Beruflich Dokumente
Kultur Dokumente
12, 2015
Bridging Anticoagulation
Primum Non Nocere
ABSTRACT
Chronic oral anticoagulation frequently requires interruption for various reasons and durations. Whether or not to bridge
with heparin or other anticoagulants is a common clinical dilemma. The evidence to inform decision making is limited,
making current guidelines equivocal and imprecise. Moreover, indications for anticoagulation interruption may be
unclear. New observational studies and a recent large randomized trial have noted signicant perioperative or peripro-
cedural bleeding rates without reduction in thromboembolism when bridging is employed. Such bleeding may also
increase morbidity and mortality. In light of these ndings, physician preferences for routine bridging anticoagulation
during chronic anticoagulation interruptions may be too aggressive. More randomized trials, such as PERIOP2 (A Double
Blind Randomized Control Trial of Post-Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo
Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism), will help guide periprocedural
management of anticoagulation for indications such as venous thromboembolism and mechanical heart valves. In the
meantime, physicians should carefully consider both the need for oral anticoagulation interruption and the practice of
routine bridging when anticoagulation interruption is indicated. (J Am Coll Cardiol 2015;66:1392403) 2015 by the
American College of Cardiology Foundation.
From the Division of Cardiovascular Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah. Both authors have
reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscripts audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
patients at low risk for TE due to overestimation of if at all possible. Unless a high bleeding-risk ABBREVIATIONS
thrombosis risk (79). There is even greater hetero- surgery is urgently needed, it is best to AND ACRONYMS
geneity of practice in those patients with intermedi- postpone the procedure until TE risk is
INR = international normalized
ate or unclear risks of bleeding or TE. Current attenuated. ratio
evidence, including the recently completed BRIDGE
AVOID OAC INTERRUPTIONS LVAD = left ventricular assist
trial (Bridging Anticoagulation in Patients Who device
Require Temporary Interruption of Warfarin Therapy NOAC = novel oral
Periprocedural warfarin interruption remains
for an Elective Invasive Procedure or Surgery) (see anticoagulant
a routine practice for many clinicians. Recent
later discussion), suggests that periprocedural OAC = oral anticoagulation
data suggest that 40% to 60% of OAC in-
bleeding rates are signicantly higher than throm- TE = thromboembolism
terruptions may be unnecessary (2,12,18). A
bosis rates in this group (2,4,1016). VTE = venous
2005 survey of dermatologic surgeons
The goal of this review is not to detail the timing, thromboembolism
revealed that 44% of them routinely interrupt
doses, or specics of bridging anticoagulation. Rather,
OAC for dermatologic surgerya procedure with low
we will review the data available to specic questions
bleeding risk (19). Other surveys similarly reveal that
that arise in clinical practice to better individualize
90% to 100% of physicians would interrupt OAC and
decision making and reduce adverse events. We have
even bridge patients who are undergoing low
limited the scope of the discussion to anticoagulant
bleeding-risk procedures regardless of TE risk (7,18).
management. The periprocedural management of an-
OAC should not be interrupted for patients un-
tiplatelet agents has been reviewed elsewhere (5,17).
dergoing low bleeding-risk procedures, particularly
CONFIRMING OAC INDICATIONS those at high risk for TE. Uninterrupted warfarin
throughout the periprocedural period is not associ-
When determining the optimal periprocedural anti- ated with elevated bleeding risk for many procedures
coagulation strategy, a critical rst step is to fully and surgeries, especially when a lower interna-
appreciate the indication for chronic OAC. In some tional normalized ratio (INR) goal of 2.0 is targeted
cases, OAC may no longer be required. For example, a (Table 2) (11,16,18,2025). Ironically, continuous
patient may present for a procedure who has been on warfarin therapy can paradoxically reduce peri-
warfarin for a single provoked deep vein thrombosis procedural bleeding relative to interrupted warfarin
that occurred more than 6 months prior. In such a with heparin bridging (20).
situation, discontinuation of OAC is most appropriate Moreover, warfarin interruption and reinitiation
and will simplify periprocedural anticoagulation can be associated with an increased incidence of
management. stroke. In 1 retrospective study, warfarin initiation
In some cases, OAC is indicated for acute treatment more than doubled the stroke risk during the rst
of an existing or recent TE (i.e., in the past 3 to week compared with nonanticoagulated, matched
6 months). Although temporary discontinuation of control subjects (26,27). This paradox may be due to
primary prevention OAC may be appropriate, treat- early depletion of the vitamin Kdependent factors,
ment of an active thrombus should not be interrupted proteins C and S, creating a hypercoagulable milieu.
High* Mitral valve prosthesis CHADS2 score 5 or 6 VTE <3 months prior
Cage-ball or tilting disc aortic CVA/TIA <3 months prior Severe thrombophilia
valve prosthesis Rheumatic valvular heart disease
CVA/TIA <6 months prior
Moderate Bileaet aortic valve and other CHADS2 score 3 or 4 VTE 312 months prior
risk factors Nonsevere thrombophilia
Recurrent VTE
Active cancer
Low Bileaet aortic valve without CHADS2 score 2 or VTE >12 months prior without
other risk factors less without prior CVA/TIA other risk factors
Data from the American College of Chest Physicians (ACCP) guidelines (5). *A true high-risk category may be difcult to objectively dene in the absence of trials demonstrating
benet of heparin bridging in such patients. Deciency of protein C, protein S, or antithrombin; antiphospholipid antibodies; multiple abnormalities. CVA risk factors include:
atrial brillation, prior CVA/TIA, hypertension, diabetes, congestive heart failure, age >75 years. Heterozygous factor V Leiden or prothrombin gene mutation.
CHADS2 congestive heart failure, hypertension, age >75 years, diabetes mellitus, and stroke; CVA cerebrovascular accident; TIA transient ischemic attack;
VTE venous thromboembolism.
Relatively major operations may also tolerate PERIPROCEDURAL TE IS UNCOMMON. The actual
continuation of OAC. For example, certain orthopedic rate of periprocedural TE for unbridged OAC in-
surgeries may also prove tolerant to uninterrupted terruptions is rare, estimated at approximately 0.53%
OAC therapy. Rhodes et al. (22) retrospectively from our review of over 23,000 OAC interruptions in
analyzed 77 patients undergoing total knee arthro- 70 studies from 1966 to 2015 (Table 3, Figure 1A)
plasty; 38 patients remained on warfarin throughout (2,4,1016,28). From the same database, the rate of TE
the perioperative period. They found no signicant for patients who are bridged is slightly higher at
difference in the rates of blood transfusion, wound 0.92%. The actual rate is likely higher in the absence
complications, or reoperation between the 2 groups. of bridging but is biased in these observational
Randomized studies appear to conrm these ob- studies by the clinicians impression of greater TE risk
servations. Two randomized prospective trials have that drives the decision to bridge.
been conducted to directly compare the safety and Rates of bleeding and TE vary by OAC indication
efcacy of uninterrupted warfarin versus bridging (Figure 1B). For atrial brillation, an individuals daily
with heparin. In a 2007 study, 214 patients on OAC risk of stroke or transient ischemic attack can be
undergoing dental extraction were randomized to approximated by dividing the annual stroke risk by
either continue warfarin or to stop warfarin and 365 days. Although one might expect more thrombosis
bridge with heparin (23). Interrupted warfarin without in the periprocedural period by invoking Virchows
bridging was not studied. There were no TE events in triad, observational studies have not borne this
either group, consistent with the low rate of TE seen hypothesis out. For example, in ORBIT-AF (Outcomes
in other studies. Importantly, nearly one-half of the Registry for Better Informed Treatment of Atrial
patients were at presumably high TE risk, with either Fibrillation) (2), the periprocedural cohort observed a
prosthetic valves or atrial brillation with valvular 0.35% 30-day stroke rate. Using the average ORBIT-AF
disease. The rate of bleeding was also similar between CHA2DS2-VASc score of 4.1, corresponding to an
patients with uninterrupted warfarin versus those annual stroke risk of approximately 4.2%, the calcu-
with heparin bridging (7.34% vs. 4.76%, respectively; lated 30-day stroke risk is surprisingly similar at 0.35%.
p > 0.05). For mechanical heart valves, the perioperative risk
BRUISE CONTROL (Bridge or Continue Coumadin of TE is approximately 1% (11). Older studies (mostly
for Device Surgery Randomized Controlled Trial), from the 1970s and 1980s) suggested a higher inci-
published in 2013, randomized 681 high-risk patients dence of perioperative TE. However, these older
undergoing pacemaker or debrillator implantation studies included patients with higher-risk valves,
to either uninterrupted OAC or interrupted OAC with such as cage-ball and tilting disc valves, which would
heparin bridging (20). Due to the high TE risk of the have been far more common in that time period (29).
study population, there was again no arm of inter- In a more contemporary study of 45 patients with
rupted OAC without bridging. The investigators found mechanical aortic and/or mitral valves who were
that heparin produced more than 4 as many clini- undergoing central nervous system surgeries be-
cally signicant pocket hematomas than in those on tween 2004 and 2012, there were no TE events during
uninterrupted warfarin (16% vs. 3.5%; p < 0.001). an average anticoagulation gap of 7 days (14). More
0.94
18.64
Values are n or % (n) unless otherwise indicated. *Denominator differs from number of cases stated (12,278) due to heterogeneity of denitions and reporting of events between studies reviewed. Dunn et al. (16) excluded from combined totals to represent the most
7.56
Total
7.33
2.19
N/A
N/A
N/A
%
Unavailable
Unavailable
Unavailable
1.9 (100)
2.8 (255)
13.3 (122)
Regarding venous thromboembolism (VTE), a
Any Bleeding
1.8 (31)
0.2 (2)
Unavailable
Unavailable
24.1 (216)
Bridged
3.7 (19)
2.7 (15)
N/A
20.0
0.8
2.3
1.7
2.7
%
Unavailable
Unavailable
1.2 (110)
0.9 (18)*
Major Bleeding
1.2 (20)
1.8 (58)
1.3 (12)
Unavailable
3.3 (211)*
3.5 (323)
3.2 (29)
6.6 (53)
3.6 (18)
2.2 (12)
0.00
0.60
0.39
0.57
0.17
0.71
0.71
%
Not Bridged
Unavailable
0.52 (65)
0.5 (17)
0.6 (6)
0.5 (9)
0.4 (4)
0.2 (3)
0.94 (93)
1.5 (12)
Bridged
0 (0)
0.8 (4)
0.3 (3)
0.6 (1)
1,813
1,176
12,278
2,280
45
4,106
22,334
1,812
39
counterparts (32).
RE-LY Randomized Evaluation of Long Term Anticoagulant Therapy With Dabigatran Etexilate.
Retrospective Cohort
Retrospective cohort
Study Type
Prospective cohort
Systematic review
20052008
20012010
19662001
20092014
20062012
20042012
20012015
11.83%
increased hospital cost ($41.72 $37.81 vs. $1,114.60
A 12% $164.90) (21).
Despite the evidence that: 1) TE events are rare in
10% Thromboembolism
the periprocedural period; 2) hemorrhage is far more
Major Bleeding common than TE with bridging; and 3) there is no
8%
Any Bleeding clear antithrombotic benet with bridging, it remains
Event Rate
F I G U R E 2 Odds Ratios for Major Bleeding and Thromboembolic Events With Bridging
A Major Bleeding
Bridging No Bridging Odds Ratio Odds Ratio
Study or Subgroup
Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Daniels et al., 2009 15 342 5 213 24.9% 1.91 [0.68, 5.33]
Garcia et al., 2008 4 108 2 1185 15.3% 22.75 [4.12, 125.68]
Jaffer et al., 2010 13 229 3 263 21.0% 5.22 [1.47, 18.54]
McBane et al., 2010 14 514 2 261 17.9% 3.63 [0.82, 16.08]
Wysokinski et al., 2008 6 204 4 182 20.8% 1.35 [0.37, 4.86]
Forest plot for major bleeding from Siegal et al. (10) demonstrates a signicant odds ratio of 3.6 for patients receiving bridging anticoagulation (A). There
is no signicant difference in thromboembolic events between bridging and nonbridging (B). CI condence interval; M-H Mantel-Haenszel.
Reprinted with permission from Siegal et al. (10).
adjusted odds ratio: 3.84; p < 0.0001) with no sig- population largely moderate risk for TE. The
nicant difference in TE events (2). primary endpoints were arterial thromboembolism
and major bleeding.
THE BRIDGE TRIAL The rate of arterial TE in the placebo group was
noninferior to the bridging group (0.4% vs. 0.3%;
In support of the mounting observational data, the p 0.01 for noninferiority). Major and minor bleeding
recently published landmark BRIDGE trial now pro- in the placebo group was signicantly less than in
vides the most compelling evidence that routine the bridging group (1.3% vs. 3.2%; p 0.005; 12%
bridging in moderate-risk patients is harmful. In the vs. 20.9%; p 0.001; respectively). There was no
BRIDGE triala randomized, double-blinded, placebo- measurable difference among myocardial infarction,
controlled noninferiority study1,884 atrial brilla- deep vein thrombosis, pulmonary embolism, or death.
tion patients (valvular and nonvalvular) who were This study conrms that no bridging is noninferior
undergoing a procedure with planned warfarin to bridging for preventing TE and is superior for
interruption were randomized to anticoagulation reducing bleeding. The assumption that any in-
bridging with the low molecular-weight heparin, creased bleeding caused by bridging is justied by a
dalteparin, or placebo (4). The reasons for OAC decrease in TE has been challenged by the BRIDGE
interruption were not specied, but importantly, trial. It appears that bridging in moderate-risk atrial
89.4% underwent procedures designated as low brillation populations causes harm without benet.
bleeding risk. The average CHADS 2 (congestive An important limitation of the BRIDGE trial
heart failure, hypertension, age >75 years, diabetes was that the population studied was limited to pa-
mellitus, stroke) score was 2.3, making the study tients whose anticoagulation indication was atrial
C EN T RA L IL LUSTR AT I ON Bridging Anticoagulation: Algorithms for Periprocedural Interrupting and Bridging Anticoagulation
N Y
N Y
Y N
Y N
N Y
Decision trees for periprocedural interruption of chronic oral anticoagulation (top) and for periprocedural bridging anticoagulation (bottom). OAC oral
anticoagulation.
brillation and to those at predominantly intermedi- mechanical heart valves, or recent venous or arterial
ate risk of TE (although 16.3% had concomitant thromboses, should be done cautiously. But the low
valvular disease). Extrapolation of the BRIDGE results arterial TE rate (0.4%) in BRIDGE patients considered
to groups with greater TE risk, such as patients to be at intermediate TE risk is reassuring. Other
with atrial brillation and higher CHADS2 scores, randomized trials are underway to address these
Anticoagulation Effect
Anticoagulation Effect Warfarin Interruption
Warfarin
Warfarin Ideal Bridging
Anticoagulation Gap
-5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5
Days from Procedure or Surgery Days from Procedure or Surgery
Anticoagulation Effect
Uninterrupted Oral Anticoagulation Anticoagulation Effect Heparin
Anticoagulation Effect
Warfarin
Warfarin Warfarin
-5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5
Days from Procedure or Surgery Days from Procedure or Surgery Days from Procedure or Surgery
Heparin
Anticoagulation Effect
Warfarin Heparin
Heparin
Warfarin
Warfarin
-5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5
Days from Procedure or Surgery Days from Procedure or Surgery Days from Procedure or Surgery
Anticoagulation Effect
Anticoagulation Effect
Warfarin
Heparin Ambulation, compression
Warfarin devices, etc. NOAC
-5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5
Days from Procedure or Surgery Days from Procedure or Surgery Days from Procedure or Surgery
Warfarin interruption produces an anticoagulation gap (A). Various strategies (C to K) attempt to emulate a theoretical ideal bridge (B). See text for
discussion. INR international normalized ratio; NOAC novel oral anticoagulant.
issues. PERIOP2 (A Double Blind Randomized Control Candidates for uninterrupted OAC are those patients
Trial of Post-Operative Low Molecular Weight at moderate or high risk for TE and who are under-
Heparin Bridging Therapy Versus Placebo Bridging going a reasonably low bleeding risk procedure
Therapy for Patients Who Are at High Risk for Arterial (Table 2). To avoid unnecessary bleeding with unin-
Thromboembolism; NCT00432796) is a placebo- terrupted OAC, also consider a lower periprocedural
controlled, double-blinded, multicenter Canadian INR goal of 2.0 (Figure 3D).
study that is randomizing moderately high-risk pa- If OAC interruption is necessary, avoid bridging
tients with mechanical heart valves and atrial bril- patients (Figure 3A) at low or moderate risk for TE
lation to dalteparin or placebo for perioperative (Table 1) (5) as long as other individualized risks (i.e.,
bridging. The primary endpoint is any major TE existing left atrial appendage thrombus or active
event, including stroke, myocardial infarction, sys- cancer) do not exist. Patient-specic bleeding risk
temic embolism, valve thrombosis, VTE, or vascular should also be assessed to help guide anticoagulation
death. decisions. One approach is to use bleeding risk cal-
culators such as a BleedMAP score (1,27). This model
A CONTEMPORARY APPROACH was derived by retrospectively analyzing 2,484 peri-
procedural OAC interruptions through the Mayo
Using the cumulative available data, our approach to Clinic Thrombophilia Center from 1997 to 2007 (41).
periprocedural anticoagulation is detailed in the BleedMAP assigns a point for each of the following:
following text (Central Illustration, Figure 3). prior bleeding (Bleed), mechanical mitral valve
First and foremost, whenever possible, avoid in- (M), active cancer (A), and low platelets (P). Higher
terrupting OAC (Central Illustration, Figures 3C and 3D). scores portend higher perioperative bleeding risk.
0.8
transitioning off of heparin as the INR approaches 2.0,
rather than after (Figure 3I) (5,15,4244). Health care
providers should also consider nonpharmacological
approaches (i.e., ambulation and compression stock-
0.4 ings) to reduce thrombotic risk when OAC interrup-
tion is necessary (Figure 3J). Bleeding avoidance
strategies and nonpharmacological approaches can be
0 effective (45).
0 12 3
BleedMAP Score
NOVEL ANTICOAGULANTS IN THE
PERIPROCEDURAL PERIOD
A higher BleedMAP score correlated with increased bleeding both in patients receiving
bridging anticoagulation (salmon) and in all patients (blue) (A). Thromboembolism did not
occur with high BleedMAP scores and was rare in general (B). Reprinted with permission Novel oral anticoagulants (NOACs) will be increasingly
from Tafur et al. (41). encountered in periprocedural scenarios. NOACs are
poised to replace warfarin for the treatment of atrial
brillation and VTE (1,46). Multiple investigators
have reviewed perioperative NOACs interruptions in
Conveniently, higher BleedMAP scores also correlate atrial brillation populations (27,28,4749). NOAC
with lower TE rates (Figure 4). interruptions occurred frequently in the RE-LY
The net clinical benet of bridging patients at (Randomized Evaluation of Long Term Anticoagulant
high risk for TE (Table 1) remains unknown and is not Therapy With Dabigatran Etexilate), ROCKET-AF
yet supported by clinical trial evidence. It should be (Rivaroxaban Once-Daily, Oral, Direct Factor Xa In-
noted that observational data has yet to demonstrate hibition Compared With Vitamin K Antagonism for
that bridging meaningfully reduces TE events, even Prevention of Stroke and Embolism Trial in Atrial
in populations with high TE risk (2,10,12,16). In Fibrillation), and ARISTOTLE (Apixaban for Reduc-
contrast, excessive hemorrhagic events have been tion in Stroke and Other Thromboembolic Events
well described. However, until clinical trial evidence in Atrial Fibrillation) studies25%, 33%, and 34%,
is available, we recommend following guideline re- respectively. Patients in these large trials did not
commendations to consider individualizing bridging experience increased TE or bleeding events peri-
anticoagulation in specic high-risk patients (Table 4). operatively, whether bridged or unbridgedeven
For example, it might be reasonable to consider those undergoing major or urgent surgical pro-
bridging in those with an unacceptably high TE risk cedures (28,48). Given their pharmacokinetic simi-
(i.e., active or recent arterial TE or mechanical mitral larities to low molecular-weight heparins (Figure 3K),
Thromboembolism Major
High-Risk OAC Risk During OAC Bleeding Guideline Recommendation Guideline Recommendation
Indication Interruption Risk (ACCP) (AHA/ACC/HRS) Considerations Favoring Not Bridging
Atrial brillation Bridging is favored (Grade 2C) No specic recommendation to bridge. Short OAC interruption (<35 days)
(CHADS2 $5) Individualize based on bleeding Concurrent dual antiplatelet therapy
and TE risk. Active bleeding
High risk of major bleeding
(BleedMAP score)
No prior TE
Sinus rhythm
Recent VTE Bridging is favored (Grade 2C) N/A Same as atrial brillation considerations
VTE >3 months prior
Recent or active Bridging is favored (Grade 2C) No specic recommendation to bridge. Same as atrial brillation considerations
arterial TE Individualize on the basis of TE >3 months prior
bleeding and TE risk.
Mechanical heart Bridging is favored (Grade 2C) No specic recommendation to bridge. Same as atrial brillation considerations
valve(s) Individualize on the basis of Aortic position only
bleeding and TE risk.
ACC American College of Cardiology; ACCP American College of Chest Physicians; AHA American Heart Association; HRS Heart Rhythm Society; OAC oral anticoagulation; TE thromboembolism;
other abbreviations as in Table 1.
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