – a reflection of the functional impact of stenosis and harbinger of further dysfunction. If atrial
fibrillation develops [a frequency of 30–40% in the MS population (17)], then anticoagulation is recom-
mended. As mentioned earlier, the highest incidence of embolus occurs in those who have already had
emboli, and these patients should have rigorously monitored anticoagulation therapy.
There has been debate regarding the optimal degree of anticoagulation. A sub-analysis of the multi-
center randomized NASPEAF (National Study for Prevention of Embolism in Atrial Fibrillation) trial
compared 184 high-embolic-risk patients with atrial fibrillation to 311 patients with atrial fibrillation and
mitral stenosis (including bioprosthetic valve replacements). Patients were randomized to achieve an
INR 2–3 or a more moderate dose anticoagulation (INR 1.4–2.4) plus 600
mg triflusal (antiplatelet agent
equivalent to 300
mg aspirin). The combined antiplatelet/moderate anticoagulant therapy compared to
anticoagulant alone significantly reduced the number of vascular events (14 vs. 29 in an intention to treat
analysis and 6 vs. 28 for “on-therapy” analysis). The study concluded that a combined regimen of mod-
erate intensity anticoagulation and antiplatelet agent is effective in mitral stenosis
(18).
Mitral Valvuloplasty
The 7th ACCP guidelines recommend a limited period of anticoagulation both before and after
mitral valvuloplasty to reduce the theoretical risk of periprocedural stroke. However, there are no
randomized control trials (RCT) to support this premise, and the data is extrapolated from prior atrial
fibrillation studies and “good sense.”
Mitral Valve Prolapse
Mitral valve prolapse (MVP) is a frequently identified form of valvular disease in adults. Once
thought to be the most common form of valvular heart disease, Freed et
al. showed that the true preva-
lence of MVP in an unselected, community-based sample of ambulatory subjects (2.4%) is lower than
previously reported (up to 15%) (19). The association of MVP and ischemic stroke has been controver-
sial, in part due to this overdiagnosis. Revision of the diagnostic criteria in the 1980s led to a reduced
incidence of MVP, casting doubt on the validity of earlier studies linking MVP to stroke. Supporting
this, Gilon et
al. showed that MVP was no more common among young patients with unexplained cer-
ebral embolic events than among control subjects (20). In contrast, Avierinos showed a small but signifi-
cant independent risk of stroke associated with MVP, conferring a lifetime excess rate of events twice
that of a comparable population; in patients without other risk factors for TE, age, and increased valve
thickness conferred higher risk (21). However, the incidence of overall TE in this population remains
low and the guidelines do not endorse antithrombotic therapy in asymptomatic patients.
In the event of a transient ischemic attack (TIA), the institution of long-term aspirin (50–162 mg/
day) therapy should be initiated. Patients with subsequent TIA on aspirin or documented systemic
embolism should progress to full anticoagulation with VKA (goal INR 2.0–3.0).
Mitral Annular Calcification
Population-based studies have shown both an increased relative risk of stroke (22) and a reduced
time to first TE event (23) in patients with mitral annular calcification compared to those without
MAC. Interestingly, although associated with all the same atherosclerotic risk factors, aortic valve
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sclerosis has not been shown to confer an increased risk of stroke (23). Patients with MAC have a
higher incidence of AF, diffuse atherosclerotic disease, left atrial enlargement, and disruption of lami-
nar flow across the valve, all of which increase the risk of TE
(24). Importantly, embolism from this
type of lesion may also be calcific, for which anticoagulation is not therapeutic. Therefore for patients
with a demonstrated TE lesion that is not calcific, the ACCP recommends anticoagulation (INR 2–3).
For the asymptomatic patient with MAC, optimal management is uncertain. Although there is an
empiric rationale for prophylactic anticoagulation, MAC is typically a degenerative process more com-
mon in elderly patients, and the ACCP encourages careful consideration of risk/benefits in this popula-
tion without severe disease. They offer the “uncertain compromise” of antiplatelet therapy with aspirin
or clopidogrel, although there are no data to support this strategy. Table
1 is a composite of the guide-
line recommendations for the management of native valve disease and antithrombotic therapy.
PROSTHETIC HEART VALVES
By current guidelines, anticoagulation is indicated for all mechanical valves, for bioprosthetic
valves in patients with high-risk features for TE, and for the first 3 months after the implantation of a
bioprosthetic heart valve, as this time period has the highest incidence of thromboembolic risk (i.e.,
before endothelialization of implanted hardware). The benefit of a bioprosthetic valve is the reduced
need for life-long anticoagulation and thus freedom from the added morbidity of vitamin K antago-
nists (VKA) in patients who (1) otherwise do not need anticoagulation, (2) are at high risk for bleed-
ing complications, or (3) cannot take VKA.
Mechanical Valves
It is well known that all current mechanical heart valves require anticoagulation with warfarin or a
VKA in order to prevent TE. However, the degree of anticoagulation necessary to prevent TE has been
a topic of considerable debate, and since 2004 three major writing groups (ACCP, ACC/AHA, ESC)
have formalized the management of these patients
(1,2,4). Their recommendations are similar, with
occasional divergence reserved for specialized situations. Table
2 shows current recommendations for
the ACCP and ACC/AHA, and Fig.
1 shows a scheme from the ESC.
While VKAs and heparin have been well studied in the PHV population, newer agents like low
molecular weight heparins have been a source of some controversy in selected populations (pregnant
women specifically) and will be addressed in the section on pregnant patients. LMWH is generally
considered an acceptable alternative to heparin for temporary or bridging therapy in non-pregnant
patients (1–4). It has been studied in multiple trials and shown to be efficacious and potentially cost
saving. Routine checking of anti-factor Xa levels (therapeutic range defined as 0.5–1.0 IU/ml) is not
typically required, with the exception of pregnant patients in whom variable plasma volumes and renal
clearance require surveillance(25) (for details, see section on pregnancy and PHV). A well-known limi-
tation to the use of LMWH is the lack of easy reversibility in the setting of a bleed (although enoxa-
parin is described as being up to 60% reversible with 1 mg protamine per 1 mg enoxaparin) (26).
Current studies report a yearly incidence of TE around 4% in patients with prosthetic valves,
whereas older analyses range up to a high of 22% annual incidence in patients without anticoagulation
(27–32). The ranges in reported incidence of stroke rates differ depending on the method of data
collection and patient-related factors (2). It is certain that the likelihood of stroke is dependent on the
type of valve (mechanical vs. bioprosthetic), the type of design (e.g., caged ball, tilting disk, bileaflet),
the material used (newer valves are less thrombogenic), the number of valves and their position (e.g.,
aortic vs. mitral). The variability in incidence is also due in part to the evolving population of
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Table 1
Succinct guidelines for native valve disease and anticoagulation
Mitral stenosis
and NSR
Only if:
Mitral stenosis
and atrial fib or
previous history
of embolism
Mitral stenosis on
anticoagulation
with additional
thromboembolic
event or TIA
Mitral valve
prolapse
Only if:
Mitral valve
valvulotomy MAC
Mobile aortic
atheromas
ACCP 2004 (1) LA ³ 55 mm:
INR 2–3
INR 2–3 INR 2–3+ASA
75–100 mg or
Dipyridamole
400 mg/day
or
Clopidogrel
75 mg/day
TIA:ASA
50–162 mg/day
Systemic embolism
on ASA:
INR 2–3
2–3 for 3
weeks
prior and 4
weeks after
procedure
If systemic
non-calcific
embolism:
INR 2–3
>4 mm by
TEE: INR
2–3
ESC 2007(3) Prior embolism
LA > 50 mm
TEE with dense
spontaneous
contrast
INR 2–3
INR 2–3 INR 2–3 NR NR NR NR
ACC/AHA
2006 (4)
Severe MS and
LA ³ 55 mm
or LA
thrombus
Indicated
a
Indicated
a
TIA or prior CVA
without risk
factors
b
:ASA
75–325 mg/day
Stroke and/or
MR, AF, atrial
thrombus:
INR 2–3
Prior stroke +
Thickened/
redundant valve
leaflets >5 mm
recurrent TIA on
aspirin:
INR 2–3
NR NR NR
NR No Recommendation provided in guidelines
a
ACC/AHA guidelines do not specify a range for anticoagulation
b
Risk factors: evidence of MR, atrial fibrillation, left atrial thrombus, echocardiographic evidence of valvular thickening > 5 mm
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