Article type : Review of Therapeutics

Accepted Article
Anticoagulation Bridge Therapy in Patients with Atrial Fibrillation: Recent Updates

Providing a Rebalance of Risk and Benefit

Candice L. Garwood1,2, Bianca Korkis1,2, Domenico Grande1, Claudia Hanni2, Amy

Morin1, Lynette R. Moser 1

1
Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health

Sciences, Wayne State University; 2 Pharmacy Department, Harper University Hospital, Detroit

Medical Center, Detroit, MI

Key Words: anticoagulation, atrial fibrillation, bridging, low molecular weight heparin,

perioperative, subtherapeutic INR, warfarin, warfarin initiation

Disclosures: There are no disclosures to make for any of the authors.

Correspondence:
Candice L. Garwood
Clinical Associate Professor
Department of Pharmacy Practice
Eugene Applebaum College of Pharmacy and Health Sciences
259 Mack Ave
Suite 2190
Detroit, MI 48201
USA
Tel.: (313) 577-5371; fax: (313) 577-5369
E-mail: cgarwood@wayne.edu

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/phar.1937
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 Abstract
Accepted Article
In 2011, we provided a review of clinical updates and controversies surrounding

anticoagulation bridge therapy in patients with atrial fibrillation. Since then, options for oral

anticoagulation have expanded with the addition of four direct oral anticoagulant (DOAC) agents

available in the United States. Nonetheless, vitamin K antagonist (VKA) therapy continues to be

the treatment of choice for patients who are poor candidates for a DOAC and for whom bridge

therapy remains a therapeutic dilemma. However, bridge therapy for patients taking a VKA

remains a therapeutic dilemma. This literature review was designed to identify evidence and

guideline and consensus statements from the last 5 years to provide updated recommendations

and insight into bridge therapy for patients using a VKA for atrial fibrillation. Since our last

review, there have been updates to at least four major international guidelines plus release of a

new consensus document addressing bridge therapy. Prospective trials and one randomized

controlled trial have provided guidance for perioperative bridge therapy. The clinical trial data

have shown that bridging with heparin is associated with a significant bleeding risk compared

with not bridging; furthermore, data have suggested that actual perioperative thromboembolic

risk may be lower than previously estimated. Notably, patients at high risk for stroke have not

been adequately represented. These findings highlight the importance of assessing thrombosis

and bleeding risk prior to making bridging decisions. Thrombosis and bleeding risk tools have

emerged to facilitate this assessment and have been incorporated into guideline

recommendations. Results from ongoing trials are expected to provide more guidance on safe

and effective perioperative management approaches for patients at high risk for stroke.

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 Introduction
Accepted Article
It is estimated that over 3 million Americans have atrial fibrillation (AF), and about half

of eligible patients with AF are receiving anticoagulant therapy.1,2 Warfarin has been available

to patients for over 50 years and continues to be one of the most widely used anticoagulants.3,4

In any given year, approximately 15–20% of patients receiving chronic anticoagulation will

undergo an invasive procedure that will warrant anticoagulation interruption.5,6 Warfarin has a

pharmacokinetic profile that includes a long onset and offset of therapeutic effect.7 As a result,

warfarin initiation, perioperative interruption for an invasive procedure, or occurrence of a

subtherapeutic international normalized ratio (INR) may result in inadequate anticoagulation and

thus are considerations for initiating bridge therapy. Anticoagulation bridge therapy refers to the

use of a short-acting parenteral anticoagulant—unfractionated heparin (UFH) or low-molecular-

weight heparin (LMWH)—during periods of inadequate anticoagulation from warfarin.

Anticoagulation management in patients with AF has changed significantly in the past 5–

10 years. Direct oral anticoagulants (DOACs) have been approved by the United States Food

and Drug Administration for use in patients with nonvalvular AF since 2010.8-11 One advantage

presented by DOACs is a short onset and offset of effect, which eliminates the need for bridging

therapy.2,12 The latest data suggest that DOAC prescribing has increased to approximately that

of warfarin and that DOACs are associated with an overall increase in oral anticoagulant

prescribing.3 However, certain factors make a patient a poor candidate for a DOAC. The

DOACs are not approved for patients with mechanical heart valves, moderate or severe mitral

stenosis, and severe hepatic impairment; in addition, none were studied in phase III clinical trials

in patients with a reduced creatinine clearance.8-11 Furthermore, concerns surrounding

concomitant treatment with dual antiplatelet therapy, DOAC affordability, and access-related

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 issues make it likely that clinicians will continue to prescribe warfarin for a substantial number
Accepted Article
of patients. Therefore, literature surrounding the use of warfarin and its management in patients

with AF continues to be relevant to current practice.

For nearly a decade, anticoagulation clinical guidelines have included recommendations

for bridge therapy for patients with AF taking warfarin.13 Nevertheless, these recommendations

have been based on observational studies and expert opinion and largely pertain to

periprocedural bridging. Minimal guidance is provided with regard to bridging anticoagulation in

other scenarios.13,14 In 2011, we reviewed the evidence surrounding bridging in patients with

AF.15 Since then, there have been a recent expert consensus statement and at least four major

North American and European clinical guidelines updated.2,12,14,16-20 Moreover, a number of

prospective trials have been published including the first randomized, placebo-controlled trial to

evaluate the benefit of perioperative bridging.5,21-23

We conducted a search of the MEDLINE database (2011–February 2017) for literature

published in the English language. We identified related studies using the following search

terms: atrial fibrillation, bridging, subtherapeutic INR, perioperative, periprocedural, low-

molecular-weight heparin, heparin, parenteral anticoagulants, warfarin, bleeding, stroke, and

warfarin initiation. Ongoing clinical trials were identified through a search of the

ClinicalTrials.gov registry. Major national and international guidelines were gathered and

evaluated. Additional literature was obtained through review of relevant references of the

identified articles.

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 Anticoagulation Bridge Therapy: Stroke and Bleeding Risk Assessment
Accepted Article
Bridge therapy is designed to reduce the window of time that patients experience

subtherapeutic anticoagulation, theoretically minimizing their thromboembolic risk. However,

bridging does carry an increased risk of bleeding.5,21-23 Therefore, the decision to bridge rests on

the balance between thrombosis risk and bleeding risk. When assessing perioperative stroke

risk, the American College of Chest Physicians (CHEST) guidelines, released in 2012, and the

newest 2017 Expert Consensus from the American College of Cardiology (ACC) recommend

stratifying a patient’s thromboembolic risk into low (<5% annual risk), moderate (5-10% annual

risk) and high (>10% annual risk) risk.14,20 Some guidelines recommend considering bridging if

stroke risk is estimated at 5–10% or more annually or if the patient has had a prior stroke or

transient ischemic attack (TIA).12,14,20

Using a mathematic appraisal, a person with AF and a 5% annual risk of stroke who was

not therapeutically anticoagulated would have a 30-day estimated rate of thromboembolism of

about 0.4% ([5%/365 days] x 30 days).24 Past analyses of varying quality and design have

suggested that the actual stroke rate perioperatively was elevated in comparison to the daily

estimated risk.25 Rates of arterial thromboembolism have ranged from as little as 0.2% to as

much as 1% of patients at 14 days to 90 days postprocedure.26-29 It was theorized that rates of

arterial thromboembolism were elevated after interruption of warfarin due to rebound

hypercoagulability and the thromboembolic risk of the procedure.30 However, new data from

large prospective studies in patients with AF, including one randomized controlled trial, have

found thrombosis rates to be lower than expected and not lessened by bridging. Rates of 30-day

arterial thromboembolism ranged from 0.3-0.5% in the bridged groups and 0.2-0.4% in the

nonbridged groups.5,22,23

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Accepted Article
Stroke Risk Assessment Tools

The CHADS2 risk score (Table 1),31-34 which is based on five major stroke risk factors

(congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, [1 point each] and prior

stroke or TIA [2 points]), became the predominant tool used to assess individualized stroke risk

in patients with AF due to accuracy and ease of use in clinical practice.31,35 Clinical guidelines

have recommended using CHADS2 in determining whether anticoagulation is indicated for

patients with AF.12,17 Although not originally validated for perioperative bridging assessment,

CHADS2 has widely served to risk stratify patients as candidates for perioperative bridge therapy

and its use is endorsed by clinical guidelines.12,14 A retrospective administrative claims database

was initially used to support CHADS2 for perioperative bridging evaluation30; however, it has

since been used in retrospective studies, substudy analyses, and prospective registries of bridging

practices.5,21,22,36 More recently, the CHADS2 risk score was employed in risk stratifying

patients for perioperative bridging in a randomized, double-blind, placebo-controlled trial.23

Thereby the use of the CHADS2 has become established as a viable risk assessment scheme for

patients with AF in the perioperative setting but has not specifically been tested as a risk

assessment tool in other bridging scenarios, such as bridging for warfarin initiation or bridging

for a subtherapeutic INR.

The CHA2DS2-VASc (congestive heart failure [1 point], hypertension [1 point], age ≥75

years [2 points], diabetes mellitus [1 point], prior stroke or TIA or thromboembolism [2 points],

vascular disease [1 point], age 65–74 years, female sex [1 point]) score was developed after the

CHADS2 score and provides a broader score range (0-9) and larger number of risk factors to

estimate annual risk of stroke in patients with AF (Table 1).32 The schema was tested in several

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 cohorts and was validated for use after finding that its discriminatory ability in low-risk patients
Accepted Article
was greater and predictability for stroke risk was improved compared with the CHADS2 score.37

The European Society of Cardiology (ESC) and the American College of Cardiology

(ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) Atrial Fibrillation

Guidelines supported the use of CHA2DS2-VASc as a preferred risk stratification tool for

patients with AF in 2012 and 2014, respectively.2,38

The CHADS2 and CHA2DS2-VASc tools were not validated specifically for perioperative

bridging assessment. However, the most recent large prospective studies described their

patients’ annual stroke risk by use of the CHADS2 score.22,23 Although use of the CHADS2 score

has become an accepted and commonplace method for risk stratification of patients requiring

warfarin interruption for surgery, the growing endorsement of CHA2DS2-VASc as a thrombosis

risk assessment may lend to its increased use for risk stratification periprocedurally. Most

recently, the 2017 ACC Expert Consensus recommends making decisions for or against

perioprocedural bridging in patients with AF based on stroke risk as estimated by the CHA2DS2-

VASc.20

Bleeding Risk Assessment Tools

Several tools are available to estimate bleeding risk, although they have not been

specifically validated in the setting of bridge therapy. The HAS-BLED (hypertension, abnormal

renal or liver function [1 point each], stroke, bleeding history or predisposition [anemia], labile

INR, elderly [age ≥65 years], drugs or alcohol concomitantly [1 point each]) score (Table 1) has

been recommended in multiple international guidelines as a bleeding risk assessment tool for

patients with AF.12,17,33,38 HAS-BLED has remained the recommended tool due to its simplicity,

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 predictive ability, and its inclusion of risk factors that can be practically managed to help reduce
Accepted Article
the patient’s bleeding risk.38 The HAS-BLED score has also been shown to correlate well with

intracranial hemorrhage risk.39 Notably, anticoagulation should not be withheld on the basis of

the HAS-BLED score; rather, risk of bleeding should be mitigated whenever possible (i.e.,

avoiding nonsteroidal antiinflammatory drugs).38 The HAS-BLED tool has not been validated or

endorsed by clinical guidelines for use specifically in patients requiring warfarin interruption for

surgery but has been used in at least one perioprocedural study to stratify patients’ bleeding risk.

In a prospective, observational, multisite registry of outpatients undergoing invasive procedures,

a high HAS-BLED score (≥ 3 points) was predictive of clinically relevant bleeding events on

multivariate regression.40 Results were unchanged if patients were treated with full therapeutic

or low doses of LMWH. Ninety-three percent of patients with a CHADS2 score ≤2 and 94% of

patients with a CHADS2 score of 3-4 received bridge therapy. This study suggests that there may

be an opportunity to mitigate bleeding risk by considering avoidance of bridge therapy in

patients undergoing periprocedural VKA interruption and who have a low CHADS2 score and

high HAS-BLED score. Future studies should evaluate the use of this tool in clinical decision

making for safe and appropriate bridging decisions in patients with AF.

The BleedMAP score is another approach to estimating patient-specific bleeding risk. It

was derived from retrospective analysis of 2484 cases of oral anticoagulant interruptions through

the Mayo Clinic Thrombophilia Center from 1997 to 2007.34 This tool assigns 1 point to each of

the following: prior bleeding, mechanical mitral valve, active cancer, and low platelet count.

Higher scores correlate to higher bleeding risk. BleedMAP includes less risk factors than HAS-

BLED and may be easier to remember and use. The inclusion of mechanical mitral valve as a

bleeding risk factor creates an interesting dilemma because patients with these valves are also

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 considered at high risk for thromboembolic events, and bridge therapy is currently recommended
Accepted Article
if warfarin is being interrupted.2,12,14,18 Although the BleedMAP score is described as a risk

calculator that can help to make patient-specific decisions about anticoagulation, its role in

bridging decisions remains unknown.

Due to the established elevated bleeding risk associated with bridging, a thorough

assessment of stroke and bleeding risks should be performed for each patient. Assessment of risk

should incorporate professional guidelines, clinical literature, and established risk tools to guide

bridging decision-making.

Clinical Guidelines and Literature on Anticoagulation Bridge Therapy

The major clinical guidelines and expert consensus documents for managing

anticoagulation in patients with atrial fibrillation were recently updated.2,12,14,16-18,20 A summary

of these guideline recommendations related to bridge therapy or perioperative anticoagulant

management can be found in Table 2. The data used to formulate the guidelines consist of

mostly small observational trials. As such, guideline recommendations on bridge therapy are

either minimal or have a low grade of evidence. The lack of strong guidance highlights the need

for additional high-quality studies.

Initiation of Therapy

Graded recommendations are provided for patients initiating oral anticoagulation for the

purpose of undergoing cardioversion2,12,17,18 and for those being anticoagulated for secondary

stroke prevention.18,19 Initiation of UFH or LMWH is recommended in patients who have not

been anticoagulated for at least 3 weeks and are either undergoing urgent cardioversion; patients

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 known to have AF for ≤ 48 hours; or patients with have no evidence of thrombus on
Accepted Article
transesophageal echocardiogram and are undergoing immediate cardioversion.2,12,17 This

recommendation is extrapolated from evidence in patients undergoing elective cardioversion

suggesting that anticoagulation reduces the risk of stroke or thromboembolism.41 Conversely,

patients with AF presenting with an acute ischemic stroke should not be rapidly

anticoagulated.18,19 Parenteral anticoagulants increase symptomatic intracranial bleeding without

a significant reduction in recurrent ischemic stroke in these circumstances.42 Patients should

instead receive early aspirin therapy until oral anticoagulation reaches therapeutic levels.

There are no graded recommendations pertaining to bridging hemodynamically stable

patients presenting with new-onset atrial fibrillation, unless undergoing cardioversion. Previous

guidelines (from 2008) suggested that bridging was unnecessary but could be considered in

“particularly worrisome patients.”43 Although “worrisome” was not defined in the

recommendation, practitioners may identify patients who have a visualized thrombus, history of

stroke, or high risk of stroke as being worrisome. Extrapolation of the recommendations for

patients undergoing urgent cardioversion is likely appropriate, as the goal of rapid

anticoagulation to prevent stroke is similar in both situations.

Perioperative Bridging

Clinical guideline recommendations for perioperative bridge therapy are largely based on

expert opinion.2,14,18,20 The majority of data are derived from relatively small retrospective

studies. All guidelines suggest a risk versus benefit approach based on an assessment of

individual patient- and surgery-related factors.

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 The 2012 CHEST guidelines provide risk-stratified recommendations for perioperative
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bridging based on the CHADS2 score, recent stroke history, or rheumatic valvular disease.14

Assuming no prior history of stroke or TIA, patients with a CHADS2 score of 0–2 are considered

to be at low risk whereas those with a score of 3–4 are considered to be moderately at risk.

Patients with a CHADS2 score of 5 or 6, a recent (within 3 months) history of stroke or TIA, or

those who have rheumatic valvular disease are considered to be at high risk. Patients with a

mechanical heart valve in the mitral position or those with an aortic caged-ball or tilting-disc

heart valve are also considered high risk. The 2012 guidelines recommend bridging patients at

high risk of stroke and avoiding bridging in low-risk patients.14 There is no graded

recommendation for bridging those at moderate risk.14 This is in contrast to 2008 CHEST

recommendations where either approach was considered acceptable in low- or moderate-risk

patients.13 The 2012 guidelines give no stratification for the risk of bleeding due to limited

evidence and a lack of prospective validation.14 Instead, surgeries are categorized by bleeding

risk and clinical consideration (Table 3).14 One specific recommendation provided is to avoid

bridging patients in the moderate-risk stratum undergoing major cardiac and carotid

endartectomy surgeries because of their high bleeding risk.14

Other major clinical guidelines offer low-grade, generalized recommendations or do not

provide graded recommendations for perioperative bridging.2,12,18 The 2014 AHA/ACC/HRS

guidelines recommend bridging patients with AF who also have mechanical heart valves because

of their high risk for stroke and thromboembolism.2 For patients at low to moderate risk, a

benefit versus harm analysis is recommended; however, no explicit guidance is given on how to

stratify patient risk.2 They suggest that patients at low risk likely do not require bridging and that

some procedures such as catheter ablations and pacemaker implantation can be performed

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 without interruption of anticoagulation, although these are not graded recommendations. The
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European Society of Cardiology suggests that there is little benefit to bridging patients with atrial

fibrillation who do not have a mechanical heart valve.18

Most recently, the ACC published the 2017 Expert Consensus Decision Pathway for

Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial

Fibrillation.20 This document provides specific guidance statements surrounding whether to

interrupt anticoagulation periprocedurally for patients with nonvalvular atrial fibrillation, and

whether or not to bridge. Bridging recommendations are based on stroke risk as assessed by

CHA2DS2-VASc risk score (low 0-4, moderate 5-6, or high ≥7) and bleeding risk. The ACC

recognizes the HAS-BLED tool as having shown some predictive value for bleeding risk in the

periprocedural setting but also acknowledges that it is limited by its modest discriminatory

performance. Instead, a bleeding risk assessment is recommended that includes the following

factors: major bleeding event within last 3 months, quantitative or qualitative platelet count

abnormality, INR above upper limit of therapeutic range, or bleeding during previous bridging or

similar procedure. For patients at low or moderate stroke risk and no history of ischemic stroke,

TIA, or systemic embolism, the ACC recommends no bridging. In contrast, if the patient is at

moderate stroke risk and has a history of stroke, TIA, or systemic embolism, without significant

bleeding risk, the clinician could consider bridging. Furthermore, for those at high stroke risk or

those who have had a recent (within 3 months) stroke, TIA, or systemic embolism, bridging is

recommended unless the patient has a history of major bleeding or intracranial hemorrhage

within the last 3 months.

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 Perioperative Bridging Studies with Warfarin and Low-Molecular-Weight Heparin
Accepted Article
The most recent evidence from both retrospective and prospective trials provides

direction beyond the clinical guidelines.5,21-23 These studies describe increased bleeding risk

with no change in the risk of thromboembolic events between the bridging and nonbridging

groups. All of these studies included patients with AF undergoing elective procedures that

required interruption of a VKA.

The first report is a meta-analysis of 34 studies that included 12,278 patients who

underwent elective surgery with interruption in their VKA therapy; 7118 patients used bridging

therapy.21 Of the 30 studies that reported the patient’s indications for VKA therapy, the most

frequent indication in patients who were bridged was AF (44%). The other indications for VKA

therapy that were included in some of the studies lend to heterogeneity among the dataset.

Pooled incidence rates of overall and major bleeding in the bridged group were 13.1% (34

studies; 95% confidence interval [CI] 0.0–45.2%) and 4.2% (24 studies; 95% CI 0.0 –11.3%),

respectively. In the nonbridged group, pooled incidence rates of overall and major bleeding were

3.4% (13 studies; 95% CI 1.1–5.8%) and 0.9% (5 studies; 95% CI 0.2–1.6%), respectively.

Most included studies did not specify the bleeding risk associated with the surgery. In addition,

the studies that did report major bleeding events had varying criteria for major bleeding. Of

note, only one randomized prospective trial was included in this meta-analysis, so the quality of

the results are limited. The findings of this meta-analysis raised questions about the safety and

efficacy of bridging practices.

The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)

is a prospective registry that includes 10,132 patients with AF.5 A substudy that pooled data

from this registry included 2200 patients who had at least one interruption for a procedure while

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 they were receiving warfarin or dabigatran. Only 24% of the reported interruption events used
Accepted Article
bridging therapy, and the bridging agents included LMWH (73%), UFH (15%), and

fondaparinux (1.1%). Within 30 days of the procedure, 3.6% of those in the bridging group

versus 1.2% in the nonbridging group experienced major bleeding (p=0.0007). In this study,

major bleeding was defined using the International Society of Thrombosis and Haemostasis

criteria.44 There were no significant differences in rates of myocardial infarction, stroke or

systemic embolism, hospitalization, and death. Since this was not a randomized trial, more

patients in the bridge group had prior cerebrovascular events, valvular disease, mechanical

valves, or congestive heart failure. The authors used logistical regression aimed at adjusting for

these differences. Although these patients may be at higher risk of thromboembolic events due to

their medical history, these adjusted and unadjusted outcomes demonstrated that bridging during

oral anticoagulant interruption may cause more major bleeding and offers no preventive benefit.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) is a trial

of patients with nonvalvular atrial fibrillation randomized to either dabigatran or open-label use

warfarin.8 A prespecified substudy analyzed the patients who had an elective procedure during

follow-up.22 This substudy evaluated the rates of bleeding and thromboembolic outcomes and

included 1424 patients receiving warfarin, of whom 27.5% were bridged. Outcomes were

reported within 30 days of the procedure, and the rates of major bleeding were higher in the

bridged group vs the nonbridged group (6.8% vs 1.6%, odds ratio [OR] 4.62, 95% CI 2.45-8.72,

p<0.001). Major bleeding criteria were derived from the International Society of Thrombosis and

Haemostasis definition.44 Interestingly, this study showed that patients who were bridged

experienced more thromboembolic events (1.8% in the bridged group vs 0.3% in the nonbridged

group, OR 6.39, 95% CI 1.64-24.8, p<0.007). It is important to note there was no protocol set

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 for the perioperative management of these patients; therefore, there was variation in the
Accepted Article
parenteral agents used as well as the duration of warfarin interruption. The mean CHADS2 score

was 2.1 in both groups. Although there were no notable differences in analyses of baseline risk

between the bridged and nonbridged groups, it is possible that there were unmeasured

differences in risk factors or unmeasured sources of bias. Whereas the number of

thromboembolic events was very small in this analysis, it raises questions about the benefit of

bridging.

BRIDGE Study

In 2015, the Bridging Anticoagulation in Patients who Require Temporary Interruption of

Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) trial was

published.23 It was the first prospective, multicenter, randomized, double-blind study of

perioperative bridging. Patients (n=1884) with AF undergoing elective procedures were

randomized to either receive bridging therapy using dalteparin 100 IU/kg subcutaneously twice

daily or placebo. Patients with bioprosthetic heart valves or mitral valve disease were included,

but patients with mechanical heart valves were excluded. The protocol for bridging was strictly

defined in this trial, and the time to reinitiation of bridging therapy was determined by the

bleeding risk of the surgery. A majority of patients (89.4%) underwent a low bleed risk surgery

and per protocol, their LMWH was restarted 12-24 hours after the procedure. The remaining

patients underwent high bleed risk surgeries and their bridging therapy was reinitiated 48-72

hours after procedure. The disproportion of low to high bleed risk surgeries reflects patterns seen

in other studies and general practice.6,45 Outcomes in this trial were reported within 30 days of

the procedure, and the incidence of major bleeding, as defined by International Society of

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 Thrombosis and Haemostasis, was lower in the nonbridging group (1.3% vs 3.2%, relative risk
Accepted Article
[RR] 0.41, 95% CI 0.20-0.78, p=0.005 for superiority).44,46 The absolute rate of arterial

thromboembolism, including stroke, systemic embolism, or TIA, was not significantly different

between groups [0.4% in the nonbridging group vs 0.3% in the bridging group, risk difference

0.1 percentage point, 95% CI -0.6 – 0.8, p=0.01 for noninferiority)]. Additionally, when

excluding patients who did not actually undergo the intended procedure, an as-treated analysis

determined that the rate of arterial thromboembolism was not significantly different between the

nonbridging and bridging groups (0.3% vs 0.4%, mean between-group difference 0.0 percentage

point, 95%CI -0.7 – 0.7, p=0.006 for noninferiority). The overall rate of arterial

thromboembolism was lower than expected (anticipated rate was 1%), which potentially affected

the power of the trial to detect the benefit of bridging. However, the observed rate of

thromboembolism (0.4%) was similar to the findings of other trials involving warfarin

interruption.5,47 Among the patients who had a thromboembolic event, the mean CHADS2 score

was 2.6, ranging from 1–4. Of note, the CHADS2 scores between the two groups were similar,

with the majority of patients in this study having a score of 0–2 (1163 patients [61.7%]). Smaller

proportions of patients had CHADS2 scores of 3–4 (663 patients [35.2%]), and CHADS2 scores

of 5–6 [n=58 (3.1%)]. This prospective randomized trial confirmed the reports of increased

bleeding risk from bridging demonstrated in the uncontrolled trials. Additionally, the results

showed that bridging is not efficacious in preventing arterial thromboembolism during these

procedures and actually generates the hypothesis that bridging increases the risk of

thromboembolism. Therefore, this trial amongst other recent evidence, impacts clinical decision

making for perioperative management of patients taking VKA therapy (Figure 1).

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 Management of Subtherapeutic INRs
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Management of VKA therapy is challenging due to the number of variables such as

dietary influences, drug-disease interactions, pharmacogenomics, drug-drug interactions, and

nonadherence, which can influence INR stability and can lend to a patient presenting with an

INR out of the therapeutic range. Practitioners have relied on clinical judgment informed by the

magnitude of the low INR value, duration of the subtherapeutic anticoagulation, the patient’s

thrombosis and bleeding risks, and possible causes of the low INR.48 The first graded

recommendations were provided by the 2012 CHEST guidelines, which do not support routinely

bridging for a single subtherapeutic INR.16 This recommendation comes from two retrospective

studies that analyzed subtherapeutic INR management in patients with both AF and mechanical

heart valves.49,50 Both studies found no significant difference in thromboembolic rates between

the bridged and nonbridged cohorts. Given the observational study designs, the evidence to

support this recommendation remains low quality. The data only address having one isolated

low INR, not several consecutive low INRs. Data from the BRIDGE trial, in which patients

were not fully anticoagulated for upwards of 10 days, further support the recommendation to

avoid bridging for isolated subtherapeutic INRs.23

Avoiding Oral Anticoagulant Interruptions

Periprocedural interruption of warfarin is common, but recent data suggest that 40–60%

of interruptions may be unnecessary.5,51 Clinicians often choose to interrupt anticoagulation and

even bridge patients who are undergoing low-bleeding risk procedures.52,53 Longstanding

guideline recommendations advocate for continuation of oral anticoagulation for very low–

bleeding risk procedures including simple dental extractions, dermatologic procedures, and

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 cataract surgery.13,14 Newer evidence highlights additional procedures, such as catheter ablation
Accepted Article
of AF and device implantation, where continuation of oral anticoagulation can be safer than

interruption or bridging.

Results of the first prospective, open-label, multicenter, randomized study comparing

warfarin continuation with LMWH bridging in 6454 patients undergoing radiofrequency catheter

ablation for AF were recently released.53 Warfarin continued through the procedure resulted in a

lower rate of 48-hour post-ablation thromboembolism (0.25% vs 4.9%, p<0.001), whereas

warfarin discontinuation with LMWH bridging was found to be a strong predictor of

periprocedural thromboembolism (OR 13, 95% CI 3.1-55.6, p<0.001). Other significant

predictors for thromboembolism were female sex, CHADS2 score ≥2, and longstanding,

persistent type AF. Major bleeding rates were similar between groups, but the rate of minor

bleeding was elevated in the LMWH group (22% vs 4.1%, p<0.001). Consequently, some of the

latest clinical guidelines have included recommendations to continue oral anticoagulation

through catheter ablation procedures rather than to interrupt therapy and bridge.2,18

The Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial

(BRUISECONTROL) is a prospective, multicenter, single-blind, randomized, controlled trial

that included patients at moderate or high risk for arterial or venous thromboembolism who were

undergoing elective cardiac device surgery (i.e., de novo device implantation, pulse generator

change, lead replacement, or pocket revision).55 Patients were randomized to receive

perioperative bridging or to continue their warfarin therapy throughout the procedure. The

bridging group consisted of 338 individuals, with the majority (89.2%) receiving therapeutic-

dose LMWH. The primary endpoint was the development of a device-pocket hematoma

requiring prolonged hospitalization, interruption of anticoagulation therapy or further surgery.

This article is protected by copyright. All rights reserved.

 The study was terminated early due to a significantly increased risk of developing a hematoma in
Accepted Article
the bridged group (16.0% in the bridged group vs 3.5% in the uninterrupted warfarin group,

p<0.001). Rates of major surgical and thromboembolic complications were similar between the

two groups and were rare (one case of cardiac tamponade and one case of myocardial infarction

in the bridged group, two thromboembolic cerebrovascular events in the uninterrupted warfarin

group). These findings are consistent with the findings of a meta-analysis in which

periprocedural continuation of warfarin during cardiac device implantation was associated with

significantly lower rates of postoperative bleeding and no significant difference in

thromboembolic rates compared with heparin bridging.56

Ongoing Clinical Trials and Future Directions

Patients with mechanical heart valves were excluded from the BRIDGE trial, and only

about 3% of total patients included had a CHADS2 score of 5-623; therefore, evidence guiding

perioperative anticoagulation management in this subset of patients is needed. A Safety and

Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients

on Long Term Warfarin Requiring Temporary Interruption of Their Warfarin (PERIOP 2) is an

ongoing multicenter, randomized, double-blind, controlled trial evaluating the effectiveness and

safety of LMWH bridging compared with no bridging in patients with mechanical heart valves or

at high risk for stroke.57 The results of this study, expected in 2017, are highly anticipated and

expected to provide important guidance surrounding the risk versus benefit of bridging with

LMWH in high-risk patients.

This article is protected by copyright. All rights reserved.

 Research on perioperative management of DOACs in patients with AF is also evolving.
Accepted Article
Current recommendations are largely based on renal clearance of the agent and the bleeding risk

of the procedure.58 In 2015, results were published for a prospective study involving patients

receiving dabigatran who required an elective surgery.59 The findings suggest that a protocol for

dabigatran interruption without heparin bridging that is based on renal function and procedure-

related bleed risk is safe and effective. Currently, investigators are recruiting patients for a

prospective study entitled the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE)

study.60 Patients being recruited include those with AF who require surgery and are taking either

apixaban, dabigatran, or rivaroxaban. The investigators aim to establish a safe and standardized

perioperative management protocol for patients taking DOACs.

Using a DOAC as a bridging agent in lieu of LMWH may seem to be an attractive

alternative. These agents are available orally and have similar onsets and durations of action and

cost less than LMWH. However, the DOACs have different mechanisms of action compared

with heparins. The INR test is relatively insensitive to dabigatran-induced anticoagulation. The

factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) may elevate the INR test, but in a

variable and unreliable manner. When administered concomitantly with warfarin postprocedure,

a patient's coagulation status may be falsely represented, masking achievement of warfarin's

therapeutic effect. Additionally, combining DOAC and warfarin for bridging purposes would

likely elevate bleeding risk, but the extent is unknown.61

A clinical trial initiated in March 2013 was designed to evaluate the safety, efficacy, and

cost benefit of dabigatran as a bridging agent instead of LMWH when warfarin was interrupted

for surgery.62 The study was closed in January 2017 due to lack of patient enrollment. Because

This article is protected by copyright. All rights reserved.

 of the practical challenges and lack of safety data, using a DOAC as a bridging agent should be
Accepted Article
avoided.

Conclusion

To bridge or not to bridge can create a significant clinical dilemma. Recent data suggest

an important rebalancing of risks and benefits in patients with AF, as bridging is not a benign

practice and is associated with significant bleeding risk. Appropriate assessment and risk

stratification should be employed to support systematic decision making in light of emerging

evidence. Furthermore, consideration can be given to continue anticoagulation through common

low bleeding risk procedures, including catheter ablation procedures and device implantation.

At this time, there are little data to support or refute the benefit of bridging in a population at

high risk for stroke, lending the importance of bleeding risk assessment to assist with clinical

decision making. When anticoagulation must be interrupted, bridging may be reasonable in

those at high risk for stroke (CHADS2 score 5-6, CHA2DS2-VASc score ≥ 7, or stroke within the

past 3 months) or who have a mechanical valve replacement. While awaiting results of

additional randomized trials, clinicians should carefully reconsider routine bridging in attempt to

“first, do no harm.”

References
1. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants

in atrial fibrillation: a systematic review. Am J Med 2010;123:638-45.

2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the

management of patients with atrial fibrillation: a report of the American College of

This article is protected by copyright. All rights reserved.

 Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart
Accepted Article
Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.

3. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National Trends in Ambulatory

Oral Anticoagulant Use. Am J Med 2015;128:1300-5 e2.

4. U.S. Department of Health and Human Services, Office of Disease Prevention and Health

Promotion. National Action Plan for Adverse Drug Event Prevention. Washington, DC:

2014;50-98.

5. Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging

during anticoagulation interruptions in patients with atrial fibrillation: findings from the

Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).

Circulation 2015;131:488-94.

6. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic

events with dabigatran compared with warfarin: results from the Randomized Evaluation

of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation

2012;126:343-8.

7. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic

Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e44S-88S.

8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with

atrial fibrillation. N Engl J Med 2009;361:1139-51.

9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial

fibrillation. N Engl J Med 2011;365:883-91.

This article is protected by copyright. All rights reserved.

 10. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients
Accepted Article
with atrial fibrillation. N Engl J Med 2011;365:981-92.

11. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with

atrial fibrillation. N Engl J Med 2013;369:2093-104.

12. Macle L, Andrade J, Atzema C, et al. Management of Atrial Fibrillation: Complete

Guidelines Listing (Online Supplement). Canadian Cardiovascular Society 2010-2016.

13. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of

antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical

Practice Guidelines (8th Edition). Chest 2008;133:299S-339S.

14. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of

antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

Chest 2012;141:e326S-50S.

15. Garwood CL, Hwang JM, Moser LR. Striking a balnace between the risks and benefits of

anticoagulation bridge therapy in patients with atrial fibrillation: clinical updates and

remaining controversies. Pharmacotherapy 2011;32:1208-20.

16. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant

therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American

College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest

2012;141:e152S-84S.

17. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of

This article is protected by copyright. All rights reserved.

 Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e531S-
Accepted Article
75S.

18. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of

atrial fibrillation developed in collaboration with EACTS: The Task Force for the

management of atrial fibrillation of the European Society of Cardiology (ESC)Developed

with the special contribution of the European Heart Rhythm Association (EHRA) of the

ESCEndorsed by the European Stroke Organisation (ESO). Eur Heart J 2016.

19. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy

for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

Chest 2012;141:e601S-36S.

20. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision

Pathway for Periprocedural Management of Anticoagulation in Patients With

Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical

Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69(7):871-98.

21. Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural

heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-

analysis of bleeding and thromboembolic rates. Circulation 2012;126:1630-9.

22. Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation

during dabigatran or warfarin interruption among patients who had an elective surgery or

procedure. Thrombosis and Haemostasis 2015;113:625-32.

23. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in

Patients with Atrial Fibrillation. N Engl J Med 2015;373:823-33.

This article is protected by copyright. All rights reserved.

 24. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.
Accepted Article
Analysis of pooled data from five randomized controlled trials. Arch Intern Med

1994;154:1449-57.

25. Dunn AS, Turpie AG. Perioperative management of patients receiving oral

anticoagulants: a systematic review. Arch Intern Med 2003;163:901-8.

26. Kovacs MJ, Kearon C, Rodger M, et al. 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 2004;110:1658-63.

27. Spyropoulos AC, Frost FJ, Hurley JS, Roberts M. Costs and clinical outcomes associated

with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging

in patients receiving long-term oral anticoagulant therapy. Chest 2004;125:1642-50.

28. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging

anticoagulation during interruption of warfarin: assessment of a standardized

periprocedural anticoagulation regimen. Arch Intern Med 2004;164:1319-26.

29. Pengo V, Cucchini U, Denas G, et al. Standardized low-molecular-weight heparin

bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or

surgery: an inception cohort management study. Circulation 2009;119:2920-7.

30. Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in

patients with and without chronic atrial fibrillation. J Thromb Haemost;8:884-90.

31. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of

clinical classification schemes for predicting stroke: results from the National Registry of

Atrial Fibrillation. JAMA 2001;285:2864-70.

This article is protected by copyright. All rights reserved.

 32. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification
Accepted Article
for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-

based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72.

33. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. 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;138:1093-100.

34. Tafur AJ, McBane R, Wysokinski WE, et al. Predictors of major bleeding in peri-

procedural anticoagulation management. J Thromb Haemost 2012;10:261-7.

35. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for

anticoagulation: stroke risk stratification in patients taking aspirin. Circulation

2004;110:2287-92.

36. Hammerstingl C, Schmitz A, Fimmers R, Omran H. Bridging of chronic oral

anticoagulation with enoxaparin in patients with atrial fibrillation: results from the

prospective BRAVE registry. Cardiovasc Ther 2009;27:230-8.

37. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc

score for refining stroke risk stratification in patients with atrial fibrillation with a

CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost 2012;107:1172-9.

38. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for

the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the

management of atrial fibrillation. Developed with the special contribution of the

European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.

39. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the

HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in

This article is protected by copyright. All rights reserved.

 patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating
Accepted Article
the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial

fibrillation) study. J Am Coll Cardiol 2012;60:861-7.

40. Omran H, Bauersachs R, Rubenacker S, Goss F, Hammerstingl C. The HAS-BLED score

predicts bleedings during bridging of chronic oral anticoagulation. Results from the

national multicentre BNK Online bRiDging REgistRy (BORDER). Thromb Haemost

2012;108:65-73.

41. Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in

the risk assessment of patients before nonanticoagulated cardioversion from atrial

fibrillation and flutter: an analysis of pooled trials. Am Heart J 1995;129:71-5.

42. Paciaroni M, Balucani C, Agnelli G, et al. Systemic thrombolysis in patients with acute

ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study. Stroke

2012;43:125-30.

43. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th

Edition). Chest 2008;133:546S-92S.

44. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific

and Standardization Committee of the International Society on Thrombosis and

Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic

medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692-4.

45. Garcia D, Alexander JH, Wallentin L, et al. Management and clinical outcomes in

patients treated with apixaban vs warfarin undergoing procedures. Blood 2014;124:3692-

8.

This article is protected by copyright. All rights reserved.

 46. Douketis JD SA, Kaatz S, et al. Perioperative bridging anticoagulation in patients
Accepted Article
with atrial fibrillation [Supplementary material]. N Engl J Med 2015;373:823-33.

47. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of

rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation:

results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with

vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation

(ROCKET AF). Circulation 2014;129:1850-9.

48. Hwang JM, Taylor TN, Sharma KP, Clemente JL, Garwood CL. Bridging for an isolated

subtherapeutic INR: an evaluation of clinical practice patterns, outcomes, and costs from

an anticoagulation clinic. J Thromb Thrombolysis 2012;33:28-37.

49. Clark NP, Witt DM, Delate T, et al. Thromboembolic consequences of subtherapeutic

anticoagulation in patients stabilized on warfarin therapy: the low INR study.

Pharmacotherapy 2008;28:960-7.

50. Dentali F, Riva N, Malato A, Saccullo G, Siragusa S, Ageno W. Incidence of

thromboembolic complications in patients with mechanical heart valves with a

subtherapeutic international normalized ratio. J Thorac Cardiovasc Surg 2009;137:91-3.

51. Clark NP, Witt DM, Davies LE, et al. Bleeding, Recurrent Venous Thromboembolism,

and Mortality Risks During Warfarin Interruption for Invasive Procedures. JAMA

internal medicine 2015;175:1163-8.

52. Douketis JD, Crowther MA, Cherian SS, Kearon CB. Physician preferences for

perioperative anticoagulation in patients with a mechanical heart valve who are

undergoing elective noncardiac surgery. Chest 1999;116:1240-6.

This article is protected by copyright. All rights reserved.

 53. Manchikanti L, Benyamin RM, Swicegood JR, et al. Assessment of practice patterns of
Accepted Article
perioperative management of antiplatelet and anticoagulant therapy in interventional pain

management. Pain physician 2012;15:E955-68.

54. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding

complications in patients undergoing catheter ablation of atrial fibrillation with different

anticoagulation management: results from the Role of Coumadin in Preventing

Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation

(COMPARE) randomized trial. Circulation 2014;129:2638-44.

55. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without

interruption of anticoagulation. N Engl J Med 2013;368:2084-93.

56. Ghanbari H, Phard WS, Al-Ameri H, et al. Meta-analysis of safety and efficacy of

uninterrupted warfarin compared to heparin-based bridging therapy during implantation

of cardiac rhythm devices. Am J Cardiol 2012;110:1482-8.

57. A safety and effectiveness study of LMWH bridging therapy versus placebo bridging

therapy for patients on long term warfarin and require temporary interruption of their

warfarin (PERIOP2). ClinicalTrials.gov. Bethesda, MD: National Library of Medicine.

Available from https://clinicaltrials.gov/ct2/show/NCT00432796?term=periop2&rank=1.

Accessed February 27, 2017.

58. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm

Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in

patients with non-valvular atrial fibrillation. Europace 2015;17:1467-507.

59. Schulman S, Carrier M, Lee AY, et al. Perioperative Management of Dabigatran: A

Prospective Cohort Study. Circulation 2015;132:167-73.

This article is protected by copyright. All rights reserved.

 60. Perioperative anticoagulant use for surgery evaluation study (PAUSE).
Accepted Article
ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. Available from

https://clinicaltrials.gov/ct2/show/NCT02228798?term=pause&rank=1. Accessed

February 27, 2017.

61. Pollack CV, Jr. Coagulation assessment with the new generation of oral anticoagulants.

Emergency medicine journal : EMJ 2016;33:423-30.

62. Validation of a novel dabigatran based peri-operative bridging anticoagulation protocol

for patients on chronic warfarin therapy. ClinicalTrials.gov. Bethesda, MD: National

Library of Medicine. Available from

https://clinicaltrials.gov/ct2/show/NCT01810237?term=dabigatran+based+peri-

operative+bridging+anticoagulation+protocol+for+patients+on+chronic+warfarin+therap

y.&rank=1. Accessed February 27, 2017.

Table 1. Stroke and Bleeding Risk Assessment Tools

Risk Type Scheme Components Points Annual Event Rate Thrombotic
Risk
Category
Thrombosis Total Stroke
Risk Score risk (%)
CHADS231 Congestive Heart Failure 1 0 1.9 Low risk
Hypertension 1 1 2.8
Age ≥ 75 years 1 2 4.0
Diabetes mellitus 1 3 5.9 Moderate
Stroke or TIA 2 4 8.5 risk
5 12.5 High risk
6 18.2

Total Stroke
Score risk (%)
CHA2DS2- Congestive Heart Failure 1 0 0 Low risk
VASc32
Hypertension 1 1 1.2

This article is protected by copyright. All rights reserved.

 Age ≥ 75 years 2 2 2.2
Diabetes mellitus 1 3 3.2
Accepted Article
Stroke or TIA 2 4 4.0
Vascular diseasea 1 5 6.7 Moderate
Age 65-74 years 1 6 9.8 risk
Sex (female) 1 7 9.6 High risk
8 6.7
9 15.2

Bleeding Total Bleed

Risk Score riska
HAS-BLED33 Hypertensionb 1 0 1.13
Abnormal liverc or renald function 1 or 2 1 1.02
(1 point each)
Stroke 1 2 1.88
Bleeding historye or 1 3 3.74
predisposition (anemia)
Labile INRf 1 4 8.70
Elderly ≥ 65 years 1 ≥5 12.5
Drugs (antiplatelets, NSAIDs) or 1 or 2
alcoholg (1 point each)

Total Bleed
Score rate (%)
BleedMAP34 Bleed, prior historyh 1 0 0.81
Mitral mechanical heart valve 1 1-2 2.6
Active cancer 1 ≥3 10.0
Platelets low 1
a
Previous myocardial infarction, peripheral artery disease, or aortic plaque.
b
Systolic blood pressure > 160 mm Hg.
c
Chronic hepatic disease (e.g., cirrhosis) or bilirubin level ≥ 2 times upper limit of normal, with aspartate
aminotransferase, alanine aminotransferase, and/or alkaline phosphatase levels ≥ 3 times upper limit of normal.
d
Dialysis, renal transplantation, or serum creatinine concentration ≥2.26 mg/dL (200 µmol/L).
e
Hemoglobin level decrease >2 g/dL and/or requiring blood transfusion.
f
Time in therapeutic range < 60%.
g
Alcohol consumption ≥8 units/week.
h
Overt bleeding and a hemoglobin level decrease of >2 g/dL or transfusion of ≥2 units of packed red blood cells,
or intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or fatal bleeding.

INR = international normalized ratio; NSAIDs = nonsteroidal antiinflammatory drugs; TIA = transient ischemic
attack.

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 Table 2. Clinical Guideline Recommendations for Bridging Practices
Accepted Article
Guideline or Expert Recommendation Class and/or Level of
Consensus Document Evidencea
Bridging at initiation of VKA therapy
CHEST17 No recommendation for routine NA
initiation of VKA

Grade 2C
UFH or LMWH are recommended if
cardioversion is urgent or the AF is ≤ 48
hours in duration with a plan for
immediate cardioversion
AHA/ACC/HRS2 No recommendation for routine No graded recommendation
initiation of VKA

UFH or LMWH are recommended if Class I, level of evidence C

patient is at high risk for stroke and AF
is ≤ 48 hours in duration with a plan for
immediate cardioversion
ESC18 Not addressed NA
CCS12 No recommendation for routine NA
initiation of VKA

UFH or LMWH are not recommended Strong recommendation,

before cardioversion if AF ≤ 48 hours in moderate-quality evidence
duration with a plan for immediate
cardioversion, but OAC should be
initiated following cardioversion

UFH or LMWH are recommended

before urgent cardioversion in high-risk Conditional recommendation,
patients (AF episode duration not moderate-quality evidence
clearly <48 hours, stroke or TIA within
6 months, rheumatic heart disease,
mechanical valve)
Bridging at initiation of OAC after TIA or Stroke
CHEST19 Initiate aspirin until therapeutic levels of Grade 1A
anticoagulation are
Achieved
AHA/ACC/HRS2 Not addressed NA
18
ESC Heparin or LMWH immediately after an Class III (harm), level of
ischemic stroke is not evidence A
recommended

Initiate aspirin until therapeutic levels of Class IIa, level of evidence B

anticoagulation are achieved
CCS12 Recommends following the AHA/ASA Strong Recommendation,
guidelines. moderate-quality evidence
Bridging for VKA Interruption for Procedures

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 CHEST14 Low-risk patients (CHADS2 score 0-2 Grade 2C
with no recent stroke/TIA); bridging
Accepted Article is not recommended

Moderate-risk patients (CHADS2 No graded recommendation

score 3-4); bridge with UFH or
LMWH or do not bridge based on an
assessment of individual patient- and
surgery-related factors

High-risk patients (CHADS2 score 5-

Grade 2C
6); bridge with UFH or LMWH

ACC/AHA/HRS2 For patients without mechanical heart Class I, level of evidence C

valves, bridging decisions should
balance stroke and bleeding risks
against duration of time patient will not
be anticoagulated
ESC18 Bridging does not seem to be beneficial, No graded recommendation
except in patients with mechanical heart
valves
CCS12 Bridging with LMWH or UFH should Conditional recommendation,
be used only in those at high risk low-quality evidence
(CHADS2 score ≥4, mechanical heart
valve, stroke/TIA within 3 months,
rheumatic heart disease)
ACC Consensus20 Low-risk patients (CHA2DS2-VASc No graded recommendation
score 0-4 with no prior stroke/TIA/SE);
bridging is not recommended

Moderate-risk patients (CHA2DS2-

VASc score 5-6 or prior stroke/TIA/SE
≥3 months previously) with increased
risk of bleeding; bridging is not
recommended

Moderate-risk patients (CHA2DS2-

VASc score 5-6 or prior stroke/TIA/SE
≥3 months previously) without
significant bleed risk: use clinical
judgment, likely bridge

Moderate-risk patients (CHA2DS2-

VASc score 5-6 or no prior
stroke/TIA/SE) without significant
bleed risk: use clinical judgment, likely
do not bridge

High-risk patients (CHA2DS2-VASc

This article is protected by copyright. All rights reserved.

 score ≥ 7 or ischemic stroke/TIA/SE
within 3 months); consider bridging
Accepted Article
Bridging for Subtherapeutic INR
ACCP16 For patients with stable therapeutic Grade 2C
INRs presenting with a single
subtherapeutic INR value, suggest
against routinely administering
bridging with heparin
ACC/AHA/HRS2 Not addressed NA
ESC18 Not addressed NA
CCS12 Not addressed NA
Ablation Procedures
ACCP17 Not addressed NA
AHA/ACC/HRS2 Ablation may have fewer No graded recommendation
complications when oral
anticoagulation is continued instead
of bridging with UFH or LMWH
ESC18 When catheter ablation of AF is Class IIa, level of evidence B
planned, continuation of oral for warfarin and C for DOACs
anticoagulation with a VKA (IIaB) or
DOAC (IIaC) should be considered
during the procedure, maintaining
effective anticoagulation
CCS12 Not addressed NA
AF = atrial fibrillation; AHA = American Heart Association; ACC = American College of Cardiology;
CHADS2=congestive heart failure, hypertension, age≥65 years, diabetes mellitus, stroke (score
doubled); CCS=Canadian Cardiovascular Society; CHEST = American College of Chest Physicians;
DOAC = direct-acting oral anticoagulant; ESC = European Society of Cardiology; HRS = Heart
Rhythm Society; INR = international normalized ratio; LMWH = low-molecular-weight heparin;
NA=not applicable; OAC = oral anticoagulant; UFH = unfractionated heparin; VKA = vitamin K
antagonist; TIA = transient ischemic attack; SE = systemic embolism.
a
Descriptions of class or level of evidence are as follows: grade 2C = weak recommendation, low- or
very low–quality evidence; class III = evidence or general agreement that the given treatment or
procedure is not useful/effective and in some cases may be harmful, use is not recommended; level of
evidence A = data derived from multiple randomized clinical trials or meta-analyses; class IIa = weight
of evidence/opinion is in favor of usefulness/efficacy, use should be considered; level of evidence B =
data derived from a single randomized clinical trial or large nonrandomized studies; grade 1A =
benefits clearly outweigh risk and burdens or vice versa; class I = benefit > risk, procedure/treatment
should be performed/administered; Level of evidence C = very limited populations evaluated, only
consensus opinion of experts, case studies, or standard of care; conditional recommendation = weak
recommendation.

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 Table 3. Bleeding Risk Stratified by Surgery or
Accepted Article
Procedure47, 55-57

Bleeding Risk Surgery or Procedure

Minor or low Gastrointestinal endoscopy

Cardiac catheterization

Cardiac device implantation

Catheter ablation of atrial fibrillation

Dental extractions

Dermatologic surgery

Cataract removal

Major or high Intraabdominal surgery

Intrathoracic surgery

Major orthopedic surgery

Peripheral arterial revascularization

Urologic surgery

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Accepted Article

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