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General Review

Systematic Review of RandomizedControlled Trials of New Anticoagulants forVenous Thromboembolism Prophylaxis inMajor Orthopedic Surgeries, ComparedWith Enoxaparin

Ricardo de Alvarenga Yoshida, Winston Bonetti Yoshida,

Francisco Humberto de Abreu Maffei, Regina El Dib, Rogerio Nunes,

and Hamilton Almeida Rollo, S~ao Paulo, Brazil

Background: In the past 10 years, new anticoagulants (NACs) have been studied for venous

thromboembolism (VTE) prophylaxis.Objective: To evaluate the risk/benefit profile of NACs versus enoxaparin for VTE prophylaxis

in major orthopedic surgery.Methods: A systematic review of double-blind randomized phase III studies was performed.

The search strategy was run from 2000 to 2011 in the main medical electronic databases in

any language. Independent extraction of articles was performed by 2 authors using predefined

data fields, including study quality indicators.Results: Fifteen published clinical trials evaluating fondaparinux, rivaroxaban, dabigatran, and

apixaban were included. Primary efficacy (any deep vein thrombosis [DVT], nonfatal pulmonary

embolism, or all-cause mortality) favored fondaparinux (relative risk [RR] 0.50; 95% CI, 0.39,0.63) and rivaroxaban (RR, 0.50; 95% CI, 0.34, 0.73) over enoxaparin, although significant

heterogeneity was observed in both series. The primary efficacy of dabigatran at 220 mg, apix-

aban, and bemiparin were similar, with RRs of 1.02 (95% CI, 0.86, 1.20), 0.63 (95% CI, 0.39,

1.01), and 0.87 (95% CI, 0.65, 1.17), respectively. The primary efficacy of dabigatran at 150

mg (RR, 1.20; 95% CI, 1.03, 1.41), was inferior to enoxaparin. The incidence of proximal

DVT favored apixaban (RR, 0.45; 95% CI, 0.27, 0.75) only. Rivaroxaban (RR, 0.45; 95% CI,

0.27, 0,77) and apixaban (RR, 0.38; 95% CI, 0.16, 0.90) produced significantly lower frequen-

cies of symptomatic DVT. The incidence of major VTE favored rivaroxaban (RR, 0.44; 95%

CI, 0.25, 0.81), only. Bleeding risk was similar for all NACs, except fondaparinux (RR, 1.27;

95% CI, 1.04, 1.55), which exhibited a significantly higher any-bleeding risk compared with enox-

aparin, and apixaban (RR, 0.88; 95% CI, 0.79, 0.99), which was associated with a reduced risk

of any bleeding. Alanine amino transferase was significantly lower with 220 mg of dabigatran,

(RR, 0.67; 95% CI, 0.79, 0.99) than with enoxaparin.Conclusions: NACs can be considered alternatives to conventional thromboprophylaxis regi-

mens in patients undergoing elective major orthopedic surgery, depending on clinical character-

istics and cost-effectiveness. The knowledge of some differences concerning efficacy or safety

profile, pointed out in this systematic review, along with the respective limitations, may be useful

in clinical practice.

Department of Surgery and Orthopedics, Botucatu School of Medi-cine, Paulista State University, Botucatu, S~ao Paulo, Brazil.

Correspondence to: Ricardo de Alvarenga Yoshida, MD, Departa-mento de Cirurgia e Ortopedia, Faculdade de Medicina de Botucatu,Universidade Estadual Paulista, Campus de Botucatu, 18618-970Botucatu, S~ao Paulo, Brazil; E-mail: [email protected]

Ann Vasc Surg 2013; 27: 355–369http://dx.doi.org/10.1016/j.avsg.2012.06.010 2013 Elsevier Inc. All rights reserved.

Manuscript received: November 5, 2011; manuscript accepted: June 14,

2013; published online: January 24, 2013.

355

mailto:[email protected]://dx.doi.org/10.1016/j.avsg.2012.06.010http://dx.doi.org/10.1016/j.avsg.2012.06.010mailto:[email protected]

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INTRODUCTION

Patients undergoing major orthopedic surgery, such

as hip or knee arthroplasty or hip fracture repair,

have a particularly high risk of developing venous

thromboembolism (VTE) as a frequent postopera-

tive complication. Without prophylaxis, the inci-

dences of phlebographic and symptomatic deepvein thrombosis (DVT) within 2 weeks postopera-

tively vary from 40% to 60% and 5% to 36%,

respectively.1,2 Pulmonary embolism incidence is

0.9% to 28% in hip arthroplasty, and can reach

1.5% to 10% in knee arthroplasty.2

International guidelines recommend the use

of anticoagulants to prevent these complications,

provided no contraindications exist. Currently, VTE

prophylaxis with low-molecular-weight heparin

(LMWH), warfarin, and unfractionated heparin in

various schemes is recommended for patients

undergoing orthopedic surgery.2

Some limitations of these anticoagulants,

including a need for subcutaneous injection, drug

interactions, or laboratory control, stimulated the

development of new anticoagulants.3,4 One pioneer

oral new anticoagulant, ximelagatran, showed

similar efficiency as LMWH and warfarin, but the

possibility of liver injury from long-term use

resulted in its withdrawal from the market.4,5

In the past 10 years, new anticoagulants

have been tested for VTEprophylaxis in major ortho-

pedic surgeries. Among these agents, phase III

studies have been completed on fondaparinux,

dabigatran, rivaroxaban, apixa ban, bemiparin,

semuloparin, and edoxaban.4,6 Isolated meta-

analyses have been published comparing fonda-

parinux versus enoxaparin7; dabigatran versus

enoxaparin8; rivaroxaban and dabigatran versus

enoxaparin9; dabigatran, rivaroxaban, and apixaban

versus enoxaparin10; apixaban versus enoxaparin11;

semuloparin versus enoxaparin12; and rivaroxaban

versus enoxaparin,13,14 but no systematic reviews

jointly compare these newer anticoagulants all

together, and therefore do not ultimately assist

clinicians in the difficult task of choosing one

agent over another for a particular patient orinstitution.

The authors performed a systematic review

of randomized clinical trials to evaluate the effec-

tiveness and safety of new anticoagulants com-

pared with enoxaparin, including published

and completed results from phase III studies,

for the prophylaxis of VTE in major orthopedic

surgery.

METHODS

Literature Search

To identify trials, the authors searched the Cochrane

Peripheral Vascular Diseases Group records, the

Cochrane Central Register of Controlled Trials

(Central, the Cochrane Library, issue 1, 2011),Medical Literature Analysis and Retrieval System

Online (MEDLINE, 1966e2011), Excerpta Medica

database (EMBASE, 1980e2011), and Literatura

Latino-Americana e do Caribe em Cîencias da Saude

(LILACS, 1982e2011), from January 2000 up to

March 2011.

In PubMed, for example, the following search

strategy was used: fondaparinux OR dabigatran

OR rivaroxaban OR apixaban OR bemiparin OR

anticoagulants OR fondaparinux OR dabigatran

OR rivaroxaban OR apixaban OR bemiparin OR

anticoagulants AND thromboembolism OR venous

thrombosis OR thrombophlebitis OR pulmonaryembolism OR orthopedic surgery OR total hip

replacement surgery OR hip-replacement surgery

OR elective hip-replacement surgery OR total knee

replacement surgery OR total hip replacement OR

total knee replacement OR major knee surgery OR

major orthopedic surgery OR total hip arthroplasty

OR total knee arthroplasty. For all databases, the

authors used a similar comprehensive search

strategy for randomized controlled trials involving

anticoagulants and thromboprophylaxis in ortho-

pedic surgery, along with related medical subject

headings and text words. The bibliographic refer-ences of relevant review articles and meta-

analyses were also examined for eligible trials.

Data Collection

The criteria for including studies were (1) completed

and published phase III randomized clinical trials

and (2) well-defined efficacy and safety outcomes.

Phase I and II (doseeresponse) studies and phase

III results available only as abstracts were excluded.

Two reviewers independently screened the trials

identified through the literature search, extracted

the data, assessed trial quality, and analyzed theresults.

Data consistency was checked by another

reviewer. Two other reviewers were consulted

whenever any disagreement arose. If consensus

was not reached, data from the trials in question

were not included unless or until the authors of

the trial were able to resolve the contentious issues.

A standard form was initially used to extract the

356 Yoshida et al. Annals of Vascular Surgery

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following information: study characteristics (design

and randomization methods), participants (sample

size, sex, age, inclusion and exclusion criteria),

interventions (dose, duration, and administration),

and outcomes (types of outcome measurements,

timing of outcomes, and adverse events).

End Points

Primary efficacy was defined as the frequency of any

DVT, nonfatal pulmonary embolism, or death from

any cause.

For the primary end point of major VTE (i.e.,

proximal DVT, nonfatal pulmonary embolism, or

death related to VTE), bilateral venography for

proximal and symptomatic DVT and entilation/

perfusion lung scanning spiral CT, or pulmonary

angiography for pulmonary embolism, was used.

The secondary outcome measurements consid-

ered in this review were

Frequency of major VTE (proximal DVT, pulmo-

nary embolism, or unexplained death) or any

DVT (proximal or distal), or symptomatic VTE

Frequency of symptomatic DVT

Proximal DVT when involving popliteal vein or

above

Frequency of any bleeding

Frequency of major bleeding was the number of

patients with: severe bleeding (i.e., fatal bleeding),

or involving a critical organ (intraocular, intraspi-

nal, pericardial, or retroperitoneal), or requiringreoperation. Also major was extrasurgical-site

bleeding, that was clinically overt and associated

with a decrease in hemoglobin level of at least 2

g/dL or requiring transfusion of 2 or more units

of whole blood or packed cells, or with other

bleeding not meeting these criteria, but classified

as severe by the central adjudication committee

Frequency of nonmajor bleeding, including clin-

ically relevant and hemorrhagic wound

complication

Frequency of alanine aminotransferase (ALT)

elevation greater than 3 times the upper normal

limit

Other End Points

Other end points, including: volume of blood loss

during surgery; volume of whole blood or red blood

cells transfused; frequency of patients receiving

transfusions; and bleeding index were not included

in the meta-analysis because they were not regis-

tered in all trials.

Assessment of Methodological Quality

The methodological quality of the included trials

was judged using the criteria described by Higgins

and colleagues.15 Therefore, random sequence

generation, allocation concealment, blinding,

incomplete outcome data, selective reporting, and

other sources of bias (e.g., baseline imbalance,source of funding bias) were recorded.

Data Analysis

Analysis was undertaken according to the Cochrane

Collaboration Handbook. A meta-analysis for each

outcome was performed using the software Review

Manager, version 5.1. Relative risk (RR) was calcu-

lated as a measure of effect with 95% CI. Effect esti-

mates were calculated using the Mantel-Haenszel

method using a random-effects model.

Potential causes of heterogeneity among the

pooled studies were explored and analyzed. Sensi-

tivity analyses were planned to investigate the influ-

ence of low versus high risk of bias in the overall

treatment effects. Subgroup analysis was designed

to investigate clinical differences among the pooled

studies. A significance level of less than 0.10 was

interpreted as evidence of statistically significant

heterogeneity. The authors consider heterogeneity

to be present when I2 is greater than 50%.16

RESULTS

Literature Search Results

Almost all the included trials were identified by the

electronic databases (Fig. 1). Melagatran and xime-

lagatran trials were excluded because both drugs

were withdrawn from the market.5 The RECORD2

trial with rivaroxaban was excluded because of

lack of information about the efficacy and safety

compared only with enoxaparin and not placebo.

Semuloparin12 (3 studies) and edoxaban (2

studies)17,18 trials were excluded because they

were available only as abstracts. Thus, 15 random-

ized controlled trials were analyzed in this review:

those for fondaparinux,19e22 rivaroxaban,23e26

dabigatran,27e30 apixaban,31e33 and bemiparin.34

Characteristics of Included Studies

All studies were double-blind and double-dummy

randomized controlled trials. Noninferiority anal-

yses were performed in all studies, except in the fon-

daparinux trials and rivaroxaban RECORD2 trial.

Superiority analyses were performed in all studies,

except the dabigatran trials. All studies had

Vol. 27, No. 3, April 2013 Review of randomized controlled trials 357

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computer-generated list allocation, except the apix-

aban trials. Central adjudication and intention to

treat were found in all studies. Mechanical prophy-

laxis was allowed in the fondaparinux and dabiga-

tran studies only.

In all studies the randomization was performed in

blocks of 4 using a computer-generated list; the

safety analyses were performed on an intention-

to-treat basis, reported independently and blinded

to the assessment of outcomes by a Central

Adjudication Committee. The studies were conduct-

ed in several centers worldwide, except PENTAM-

AKS19 and the trial for bemiparin,34 which were

conducted at the national level. The major ortho-

pedic procedures included total hip replacement

surgery in 7 studies, total knee replacement surgery

in 7, and hip fracture surgery in 1 (Table I). The

enoxaparin dosing regimen of 40 mg subcutane-

ously once daily (i.e., European standard) was eval-

uated in 11 studies, whereas 30 mg subcutaneously

Fig. 1. Flow chart of study selection.


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twice daily (United States standard) was assessed in

4 studies (Table I). Drug administration was oral for

dabigatran, rivaroxaban, and apixaban and subcuta-

neous for fondaparinux and bemiparin. All of the

new anticoagulant regimens started immediately

after surgery. The use of graduated elastic stockings

was allowed in 7 studies and was not specified in the

other 8 studies. Planned pneumatic compression

prophylaxis was an exclusion criterion in all studies.

Safety and mortality outcomes were adjudicated by

an independent committee in all studies. All-cause

mortality, regardless of the dosage used during and

after treatment, was considered for analysis.

Bleeding index, hemoglobin decrease, transfusions

volumes, frequency of patients receiving transfu-

sions, and drainage volumes were not consistently

reported in all trials, thus impairing meta-analysis

evaluation. However, frequencies and means,

when reported, were generally similar among

groups. Therefore, the included studies were deter-mined to present a low risk of bias.

Sources of clinical heterogeneity were identified,

particularly with regard to the type of surgery (hip

or knee surgery), timing and dosages of enoxaparin

(40 mg once daily or 30 mg twice daily), different

primary efficacy definitions, follow-up period, and

use of graduated compression stockings (Table I).

A substantial statistical heterogeneity was also

seen in the following pooled data: (1) primary effi-

cacy of rivaroxaban and apixaban (Fig. 2); (2) prox-

imal DVT with fondaparinux and rivaroxaban

(Fig. 3); (3) symptomatic DVT of dabigatran at 220and 150 mg (Fig. 4); (4) pulmonary embolism for

apixaban; and (5) major bleeding with fondapari-

nux (Table II).

Primary Efficacy

Statistically significant differences favored fonda-

parinux (RR, 0.50; 95% CI, 0.39, 0.63) and rivarox-

aban (RR, 0.50; 95% CI, 0.34, 0.73) versus mixed

doses of enoxaparin in the overall treatment effect

for primary efficacy. However, heterogeneity found

in both comparisons did not allow consistent

conclusions about pooled data (Fig. 2).

No statistically significant difference was seen

between dabigatran at 220 mg (RR, 1.02; 95% CI,

0.86, 1.20), apixaban (RR, 0.63; 95% CI, 0.39,

1.01), or bemiparin (RR, 0.87; 95% CI, 0.65, 1.17)

versus enoxaparin (mixed doses) in primary effi-

cacy. Apixaban and dabigatran at 220 mg, were

similar to enoxaparin, but they did not even satisfy

the noninferiority criterion in 2 original trials

comparing 30 mg of enoxaparin twice daily.29,31

Furthermore, a statistically significant difference in

primary efficacy was seen favoring enoxaparin T a b l e

I . M a i n c h a r a c t e r i s t i c s a n d s o u r c e s o f h e t e r o g e n e i t y o f

t h e s e l e c t e d t r i a l s

N a m e

E P H E S U S

P E N T H

A T L O N

P E N T A M A K S

P E N T H I F R A

R E C

O R D 1

R E C O R D 2

R E C O R D 3

R E C O R D 4

R E -

M O D E L

R E -

N O V A T E

R E -

M O B I L I Z E

A D V A N

C E - 1

B e m i p a r i n

M e a n a g e / g r o u p s

6 6 . 0 / 6 7 . 0

6 7 . 0 / 6 7 . 0

6 7 . 5 / 6 7 . 5

7 6 . 8 / 7 7 . 3

6 3 . 1

/ 6 3 . 3

6 1 . 4 / 6 1 . 6

6 7 . 6 / 6 7 . 6

6 4 . 4 / 6 4 . 7

6 7 e 6 8 /

6 8 . 0

6 5 e 6 3 / 6 4 . 0

6 6 . 2 e 6 5 . 9 /

6 6 . 3

6 5 . 9 / 6 5 . 7

7 0 . 5 / 6 8 . 9

S a m p l e s i z e / g r o u p s

( ‘ ‘ p e r p r o t o c o l ’ ’ ) a

9 0 8 / 9 1 9

7 8 7 / 7 9 7

3 6 1 / 3 6 3

6 2 6 / 6 2 4

1 5 9 5

/ 1 5 5 8

8 6 4 / 8 6 9

8 2 4 / 8 7 8

9 6 5 / 9 5 9

5 2 6 / 5 0 3 /

5 1 2

8 7 4 / 8 8 0 /

8 9 7

6 4 9 / 6 0 4 / 6 4 3

1 1 5 7 / 1 1 3 0

1 6 5 / 1 6 8

D r u g

F o n d a p a r i n u x

R i v a r o x a b a n

D a b i g a t r a n

A p i x a b a n

B e m i p a r i n

D o s i s

2 . 5 m g s u b c u t a n e o u s l y e v e r y d a y

1 0 m

g o r a l l y e v e r y d a y

1 5 0 o r 2 2 0 m g o r a l l y e v e r y d a y

2 . 5 m g o

r a l l y

t w i c e

a d a y

3 5 0 0 I U

s u b c u t a n e o u s l y

e v e r y d a y

F i r s t d o s i s t i m i n g a

4 e 8 h A S

4 e 8 h A

S

4 e 8 h A S

4 e 8 h A S

6 e 8

h A S

6 e 8 h A S

6 e 8 h A S

6 e 8 h A S

1 e 4 h A S

1 e 4 h A S

6 e 1 2 h A S

1 2 e 2 4 h

A S

1 2 h B S

E n o x a p a r i n a

4 0 m g e v e r y

d a y

3 0 m g t w i c e

a d a y

3 0 m g t w i c e a d a y

4 0 m g e v e r y d a y

4 0 m

g

e v

e r y

d a y

4 0 m g e v e r y

d a y


3 0 m g t w i c e

a d a y

4 0 m g e v e r y

d a y

4 0 m g e v e r y

d a y

3 0 m g t w i c e a

d a y

3 0 m g t w i c e

a d a y


S u r g e r y a

T H R

T H R

T K R

H i p f r a c t u r e

T H R

T H R

T K R

T K R

T K R

T H R

T K R

T K R

T K R

P r i m a r y e f fi c a c y a

5 e 1 1 d

3 0 e 4

2 d

3 0 e 4 2 d

1 3 e 1 7 d

1 3 e 1 7 d

6 e 1 0 d

2 8 e 3 5 d

1 2 e 1 5 d

1 0 e 1 4 d

8 e 1 2 d

F o l l o w - u p a

3 5 e 4 9 d

6 1 e 7

4 d

6 1 e 7 4 d

4 0 e 4 9 d

4 0 e 4 9 d

3 m o

2 m o

6 w k

R a n d o m i z e d

2 3 0 9

2 2 7 5

1 0 4 9

1 7 1 1

4 5 4 1

2 5 0 9

2 5 3 1

3 1 4 8

2 1 0 1

3 4 9 4

2 6 1 5

3 1 9 5

3 8 1

A S , a f t e r s u r g e r y ; B S , b e f o r e s u r g e r y ; T H R , t o t a l h i p r e p l a c e m e n t ; T K R , t o t a l k n e e r e p l a c e m e n t .

a S o u r c e s o f h e t e r o g e n e i t y .


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(RR, 1.20; 95% CI, 1.03, 1.41) compared with dabi-

gatran (150 mg) and enoxaparin (mixed dosages).

Proximal DVT . Only apixaban (RR, 0.45; 95% CI,

0.27, 0.75) showed significantly better results

regarding proximal DVT frequency compared with

enoxaparin treatment (Fig. 3).

Symptomatic DVT . Rivaroxaban and apixaban pre-

sented significant reductions in symptomatic DVT

Fig. 2. Random effects of risk ratio (95% CI) of primary efficacy rates with new anticoagulants in relation to

enoxaparin.


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versus enoxaparin (RR, 0.45; 95% CI, 0.27, 0.77 and

RR, 0.38; 95% CI, 0.16, 0.90, respectively). The

other new anticoagulant trials have shown equiva-

lent results (Fig. 4).

Major VTE . Major VTE (i.e., proximal DVT, pulmo-

nary embolism, or unexplained death) results

favored only rivaroxaban studies (RR, 0.44; 95%

CI, 0.25, 0.81; Fig. 5).

Pulmonary Embolism. No statistically significant

difference was seen between the new

Fig. 3. Random effects of risk ratio (95% CI) of proximal DVT rates with new anticoagulants in relation to enoxaparin.


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anticoagulants versus enoxaparin regarding

pulmonary embolism frequency (Table II).

Any Bleeding. Any-bleeding results (Fig. 6) favored

enoxaparin over fondaparinux (RR, 1.27; 95% CI,

1.04, 1.55), and apixaban over enoxaparin (RR,

0.88; 95% CI, 0.79, 0.99). The other new

anticoagulants presented overall similar results to

those for enoxaparin.

Major Bleeding/Minor Bleeding/Clinically Relevant

Nonmajor Bleeding. Similar results were observed

in minor and nonmajor bleeding for all new antico-

agulants compared with enoxaparin treatment. The

Fig. 4. Random effects of risk ratio (95% CI) of symptomatic DVT rates with new anticoagulants in relation to

enoxaparin.


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same occurred with major bleeding and clinically

relevant nonmajor bleeding, except for with the

dabigatran 150-mg dosing regimen, the results of

which favored enoxaparin (Table II).

Death. No statistically significant difference was

seen between the groups regarding the frequency

of deaths during the study period (Table II).Liver Enzyme Elevation. Liver enzyme elevation

was not evaluated in fondaparinux studies. Studies

with the dabigatran 220-mg dosing regimen (RR,

0.67; 95% CI, 0.79, 0.99) presented more favorable

results than those with enoxaparin (Fig. 7).

DISCUSSION

Previous meta-analyses of fondaparinux7; dabiga-

tran8; rivaroxaban and da bigatran35; apixaban11;

semuloparin12; rivaroxaban13,14; and rivaroxaban,

dabigatran, and apixaban10,36 have shownsegmental comparative results of the several trials

involving these new anticoagulants. In these

studies, inclusion criteria differed somewhat, and

statistical analyses were variable among them,

including odds ratio (OR) or RR with fixed or

random effects calculations. Furthermore, hetero-

geneity was not always considered in the generated

conclusions, and therefore panoramic comparisons

were troublesome. Pooled analyses were also per-

formed for rivaroxaban37 and dabigatran,38 but the

populations included were not per-protocol, as in

the original reports, and may, in the presence ofheterogeneity, inadvertently lead to fragile conclu-

sions.39 Therefore, no previous systematic review

was conducted summarizing all new anticoagulant

trials (publications after 2000) in a unique meta-

analysis. Nevertheless, all comparisons of new anti-

coagulant products were indirect, and therefore

studies comparing them directly will be important

in the future. Comparison of large observational

registries also reveals differences among real-life

patient populations, which hampers extrapolation

of clinical trial data to clinical practice. Differences

in end point definitions and clinical heterogeneity

in a group of comparisons also preclude adequate

indirect comparison of some anticoagulant agents.40

Probable sources of heterogeneity identified in

the plotted results included type of surgery (hip or

knee surgery), timing and dosages of enoxaparin

(40 mg once daily or 30 mg twice daily), different

primary efficacy definitions, follow-up period, and

use of graduated compression stockings (Table I).

The new anticoagulants were administered after

surgery in all included studies, but enoxaparin

timing varied from 40 mg once daily (before

surgery) to 30 mg twice daily (after surgery). The

administration of anticoagulant after surgery tends

to reduce bleeding complications.41 Therefore,

although studies were similar in the type of inter-

ventions and in assessing similar populations,

some differences were still seen among them, even

after a subgroup analysis, suggesting a need for

caution in the interpretation for certain outcomes.

Because of heterogeneity of total results, only

subtotal analyses were performed in this study.

However, safety comparisons did not show signif-

icant heterogeneity, in contrast to some efficacy

comparisons. Subgroup analysis reduced heteroge-

neity in some of them, but not consistently. Sub-

grouping hip and knee surgery did not reduce

meta-analysis heterogeneity, as also shown by Cao

et al13 for primary efficacy outcome.

In this systematicreview, fondaparinuxand rivar-

oxaban were associated with a significantly lower

rate of total VTE than enoxaparin in hip and kneesurgery. However, the definition of primary efficacy

in the fondaparinux trials did not include death by

any cause, because these trials were conducted

before the European Medicines Agency (EMEA)

issued the definition, which represents a limitation

because many cases of sudden death are not clarified

through autopsies andcouldbe relatedto pulmonary

embolism. Limited conclusions are also provided by

heterogeneity found regarding primary efficacy

and proximal DVT for rivaroxaban when subtotals

were calculated. No advantages of other new anti-

coagulants were observed for this outcome insubtotal group analysis. Symptomatic DVT and prox-

imal DVT results favored apixaban; furthermore,

symptomatic DVT and major DVT also favored rivar-

oxaban, both without significant heterogeneity.

Any bleeding-related complications were less

frequent with apixaban and more frequent in the

composite of fondaparinux trials. Therefore, fonda-

parinux efficacy was gained at the expense of an

increased risk of any bleeding-related complica-

tions, even with the advantage of postoperative

starting time. The other anticoagulants did not

produce significant any bleeding-related complica-

tions, but the bemiparin subgroup meta-analysis

consisted of only 1 trial. No significant difference

in minor and nonmajor bleeding was seen between

all new anticoagulants and enoxaparin treatment,

nor was any seen between major bleeding and clin-

ically relevant nonmajor bleeding, except with the

dabigatran 150-mg dosage regimen, the results of

which favored enoxaparin.

Some authors have questioned the safety records

of rivaroxaban. Significant bleeding was observed

with rivaroxaban only when 2 separate safety


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outcomes were grouped: clinically relevant

nonmajor bleeding and major bleeding.42,43 Others

believe that surgical-site bleeding should be

included in rivaroxaban trials, because in studies

in which surgical-site bleeding was excluded from

the definition, major bleeding rates were

Fig. 5. Random effects of risk ratio (95% CI) of major VTE rates with new anticoagulants in relation to enoxaparin.


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approximately 10-fold lower than in those that

included surgical-site bleeding.41,44 Huisman et al9

concluded that, compared with rivaroxaban, enoxa-

parin had a 2-fold higher risk of symptomatic VTE

plus all-cause mortality (1.2% vs 0.6%; OR, 2.04;

95% CI, 1.32e3.17; P < 0.001) but showed

a significantly lower risk of the composite of major

bleeding and clinically relevant nonmajor bleeding

(2.5% vs 3.1%; OR, 0.79; 95% CI, 0.62e0.99; P ¼

0.049). Nevertheless, further phase IV trials are

necessary to answer questions on safety concerns

not yet completely answered in phase III trials. In

Fig. 6. Random effects of risk ratio (95% CI) of rates of any bleeding with new anticoagulants in relation to

enoxaparin.


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REVIEWERS’ CONCLUSIONS

Implications for Practice

The comprehensive meta-analysis of fondaparinux

and rivaroxaban trials tended to show significant

superiority in primary efficacy compared with enox-

aparin for preventing VTE in major orthopedicsurgeries; however, significant heterogeneity

precluded any strong conclusions on this aspect.

Fondaparinux showed significant risk for any

bleeding-related complications, and rivaroxaban

did not show any risk of bleeding. The pooled anal-

ysis showed that dabigatran at 220 mg was noninfe-

rior to enoxaparin at 40 mg once daily, with similar

bleeding risk. Despite similar efficacy in this meta-

analysis, dabigatran and apixaban did not meet the

prespecified noninferiority goal with enoxaparin at

the standard US dosage (30 mg twice daily).

Major VTE rates and symptomatic DVT rates were

less frequent in rivaroxaban series. Symptomaticand proximal DVTs were less frequent with the

use of apixaban. Apixaban series were also associ-

ated with reduced bleeding risk (any bleeding-

related complication and clinically relevant

nonmajor bleeding). Other safety outcomes were

similar to enoxaparin for all new anticoagulants,

although information about the bleeding index,

hemoglobin decrease, transfusion volumes, transfu-

sion frequencies, and drainage volumes were not

consistently reported in all articles included in the

analysis. Hepatic enzymes alteration, especially

ALT elevation exceeding 3 times the upper limit ofnormal, in trials in which this outcome was deter-

mined, was generally similar or even less frequent

particularly with dabigatran at 220 mg.

The knowledge of some differences concerning

efficacy or safety highlighted by this meta-analysis

may be useful in clinical practice. All are synthetic

drugs and, except for fondaparinux, all are oral anti-

coagulants. Fondaparinux and rivaroxaban tended

to have better efficacy results, and the others (dabi-

gatran and apixaban) had similar efficacy to enoxa-

parin, with generally low risk of bleeding.

Therefore, these new anticoagulants can be consid-

ered attractive alternatives to conventional throm-

boprophylaxis regimens in patients undergoing

elective major orthopedic surgery, depending on

clinical characteristics and cost-effectiveness.

The authors are grateful to Dr. Sylvia Haas for her suggestions.

Conflicts of interest: Winston Bonetti Yoshida is a member of

the advisory board for Bayer, Brazil. Rogerio Nunes is the

Medical Manager of Bayer, Brazil. Francisco de Humberto

Abreu Maffei is a member of the advisory board for Bayer,

Brazil. Regina El Dib and Ricardo A. Yoshida have no conflicts

of interest to declare.

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