Pharmacological Sciences 2015; 19: 1461-1479 Risk of ...

Abstract. – OBJECTIVE: Periproceduralmanagement of warfarin remains challenging inpatients requiring electrophysiological devicesurgery. For patients at high risk of throm-boembolic events, guidelines recommendbridging therapy with heparin; however, thisstrategy is associated with a high risk of pockethematoma. This paper systematically reviewsstudies appraising the risk of pocket hematomawith different perioperative anticoagulationstrategies.

METHODS: All relevant studies identified inMEDLINE/PubMed, The Cochrane CollaborationCENTRAL, clinicaltrials.org and in bibliogra-phies of key articles. Estimates were combinedusing a fixed effects model. Heterogeneity wasassessed by p values of χχ2 statistics and I2.Publication bias was assessed by visual exami-nation of funnel plots and by Egger test. Fifteenstudies enrolling 5911 patients met all inclusioncriteria and were included in this review.

RESULTS: Heparin bridging compared withno heparin was associated with increased riskof pocket hematoma (OR = 4.47, 95% CI 3.21-6.23, p < 0.00001), and prolonged hospital stay(9.13 ± 1.9 days vs. 5.11±1.39 days, p < 0.00001).Warfarin continuation was not associated withincreased pocket hematoma compared to war-farin discontinuation (p = 0.38), but was associ-ated with reduced risk of pocket hematomacompared with heparin bridging (OR = 0.37,95% CI 0.2-0.69, p = 0.002). Thromboemboliccomplications were reduced with heparin bridg-

European Review for Medical and Pharmacological Sciences

Risk of pocket hematoma in patients on chronicanticoagulation with warfarin undergoing electrophysiological device implantation:a comparison of different peri-operative management strategies

R. PROIETTI1,2, I. PORTO3, M. LEVI2, A. LEO3, V. RUSSO4, E. KALFON2,5, G. BIONDI-ZOCCAI6, J.-F. ROUX2,7, D.H. BIRNIE8, V. ESSEBAG2,9

1Cardiology Department, Luigi Sacco Hospital, Milan, Italy2Division of Cardiology, McGill University Health Centre, Montréal, Canada3Institute of Cardiology, Department of Cardiovascular Medicine, Catholic University of the SacredHeart, School of Medicine, Rome, Italy4Chair of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy5Department of Cardiology, Galilee Medical Center, Nahariya, Israel6Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy7Cardiology Division, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada8Heart Institute, University of Ottawa, Ottawa, Canada9Division of Cardiology, Hopital Sacré-Cœur de Montreal, Montreal, Canada

Corresponding Author: Vidal Essebag, MD, Ph.D; e-mail: [email protected] 1461

ing vs. no heparin (0.50% vs.1.07%, p = 0.02),and no significant differences were reportedbetween heparin bridging vs. warfarin continua-tion (p = 0.83).

CONCLUSIONS: Heparin bridging is associ-ated with a higher risk of pocket hematoma anda prolonged hospital stay. Perioperative contin-uation of warfarin reduces the occurence ofpocket hematoma compared with heparinbridging without any significant differences inthromboembolic complications.

Key Words:Heparin, Coagulation, Warfarin, Device, Pacemaker,

Hematoma, Pocket, Electrophysiological.

Introduction

An increasing number of patients requiringpermanent pacemaker (PM) or implantable car-dioverter defibrillator (ICD) implantation, ashigh as 35-45%1,2, are taking the oral anticoagu-lant (OAC) warfarin for different indicationssuch as valve replacement, atrial fibrillation, orhigh risk of embolic stroke. To reduce hemor-rhagic risk in these patients, it is common prac-tice to postpone device implantation until the in-ternational normalized ratio (INR) has returnedto < 1.5 by withholding warfarin and/or adminis-

2015; 19: 1461-1479

1462

tering coagulation factors or vitamin K. Warfarinis generally restarted the night after the proce-dure3. Nevertheless, sub-therapeutic anticoagula-tion exposes patients with atrial fibrillation to po-tential thromboembolic complications, with acalculated daily risk ranging from 0.01% to0.05%4,5. For this reason, perioperative bridgingwith heparin is currently recommended by theAmerican College of Chest Physicians6 in pa-tients at moderate-to-high risk for arterial throm-boembolic events. Heparin is expected to reducevenous and arterial thromboembolism by 66% to80%7. Heparin bridging, however, is associatedwith an increased risk of bleeding events and inparticular of pocket hematoma8, a common com-plication often resulting in a longer postoperativehospital stay. A recent study9 has also highlightedthe strong link between pocket hematoma and re-intervention, the latter an independent predictorof ICD infections.In summary, there are three perioperative anti-

coagulation strategies that one can employ: (1)continue warfarin; or (2) stop warfarin withoutperi-operative bridging therapy; or (3) stop war-farin and maintain anticoagulation with peri-op-erative heparin bridging.The recently published BRUISE CONTROL

study10 was a large randomized trial evaluatingthe safety of performing PM or ICD surgery with-out interruption of warfarin therapy. The studyrandomized 681 patients with an annual throm-boembolic risk of > 5% to continued warfarin vs.heparin bridging. The primary outcome of clini-cally significant device-pocket hematoma oc-curred in 3.5% of the warfarin group compared to16% in the heparin group (relative risk 0.19; 95%confidence interval, 0.10 to 0.36; p < 0.001). The current systematic review summarizes the

evidence derived from previously published pri-marily observational studies regarding the risk ofpocket hematoma associated with different peri-operative strategies in patients treated with war-farin undergoing PM/ICD implantation, poolingthem with meta-analytic methods and comparingto the randomized controlled trial results ofBRUISE CONTROL.

Methods

This systematic review was performed inkeeping with Preferred Reporting Items for Sys-tematic Reviews and Meta-Analyses (PRISMA)guidelines11.

Data Sources and SearchesTo identify studies eligible to be included in

this review, two independent reviewers (AL andIP) systematically searched relevant articles pub-lished between January 1990 and December2010 in MEDLINE/PubMed, The Cochrane Col-laboration CENTRAL, and clinicaltrials.org.Studies were included if they compared the useof different perioperative anticoagulation strate-gies in patients undergoing PM/ICD implantationif at least a portion of these patients were receiv-ing oral anticoagulation therapy with warfarin.Further studies were sought by means of manualsearch of secondary sources including referencesfrom primary articles. Divergences were resolvedby consensus. Keywords were: ‘pacemaker’, ‘implantable car-

dioverter–defibrillator’, ‘cardiac resynchroniza-tion’, ‘biventricular pacemaker’, ‘biventricular de-fibrillator’ ‘implantation’, ‘device surgery’, ‘car-diac rhythm devices’, ‘anticoagulation’, ‘war-farin’, ‘complications’, ‘bleeding’, ‘hemorrhage’,‘hemorrhagic complications’, ‘pocket hematoma’. The main inclusion criterion for selecting

studies was direct comparison of different peri-operative anticoagulation strategies. Exclusioncriteria were publication as abstract and unpub-lished data. The quality of studies was scored us-ing The Cochrane Collaboration tool for assess-ing risk of bias for randomized controlled trials12

and the Newcastle-Ottawa quality assessmentscale13 for non-randomized studies. The primary end point was pocket hematoma,

defined according to the criteria used in eachstudy as a palpable mass that protruded > 2 cmanterior to the pulse generator and lead, or as apalpable swelling of the PM/ICD pocket exceed-ing the size of the generator.Secondary end points were total length of hos-

pital stay (in days) and thromboembolic compli-cations, defined as a composite of cerebrovascu-lar events (stroke and transient ischemic attacks(TIA) and deep vein thrombosis (DVT).

Statistical Analysis Three separate analyses were performed: com-

paring primary and secondary outcome measuresfor heparin bridging vs. no heparin bridging,warfarin continuation vs. no warfarin continua-tion and warfarin continuation vs. heparin bridg-ing. Binary outcomes from individual studieswere combined with a fixed effect model, leadingto compute pooled odds ratios (ORs) with theircorresponding 95% confidence intervals. Chi

R. Proietti, I. Porto, M. Levi, A. Leo, V. Russo, E. Kalfon, G. Biondi-Zoccai, J.-F. Roux, et al.

Risk of pocket hematoma and warfarin compared to heparin: a metaanalysis

1463

no warfarin continuation and warfarin continua-tion vs. heparin bridging26, and 3 studies com-pared all three perioperative strategies27-29. Twostudies were randomized trials24,25, while the re-maining were registries. Agreement between in-vestigators regarding data search was good (Kap-pa = 0.9) (Table I).

Heparin Bridging vs. no HeparinOverall, 10 of the included studies compared

heparin bridging vs. no heparin1,17-21,26-29. Thesestudies involved 1637 patients (61% male) treat-ed with heparin bridging and 2411 (59% male)treated without heparin (1770 patients not on an-ticoagulation and 641 patients in whom antico-agulants were stopped without bridging). Of the2278 patients on anticoagulation, indications fororal anticoagulation were atrial fibrillation/flut-ter (65%), prosthetic heart valves (21%), leftventricular dysfunction (9%), or intracardiacthrombus/deep vein thrombosis/pulmonary em-bolism/stroke prophylaxis (5%). Of the 1757cases for which data was available, the type ofimplant was PM in 54% (49% DDD, 5% VVI,3% replacements), ICD in 36% (14% DDD,21% single chamber ICD and 1% replacements),cardiac resynchronization therapy (CRT) in 7%.Heparin bridging compared with no heparin

revealed a cumulative OR for pocket hematomaof 4.47 (95% CI 3.21-6.23) (Figure 2 a), with nosignificant heterogeneity among studies (I2 = 0%;

square test (χ2 test) and I2 were calculated14,15 toexplore statistical heterogeneity and inconsisten-cy, respectively. Finally, small study effect/publi-cation bias was appraised by means of funnelplot inspection and Egger regression test16. Atwo-tailed p value < 0.05 was considered statisti-cally significant. In order to confirm the abovefindings, we repeated meta-analytic computa-tions using multivariable adjusted estimatesstemming from individual observational studies,and pooling them with a generic-inverse-varianceweighting.Statistical analysis was performed using Re-

view Manager (RevMan) 5.0.16 (The NordicCochrane center, The Cochrane collaboration,Copenhagen, Denmark, 2008) and SPSS 11.0(SPSS, Inc., Chicago, IL, USA).

Results

Search Results and Study IdentificationWe identified 192 articles of which 15 met all

inclusion and exclusion criteria (Figure 1). These15 studies enrolled 5911 patients and were in-cluded in this review. Of these, 6 studies com-pared heparin bridging vs. no bridging1,17-21, 3studies compared warfarin continuation vs. nowarfarin continuation2,22,23, 2 studies comparedwarfarin continuation vs. heparin bridging24,25, 1study compared both warfarin continuation vs.

Figure 1. Flow diagram of study selection.

1464


Study and year

Total Patients/

Preimplantation

Postimplantation

Procedural INR

Pocket hem

atoma

Thromboem

bolic

Study type and

Patients under OAC

Treatm

ent (n)

Treatm

ent (n)

(PE) n (%)

complications and

PE definition

(indication)

hospital stay

Quality assessment

of trials

Goldstein et al, 1998

251/37

Group a: 37 Warfarin

Group a: 2,5

Group a: 0 (0%

)No thromboem

bolic

group

events

Retrospective study

Group b: 113 no

Group b: 1.1

Group b: 0 (0%

)warfarin group

PE definition:

not defined

Selection:

****;

Com

parability:

* ;Outcome:

*** ;

Michaud et al, 2000

192/49

Group a: 49 patients

All patients had an

Group a:

Group a:

consecutively

INR < 1.5 on the

10 PE (20%),

no thromboem

bolic

Retrospective study

• 37% M

Vrandom

ized to:

day of surgery

event

• 61% AF

a) iv heparin after 6h (26)

• 2%

DPV

b) iv heparin 24h

postoperatively, all

patient received

warfarin starting

the evening of surgery

(30 AF, 18 mechanical

valve, 1 deep venous

thrombosis)

PE definition:

Group b: 28 patients

Group b: 1 of 28 (4%

)Group b: a stroke

palapable mass that

received only

protunded ≥ 2 cm

postoperatory warfarin

Group c: 2

Group c: no

anterior to the pulse

(reinstituted the night

of 115 (2%

)• 6 PE of 26 patients (22%

)thromboem

bolic event

generatoriand lead(S)

of surgical procedure)

iv heparin after 6h

• 4 PE

of 23 patients (17%)

iv heparin 24h

postoperatory (P0,7)

Group c: 115 no

Hospital stay:

Com

parability:*;

anticoagulation

Post operative days

Outcome:***;

was longer in the bridge

group in com

parison

with warfarin group

and control group

(3.6 ± 2.9 vs 2,3 ± 1.1

vs 2.5± 2.5; p

= 0.002)

Table I.S

tudies evaluating the occurrence of pocket hem

atom

a post PM/ICD im

plantation in patients with indication for OAC.

Tabl

e co

ntin

ued

1465


Study and year

Study type and

PE definition

Total Patients/

Preimplantation

Postimplantation

Procedural INR

Pocket hem

atoma

Thromboem

bolic

Quality assessment

Patients under

Treatm

ent (n)

Treatm

ent (n)

(PE) n (%)

complications and

of trials

OAC(indication)

hospital stay

Giudici et al, 2004

1025/473

Retrospective study


Group a: (procedural INR

Group a: 12 (2.55%

) Group a: no

without reversal of oral

> 1.5 with a mean of INR

thromboem

bolic events

anticoagulation

2.6 ± 1 and a range of 1.5-7.5).

PE definition: not defined

Group b: 555 non

Group b: < 1.2

Group b: 12 (2.16%

) Group b: a C

VA

Selection:

*** ;

anticoagulant group

Com

parability:

* ;(included patients whose

Exposure:

*** ;

warfarin had been

discontinued or reversed

(3) and patients on no

anticoagulant therapy)

Marquie et al, 2004


Group a: in 89 patients

INR pre surgery was


No thromboem

bolic

Case control

a) For M

V (38 with

heparin was reinitiated

controlled wasbelow

with heparin

events

mechanical valve)

post-operative (all

1.2 and aptt 45 s

postprocedural: 21

suspension of

patients with M

Vpatients with severe

anticoagulant 3 days

and 51 pt w

ith AF).

AEs with 14 pocket

(acenocoum

arol) and

Coumadin were

hematom

as4 days (warfarin,

reinstituted and heparin

fluindione and

suspended when INR

phenindione) susbstitue

targetwas reached

it with heparin iv (aptt 60s)

PE definition:

until 5h prior to surgery.

not defined

heparin subcutaneous

Selection:

**;

(30) until 12h or heparin

Com

parability:

* ;IV (30) b) In AF group the

Exposure:

*** ;

substitution with heparin

was made according to

referring physician

preference using

subcutaneous hepain

until 12h surgery

Group b: 89 controls cases

Group b: no anticoagulant

Group b: 7 patients with

Hospital stay:

matched for gender age

severe AEs

was prolonged from 7

and surgical details

with 1 pocket hem

atom

adays in bridge group

when compared with

control cases (14 ± 6.6

7.3 ± 3.9; p

< 0.0001)

Table I.C

onti

nued

.Studies evaluating the occurrence of pocket hem

atom

a post PM/ICD im


Tabl

e co

ntin

ued

1466


Study and year

Study type and

PE definition

Total Patients/

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

Pocket hem

atoma

complications and

of trials

OAC(indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Wiegard et al, 2004

1865/1033

Group a: (n = 1033)

Group a (Bridging therapy):

All implantation INR Group a: B

ridging therapy

Group a:

oral anticoagulant

were divided intotwo groups

< 1.5

n = 79 (7.67%

)2 stroke

Retrospective study

• 67% AF

therapy was

1) High dose heparinization

High dose heparinization

4 venous thrombosis

• 16% M

Vdiscontinued 1-5

(n = 551):

n = 65 (11.6%

)PE

definition: any

• 14% LV

days before

a) bolus adm

inistration of

• 28% with bole + infusion

palpable swelling of

• 2%

DEP

implantation and

2500-5000U

I heparin

heparin

the PM

pocket exceeding

was replaced by

followed by continuous

• 8%

with subcutaneous UFH

the size of the generator

heparin as soon as

infusion (targeted aPT

T• 11,6% with IV heparin

the INR decreased

levels were 40 to 60 s)

• 16.1% with subcutaneous

Selection:

****;

to < 2. B

efore

b) heparin infusion without

LMWH

Com

parability:

* ;implantation, therapy

bolus administration, with iv

Low

-dose heparin:

Outcome:

*** ;

with IV heparin was

heparin, subcutaneousUFH

n = 14 (2.9%)

interruptedat least

or by LMWH

for 3h, U

FH for 6h

2) Low

-dose heparin (n = 482)

and LMWH for 12h

a) low dose heparin therapy for

1 to 5 days after implantation

then oral anticoagulant was

restarted with high-dose

or low dose

Group b: (n = 765)

Group b: control group

Group b: n = 19

Group b:

control group

received low dose heparin

(2.5%)

3 stroke

without O

AC

for prophylaxis of deep

10 venous thrombosis

indication

venous thrombosis

Milic et al, 2005

81/81

Group a: 40 patients iv

Group a: postoperative iv

Group a: 5(%

); 2 minor and

Group a: no

• 6%

MV

heparin. Treatment w

ith

heparin was infused 8h after

3 significant (2 receiving

thromboem

bolic events

• 89% AF

heparin was discontinued

implantation at 1000U

/h

evacuation)

• 4%

DVT

6 h before intervention

without a bolus dose (target

Prospective

aptt 1.5-2.2 tim

es the control

random

ized study

value). A

nd coumadin restarted

the night of surgical procedure

PE definition:


Group b: w

arfarin continuation

Group b: 1.8-3.8

Group b: 5(%

); 4 minor and Group b: a patient in the

a palpable mass that

received w

arfarin for

1 significant

control group developed

protruded > 2 cm

long term

a stroke 2 days

postoperatively

Allocation sequence: yes

Hospital stay:

Allocation concealed: yes

Patients treated with

Blinding: no

heparin remain in the

Com

plete outcom

e data: yes

hospital a mean of 4,3 ± 2.8

Full reporting: yes

postoperative days Vs 2,6 ±1.3

inpatients treated with warfarin

Table I.C

onti

nued


atom

a post PM/ICD im


Tabl

e co

ntin

ued

1467


Study and year

Study type and

PE definition

Total Patients/

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

Pocket hem

atoma

complications and

of trials

OAC (indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Robinson et al, 2009

148/148

2 Preoperative strategies:

Group a: postoperative

Patients with pocket

Group a: 17 (23%

)No thromboem

bolic

• 73% AF/flutter

1) LMWH until evening

LMHW at 3 days with

hematom

a had a slighty

event

Retrospective study

• 12% LVD

prior and reinitiated

warfarin (74; nopre 7;

higher INR on the day

• 10% M

V

on postoperative day 3 (106)

pre 67)

of surgery (1.24 vs 1.17)

• 2%

IT

2) LMWH omitted on the

Group b: no postoperative

Group b: 6 (8.1%

)• 1%

DEP

evening before surgery (42)

LMHW warfarin first days

• 1%

Stroke prophylaxis

(74; nopre 35; pre 39)

PE definition:

A palpable swelling

of the PM

pocket,

exceeding the size

of the generator,

that require reoperation

or interruption of oral

anticogulation.

Selection:

****;

Com

parability:

* ;Outcome:

*** ;

Cheng et al, 2009

109/109

2 Preoperative strategies:


Group a: 3

Group a: no

• 100%

MV

1) 51 patients with warfarin

prescribed with low-

thromboem

bolic event

Retrospective study

suspended 3 days before

molecular-weight

surgery

heparin post-operatively

PE definition:

2) 58 patients suspended

palpable and visible

< 3 days or not at all


Group b: 2

Group b: one

soft mass in the PM

no heparin

patient developed stroke

pocket with or

without the need

of evacuation.

Selection:

*** ;

Com

parability:

* ;Outcome:

*** ;

Table I.C

onti

nued


atom

a post PM/ICD im


Tabl

e co

ntin

ued

1468


Study and year

Study type and

PE definition

Total Patients/

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

Pocket hem

atoma

complications and

of trials

OAC (indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Amara et al, 2009

461/ 106

Group a: 30 (6.5%) had oral

Group a: bridge therapy

INR < 1.5

Group a: 6/30 (20%

) No thromboem

bolic

Retrospective study

• 90% AF

anticoagulant suspended

postoperative heparin

in the bridge group

event

• 10% M

V72h before surgery and

10000U

I/24h) 12h post

PE definition: palapable

switched to heparin/LMWH.

procedure plus AOC 24

mass that protruded

Therapy with IV heparin was

post procedure/patient with

≥ 2 cm

anterior to the

interrupt at least for 6h, and

LMHW 48 h post procedure

pulse generator and

LMWH for 12h suspended

lead (S)

Group b: 76 patients had

Group b: suspension

Group b: 2/76 (2.6) in

Selection:

****;

their oral anticoagulant

anticoagulant (objective

the OAC without bridging

Com

parability:

* ;disrupted for 48 h before

INR 1.5) and restarted the

(p< 0.05)

Outcome:

*** ;

procedure

night post procedure

Group c: 355 control group

Group c: no anticoagulant

Group c: 10/355 (2.8%)

Hospital stay:

in the control group

was longer in the

(p< 0.006)

bridge group in

comparison with

OAC and control group

(9 vs 7 vs 6 days

p= 0.006)

Tischenko et al, 2009

272/155

Group a: 117 patients on

Group a: 2.2 ± 0.4

Group a: 9 (7.7%

), and

no thromboem

bolic

• 74% AF

long-term warfarin without

(target INR 2-3)

one required surgical

event

Case control

• 18.7% Previous

interruption of warfarin

revision (0.9%

).

TIA/ICTUS

• 10.3% VM


Group b: w

arfarin and

Group b: 1.2 ± 0.2 Group b: 9 (23.7%,

• 3.2 DVT

who underwent interruption

dalteparin were restarted 24 h

p= 0.012); 3 of whom

PE definition:

of warfarin therapy

after surgery and

required reoperation

a palpable tense

5 days before and bridging

cotinnuedntil INR was > 2

(7.9%,

p= 0.046).

swelling causing

with dalteparin

severe pain that

(200U/kg SC

OD) on days

required prolonged

3.2 and 1 before procedure

hospitalization and/or

discontinuation

Group c: 117 age and

Group c: normal

Group c: 5 (4.3%

), none

of OAC or surgical

sex matched controls

of which

evacuation or blood

not taking warfarin

required revision (p= 0.41).

transfusion or increm

ental

outpatient follow-up

Selection:

*** ;

Com

parability:

* ;Exposure:

*** ;

Table I.C

onti

nued


atom

a post PM/ICD im


Tabl

e co

ntin

ued

1469


Study and year

Study type and

PE definition

Total Patients/

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

Pocket hem

atoma

complications and

of trials

OAC (indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Tolosana et al, 2009

101/101

Group a: bridging from

OAC to

Group a: started 24h after

Group a: 1.1 ± 0.2

Group a: 4/51 patients (7.8%)

No thromboem

bolic

heparin infusion 51 pt. O

AC

implantation with bolus of

from

heparin group developed

events

Prospective

was discontinued 4 days before

60 UI/kg and infusion

pocket hem

atom

a following

random

ized study

and IV heparin was started

rate with aPT

T of 55-70 sec.

implant. One hem

atom

a

at INR < 2 and stopped

OAC restart the night of

required evacuation (1.9 vs.

PE definition:

6h before he im

plant

the procedure. Heparin was

2%,

p= 1.00).

a palpable mass

stopped when INR > 2

that protrunded > 2 cm

Group b: m

aintenance of OAC

Group b: 2 ± 0.3

Group b: 4/50 (8.0%) from

the

anterior to pulse generator

OAC group developed pocket

hematom

a following the implant

(p= 1.00). O

ne hem

atom

a required evacuation (1.9 vs. 2%,

p= 1.00).

Allocation sequence: yes

Hospital stay:

Allocation concealed: yes

was longer in the heparin

Blinding: single

group [median of 5 (4-7)

Com

plete outcom

e vs. 2 (1-4) days;

data: yes

p< 0.001].

Full reporting: yes

Thal et al, 2010

200/58

Group a: W

arfarin (53),

Group a: 1.9± 0.6

Group a: 1 (1.88%)

No thromboem

bolic

events

Retrospective study

Group b: A

SA (82),

Group b: 1 (1.21%)

PE definition:

Group c: clopidogrel (2)

Group c: 0 (0%

)Not reported

Group d: dual antiplatelet

Group d: 5 (25%)

Selection:****;

therapy (DAPT, 15 and 5 DAPT

Com

parability:*;

+ Warfarin)

Outcome:***;

Group e: control group 43

Group e: 0 (0%

Table I.C

onti

nued


atom

a post PM/ICD im


Tabl

e co

ntin

ued

1470


Study and year

Study type and

PE definition

Total Patients/

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

Pocket hem

atoma

complications and

of trials

AOC (indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Ahm

ed et al, 2010

459/459

Group a: 222 Continued

Group a: 2.57 ± 0.49

Group a: 1 (0.45%

) in

Group a: no

• 51.8% FA

warfarin group

(range 1.5-4.7)

the continued warfarin

complication

• 6.9%

MV

group

Retrospective study

• 5.8%

DVT

Group b: 123 Bridging group.

Group b: Intravenous heparin was

Group b: 1.33 ± 0.20

Group b: 7 (5.7%) in

Group b: one

• 0.87% Left

Warfarin was discontinued

restarted without bolus adm

inistration

the bridging group,

TIA within 3 days

ventricular throm

bus

3 to 5 days prior to the surgery

12 hours after the procedure.

and

postoperatively (0.8%)

PE definition:

or the INR was normalized

The last dose of subcutaneous

a palpable tense swelling

by coagulation factors or

enoxaparin (1 mg/kg q12h) was given

causing severe pain that

vitamin K. Patients received

12 to 18 hours prior to the procedure

required rolonged

bridging therapy when INR was

and restarted 24 hours after the

hospitalization and/or

expected to be subtherapeutic.

procedure. Warfarin was reinstituted

discontinuation of AOC

Intravenous heparin was

in the evening of the day of surgery.

or surgical evacuation

discontinued 4 to 6 hours prior

Bridging therapy was discontinued

or blood transfusion

to the procedure.

when INR reached the therapeutic range

Selection:

****;

Group c: 114 Anticoagulation

Group c: W

arfarin was restarted in

Group c: 1.35 ± 0.32

Group c: 2 (1.75%

) in

Group c: 4 TIA

Com

parability:

* ;withheld group. W

arfarin was

the evening of the day of surgery.

the anticoagulation

within 3 days

Outcome:

*** ;

discontinued 3 to 5 days prior

Patients did not receive bridging

withheld group.

postoperatively (3.5%)

to the procedure or the INR

therapy perioperatively.

had anticoagulation

was normalized by coagulation

withheld

factors or vitamin K. D

evice

procedure was performed

when INR was < 1.5.

Ghanbari et al, 2010

123/49

Group a: 29 had oral

Group a: intravenous heparin or low

INR 1.35 ± 0.27

• 90% FA

anticoagulants suspended 4

molecular weight heparin

• 10% M

Vdays before surgery and

Retrospective study

switched to heparin/LMWH.

PE definition:

Therapy with IV heparin was

a palpable mass that

interrupt at least for 4h, and

protrunded > 2 cm

LMWH for 12h suspended

Selection:

****;

Group b: 20 continued

Group b: W

arfarin continuation

INR 2.39 ± 0.29

Group b: 1

Com

parability:

* ;warfarin group

With INR target 2-3

Outcome:

*** ;

Group c: 74 control group

Group c: no anticoagulant

INR 1.12 0.14

Group c: 3

Hospital stay:

Post operative days was

longer in the bridge

group in com

parison with

warfarin group and

control group

(3.7± 3.2 vs 2.9 ± 2.7

vs 1.6 ± 1.6; p

< 0.001)

Table I.C

onti

nued


atom

a post PM/ICD im

plantation in patient with indication for A

OC.

Tabl

e co

ntin

ued

p for heterogeneity = 0.49) despite statistical evi-dence of small study effect/publication bias (p =0.01) (Figure 2 b).Four studies17,18,20,26 showed that heparin bridg-

ing significantly prolonged the duration of hospi-tal stay (9.13± 1.94 days vs. 5.11±1.39 days),with a weighted mean difference (WMD) of 2.43days (95% CI 1.79-3.08, p < 0.00001) (Figure 3).

Warfarin Continuation vs. no Warfarin Continuation We have included in our meta-analysis 7 stud-

ies2,22,23,26-29 comparing warfarin continuation vs.no warfarin continuation. These studies involved970 patients (53% male) undergoing PM/ICDimplantation while on anticoagulation and 1529patients (55% male) not on anticoagulation. Indi-cations for anticoagulation were: atrial fibrilla-tion/flutter (79%), prosthetic heart valve (14%)and intracardiac thrombus/deep vein thrombo-sis/pulmonary embolism/stroke prophylaxis(9%). Of the 837 cases for which data was avail-able, the, type of implant was PM in 54% (36%DDD, 8% VVI, 9% replacements), ICD in 44%(13% DDD, 31% single chamber ICD), and CRTin 2%. Our analysis showed that the rate of pock-et hematoma did not significantly differ if war-farin was continued or not (2.68% vs. 2.03%, OR= 1.28, 95% CI 0.73-2.26, p = 0.38) (Figure 2 a).No significant heterogeneity among studies wasdetected (I2 = 0%; p heterogeneity = 0.64) and nosmall study effect/publication bias was observed(Figure 2 b). We could not determine whether ei-ther strategy significantly prolonged the durationof hospital stay as only one study reported suchdata26.

Warfarin Continuation vs. Heparin Bridging We have analysed 5 studies comparing war-

farin continuation with heparin bridging. Thesestudies24,25,27-29 involved 476 patients in whom an-ticoagulation was not stopped and 406 patientstreated with heparin bridging. A significantly re-duced risk of pocket hematoma with warfarincontinuation was evident, with a cumulative ORof 0.37 (95% CI 0.2-0.69, p = 0.002), withoutsignificant heterogeneity among studies (I2 =42%; p for heterogeneity = 0.14) (Figure 2 a).Funnel plots and Egger test revealed no smallstudy effect/publication bias (Figure 2 b). Wecould not determine whether either strategy sig-nificantly prolonged the duration of hospital stayas only three studies reported such data24-26.

1471


Study and year

Study type and

PE definition

Total Patients/

Pocket

Thromboem

bolic

Quality assessment

Patients under

Preimplantation

Postimplantation

hem

atoma

complications and

of trials

OAC (indication)

Treatm

ent (n)

Treatm

ent (n)

Procedural INR

(PE) n (%)

hospital stay

Tompkins et al, 2010

1388/450

Group a: 258 warfarin interrupted

INR < 1.5

Group a: 6

Group a: 1 stroke/TIA

and 1 DVT

Retrospective study

Group b: 46 Warfarin continuation

Group b: 0

Group b: no

thromboem

bolic event

PE definition:

Group c: 154 bridging therapy

INR > 1.5

Group c: 10

Group c: 1 stroke/TIA

Not defined

Selection:

****;

Group d: 255 control

Group d: 3

Group d: 4 DVT

Com

parability:

* ;Outcome:

*** ;

Group e: A

spirin 536

Group e: 17

Group e: 5 DVT

Group f: 139 DAPT

Group f: 5

Group f: 1 stroke/and 1 DVT

Table I.C

onti

nued


atom

a post PM/ICD im


1472

Thromboembolic ComplicationsFourteen1,2,17-25,27-29 of the 15 studies included

in this meta-analysis reported data about throm-boembolic complications, which were rare inthese studies. Among the 5780 patients included,the rate of perioperative stroke/transient ischemiawas 0.40% (n = 23) and the rate of DVT was0.42% (n = 24). There was a significant reductionin the thromboembolic complications end pointwith heparin bridging vs. no heparin (0.50% vs.1.07%; OR = 0.39, 95% CI 0.18-0.85, p = 0.02)and a strong trend toward reduction in throm-boembolic complications with warfarin continua-tion compared with no warfarin continuation (0%vs. 0.76%; OR = 0.21, 95% CI 0.04-1.14, p =0.07) (Figure 4 a), mainly due to reduction inDVT rate (Figure 4 b). No significant differences

in thromboembolic complications were reportedbetween the groups of heparin bridging vs. war-farin continuation (0.21% vs. 0.49%; p = 0.83).

Multivariable AnalysisThe meta-analytic computations using pooled

multivariable adjusted estimates confirmed theabove findings. Heparin bridging vs. no heparinwas associated with a higher risk of pockethematoma (OR 5.58, 95% CI 3.76-8.29, p <0.0001). Warfarin continuation vs. heparin bridg-ing was associated with a significantly reducedrisk of pocket hematoma (OR 0.41, 95% CI 0.22-0.77, p = 0.005) (Figure 5). Moreover, this analy-sis also confirmed a significant reduction inthromboembolic complications with heparin


Figure 2A. Forest Plot for Odds Ratio of pocket hematoma associated with the use of different periproceduralstrategies.

bridging vs. no heparin (OR 0.44, 95% CI 0.22-0.91, p = 0.03) and a trend toward a reduction inthromboembolic complications with warfarincontinuation compared with no warfarin continu-ation (OR 0.26 95% CI 0.05-1.48, p = 0.13) (Fig-ure 6).

Discussion

The perioperative management of patients onOAC who require PM/ICD implantation is still amatter of debate. European guidelines on non-cardiac surgery30 and the American College ofChest Physicians guidelines on perioperativemanagement of antithrombotic therapy (6) rec-ommend discontinuation of OAC with heparinbridging at doses prolonging aPTT to 60 secondsin patients with a prosthetic valve and in patientsconsidered at high risk of thromboembolicevents. Nevertheless, several studies using differ-ent protocols have demonstrated that heparinbridging is associated with a higher risk of hem-orrhagic complications8,20,21,28,29; some investiga-tors have even recommended against this strategybecause of higher perioperative bleeding risk31.The efficacy and low risk of warfarin continua-tion strategy was initially suggested by two pre-vious small studies22,28. Goldstein et al22 demon-strated the safety of outpatient PM placement in37 patients on OAC (mean INR 2.5). Al-Khadraet al33 reported no hematoma or other bleedingcomplications in 47 patients undergoing deviceimplantation on OAC (mean INR 2.3). In our meta-analysis, warfarin continuation did

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Figure 2B. Funnel plots of trials included in the meta-analysis. a, Bridging therapy vs control, b, warfarin con-tinuation vs no warfarin continuation, c, warfarin continu-ation vs bridging therapy. p values are derived from Eg-ger’s test.

Figure 3. Hospital stay (days) - Forest Plot for weighted mean difference (WMD) of hospital stay (days) with the use of he-parin bridging therapy vs no bridging therapy.

a

b

c

1474

not increase the risk of bleeding compared withwarfarin discontinuation (2.68% vs. 2.03%, p =0.38). Furthermore, when compared to a heparinbridging strategy, warfarin continuation was asso-ciated with a 60% reduction in risk of pockethematoma in patients who underwent PM/ICDsurgery. The increased risk of hematoma with he-parin was independent of the choice of unfraction-ated heparin vs. low molecular weight heparin, aspreviously suggested18,32-34. These findings werevalidated in the randomized BRUISE CONTROLtrial that showed a significantly lower rate of de-vice-pocket hematoma in patients undergoingPM/ICD surgery without interruption of warfarintherapy, as compared with bridging therapy withheparin (3.5% vs. 16.0%, p = 0.001)10. Of note,continued warfarin therapy was not associated

with any major perioperative bleeding events. Our meta-analysis showed no significant dif-

ference in thromboembolic complications be-tween the groups of heparin bridging vs. war-farin continuation (0.21% vs. 0.49%; p = 0.83).In the BRUISE CONTROL study there were nothromboembolic events in the heparin-bridginggroup, while two patients with atrial fibrillationand high CHADS2 scores in the continued-war-farin group had embolic events (in the contextof sub-therapeutic INRs). Importantly, ourmeta-analysis found that strategies involvingcomplete interruption of anticoagulation (i.e.warfarin discontinuation without bridging vs.heparin bridging or continued warfarin) wereassociated with a greater than twofold risk ofthromboembolism. This highlights the impor-


Figure 4A. Composite of Stroke/TIA and DVT - Forest Plot for Odds Ratio of composite of stroke/TIA and DVT with the useof different periprocedural strategies.

tance of avoiding interruption of anticoagula-tion particularly in patients at high risk ofthromboembolism.The analysis of the 4 studies that reported the

length of hospital stay17,18,20,26 showed that the he-parin bridging also significantly prolonged hospi-talization. These results confirm that continuationof warfarin without heparin bridging seems to of-fer the best compromise for minimizing perioper-ative bleeding without increasing thromboembol-ic risk. Similar rates of pocket hematoma have been

reported in patients with a wide range of proce-dural INR values from supra- to sub-therapeu-tic, suggesting that operator experience and in-traoperative pocket management might play animportant role1. Other methods of reducing

pocket hematoma have been considered. Milicet al25 reported that in 81 patients with an indi-cation for OAC, a fibrin sealant prior to woundclosure was associated with a 0% hematomarate vs. 25% rate of hematoma in the controlgroup (p < 0.05). A portable drainage deviceprior to wound closure was also reported to sig-nificantly reduce the risk of pocket hematomaalso in the study by Wang et al35.

Limitations

Our meta-analysis is a pooled analysis, notbased on individual data, and a propensityscore approach could not be used. Our study ismainly based on observational, non-random-

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Figure 4B. Composite of Stroke/TIA - Forest Plot for Odds Ratio of stroke/TIA with the use of different periprocedural strategies.

1476

ized data, and differences in baseline charac-teristics, drug therapies, procedural techniquesand operator experience cannot be excluded. Asmall study effect/publication bias may be pre-sent.

Conclusions

Our analysis suggests an increased risk ofpocket hematoma in patients requiring OACwho undergo electrophysiological device im-plantation with interruption of warfarin therapyand employment of a heparin bridging strategy.On the other hand, the perioperative continua-tion of warfarin reduces the occurence of clini-

cally significant device-pocket hematoma andthe duration of hospital stay, without any in-crease in thromboembolic events. These find-ings, based on observational studies and twounderpowered negative randomized studies,were confirmed by the large multicentre ran-domized controlled BRUISE CONTROL trial.In light of evidence suggesting increased riskof thromboembolism when warfarin is discon-tinued without heparin bridging, continuedwarfarin with avoidance of post-operative he-parin appears to be the safest strategy for pa-tients at high risk of thromboembolism under-going implantable cardiac electronic deviceprocedures. Future guidelines should recom-mend favouring continuation of warfarin rather


Figure 5. Forest Plot for Odds Ratio of pocket hematoma with the use of different peri-procedural strategy using pooled multi-variable adjusted estimates.

than post-operative heparin bridging and futureclinical trials are required to guide optimalmanagement of concurrent anti-platelet therapyor novel oral anticoagulants.

–––––––––––––––––-––––Conflict of InterestThe Authors declare that they have no conflict of interests.

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