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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 2
Summary of guideline recommendations for antithrombotic therapy for prosthetic
ACCP guidelines (1): recommendations for prosthetic heart valves – mechanical
Use warfarin or other vitamin K antagonist bridged with UFH or LMWH until the INR is stable and at goal for 2 days.When VKA must be discontinued,
use LMWH for bridging
Goal INR 2.5 (range 2.0–3.0) Goal INR 3.0 (range 2.5–3.5) Goal INR 3.0 (range 2.5–3.5)+ASA 75–100 mg/day
Aortic position St. Jude Medical or
CarboMedics bileaflet mechanical
valves without other risk factors
Mitral position tilting disk and bileaflet
mechanical valves
Mechanical valves in the setting of additional risk
factors
a
Systemic embolism despite a therapeutic
INR
Caged ball or caged disk valves
ACCP guidelines (1): recommendations for prosthetic heart valves – bioprosthetic
Warfarin or other vitamin K antagonist with UFH or LMWH bridging until the INR is stable and at goal for 2 days
Goal INR 2.5 (range 2.0–3.0)for a limited
time period
Goal INR 2.5 (range 2.0–3.0) ASA 75–100 mg/day
Bioprosthetic MV for the first 3 months
after valve implant
Bioprosthetic AV for the first 3 months
after valve insertion OR aspirin
80–100
mg/day
Bioprosthetic valves and a history of sys-
temic embolism, for 3–12 months
Bioprosthetic valves with: Left atrial
thrombus at surgery
Atrial fibrillation
Bioprosthetic valve, sinus rhythm without a history
of atrial fibrillation
Bioprosthetic AV for the first 3 months after valve
insertion (or VKA with a goal INR 2–3)
ACC/AHA guidelines (4): prosthetic heart valves – mechanical and bioprosthetic
INR 2.0–3.0 INR 2.5–3.5 ASA 75–100 mg/day Warfarin+ASA 75–100 mg/day
Aortic position mechanical valve:
bileaflet or Medtronic HallBioprosthetic
AVR + risk factors
a
Aortic or mitral bioprosthetic valve:
For 3 months after implant and no risk
factors
Aortic position mechanical valve:
For 3 months after implant
Bileaflet or Medtronic Hall + risk
factors
a
(with option of ASA)
Starr-Edwards or disc valves (other
than Medtronic Hall)
Mechanical MV (any type)
Bioprosthetic MV + risk factors
a
Aortic or mitral bio-
prosthesis and no
risk factors
Mechanical or bioprosthetic
heart valves + risk factors
a
ASA 75–325 mg/day INR 3.5–4.5OR Clopidogrel
75 mg/day
Patients who are unable
to take VKA after
MV replacement or
AVR
High-risk
a
patients with
prosthetic heart valves when
aspirin cannot be used
INR international normalized ratio, AVR aortic valve replacement, MV mitral valve, VKA vitamin K antagonist
a
Risk factors include: AF, myocardial infarction, left atrial enlargement, endocardial damage, or low ejection fraction, prior thromboembolism, left ventricular
dysfunction, and a hypercoagulable state
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implanted valves (i.e., TE incidence has decreased as older generations of more thrombogenic valves
are replaced or their hosts die).
Further confounding the definition of an optimal INR is the variability of INR levels in a single
patient over time. The value of a recommended INR goal is based on the expectation that patients are
actually at goal. Kulik et al. show subtherapeutic INRs are recorded in up to 50% of patients followed
in large studies
(33). Further, Kulik showed that TE events occurring early (but after the first 6 months
of anticoagulation to permit time for endothelialization) are up to seven times greater than those
occurring later. They go on to suggest that this trend is due to improved compliance and familiarity
with VKA. Ultimately, all the guidelines recommend that tailoring therapy to the individual patient
with their particular set of risk factors is necessary to attain the most appropriate level of
anticoagulation.
While the likelihood of TE can be reduced by increasing the level of anticoagulation, this benefit
is counterbalanced by an increased risk of both major and minor bleeding. A similar dilemma exists
for aspirin, particularly if the median INR is >3.0 (1), and so the ACCP limits their recommendation
of adding aspirin only to certain patient subsets felt to pose a higher risk. In contrast, a best evidence
review of all published data from 1966 to 2004 concluded that low-dose aspirin (80–100 mg daily) in
addition to warfarin reduces all cause long-term mortality (NNT = 19), with significant reductions in
thromboembolism, and the increased bleeding was significant only for minor bleeds (34).
Guidelines and Recommendations
Although there are a few specific items of discrepancy, the three major guideline formats are similar
(1,3,4). The recommendations can be found in Table 2. The degree of anticoagulation for aortic valves
is generally accepted as an INR of 2–3. Mitral valves are recommended to have a higher INR goal of
2.5–3.5, and aspirin can be added for additional risk factors or embolus in the setting of therapeutic
anticoagulation. The ESC guidelines for anticoagulation with PHV can be thought of as stepwise
Thromboembolic Risk is
dependant on 2 factors:
Thrombogenicity of the
mechanical valve
Presence or absence of
risk factors
Low
Medium High
Medtronic Hall
St Jude Medical
(without Silzone)
CarboMedics AVR
INR 2.5
Bileaflet Valve s
with insufficient
data
Bjork-Shiley
INR 3.0
Lillehei Kaster
Omniscience
Starr Edwards
INR 3.5
Atrial Fibrillation,
Left Atrial Dimension
>50mm,
Mitral Valve Gradient,
LVEF <35%
Spontaneous Echo Contrast
Additional Prosthetic Valve
Hypercoagulable State
+ INR 0.5
Fig. 1. General principles of thromboembolic risk according to the ESC. [Adapted from ESC Guidelines (2,3).]
Optimal INR is determined by inherent valve thrombogenicity and addition of applicable risk factors.
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levels of anticoagulation based on the inherent valve thrombogenicity and superimposed risk factors
(see Fig.
1). Specific circumstances are discussed below.
Bioprosthetic Valves
The advantage of bioprosthetic valves is their decreased thrombogenicity, making lifelong antico-
agulation unnecessary in the absence of TE risk factors. Low-dose aspirin (75–100
mg) is universally
recommended, with increased doses (up to 325
mg) appropriate for compelling reasons (status post
percutaneous intervention or stroke), or in the event that a patient has the indication for VKA, but
cannot take warfarin. Warfarin is endorsed in the setting of TE risk factors (atrial fibrillation, prior
TE, LV dysfunction, hypercoagulable state). If warfarin is used, then the patient should be bridged
with unfractionated heparin or low molecular weight heparin until therapeutic INRs are established
for 2 days.
While all three guidelines support the use of routine anticoagulation after bioprosthetic valve
implantation for the first 90 days with at least aspirin or warfarin if possible, the data supporting this
practice are conflicting. After 3 months, the valve is considered to be endothelialized and treated as a
native valve early postoperatively with the addition of lifelong low-dose aspirin. However, recent
reviews highlight that no study has shown anticoagulation with VKA leads to a reduction or increase
in adverse outcomes
(35,36); the authors conclude that with more research, aspirin alone may suffice
for TE prophylaxis in the first 90 days after implantation, effectively removing the indication for
warfarin in this setting (36).
PREGNANCY AND ANTICOAGULATION
In patients with prosthetic valves, persistent high-grade reliable anticoagulation is necessary to
reduce the incidence of valve thrombosis and thromboembolism. Pregnancy itself is not only a pro-
coagulant state, but is associated with an asymmetric risk/benefit; that is, the benefits associated with
anticoagulation must be weighed against the risks attendant to both the fetus and mother. Bleeding
(both fetal and maternal) as well as the teratogenic effect of the anticoagulant lie on one end of the
spectrum with strokes and valve thrombosis at the other. While warfarin and other coumarin derivatives
cross the placenta with demonstrated potential for teratogenic and hemorrhagic side effects, unfrac-
tionated and low molecular weight heparins do not cross and are safer for the fetus. However, retro-
spective cohorts have shown that this protection to the fetus comes at the expense of a higher
incidence of maternal complications. Coumadin use for the entirety of pregnancy is associated with
lowest all-cause maternal mortality and TE (1.8 and 3.9%, respectively), but a high rate of embryopa-
thy (>6.4%) (37). Exchange of VKA for heparin at or prior to week 6 and continuing through the first
trimester reduced the incidence of embryopathy to 0%, but increases the risk of valve thrombosis
(9.2%) (37). However, none of the anticoagulation regimens markedly impacts the incidence of sponta-
neous abortion or fetal demise (ranges of 23.8–24.8% and 26.5–42.9%, respectively) (37).
It should be noted that recommendations are hampered by a paucity of data in this area, with a notable
lack of randomized controlled trials evaluating the various methods of anticoagulation for these patients.
Therefore data are based on literature reviews of case series and retrospective cohorts with consensus
agreements. With no well-defined optimal method of anticoagulation, warfarin, unfractionated heparin,
and most controversially low molecular weight heparin are the available options.
Warfarin has not been shown to cause an anticoagulant effect in breast milk fed infants, and may
be resumed after delivery. Provided the mother is hemodynamically stable, the ACC recommends
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resumption of unfractionated heparin to therapeutic levels 4–6 h after delivery as a bridge (4) until
INR returns to goal.
Subcutaneous BID dosing of UFH derived to keep the PTT at least twice normal (i.e., in the thera-
peutic range) 6
h after administration for the duration of the pregnancy is an option. However,
long-term exposure to UFH yields an increased risk of heparin-induced thrombocytopenia (HIT)
and heparin-induced osteoporosis(HIO), as well as evidence of variable anticoagulation: as adjusted
dose heparin alone has the highest incidence of TE complications (29% in one study)
(38). Two
leading reviews offer similar recommendations suggesting if UFH is used, high doses (35,000–
40,000 units split BID) should be given and titrated to keep the PTT therapeutic in a range of
2–2.5× normal
(37,39).
Given its convenient ease of administration, presumed lack of teratogenicity, reduced incidence of
HIT and HIO, and typically weight-based formulation, LMWH is one of the more appealing anticoagu-
lation agents for the pregnant population. However, the degree of anticoagulation turns out to be less
certain for weight-based dosing in pregnant women, and the vital necessity to assure adequate levels of
anticoagulation has made for controversy regarding its use. In a study comparing enoxaparin to warfarin
and UFH in pregnant women with prosthetic valves, two deaths (out of seven) from acute valve throm-
bosis led to the early termination of the study and a labeling change from the makers of Lovenox.
Ultimately revised, according to Sanofi-Aventis and the package insert “the use of Lovenox has not been
adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has
not been adequately studied for long-term use in this patient population”
(26). However, anti-factor Xa
levels were subtherapeutic in one patient, were unclear in the other
(40), and further reviews of all avail-
able data suggest LMWH compared to UFH may be a safe and effective option in patients with mechani-
cal prosthetic heart valves but require vigilant dosing to account for changes in clearance (40). A scheme
proposed by Elkayam
(39) is shown compared to the recommendations of the ACC/AHA and ACCP in
Table
3. Endorsing a monitored regimen, a review of 51 pregnancies with monitored anti-factor Xa
levels had only one reported thromboembolic complication
(41). As such, recommendations have been
made to monitor weekly anti-factor Xa levels in the first trimester as plasma volume and creatinine
clearance fluctuate. Thereafter it is left to the discretion of the treating physician (40).
A recent study evaluating nadroparin (available in Europe) substitution from weeks 6–12 and at
delivery compared to coumarin derivative and aspirin throughout the pregnancy in 25 women over 31
pregnancies, showed less fetopathy and markedly more live and healthy births in the former group.
Although this benefit was balanced by an increase in maternal death and valve thrombosis, the incidence
was too small to be significant (42).
The 7th ACCP Conference on Anticoagulation and Thrombolytic Therapy concluded that a
definitive recommendation was not possible due to the lack of studies and data, but recommenda-
tions based on what evidence is available are shown in Table
3. In sum, there is no ideal plan as
all carry varied risk either to the mother or to the fetus. However, of utmost importance is a
detailed discussion and therapeutic plan in conjunction with the patient, cardiologist, and high-
risk obstetrician, being sure that all parties are aware of the risks of bleeding, fetal wastage, tera-
togenesis, and mortality. Ideally, this discussion happens prior to conception, so that frequent
pregnancy testing and UFH or LMWH substitution can occur when pregnancy is achieved.
However, any of the three regimens are possible: (1) Warfarin with initiation of UFH or LMWH
from conception until week 13 and late into the third trimester or at delivery (to avoid an antico-
agulated fetus) with a goal INR 3.0 (range 2.5–3.5). For bileaflet aortic valves without concurrent
atrial fibrillation or impaired ventricular function, a goal of 2.0–3.0 is acceptable. (2) Aggressive
dose-adjusted UFH throughout the pregnancy. (3) Dose-adjusted LMWH throughout the
pregnancy.
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All guidelines agree that VKA should be changed to UFH or LMWH in the middle of the third
trimester prior to delivery in order to reduce bleeding complications at time of delivery, with UFH
carrying the additional ease of brisk reversibility.
PROSTHETIC VALVE THROMBOSIS
Thrombotic and bleeding calamities comprise the majority of complications in patients with pros-
thetic valves. Prosthetic valve thrombosis (PVT) occurs most often with mechanical prostheses and
to a lesser extent, early after implantation of bioprosthetic valves (i.e., before endothelialization of
the suture zone); it is more common in right-sided prostheses compared to left sided, and more common
Table 3
A comparison of anticoagulation schemes for pregnant women with PHV
6–12 weeks 13–35 weeks 36 weeks–delivery
7th ACCP (1)3
methods
(1)
LMWH q 12 h
(4 h anti-Xa 1.0–1.2)
or
SC UFH BID
(35,000–40,000 U/day)
Q 6 h aPTT “therapeutic”
Warfarin
(INR 2.5–3.5)
(2.0–3.0 for
bileaflet AV)
LMWH
or
SC UFH
(2) Aggressive dose-adjusted UFH
(3) Aggressive dose-adjusted
LMWH
“Some women at high risk”
should have 75–162 mg
aspirin daily added to the
regimen throughout
ACC/AHA (4) Avoid warfarin
Continuous(IV)/Dose-adjusted
(SC) UFH
(goal q 6 h aPTT 2× control)
or
Dose-adjusted LMWH BID
(4 h anti-Xa 0.7–1.2)
Warfarin
(INR 3.0)
or
Continuous/Dose-
adjusted UFH
or
Dose-adjusted LMWH
Continuous/Dose-adjusted
UFH (2–3 week prior to
planned delivery)
Resume 4–6 h after delivery
is completed
Aspirin 75–100 mg daily starting in second trimester
Elkayam et al.
(39)
High Risk
a
Warfarin (INR 2.5–3.5) IV UFH (aPTT 2.5–3.5×) +
aspirin 80–100 mg daily
or
SC UFH (aPTT > 2.5×)
or
LMWH (predose anti-Xa ~0.7)
Warfarin (INR 3.0)
Low Risk
b
SC UFH (aPTT 2.0–3.0×)
or
LMWH (4 h anti-Xa ~0.6)
Low Risk
b
SC UFH (aPTT 2.0–3.0×)
or
LMWH (predose anti-Xa ~0.6)
Warfarin (INR
2.5–3.0)
SC UFH
or
LMWH
a
High-risk valves are older generation mechanical prosthetic valves, those in mitral position, atrial fibrillation, and a
history of thromboembolism on anticoagulation
b
Low-risk valves are newer generation or those in aortic position
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in the mitral than aortic position. The incidence of obstructive PVT is estimated at 0.3–1.3% patient-years.
Thromboemboli occur more commonly (0.7–6% patient-years), and small, non-obstructing thrombi
are surprisingly common (an incidence as high as 24% in the first postoperative year)
(43,44). Thus,
PVT should be considered in any patient with a prosthetic valve presenting with an embolic event,
shortness of breath, or fatigue. The clinical presentation is variable, depending to a large extent on
the presence and degree of prosthetic obstruction. The duration of symptoms is not particularly help-
ful, as valve dysfunction can evolve slowly, permitting cardiac compensation with mounting throm-
bus or pannus burden and progressive impairment, or abrupt valvular failure leading to sudden
cardiac compromise. PVT can be due to outflow obstruction by the mass of the thrombus or pannus
or by impairing leaflet mobility (Figs.
2 and 3). Inadequate anticoagulation has been shown to be the
most potent factor in the pathogenesis of valve thrombosis
(45); therefore non-compliance or
planned interruption of anticoagulation in particular as well as a new prothrombotic environment or
low-flow state should further raise suspicion. Although rare, native valve thrombosis has been
described, typically in the aortic position and associated with valvular abnormalities or a hyperco-
agulable state
(46–51). Valvular dysfunction can be due to thrombus, pannus (an excessive cicatrical
inflammatory response to the foreign valve surface usually seen in proximity to the suture site), or
frequently, a combination of the two. Even in the presence of distinct clinical clues (e.g., inadequate
anticoagulation, recent implantation, prothrombotic milieu), it is important to try and differentiate
between the two, as pannus ingrowth is not treatable with fibrinolytics. One small study of 24
Fig. 2. Thrombosed mechanical valve intraoperative view of a bileaflet mechanical mitral valve with obstructive
thrombus before (left panel), during (middle panel), and after (right panel) thrombectomy (Courtesy of Dr. A.
Cobanoglu, University Hospitals Case Medical Center).
Fig. 3. Thrombosed bioprosthetic homograft with frozen leaflets due to thrombus. (Courtesy of Dr. A. Markowitz,
University Hospitals Case Medical Center.) RC right coronary cusp; NC non-coronary cusp; LC left coronary cusp.
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patients evaluated clinical and echocardiographic parameters (TEE) to distinguish between pannus
and thrombus: 92% of thrombi were soft masses, pannus tended to be smaller and denser, and a
videointensity ratio (videointensity of the mass compared to that of the prosthetic valve) was lower
in thrombi: a ratio < 0.70 had a positive predictive value of 87% and a negative predictive value of
89% for thrombus (52).
Diagnosis
The physical examination as well as imaging modalities are employed to assist diagnosis. A change
in heart sounds, muffled prosthetic clicks, new murmurs, and signs of heart failure or embolism should
heighten concern and further imaging should be pursued without delay. A subtherapeutic INR, inflam-
matory markers, and elevated D-dimer may be seen. While transthoracic and transesophageal echocar-
diography are the mainstay of bedside evaluation, fluoroscopy can confirm the diagnosis with
mechanical prostheses by showing restricted leaflet movement, or with contrast injection to demon-
strate valvular reflux. However, cinefluoroscopy is less valuable in cases of non-obstructive PVT.
If thrombosis is the cause of valve dysfunction, it is important to investigate the etiology, as merely blaming
the valve, patient, or medical compliance and intensifying the antithrombotic regimen may hide another
diagnosis such as malignancy, endocarditis, or paroxysmal or asymptomatic atrial fibrillation.
Echocardiography allows direct visualization of the prosthesis and estimation of valvular gradients,
flows, and effective orifice areas. For a mitral prosthesis, a mean gradient (measured by planimetry
of diastolic mitral inflow) greater than 8
mmHg and an effective orifice area less than 1.4 cm
2
(meas-
ured by pressure half-time) suggest PVT. Values for aortic PVT include a mean transaortic gradient
greater than 45 mmHg and an obstructive index (the ratio of LV outflow tract to peak aortic velocity)
less than 0.25
(53). However, prosthesis size in conjunction with underlying hemodynamics must be
taken into account; although reference tables are available for the different prostheses, the most valu-
able reference is a patient’s baseline postoperative echocardiogram (e.g., at the first postoperative
office visit). A transesophageal echocardiogram should be performed if any clinical suspicion persists
after a transthoracic examination. Thrombi may be sized (see below) and to a certain extent, differen-
tiated from pannus, sutures, vegetations, and fibrous strands. Because of acoustic shadowing from the
esophageal window, the ventricular surface of prosthesis is often poorly visualized; for this reason,
the transthoracic and transesophageal approaches should be considered complimentary.
Treatment
Treatment consists of anticoagulation with heparin, fibrinolysis, thrombectomy, or valve replace-
ment in both pregnant and non-pregnant patients (54). Lysis and surgery carry both morbidity and
mortality rates proportional to NYHA class (55). Streptokinase, urokinase, and recombinant tissue
plasminogen activator have all been used successfully for lysis. Traditionally, surgery has been con-
sidered first line therapy with left-sided PVT, given the risk of TE with lysis. Though carrying the
added morbidity and mortality of reoperation, surgery has a reduced risk of thromboembolism, stroke,
and hemorrhage. For those too unstable or decompensated for surgery, fibrinolysis is considered a
feasible alternative. However, there is debate endorsing the use of fibrinolytics, and optimal manage-
ment is unclear beyond the recognition that rational decision-making and therapy should be tailored
to the set of circumstances particular to each patient (location of the valve, hemodynamic stability,
degree of obstruction, size of thrombus, comorbidities, and services available at the institution).
The ACC/AHA guidelines (Fig. 4) endorse surgery as a “reasonable” (Class IIa) first line management
with fibrinolysis reserved for specific situations. However, the lack of Class I therapeutic recommenda-
tions reflect the sources of data from small cohorts and case studies. The ACC/AHA document deems
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fibrinolysis reasonable for right-sided valves with NYHA class III-IV symptoms. Citing ineffectiveness
and a 12–15% incidence of cerebral emboli, the ACC/AHA reserve lysis with left-sided thromboses to
patients with small clot burden and minor symptoms (NYHA class I-II) or with severe failure (NYHA
III-IV) if they are high surgical risk or if surgery is unavailable (4). The ESCs recommendations are con-
gruent but more aggressive than the ACC/AHA. Acknowledging that any therapy is high risk, surgery for
critically ill patients without serious comorbidities is given a Class I indication. Fibrinolysis is recom-
mended only for patients not likely to survive surgery or with right-sided prostheses.
In marked distinction, supporting fibrinolysis since 1997 (56) Lengyel et al. writing for the Society
for Heart Valve Disease in 2005 published recommendations reiterating support for fibrinolysis as the
first line therapy independent of position, NYHA class, or thrombus size (57). A meta-analysis from
the same author reported improved outcomes over the last 30 years with a lower overall lower embolic
rate than cited by the AHA guidelines (4%), improved success (90%), and low mortality (2.5%) (58).
Further, if lytic therapy fails to improve valve hemodynamics, the patient can still be taken to surgery.
Serial TEEs are strongly recommended during lytic therapy to monitor hemodynamics and cardiac
response to lytic intervention (57). The embolic risk of lytic use is directly proportional to the size of
Fig. 4. Management of prosthetic valve thrombosis according to the ACC/AHA (4).
Table 4
Indications for surgical management of PVT
Obstruction from endocarditis
Abscess
Large thrombus
Mobile mass
Thrombolytic therapy failure
Adapted from Lengyel et al. (56)
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the clot. Tong et al. showed the odds of a complication increase as a linear function by 2.41 for every
1
cm
2
of thrombus, but that a thrombus area of <0.8 cm
2
identified patients at low risk for complications
independent of NYHA class
(59). These data can help to define a group of patients that would benefit
from fibrinolytics regardless of their degree of illness. Clearly not all patients are candidates for lytic
therapy, and the surgical indications and lytic contraindications are shown in Tables 4 and 5.
Valve thrombosis in pregnant patients is not well addressed in the ACCP, ACC/AHA, or ESC
guidelines. In recent publications, the prevailing opinion proposes lytic therapy as first line treatment
(in the absence of contraindications) due to the attendant risks of anesthesia and surgery to the mother
and fetus (54,59,60).
While anticoagulation alone may be used for smaller thrombi, especially if lytics are contraindi-
cated, this strategy is inadequate for thrombi greater than 5
mm (57).
Prevention
Following a TE event, attention should be focused on ameliorating or reversing the potential risk
factors and optimizing the consistency of anticoagulation. A regimen can be enhanced by adding ASA
or increasing goal INR by 0.5 to a maximum of 3.5–4.5. If ASA is added, it should be low dose
(<100
mg/day) and used with INR < 2.5–3.5 (2). While 20% of PVT treated with lytics will recur,
more than 90% of those can be treated successfully with repeated fibrinolysis
(61).
MISCELLANEOUS TOPICS: WITHOLDING ANTICOAGULATION, BRIDGING
THERAPY, OVER-ANTICOAGULATION, BLEEDING EMERGENCIES
Withholding Anticoagulation
The theoretical risk of withholding chronic anticoagulation on a daily basis is low. For a patient at
the highest risk with a normal INR (an estimated yearly risk of TE = 20%) the additive daily risk is
0.20/365
= .055%. Thus, the risk of TE while holding anticoagulation for 1 week would be
0.055% × 7 = 0.38%. A small retrospective study examining bleeding events in patients with PHVs
found no thrombotic complications in patients with anticoagulation held for up to 3 weeks (62). Those
patients on chronic anticoagulation presenting for surgery with a low risk of bleeding can ideally have
surgery without reversal (often cited examples are dermatologic and ophthalmologic procedures or
dental extractions). If therapy must be suspended then a decision regarding thromboembolic risk and
whether to bridge the patient with a parenteral anticoagulant must be made. Usually at least 81 mg of
Table 5
Patients at risk for adverse outcomes from fibrinolytic therapy
Active internal bleeding
History of hemorrhagic stroke
Recent cranial trauma or neoplasm
Hemorrhagic retinopathy
Large thrombi
Mobile thrombi
Hypertension (>200/120)
Hypotension or shock
NYHA Class III–IV
Adapted from Bonow et al. (4)
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aspirin can be tolerated during the surgery to provide a margin of protection, but if aspirin or ADP
antagonists need to be stopped, 5 to 7 days provide adequate washout. Oral anticoagulation is usually
stopped 48 to 72
h prior to surgery and the patient is either admitted for continuous infusion UFH or
allowed to remain at home for self-administrated LMWH (BID UFH is less commonly used).
However, not all PHVs require an anticoagulant bridge, and as per the ACC/AHA: for low-risk
patients (bi-leaflet AVR with no risk factors) a heparin bridge is usually unnecessary; and warfarin
can then be restarted 24
h following surgery. For all other situations, bridging should begin when the
INR drops below 2, and resumed 4–6
h after surgery is completed as hemodynamic stability permits.
Heparin is discontinued once the INR is therapeutic again.
Bridging Therapy
There are two scenarios that classically invoke the issue of “bridging therapy,” that is, the use of a
“bridging” anticoagulant to provide seamless anticoagulation therapy during times of stoppage or
initiation of oral VKA: (1) initiation of anticoagulation after new prosthetic valve implantation, and
(2) the stoppage of anticoagulation in anticipation of a surgery with high bleeding risk that requires
normalization of INR. The issue of initiation of anticoagulation with UFH or LMWH is still a subject
of continued debate, given the large risk of hemorrhagic complications after valve surgery compared
to the thromboembolic risks of a foreign surface, turbulent prosthetic flow, and a postoperative pro-
thrombotic state (see section regarding new valve implantation for details).
In general, there are two options for parenteral anticoagulant: UFH or LMWH (enoxaparin and
dalteparin in most studies). Continuous intravenous UFH has traditionally been the agent of choice.
However, the use of LMWH has been increasingly frequent despite the relatively limited data avail-
able for its use compared to heparin. The justification for LMWH advantage over UFH includes the
daily or q 12
h dosing (reducing the patient tethering to intravenous infusions), the simplicity of sub-
cutaneous injections, ease of self-administration, fewer dosing errors, less underdosing with a weight-
based algorithm (thus faster therapeutic levels), reduced incidence of heparin-induced thrombocytopenia,
and during long-term administration, less osteoporosis. A major advantage of UFH over LMWH is
its straightforward and rapid reversibility. Although the unit cost of LMWH is seven times more
expensive than UFH, when the associated cost of administration, lab testing, nursing assistance, and
extra hospital days are factored into the equation, LMWH often ends up being a more cost-effective
option (25,40,63,64).
When patients with prosthetic valves need to have their oral anticoagulation interrupted for inva-
sive procedures, the simplicity and reduced patient discomfort from fewer blood draws makes LMWH
desirable. This has been shown to be an effective method of bridging anticoagulation in 116 patients
(31 with mitral valve replacements, 76 aortic valve replacements, 9 double valve replacements).
There was one major bleeding complication, no valve thrombosis, and minor bleeding occurred in 10
patients (65). Routine monitoring of anti-Xa levels in the absence of renal failure (serum creatinine
>1.5 or creatinine clearance <30 ml/min) or pregnancy is not warranted. When checked, then levels
should be 0.5–1.0 IU/ml, checked pre-dose as well as 3–4 h after administration, and the goal should
be maintained at high levels (~0.7 IU/ml) (40). However, in counterpoint to the recommendations of
Seshadri et al., the ESC endorses the use of UFH over LMWH. They acknowledge that LMWH can
be used, but has limited data and is best tailored with anti-Xa levels if possible.
One of the expected complications of VKA therapy is over-anticoagulation. Management can usually
be conservative, with simple holding or reduction of further doses of warfarin until the INR trend
returns to therapeutic range. The risk of hemorrhage increases markedly for INR > 6 (up to 4% of
patients treated with simple withholding of warfarin) (66), and so at this level caution and further
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