To bridge or not to bridge: these are the questions

Robert W. Harrison • Thomas L. Ortel •

Richard C. Becker

Published online: 24 April 2012

� Springer Science+Business Media, LLC 2012

Introduction

Two million patients in North America and more than four

million patients in the European Union carry a diagnosis of

chronic atrial fibrillation (AF) [1]. AF is associated with

significant morbidity and mortality, including an increased

risk of stroke and thromboembolism. The incidence of

stroke ranges from 1.9 to 18.2 % per year depending on the

number of associated risk factors [2]. Oral anticoagulation

(OAC), traditionally with warfarin, reduces the risk of

stroke by approximately two-thirds [1] and has become the

standard of care for managing patients at all but the lowest

levels of risk. Thus, the decision to initiate OAC is rela-

tively straightforward with a strong foundation of sup-

porting evidence. However, every year, twenty to 50 % of

patients [3] with AF will be asked to interrupt OAC for of

an elective surgery or procedure. Despite the frequency

with which this scenario arises, the optimal strategy for

managing OAC in the peri-procedural period has not been

established.

Clinicians have three options for managing peri-proce-

dural anticoagulation. First, OAC can be continued during

procedures associated with low rates of bleeding. Second,

OAC can be interrupted for several days prior to the pro-

cedure and resumed immediately following the procedure.

Third, OAC can be interrupted with bridging anticoagula-

tion, using either heparin or low molecular weight heparin

(LMWH), administered during the sub-therapeutic win-

dow. The safety of continuing OAC during procedures

with a low risk of bleeding has been established. Minor

dental, dermatological, and ophthalmologic procedures are

associated with low rates of bleeding and the most recent

American College of Chest Physicians (ACCP) guidelines

recommend continuation of OAC in these settings [4].

Additionally, the American Society for Gastrointestinal

Endoscopy supports continued anticoagulation during low

risk endoscopic procedures [5]. There is also mounting

evidence that cardiovascular procedures, including pace-

maker and defibrillator implantation, ablations, and coro-

nary angiography can safely be performed on therapeutic

OAC. Despite existing recommendations and guidelines,

nearly half of requests to interrupt OAC are for ‘‘guideline

discordant’’ procedures [3].

There remains, however, a broad spectrum of proce-

dures for which interruption of OAC is necessary. These

instances require a clinician to carefully weigh the risks of

a thromboembolic event in the absence of therapeutic

anticoagulation versus the risk of bleeding with bridging

anticoagulation. An informed decision on bridging requires

(1) the assessment of each patient’s risk of thromboem-

bolism and bleeding, (2) an understanding of the efficacy

and safety of bridging anticoagulation, and (3) proficiency

with a management strategy for bridging anticoagulation

which includes acceptance of bridging on behalf of the

patients and surgeons. However, the current evidence is

insufficient to address each of these requirements, leading

to widely variable practice patterns [6]. Specific areas of

uncertainty are addressed below.

Arterial thromboembolism risk stratification

Few studies, most of which are retrospective in nature,

have investigated the peri-procedural risk of arterial

thromboembolism in AF patients undergoing invasive

procedures in the absence of bridging therapy. Garcia et al.

R. W. Harrison � T. L. Ortel � R. C. Becker (&)

Duke University, Medical Center, Durham, NC 27705, USA

e-mail: becke021@mc.duke.edu

123

J Thromb Thrombolysis (2012) 34:31–35

DOI 10.1007/s11239-012-0732-8

[7] prospectively studied a cohort of 550 patients with AF

undergoing 590 interruptions of warfarin. Most of the

procedures were minor in nature, and a small minority

(2.5 %) of patients received bridging therapy. The inci-

dence of arterial thromboembolism was 0.6 %, none of

which occurred in patients receiving bridging therapy.

Blacker et al. [8] studied a cohort of anticoagulated AF

patients undergoing endoscopic procedures who either had

anticoagulation continued or adjusted. None of the 438

patients who continued anticoagulation experienced a

stroke, whereas stroke occurred in 12/987 patients who had

their anticoagulation adjusted for a peri-procedure risk of

1.06 % (95 % CI 0.55–1.84). The lowest stroke risk,

0.31 % (95 % CI 0.04–1.13), was observed in AF patients

with normal valves undergoing routine procedures. Finally,

in a large administrative database, 1.8 % of patients with

AF had a stroke within 30 days of surgery [9]. Compared

with patients without AF, patients with AF had twice the

odds of peri-procedural stroke with an odds ratio of 2.1

(95 % CI 2.0–2.3). Thus, the risk of peri-procedural stroke

ranges between 0.3 and 1.8 % in patients with AF.

High risk subgroups of patients are likely to have a risk

of thromboembolism which exceeds the overall population

rate of 1.8 %. There is little evidence, however, to guide

further risk stratification. The individual components of the

CHADS2 score were significant predictors for peri-opera-

tive stroke in the administrative database described previ-

ously. However, the predictive value of the CHADS2 score

was not specifically assessed. Conversely, in the study by

Garcia et al. [7], all of the arterial thromboses occurred in

AF patients with a CHADS2 score of two or less. Proce-

dural characteristics are also important in stratifying

thrombosis risk among patients undergoing coronary artery

bypass surgery, valve surgery, or vascular surgery-collec-

tively having 30-day risk of stroke of *3 % [9].

The 2012 ACCP guidelines recommend risk stratifying

AF patients according to their CHADS2 score (Table 1)

[4]. While these guidelines are based on the available

evidence, they have not been prospectively validated in the

peri-procedural setting. A clinically translatable model for

predicting the risk of arterial thromboembolism will need

to incorporate both patient and procedural characteristics,

but no such model is currently available.

Efficacy of bridging to reduce the risk of arterial

thromboembolism

Bridging therapy is based on the logical assumption that

provision of therapeutic anticoagulation during interruption

of chronic OAC will lower the risk of arterial thrombo-

embolism. Several strategies have evaluated the use of

heparin or low molecular weight heparin as bridging anti-

coagulation in patients on chronic OAC. While very few

studies have strictly evaluated patients with AF, most have

presented outcomes in the subset of patients with AF

(Table 2). Most of the studies employed a LMWH at

therapeutic or sub-therapeutic doses, depending on patient

risk. The peri-procedural risk of arterial TE in these studies

ranges between zero and 2.7 %.

Although these studies are valuable in demonstrating the

feasibility of bridging anticoagulation, they are not suffi-

cient, for two reasons, to establish the effectiveness of

bridging. First, these studies have tended to enroll patients

for whom bridging was deemed necessary, which suggests

a higher risk profile compared with the aforementioned

studies where bridging was not employed. Thus, a com-

parison between the observed event rates between studies

of bridging and those that did not employ bridging is not

appropriate. Second, none of the bridging anticoagulation

studies employed a control arm.

The 2012 ACCP guidelines (Table 1) recommend

bridging therapy for patients at high risk of TE and no

bridging therapy in patients at low risk for TE [4]. These

recommendations receive a level of evidence 2C which

corresponds to a weak recommendation with low quality

Table 1 2012 ACCP guidelines4: peri-procedural management of antithrombotic therapy in patients with atrial fibrillation

Risk Definition Management recommendations

Low CHADS2 score 0–2 (assuming no prior CVA) Recommend no-bridging instead of bridging anticoagulation

during interruption of VKA therapy (grade 2C).

Moderate CHADS2- score 3 or 4 No recommendation given. Consider individual patient

and surgery-related factors in choosing a bridging

or no-bridging approach.

High CHADS2 score of 5 or 6, or CVA within 90 days,

or rheumatic valvular heart disease

Recommend bridging anticoagulation instead

of no bridging during interruption of VKA

therapy (grade 2C).

CVA cerebrovascular event (stroke or transient ischemic attack); VKA vitamin K antagonist (warfarin) therapy

CHADS2 score: 1 point for each of age C75 years, hypertension, heart failure, diabetes, and 2 points for prior stroke or transient ischemic attack.

Adapted from Douketis et al (2012) Chest 141(2 suppl):e3265–e3505 [4]

32 R. W. Harrison et al.

123

supporting data. Highlighting the clinical equipoise for

bridging patients at moderate risk for TE, the guidelines

make no recommendation for or against bridging therapy,

suggesting that the decision needs to be based on individual

and surgery-related factors. This is a change from the 2008

ACCP guidelines which recommended, with a level of

evidence 2C, bridging anticoagulation in moderate risk

patients [10]. The weak level of evidence available to

support these recommendations highlights the need for

randomized clinical trials.

Risk of bleeding with bridging therapy

Although evidence for a benefit from bridging is lacking,

bleeding has been shown to be more common in patients

receiving peri-operative therapeutic dose heparin or

LMWH. The risk of bleeding, like the risk of thrombo-

embolism, is strongly influenced by both patient and sur-

gical characteristics. Estimation of bleeding risk with

bridging therapy based on the available studies is limited

by their heterogeneous populations, wide variety of sur-

geries and procedures, and non-standardized definitions of

bleeding. The overall rates of major bleeding vary between

0.4 and 6.7 % (Table 2). Higher rates have been reported in

patients undergoing major surgeries, which are typically

defined as intra-abdominal, intra-thoracic, major orthope-

dic, vascular, or urologic surgeries, or surgeries lasting

longer than 1 h. Despite an overall bleeding rate of 3.5 %,

major bleeding occurred in 20 % of patients undergoing

major surgery in the PROSPECT trial [11]. Tafur et al.

evaluated the risk of bleeding in patients on OAC and

found an overall major bleeding rate of 2.1 % at 3 months.

Predictors of major bleeding were the presence of a

mechanical mitral valve, active cancer, prior bleeding and

re-initiation of heparin within 24 h of the procedure (HR

1.9, 95 % CI 1.1–3.4) [12].

Similar to the risk of thromboembolism, risk scores such

as HAS-BLED [13] and HEMORR2HAGES [14] have

been validated in patients on chronic warfarin therapy, but

Table 2 Studies investigating the use of heparin or LMWH as peri-procedural bridging anticoagulation in patients with AF

Study Design Population n Bridging Arterial TE Major

bleeding

Douketis et al

[15]

Prospective

cohort

AF or prosthetic

valve who

require bridging

Total: 650

AF: 346

Dalteparin (therapeutic) 4/346 (1.2 %) 4/346 (1.2 %)

Dunn et al [11] Prospective

cohort

AF or DVT who

require bridging

Total: 260

AF: 176

Enoxaparin (therapeutic) 4/176 (2.3 %) 9/260 (3.5 %

of overall

cohort)

Hammerstingl

et al [16]

Prospective

registry

AF AF: 703 Enoxaparin (therapeutic to

moderate and high risk, low-

dose to all others)

0/703 (0.0 %) 3/703

(0.42 %)

Jaffer et al

[17]

Prospective

cohort

Chronic OAC who

require bridging

Total: 69

AF: 27

LMWH (therapeutic) 0/27 (0.0 %) 2/69 (2.9 %)

Kovacs et al

[18]

Prospective

cohort

AF or prosthetic

valve with

CHADS2 C 1

Total: 224

AF: 112

Dalteparin (therapeutic) 3/112 (2.7 %) 15/224 (6.7 %

of overall

cohort)

Malato et al

[19]

Prospective

cohort

Chronic OAC who

require bridging

Total: 328

AF: 180

LMWH (therapeutic to high

risk, low-dose to all others)

3/180 (1.7 %) 7/328 (2.1 %

of overall

cohort)

Pengo et al

[20]

Prospective

cohort

Chronic OAC who

require bridging

Total: 1262

AF: 653

LMWH (therapeutic to high

risk, low-dose to all others)

1/653 (0.2 %) 15/1,262

(1.2 % of

overall

cohort)

Spyropoulos

et al [21]

Prospective

Registry

Chronic OAC who

require bridging

Total: 901

AF: 349

Heparin (n = 164)

LMWH (therapeutic, n = 668)

8/901 (0.9 %). AF

specific outcomes

not available

31/901 (3.4 %

of overall

cohort)

Wysokinski

et al [22]

Retrospective

cohort

Non-valvular AF ?Bridging:

204

-Bridging:

182

Heparin or LMWH in high risk

patients

?Bridging: 2/204

(1.0 %)

-Bridging: 1/182

(0.6 %)

?Bridging:

6/204

(3.0 %)

-Bridging:

4/182

(2.3 %)

AF atrial fibrillation; LMWH low molecular weight heparin; OAC oral anticoagulation; DVT deep vein thrombosis; TE thromboembolism

To bridge or not to bridge 33

123

no peri-operative bleeding models have been developed to

incorporate patient and procedural characteristics.

Future directions

Critical areas of uncertainty in the peri-procedural man-

agement of anticoagulation in patients with AF include the

following:

1. There is little evidence, and no prospective evidence,

to guide clinicians in further stratifying the risk of TE

in AF patients undergoing invasive procedures. There

is evidence that the risk of TE increases with higher

CHADS2 scores, but a model based on CHADS2 alone

does not incorporate procedural details which may

contribute to the risk of TE.

2. The ability of bridging anticoagulation with LMWH to

lower the risk of peri-procedural TE has not been

demonstrated in a prospective manner. Two ongoing

clinical trials—BRIDGE (ClinicalTrials.gov identifier

NCT00786474), and PERIOP-2 (ClinicalTrials.gov

identifier NCT00432796)—will help to answer this

question.

3. The incorporation of newer oral anticoagulants into a

bridging strategy has been described in case reports,

but there is no evidence to support the peri-procedural

use of these anticoagulants.

The ongoing, National Institutes of Health-supported,

BRIDGE trial is a randomized clinical trial to test the

efficacy and safety of bridging anticoagulation. BRIDGE

will enroll 3,626 adults with AF or atrial flutter who have

been receiving warfarin for at least 3 months with a goal

INR of 2–3 and who require temporary interruption for a

procedure or surgery. Patients must have at least one

CHADS2 risk factor to be included. Exclusion criteria

include other indications for anticoagulation (prosthetic

heart valve, venous thromboembolism), recent stroke or

recent bleeding, severe renal insufficiency, and certain

high-risk surgeries (cardiac, intra-cranial, or intra-spinal).

Subjects will be randomized to receive therapeutic dal-

teparin or placebo before and after their procedure until

warfarin is resumed and a therapeutic INR achieved.

BRIDGE is designed to test the hypothesis that not

administering bridging anticoagulation is not inferior to the

administration of bridging anticoagulation in the preven-

tion of stroke, TIA or systemic embolism. The primary

safety endpoint is major bleeding.

PERIOP-2 is also designed to study the safety and efficacy

of dalteparin in patients who are at risk for arterial throm-

boembolic events due to peri-procedural interruption of

chronic warfarin therapy. PERIOP-2 is designed to enroll

1,773 patients from who have AF and risk factors for stroke

or who have a prosthetic heart valve requiring long term

anticoagulation. All patients receive therapeutic dalteparin

prior to their procedure but will be randomized to dalteparin

or placebo following their procedure. The primary outcome

is major thromboembolic events, and secondary outcomes

include major and minor bleeding, minor thromboembolic

events, and overall survival through 90 days.

Results from these trials will provide critical insight into

the safety and efficacy of bridging anticoagulation and

perhaps provide information on subgroups of patients and

procedures for which bridging may or may not be benefi-

cial. Furthermore, they will provide a solid foundation for

design and conduct of future bridging trials with newer oral

anticoagulants.

References

1. Fuster V, Ryden LE, Cannom DS et al (2011) ACCF/AHA/HRS

focused updates incorporated into the ACC/AHA/ESC 2006

guidelines for the management of patients with atrial fibrillation:

a report of the american college of cardiology foundation/

American heart association task force on practice guidelines

developed in partnership with the European society of cardiology

and in collaboration with the European heart rhythm association

and the heart rhythm society. J Am Coll Cardiol 57(11):e101–

e198

2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW,

Radford MJ (2001) Validation of clinical classification schemes

for predicting stroke: results from the national registry of atrial

fibrillation. J Am Med Assoc 285(22):2864–2870

3. Skolarus LE, Morgenstern LB, Froehlich JB, Lisabeth LD,

Brown DL (2011) Guideline-discordant periprocedural interrup-

tions in warfarin therapy. Circ Cardiovasc Qual Outcomes.

4(2):206–210

4. Douketis JD, Spyropoulos AC, Spencer FA et al (2012) Periop-

erative management of antithrombotic therapy. Antithrombotic

therapy and prevention of thrombosis, 9th edn. American college

of chest physicians evidence-based clinical practice guidelines.

Chest 141(2 suppl):e3265–e3505

5. Eisen GM, Baron TH, Dominitz JA et al (2002) Guideline on the

management of anticoagulation and antiplatelet therapy for

endoscopic procedures. Gastrointest Endosc 55(7):775–779

6. Douketis JD, Crowther MA, Cherian SS (2000) Perioperative

anticoagulation in patients with chronic atrial fibrillation who are

undergoing elective surgery: results of a physician survey. Can J

Cardiol 16(3):326–330

7. Garcia DA, Regan S, Henault LE et al (2008) Risk of thrombo-

embolism with short-term interruption of warfarin therapy. Arch

Intern Med 168(1):63–69

8. Blacker DJ, Wijdicks EF, McClelland RL (2003) Stroke risk in

anticoagulated patients with atrial fibrillation undergoing endos-

copy. Neurology 61(7):964–968

9. Kaatz S, Douketis JD, Zhou H, Gage BF, White RH (2010) Risk

of stroke after surgery in patients with and without chronic atrial

fibrillation. J Thromb Haemost 8(5):884–890

10. Douketis JD, Berger PB, Dunn AS et al (2008) The perioperative

management of antithrombotic therapy: American college of

chest physicians evidence-based clinical practice guidelines (8th

edn). Chest 133(6 Suppl):299S–339S

34 R. W. Harrison et al.

123

11. Dunn AS, Spyropoulos AC, Turpie AG (2007) Bridging therapy

in patients on long-term oral anticoagulants who require surgery:

the prospective peri-operative enoxaparin cohort trial (PROS-

PECT). J Thromb Haemost 5(11):2211–2218

12. Tafur AJ, McBane R, IInd, Wysokinski WE et al (2011) Pre-

dictors of major bleeding in peri-procedural anticoagulation

management. J Thromb Haemost 10(2):261–267

13. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY

(2010) A novel user-friendly score (HAS-BLED) to assess 1-year

risk of major bleeding in patients with atrial fibrillation: the Euro

heart survey. Chest 138(5):1093–1100

14. Gage BF, Yan Y, Milligan PE et al (2006) Clinical classification

schemes for predicting hemorrhage: results from the national

registry of atrial fibrillation (NRAF). Am Heart J 151(3):713–719

15. Douketis JD, Johnson JA, Turpie AG (2004) Low-molecular-

weight heparin as bridging anticoagulation during interruption of

warfarin: assessment of a standardized periprocedural anticoag-

ulation regimen. Arch Intern Med 164(12):1319–1326

16. Hammerstingl C, Schmitz A, Fimmers R, Omran H (2009)

Bridging of chronic oral anticoagulation with enoxaparin in

patients with atrial fibrillation: results from the prospective

BRAVE registry. Cardiovasc Ther 27(4):230–238

17. Jaffer AK, Ahmed M, Brotman DJ et al (2005) Low-molecular-

weight-heparins as periprocedural anticoagulation for patients on

long-term warfarin therapy: a standardized bridging therapy

protocol. J Thromb Thrombolysis 20(1):11–16

18. Kovacs MJ, Kearon C, Rodger M et al (2004) Single-arm study of

bridging therapy with low-molecular-weight heparin for patients

at risk of arterial embolism who require temporary interruption of

warfarin. Circulation 110(12):1658–1663

19. Malato A, Saccullo G, Lo Coco L et al (2010) Patients requiring

interruption of long-term oral anticoagulant therapy: the use of

fixed sub-therapeutic doses of low-molecular-weight heparin.

J Thromb Haemost 8(1):107–113

20. Pengo V, Cucchini U, Denas G et al (2009) Standardized low-

molecular-weight heparin bridging regimen in outpatients on oral

anticoagulants undergoing invasive procedure or surgery: an

inception cohort management study. Circulation 119(22):2920–

2927

21. Spyropoulos AC, Turpie AG, Dunn AS et al (2006) Clinical

outcomes with unfractionated heparin or low-molecular-weight

heparin as bridging therapy in patients on long-term oral anti-

coagulants: the REGIMEN registry. J Thromb Haemost 4(6):

1246–1252

22. Wysokinski WE, McBane RD, Daniels PR et al (2008) Peripro-

cedural anticoagulation management of patients with nonvalvular

atrial fibrillation. Mayo Clin Proc 83(6):639–645

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