Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service

December 2012

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center 

Durham Veterans Affairs Healthcare System

Durham, NC

John W. Williams Jr., M.D., M.H.Sc., Director

Comparative Effectiveness

of Newer Oral Anticoagulants

and Standard Anticoagulant 

Regimens for Thromboprophylaxis

in Patients Undergoing Total Hip

or Knee Replacement

Investigators:

Principal Investigator:

Soheir S. Adam, M.D.

Co-Investigators:

Jennifer R. McDuffie, Ph.D.

Paul F. Lachiewicz, M.D.

Thomas L. Ortel, M.D., Ph.D.

John W. Williams Jr., M.D., M.H.Sc.

Research Associate:

Avishek Nagi, M.S.

Medical Editor:

Liz Wing, M.A.
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Comparative Effectiveness of New Oral Anticoagulants

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PREFACE

Quality Enhancement Research Initiative’s (QUERI’s) Evidence-based Synthesis Program (ESP) 

was established to provide timely and accurate syntheses of targeted healthcare topics of particular 

importance to Veterans Affairs (VA) managers and policymakers, as they work to improve the 

health and healthcare of Veterans. The ESP disseminates these reports throughout VA.

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The ESP 

Centers generate evidence syntheses on important clinical practice topics, and these reports help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and performance 

measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW Jr. 

Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens 

for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement. VA ESP Project 

#09-010; 2012.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) 

Center located at the Durham VA Medical Center, Durham, NC, funded by the Department of 

Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health 

Services Research and Development. The findings and conclusions in this document are those of 

the author(s) who are responsible for its contents; the findings and conclusions do not necessarily 

represent the views of the Department of Veterans Affairs or the United States government. 

Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. Potential conflicts of interest: Dr. Ortel: Grants–GlaxoSmithKline, 

Eisai, Daichi Sankyo, Pfizer, Instrumentation Laboratory; Consultancy–Boehringer Ingelheim, 

Pfizer, Instrumentation Laboratory. No other investigators have any affiliations or financial 

involvement (e.g., employment, consultancies, honoraria, stock ownership or options, expert 

testimony, grants or patents received or pending, or royalties) that conflict with material presented 

in the report. To limit conflict of interest, Dr. Ortel participated in the design and critical review of 

the report but did not participate in data abstraction or drafting of the report. 
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TABLE OF CONTENTS

Executive Summary

Background......................................................................................................................................................1

Methods...........................................................................................................................................................2

Data Synthesis.................................................................................................................................................2

Rating the Body of Evidence...........................................................................................................................2

Peer Review.....................................................................................................................................................3

Results .............................................................................................................................................................3

Recommendations for Future Research...........................................................................................................9

Conclusion.......................................................................................................................................................9

Abbreviations Table.......................................................................................................................................10

Introduction

Pharmacological Treatment Options for VTE Thromboprophylaxis............................................................11

Methods

Topic Development........................................................................................................................................13

Analytic Framework......................................................................................................................................13

Search Strategy..............................................................................................................................................14

Study Selection..............................................................................................................................................14

Data Abstraction ............................................................................................................................................15

Quality Assessment .......................................................................................................................................16

Data Synthesis...............................................................................................................................................16

Rating the Body of Evidence.........................................................................................................................17

Peer Review...................................................................................................................................................18

Results

Literature Search ...........................................................................................................................................19

Study Characteristics.....................................................................................................................................20

Participant Characteristics.............................................................................................................................22

KQ 1. Comparative effectiveness of newer oral anticoagulants and standard drug classes..........................23

KQ 2. Comparative effects of combined pharmacological and mechanical modalities................................27

KQ 3. Comparative efficacy of newer oral anticoagulants............................................................................28

Summary and Discussion

Summary of Evidence by Key Question .......................................................................................................30

Clinical and Policy Implications ...................................................................................................................34

Applicability..................................................................................................................................................36

Strengths and Limitations..............................................................................................................................36

Recommendations for Future Research.........................................................................................................36

Conclusion.....................................................................................................................................................37

References..............................................................................................................................................................38
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Appendix A Search Strategies.............................................................................................................42

Appendix B Excluded Studies...............................................................................................................43

Appendix C Sample Data Abstraction Form..................................................................................46

Appendix D Criteria Used in Quality Assessment of Systematic Reviews.......................49

Appendix E Peer Review Comments ..................................................................................................52

Appendix F Glossary ...............................................................................................................................56

Figures

Figure 1. Analytic framework for the comparative effectiveness of newer oral anticoagulants..............13

Figure 2. Literature flow diagram.............................................................................................................19

Tables

Table 1. Summary of the strength of evidence for KQ 1 ..........................................................................5

Table 2. Summary of the strength of evidence for KQ 3 ..........................................................................8

Table 3. Evidence gaps and future research..............................................................................................9

Table 4. Summary of inclusion and exclusion criteria............................................................................15

Table 5. Characteristics of included systematic reviews.........................................................................21

Table 6. Characteristics of patient samples.............................................................................................22

Table 7. Summary of the strength of evidence for KQ 1 ........................................................................31

Table 8. Summary of the strength of evidence for KQ 3 ........................................................................33

Table 9. U.S. guideline recommendations related to specific thromboprophylaxis strategies................35

Table 10. Evidence gaps and future research............................................................................................37
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EXECUTIVE SUMMARY

BACKGROUND

Venous thromboembolic (VTE) events are important causes of morbidity in elective total 

hip replacement (THR) and total knee replacement (TKR) procedures. Current guidelines 

recommend thromboprophylaxis in patients undergoing THR or TKR, although the American 

Academy of Orthopaedic Surgeons (AAOS) guidelines suggest individual assessment of 

patients when choosing the specific thromboprophylaxis strategy. Low molecular weight 

heparin (LMWH) and adjusted-dose warfarin are the most commonly used anticoagulants for 

thromboprophylaxis in the United States, but a number of other treatment options are available, 

including unfractionated heparin, aspirin, mechanical devices, and newer oral anticoagulants.

Prior to 1980, rates of symptomatic VTE were 15 to 30 percent. However, improved surgical 

care and techniques have decreased the rate of symptomatic VTE. A recent analysis that 

incorporated data from trials and observational studies estimated the contemporary 35-day rate of 

symptomatic VTE without thromboprophylaxis at 4.3 percent. 

Pharmacological thromboprophylaxis for THR or TKR surgery decreases VTE by approximately 

50 percent but with the tradeoff of increased bleeding. The risk of bleeding is a concern because 

bleeding can lead to infections, reoperation, delayed wound healing, and extended hospital 

stay. The choice of which antithrombotic thus becomes pivotal for balancing the prevention of 

thromboembolism with the risk of bleeding. Newer oral anticoagulants have been developed 

with the goal of overcoming the limitations of warfarin and the available parenteral agents. 

These newer anticoagulants belong to two drug classes, based on their target coagulation protein: 

factor Xa (FXa) inhibitors and direct thrombin inhibitors (DTIs). These drugs are given as fixed 

oral doses and have the advantage of a more predictable anticoagulant effect, eliminating the 

need for monitoring when used for short-term thromboprophylaxis. Disadvantages of newer 

oral anticoagulants include the lack of specific antidotes to reverse their anticoagulant effect in a 

timely fashion in case of bleeding, and drug costs.

Given the emerging data on new oral anticoagulants, this report was commissioned by the VA to 

examine the following key questions (KQs):

KQ 1. For patients undergoing total hip or total knee replacement, what is the comparative 

effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight 

heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the 

incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE 

events, total mortality, and bleeding outcomes?

KQ 2. For patients undergoing total hip or total knee replacement, what are the effects of 

combined pharmacological and mechanical modalities versus pharmacological treatment alone 

on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, 

and bleeding outcomes?

KQ 3. For patients undergoing total hip or total knee replacement, what is the comparative 

efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively 

confirmed VTE, other VTE events, total mortality, and bleeding outcomes?
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METHODS

During the topic development phase of this study, we identified a number of published highquality systematic reviews that addressed our KQs. We conducted a synthesis of these reviews 

as they pertained to the KQs and the Veteran population and followed a standard protocol for 

all steps of this review. We searched MEDLINE® (via PubMed®), Embase®, and the Cochrane 

Database of Systematic Reviews for systematic review publications comparing the newer oral 

anticoagulants to other types of anticoagulation (aspirin, warfarin, LMWH, unfractionated heparin, 

etc.) from January 2009 through September 2012. Our search strategy used the National Library of 

Medicine’s medical subject headings (MeSH) keyword nomenclature and text words for newer oral 

anticoagulants, the conditions of interest, and validated search terms for systematic reviews. 

Using prespecified inclusion and exclusion criteria, two reviewers assessed titles and abstracts 

for relevance to the KQs. Full-text systematic reviews identified by either reviewer as 

potentially relevant were retrieved for further review. Select data from published reports were 

then abstracted into the final abstraction form by a trained reviewer. All data abstractions were 

confirmed by a second reviewer. We also abstracted data necessary for assessing the quality 

of systematic reviews, adapted from the AMSTAR criteria. Based on these criteria, systematic 

reviews were categorized as good, fair, or poor quality. Poor-quality reviews were excluded.

DATA SYNTHESIS

We categorized each systematic review by the key research questions they addressed and 

critically analyzed them to compare their characteristics, methods, and findings. We summarized 

the key findings and conclusions from each included review and produced summary tables 

for comparison across reviews. We prioritized the evidence from these reviews by the quality 

of methodological designs, more complete drug comparisons, and detailed information about 

population, specific drug intervention, and definitions of outcomes. In addition to summary 

measures of relative effects (e.g., risk ratios), we report absolute risk differences in the summary 

strength of evidence tables. For these estimates, baseline risk for patients treated with LMWH— 

the common comparator for newer anticoagulants—was estimated for each major outcome as 

symptomatic deep vein thrombosis (DVT), 9 per 1000 patients; nonfatal pulmonary embolism 

(PE), 3 per 1000 patients; mortality, 3 per 1000 patients; and major bleeding, 7 per 1000 patients.

Our synthesis focused on identifying patterns in efficacy and safety of the different drugs. 

To determine the consistency of results and conclusions, we then compared each additional 

review that addressed the same key question. If findings or conclusions differed importantly 

across reviews, we analyzed potential reasons for discrepancies such as the primary literature 

included, inclusion/exclusion criteria, differences in outcome definition, analytic approach, and 

conflict of interest. Because total hip and knee replacement have distinct primary endpoints, we 

examined the groups of studies as they pertained to these diagnoses separately.

RATING THE BODY OF EVIDENCE

In addition to rating the quality of individual studies, we evaluated the overall quality of the 

evidence for each KQ. In brief, this approach requires assessment of four domains: risk of bias, 

Return to Contents
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consistency, directness, and precision. For risk of bias, we considered study design using the quality 

assessments of the primary literature reported in the systematic reviews. We used results from metaanalyses when evaluating consistency, precision, strength of association, and whether publication 

bias was detected. Optimal information size and consideration of whether the confidence interval 

crossed the clinical decision threshold for a therapy were also used when evaluating precision.

PEER REVIEW

A draft version of the report was reviewed by technical experts and clinical leadership. A 

transcript of their comments can be found in the appendix, which elucidates how each comment 

was considered in the final report.

RESULTS

Our search for systematic reviews (SRs) identified 182 unique citations from a combined 

search of MEDLINE via PubMed, Embase, the Cochrane Database of Systematic Reviews, 

and bibliographies of key articles. After applying inclusion and exclusion criteria at both the 

title-and-abstract and full-text review levels, the final set of articles used in this evidence report 

consisted of six recently published, high-quality systematic reviews.

All of the SRs compared newer oral anticoagulants with other drug classes used for 

thromboprophylaxis in THR or TKR (KQ 1), but specific strategies varied. Two SRs used 

random-effects meta-analyses to compare drug classes as a whole (e.g., FXa inhibitors versus 

LMWH) while the other four SRs compared individual drugs, some analyzing THR and TKR 

studies separately. Two of the six SRs compared one newer oral anticoagulant with another (KQ 

3) though all results were based on indirect comparisons; i.e., through common comparison with 

enoxaparin. Only one SR compared a pharmacological agent plus mechanical modality versus 

pharmacologic prophylaxis alone (KQ 2). 

All reviews assessed the quality of included trials, and overall quality was judged to be 

good. Publication bias was assessed and did not indicate bias that would favor newer oral 

anticoagulants. Three of the SRs were unfunded and reported no conflicts of interest. One SR 

was unfunded but did report a conflict of interest for one author. Two SRs were funded by 

government agencies. 

Key Question 1. For patients undergoing total hip or total knee replacement, 

what is the comparative effectiveness of newer oral anticoagulants and standard 

drug classes (low molecular weight heparin, injectable factor Xa inhibitors, 

unfractionated heparin, warfarin, aspirin) on the incidence of symptomatic, 

objectively confirmed venous thromboembolism (VTE), other VTE events, total 

mortality, and bleeding outcomes?

Key Points 

• For all-cause mortality and nonfatal PE, there were no important differences between 

oral FXa inhibitors and LMWH (high strength of evidence). Using a base rate of 9 events 
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per 1000 patients with LMWH, FXa inhibitors were associated with lower symptomatic 

DVT (4 fewer events per 1000 patients; 95% CI, 3 to 6). Overall, FXa inhibitors were 

associated with an increased risk of major bleeding, but major bleeding did not differ 

importantly at low to moderate doses (moderate strength of evidence). Based on subgroup 

analyses, there was not a consistent pattern of differences in treatment effects for THR 

and TKR.

• There were fewer studies evaluating oral DTIs than oral FXa inhibitors; all trials 

compared dabigatran with enoxaparin. Although estimates of effect were often imprecise, 

there were no significant differences between oral DTIs and enoxaparin for any major 

outcome.

• Neither oral FXa inhibitors nor DTIs have been compared directly with adjusted-dose 

warfarin, oral antiplatelet drugs, or unfractionated heparin in existing SRs.

FXa inhibitors. Rivaroxaban and apixaban are the most commonly studied FXa inhibitors, and 

rivaroxaban is the only FXa inhibitor marketed in the United States. The risk of symptomatic 

DVT was reduced with FXa inhibitors compared with LMWH, while the risks of nonfatal PE 

and mortality were not significantly different (all high strength of evidence). The estimated 

absolute risk difference was 4 fewer symptomatic DVT events for each 1000 patients receiving 

thromboprophylaxis with FXa inhibitors over 5 weeks compared with LMWH. However, 

these benefits were offset by an increase in major bleeding (moderate strength of evidence).

The absolute risk difference was 2 more major bleeding events per 1000 patients receiving 

thromboprophylaxis with FXa inhibitors over 5 weeks. Higher doses of FXa inhibitors, but not 

intermediate or low doses, were associated with increased major bleeding. Subgroup analysis 

by specific drug and type of surgery showed a reduced risk of bleeding with apixaban compared 

with LMWH in TKR but not in THR; risk of major bleeding with rivaroxaban did not differ 

significantly for either surgery. No reviews identified trials comparing oral FXa inhibitors with 

warfarin, unfractionated heparin, or oral antiplatelet agents.

Direct thrombin inhibitors. Dabigatran is the only FDA-approved oral DTI and the only 

DTI evaluated in existing SRs. Compared with LMWH, dabigatran was not associated with 

significant differences for any outcome examined. The strength of evidence was low for 

most outcomes due to few events and imprecise estimates of effect; also, effects on mortality 

varied substantially across studies. In addition to the major outcomes, a subgroup analysis in 

one SR found no significant difference between both treatment groups on bleeding requiring 

rehospitalization. No reviews identified trials comparing oral DTIs with warfarin, unfractionated 

heparin, or oral antiplatelet agents. Table 1 summarizes the findings and strength of evidence 

for the effects of newer oral anticoagulant drug classes compared with enoxaparin in patients 

undergoing THR or TKR surgery.
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gth of evidence for KQ 1 

Domains Pertaining to SOE

Effect Estimate (95% CI) SOE Number of Studies 

(Subjects)

Study Design/ 

Quality

Consistency

Directness

Precision

Publication Bias

22,838) RCT/Good Consistent

Direct

PreciseNone detected

OR=0.95 (0.55 to 1.63)RD=0 (2 fewer to 1 more) deaths/1000 patients

High

22,877) RCT/Good Consistent

Direct

PreciseNone detected

OR=0.46 (0.30 to 0.70)RD=4 fewer (3 to 6 fewer) events/1000 patients

High

26,998) RCT/Good Consistent

Direct

PreciseNone detected

OR=1.07 (0.65 to 1.73)RD=0 (1 fewer to 2 more) events/1000 patients

High

31,424) RCT/Good Inconsistent

Direct

PreciseNone detected

OR=1.27 (0.98 to 1.65)RD=2 more (0 to 4 more) events/1000 patients

Moderate

0,080) RCT/Good Inconsistent

Direct

ImpreciseNone detected

TKR 

RR=1.06 (0.36 to 3.12)RD=0 (2 fewer to 6 more) events/1000 patients

THR 

RR=1.17 (0.04 to 36.52)RD=0 (3 fewer to 107 more) events/1000 

patients

Low

0,264) RCT/Good Consistent

Direct

ImpreciseNone detected

RR=0.82 (0.17 to 3.99)RD=2 fewer (7 fewer to 27 more) events/1000 

patients

Low

0,264) RCT/Good Consistent

Direct

ImpreciseNone detected

OR=0.69 (0.31 to 1.54)RD=1 fewer (2 fewer to 2 more) events/1000 

patients

Low

0,264) RCT/Good Consistent

Direct

ImpreciseNone detected

RR=0.94 (0.58 to 1.52)RD=0 (3 fewer to 3 more) events/1000 patients

Moderate

otics

NA NA NA Not estimable Insufficient

nd Gómez-Outes, 2012; risk difference calculated; SOE ratings from Sobieraj, 2012.

may be some differences for hip versus knee replacement (different baseline risk and different duration of anticoagulation in existing studies); there is some 

oses increase risk of bleeding.

DVT=deep vein thrombosis; DTI=direct thrombin inhibitor; FXa=factor X inhibitor; LMWH=low molecular weight heparin; NA=not applicable; OR=odds 

andomized controlled trial; RD=risk difference; RR=risk ratio; SOE=strength of evidence; THR=total hip replacement; TKR=total knee replacement
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Key Question 2. For patients undergoing total hip or total knee replacement, what 

are the effects of combined pharmacological and mechanical modalities versus 

pharmacological treatment alone on the incidence of symptomatic, objectively 

confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

Key Points

• In the included SRs, no studies were identified that compared the combination of newer 

oral anticoagulants and mechanical thromboprophylaxis with pharmacological treatment 

alone.

• Few studies compared older antithrombotics (LMWH, oral antiplatelet agents, or 

unfractionated heparin) combined with mechanical prophylaxis to pharmacological or 

mechanical prophylaxis alone. 

• The strength of evidence is insufficient to determine the comparative effectiveness for 

combined pharmacological and mechanical prophylaxis compared with pharmacological 

prophylaxis alone for all major outcomes prioritized for this report. 

No reviews identified trials comparing newer oral anticoagulants combined with mechanical 

prophylaxis to pharmacological prophylaxis alone. Even when considering standard treatments, 

very little data are available comparing combined-modality thromboprophylaxis and pharmacologic 

prophylaxis only. One SR found moderate strength of evidence that combined-modality 

thromboprophylaxis was associated with a decreased risk of overall DVT (including asymptomatic 

events) compared with pharmacologic prophylaxis alone. The evidence was insufficient for all other 

outcomes.

Key Question 3. For patients undergoing total hip or total knee replacement, 

what is the comparative efficacy of individual newer oral anticoagulants on the 

incidence of symptomatic, objectively confirmed VTE, other VTE events, total 

mortality, and bleeding outcomes?

Key Points

• No clinical trials directly compared newer oral anticoagulants with each other for 

thromboprophylaxis of THR or TKR.

• The included SRs did not estimate the comparative efficacy of newer oral anticoagulants 

for symptomatic DVT, nonfatal PE, all-cause mortality, or surgical site bleeding.

• Based on indirect comparisons, there were few differences between newer oral 

anticoagulants for the outcomes examined. Rivaroxaban was associated with more 

major bleeding than apixaban (RR 1.59; 95% CI, 0.84 to 3.02). In contrast, the risk of 

symptomatic VTE was lower for rivaroxaban than apixaban or dabigatran, but confidence 

intervals included the possibility of a chance association.

Only indirect comparisons of rivaroxaban, apixaban, and dabigatran were performed through 

common comparison with LMWH. These comparisons were made for only two of our major 

outcomes—symptomatic VTE (DVT or PE) and major bleeding. There were no significant 

differences in treatment effect for symptomatic VTE or major bleeding. Because these indirect 

comparisons are subject to confounding and the treatment effects were imprecise, we considered 
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the strength of evidence low. Other outcomes reported included clinically relevant bleeding and 

net clinical endpoints. Rivaroxaban was found to be associated with an increased risk of clinically 

relevant bleeding, but there was no significant difference in net clinical endpoints (symptomatic 

VTE, major bleeding, and death). Table 2 summarizes the findings and strength of evidence for 

between-drug comparisons of newer oral anticoagulants in patients undergoing THR or TKR.
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gth of evidence for KQ 3

Domains Pertaining to SOE

Effect Estimate (95% CI) SOE 

ber 

dies 

cts)

Study Design/ 

Quality

Consistency

Directness

Precision

Publication Bias

ana

NA NA NA Outcome not reported Insufficient

NA NA NA Outcome not reported InsufficientNA NA NA Outcome not reported Insufficient

) RCT/Good NA

Indirect

Imprecise None detected

Rivaroxaban vs. dabigatran

RR=0.68 (0.21 to 2.23) RD=3 fewer (11 fewer to 4 more) events/1000 patients

Rivaroxaban vs. apixaban

RR=0.59 (0.26 to 1.33)

RD=4 fewer (9 fewer to 1 more)/1000 patients

Apixaban vs. dabigatran RR=1.16 (0.31 to 4.28) RD=1 more (7 fewer to 8 more)/1000 patients

Low

LowLow

) RCT/Good NA

Indirect

Imprecise None detected

Rivaroxaban vs. dabigatran

RR=1.37 (0.21 to 2.23); RD=4 more (2 fewer to 11 more) events/1000 patients

Rivaroxaban vs. apixaban

RR=1.59 (0.84 to 3.02);RD=5 more (2 fewer to 12 more)/1000 patients

Apixaban vs. dabigatran

RR=1.16 (0.31 to 4.28);

RD=0 (8 fewer to 7 more)/1000 patients

Low

LowLow

osis; NA=not applicable; NR=not reported; PE=pulmonary embolism; RCT=randomized controlled trial; RD=risk difference; RR=risk ratio; SOE=strength of 

sm
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RECOMMENDATIONS FOR FUTURE RESEARCH

We used a structured framework to identify gaps in evidence and classify why these gaps exist 

(Table 3).

Table 3. Evidence gaps and future research

Evidence Gap Reason Type of Studies to Consider

Absence of direct comparisons between 

newer anticoagulant drugs

Insufficient information Multicenter RCTs

High-quality network meta-analyses

Observational comparative 

effectiveness studies

Absence of direct comparisons between 

newer anticoagulants and agents other 

than LMWH

Insufficient information Multicenter RCTs 

Observational comparative 

effectiveness studies 

Absence of comparisons between 

combined treatment with newer 

anticoagulants and mechanical 

thromboprophylaxis to pharmacological 

or mechanical thromboprophylaxis alone

Insufficient information Multicenter RCTs 

Observational comparative 

effectiveness studies 

Adverse effects with long-term use and 

in usual clinical practice

Insufficient information Observational studies

Abbreviation: LMWH=low molecular weight heparin; RCT=randomized controlled trial

CONCLUSION

For THR or TKR, the 35-day rate of symptomatic VTE without thromboprophylaxis is estimated 

to be 4.3 percent. Pharmacological thromboprophylaxis decreases VTE by approximately 50 

percent but with the tradeoff of increased bleeding. Newer oral anticoagulants have a more 

convenient route of administration compared with LMWH, and unlike adjusted dose warfarin, 

they do not require regular laboratory monitoring. Compared with LMWH, FXa inhibitors 

are associated with a reduced risk of symptomatic DVT, but mortality and nonfatal PE are not 

significantly different, and the risk of major bleeding episodes is increased. 

There are no available studies on head-to-head comparisons of these novel anticoagulants. 

Longer clinical experience and direct drug-drug comparisons are needed to better assess the 

risk-to-benefit ratio of newer oral anticoagulants for surgical thromboprophylaxis. Based on 

current evidence, newer anticoagulants—particularly FXa inhibitors—are a reasonable option for 

thromboprophylaxis in patients undergoing total hip replacement or total knee replacement.
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ABBREVIATIONS TABLE

CI confidence interval

DTI direct thrombin inhibitor

DVT deep vein thrombosis

FDA U.S. Food and Drug Administration

FXa factor Xa inhibitor

INR international normalized ratio

KQ key question

LMWH low molecular weight heparin

MeSH medical subject heading

NA not applicable

NR not reported

OR odds ratio

PE pulmonary embolism

RCT randomized controlled trial

RD risk difference

RR risk ratio

SOE strength of evidence

THR total hip replacement

TKR total knee replacement

VA Department of Veterans Affairs

VHA Veterans Health Administration

VKA vitamin K antagonist

VTE venous thromboembolism
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EVIDENCE REPORT

INTRODUCTION

Venous thromboembolic (VTE) events are important causes of morbidity in elective total hip 

replacement (THR) and total knee replacement (TKR) procedures, which are being performed 

with increasing frequency in an aging population. Because of the substantial risk of VTE, 

current guidelines recommend thromboprophylaxis in patients undergoing THR or TKR.1-3 Low 

molecular weight heparin (LMWH) and adjusted-dose warfarin are the most commonly used 

anticoagulants for thromboprophylaxis in the United States,4 but a number of pharmacological 

treatment options are available including unfractionated heparin, aspirin, and newer oral 

anticoagulants. These drug classes differ in practical applications such as a predictable doseresponse and the need for laboratory monitoring, oral versus injection administration, dosing 

frequency, drug-drug interactions, and the availability of an appropriate reversal mechanism in 

case of over anticoagulation. In addition, mechanical thromboprophylaxis, most frequently used 

in combination with anticoagulants, is commonly used in the United States. 

Risk factors for VTE include venous stasis, endothelial injury, and hypercoagulability. Venous 

stasis can result from the positioning of the limb, localized postoperative swelling, or limited 

mobility in the postoperative period.5,6 Endothelial injury can result from positioning and 

manipulation of the limb.5,7 Markers of thrombin generation, indicating hypercoagulability, 

have been shown to be elevated in total hip arthroplasty.8

 Prior to 1980, rates of symptomatic 

VTE were 15 to 30 percent. However, changes in surgical care, including earlier ambulation, 

and changes to surgical technique that are less invasive and possibly less thrombogenic have 

decreased the rate of symptomatic VTE. A recent analysis that incorporated data from trials and 

observational studies estimated the contemporary 35-day rate of symptomatic VTE without 

thromboprophylaxis at 4.3 percent.1

Pharmacological thromboprophylaxis for THR or TKR surgery decreases VTE by approximately 

50 percent but with the tradeoff of increased bleeding.9

 Surgical procedures may also increase 

bleeding risk; major bleeding is estimated to occur in 1.5 percent of patients undergoing THR or 

TKR, even without thromboprophylaxis.1 The risk of bleeding is a concern because bleeding can 

lead to infections, reoperation, delayed wound healing, and extended hospital stay.10 Considering 

both benefits and risks, guideline panels have issued moderate to strong recommendations for 

thromboprophylaxis in patients without a contraindication.1-3 The choice of which antithrombotic 

thus becomes pivotal for balancing the prevention of thromboembolism with the risk of bleeding. 

Pharmacological Treatment Options for VTE 

Thromboprophylaxis

The most commonly used anticoagulants are LMWH, fondaparinux, and warfarin.4,11,12

Unfractionated heparin and antiplatelet agents are rarely used. The efficacy and safety of LMWH 

for postoperative thromboprophylaxis has been established in more than 30 studies.3,9,13 LMWH 

binds to antithrombin and accelerates the inhibition of thrombin and factor X. LMWH has a long 

half-life, which allows a once-daily dosing schedule and good bioavailability after subcutaneous 
12

Comparative Effectiveness of New Oral Anticoagulants

for Thromboprophylaxis Evidence-based Synthesis Program

injection. Disadvantages of LMWH include the need for parenteral administration, high drug 

cost, and a small risk of heparin-induced thrombocytopenia.14 Similarly, fondaparinux has 

good bioavailability when given once daily subcutaneously. Due to the length of the molecule, 

fondaparinux mainly acts by catalyzing the inhibition of factor Xa (FXa) with essentially no 

inhibition of thrombin.15

For nearly 50 years, warfarin has been successfully used for prophylaxis and treatment of 

VTE. Warfarin is administered orally once daily and is inexpensive. However, it has several 

disadvantages, including the need for regular monitoring with international normalized ratio 

(INR) and numerous interactions with a host of drugs, herbs, and dietary products. Its delayed 

onset of action can leave patients unprotected in the early postoperative period. In fact, registry 

data show that surgeons using warfarin are less likely to meet guideline recommendations than 

with other agents due to failure to meet the target INR.4

Newer oral anticoagulants have been developed with the goal to overcome the limitations 

of warfarin and the available parenteral agents. These new anticoagulants belong to two 

drug classes, based on their target coagulation protein: FXa inhibitors and direct thrombin 

inhibitors (DTIs). These are given as fixed oral doses and have the advantage of a more 

predictable anticoagulant effect, eliminating the need for monitoring when used for short term 

thromboprophylaxis. Disadvantages of newer oral anticoagulants include drug costs and the 

lack of specific antidotes to reverse their anticoagulant effect in a timely fashion in case of 

bleeding. Rivaroxaban, an oral FXa inhibitor, was approved on July 1, 2011, by the U.S. Food 

and Drug Administration (FDA) for prophylaxis of VTE in adults undergoing orthopedic surgery. 

Other oral FXa inhibitors that are currently under clinical development include apixaban, 

edoxaban, and betrixaban. Apixaban is under FDA review for thromboprophylaxis in orthopedic 

surgery. Dabigatran etexilate is an oral DTI that has been approved in the United States for 

stroke prevention in atrial fibrillation. Renal excretion is the predominant elimination pathway 

for dabigatran, with more than 80 percent of systemically available dabigatran eliminated 

unchanged.16 Dabigatran has a better drug interaction profile compared with warfarin and is 

currently under review for FDA approval in patients undergoing elective orthopedic surgery.

Given the emerging data on new oral anticoagulants, this report was commissioned by 

the VA to assess the comparative effectiveness of newer oral anticoagulants and standard 

thromboprophylaxis regimens in total hip and knee replacement surgery.
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Comparative Effectiveness of New Oral Anticoagulants

for Thromboprophylaxis Evidence-based Synthesis Program

METHODS

TOPIC DEVELOPMENT

This review was commissioned by the VA’s Evidence-based Synthesis Program. The topic was 

nominated after a topic refinement process that included a preliminary review of published 

peer-reviewed literature, consultation with internal partners and investigators, and consultation 

with key stakeholders. We further developed and refined the key questions (KQs) based on a 

preliminary review of published peer-reviewed literature in consultation with VA and non-VA 

experts.

The final KQs were:

KQ 1. For patients undergoing total hip or total knee replacement, what is the comparative 

effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight 

heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the 

incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE 

events, total mortality, and bleeding outcomes?

KQ 2. For patients undergoing total hip or total knee replacement, what are the effects of 

combined pharmacological and mechanical modalities versus pharmacological treatment alone 

on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, 

and bleeding outcomes?

KQ 3. For patients undergoing total hip or total knee replacement, what is the comparative 

efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively 

confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

ANALYTIC FRAMEWORK

We followed a standard protocol for all steps of this review; certain methods map to the PRISMA 

checklist.17 Our approach was guided by the analytic framework shown in Figure 1.

Figure 1. Analytic framework for the comparative effectiveness of newer oral anticoagulants

Adverse effects 

of treatment

Rates of venous 

thromboembolic 

events and bleeding

•	 Anticoagulants including LMWH, FXa 

inhibitors, unfractionated heparin, 

warfarin, aspirin

•	 Combined pharmacological and 

mechanical interventions

Adults having total 

hip or total knee 

replacement surgery

KQs 1–3

All-cause mortality

Abbreviations: FXa=factor Xa; KQs=key questions; LMWH=low molecular weight heparin 
14

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SEARCH STRATEGY

During the topic development phase of this study, we identified a number of published highquality systematic reviews that addressed our KQs. We concluded that a synthesis of these 

reviews as they pertained to the KQs and the Veteran population would be the most effective 

approach to summarizing the evidence. This approach is particularly useful when different 

intervention options or outcomes are evaluated in multiple recent reviews and when the 

audience is policymakers. We searched MEDLINE® (via PubMed®), Embase®, and the Cochrane 

Database of Systematic Reviews for systematic review publications comparing the newer oral 

anticoagulants to other types of anticoagulation (aspirin, warfarin, LMWH, unfractionated 

heparin, etc.) from January 1, 2009, through May 30, 2012. Our search strategy used the 

National Library of Medicine’s medical subject headings (MeSH) keyword nomenclature and 

text words for newer oral anticoagulants, the conditions of interest, and validated search terms 

for systematic reviews.18,19

Our final search terms included new or novel oral anticoagulants; DTIs, including dabigatran, 

FXa inhibitors, including edoxaban, rivaroxaban, apixaban, betrixaban, YM150; the MeSH 

descriptor “orthopedic procedures”; and terms for the specific procedures of interest, total knee 

replacement or total hip replacement surgery. We limited the search to systematic reviews and 

meta-analyses and articles published in the English language involving human subjects 18 years 

of age and older. The full search strategy is provided in Appendix A. We supplemented the 

electronic searches with a manual search of citations from a set of key systematic reviews20-23

and clinical guidelines.1,24 We developed our search strategy in consultation with an experienced 

search librarian and updated the search during the course of analysis so as not to miss any recent, 

pertinent reviews; the last update was conducted September 2012. A supplementary search of 

the primary literature was conducted in September 2012 to identify relevant trials published 

since May 2012. All citations were imported into an electronic database (DistillerSR; Evidence 

Partners, Inc., Manotick, ON, Canada) for citation screening.

STUDY SELECTION

Using prespecified inclusion and exclusion criteria, two reviewers assessed titles and abstracts 

for relevance to the KQs. Full-text systematic reviews identified by either reviewer as potentially 

relevant were retrieved for further review. Each article retrieved was examined by two reviewers 

against the eligibility criteria. Disagreements on inclusion, exclusion, or major reason for 

exclusion were resolved by discussion or by a third reviewer. 

The criteria to screen articles for inclusion or exclusion at both the title-and-abstract and full-text 

screening stages are detailed in Table 4. Studies excluded at the full-text review stage are listed 

with the reasons for exclusion in Appendix B.
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Table 4. Summary of inclusion and exclusion criteria 

Study 

Characteristic Inclusion Criteria Exclusion Criteria

Population Adults (≥18 years) of age undergoing elective 

orthopedic surgery for total hip or total knee 

replacement

Pregnant women

Intervention KQ 1: Newer oral anticoagulants: Direct thrombin 

inhibitors and factor Xa inhibitors

KQ 2: Combined pharmacological and mechanical 

modalities

KQ 3: Newer oral anticoagulants

Newer anticoagulants requiring 

intravenous or subcutaneous 

administration

Comparator KQ 1: Warfarin, low molecular weight heparin, 

unfractionated heparin, aspirin

KQ 2: Pharmacological treatment alone

KQ 3: Within-class or between-class comparison with 

another newer oral anticoagulant

Comparators other than those 

specified by the KQ inclusion criteria

Outcome Primary outcomes: Symptomatic, objectively confirmed 

deep vein thrombosis or pulmonary embolism

Secondary outcomes: Major bleeding, surgical-site 

bleeding, or mortality

No relevant outcomes

Timing Outcomes reported >1 week postoperatively Less than 1 week postoperatively

Setting Inpatient surgical settings None

Study design Systematic reviews that evaluated randomized 

controlled trials (RCTs) or secondary data analysis 

from an RCT

Not an SR of at least fair or good 

quality

Publications English-language only

Published from 2009 to present

Peer-reviewed article

Non-English language publication

Published before 2009

Abbreviations: KQ=key question; RCT=randomized controlled trial

DATA ABSTRACTION 

Before general use, the abstraction form templates designed specifically for this report were 

pilot-tested on a sample of included articles and revised to ensure that all relevant data elements 

were captured and that there was consistency and reproducibility between abstractors. Select data 

from published reports were then abstracted into the final abstraction form by a trained reviewer 

(Appendix C). All data abstractions were confirmed by a second reviewer. Disagreements were 

resolved by consensus or by obtaining a third reviewer’s opinion when consensus could not be 

reached. We abstracted the following key information for each included study: 

• Systematic review design features

○ Databases used in searches and dates of searches

○ Inclusion/exclusion criteria

○ Number of primary studies that apply to each KQ

○ Method of analysis

○ Types of comparisons

○ Tests for heterogeneity

○ Assessment of publication bias
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• Characteristics of the included studies

○ Average or range of ages included

○ Average or range of sex distribution

○ Inclusion of Veteran Health Care Facilities

○ Indication for anticoagulation

○ Baseline bleeding risk or factors associated with increased risk (e.g., creatinine >1.5, 

history of gastrointestinal bleeding), if given

○ Countries included in primary studies

○ Study drug and comparator, route of administration, and dosage

○ Length of treatment and followup duration 

○ Funding source

• Results of the systematic review

○ Number of studies and subjects and completion rates

○ Quality of the primary literature and strength of evidence, if given

○ Outcomes (including definition of outcome, if given)

○ Results from subgroup or sensitivity analyses

○ Author conclusions

In addition, we examined included articles for subgroup analyses of particular relevance to the 

population served by Veterans Health Administration. Data on the inclusion of Veteran Health 

Care Facilities was not provided at the systematic review level; therefore, we returned to the 

primary literature to abstract this information. 

QUALITY ASSESSMENT

We also abstracted data necessary for assessing the quality of systematic reviews, adapted 

from the AMSTAR criteria.25-27 These key quality criteria consist of (1) search methods are 

adequate for replication and are comprehensive, (2) selection bias is avoided, (3) data are 

abstracted reliably, (4) characteristics of primary literature are reported and quality is assessed 

appropriately, (5) results are synthesized using appropriate methods, (6) publication bias is 

assessed, (7) conflict of interest is reported, and (8) conclusions are supported by results. We 

supplemented these criteria for studies that used multiple treatment comparisons based on the 

guidance by Mills et al.28 Based on these criteria, systematic reviews were categorized as good, 

fair, or poor quality (Appendix D). Poor-quality reviews were excluded. The criteria were applied 

for each study by the reviewer abstracting the article; this initial assessment was then overread 

by a second reviewer. Disagreements were resolved between the two reviewers or, when needed, 

by arbitration from a third reviewer.

DATA SYNTHESIS

We categorized each systematic review by the key research questions they addressed and 

critically analyzed them to compare their characteristics, methods, and findings. We summarized 

the key findings and conclusions from each included review and produced summary tables for 

comparison across reviews. We prioritized the evidence from these reviews by higher quality of 

methodological designs, more complete drug comparisons (e.g., by class and drug rather than 
17

Comparative Effectiveness of New Oral Anticoagulants

for Thromboprophylaxis Evidence-based Synthesis Program

by drug only), and more detailed information about population, specific drug intervention (e.g., 

dosage), and definitions of outcomes. In addition to summary measures of relative effects (e.g., 

risk ratios), we report absolute risk differences in the summary strength of evidence tables. For 

FXa inhibitors, we used the risk differences reported by Neumann et al.20 To standardize the 

reporting of risk differences, which are dependent on the baseline risk of events, we adopted the 

approach used by Neumann et al. for other drugs. Risk difference was estimated by using the 

baseline risk from the control group and the risk ratio from the relevant meta-analysis. Baseline 

risk for patients treated with LMWH, the common comparator for newer anticoagulants, was 

estimated for each major outcome as symptomatic deep vein thrombosis (DVT), 9 per 1000 

patients; nonfatal pulmonary embolism (PE), 3 per 1000 patients; mortality, 3 per 1000 patients; 

and major bleeding, 7 per 1000 patients.20

Our synthesis focused on documenting and identifying patterns in efficacy and safety of the 

different drugs. To determine the consistency of results and conclusions, we then compared 

each additional review that addressed the same key question. If findings or conclusions differed 

importantly across reviews, we analyzed potential reasons for discrepancies such as the primary 

literature included (both the type of studies and the dates of the searches), review inclusion/

exclusion criteria, differences in outcome definition, analytic approach, and conflict of interest. 

In the event that our supplemental search of the primary literature identified additional eligible 

studies, we planned a qualitative summary of these studies to determine if the outcomes observed 

were consistent with the results from the systematic reviews. However, our search did not 

identify any additional relevant RCTs.

RATING THE BODY OF EVIDENCE

In addition to rating the quality of individual studies, we evaluated the overall quality of the 

evidence for each KQ as described in the Methods Guide for Effectiveness and Comparative 

Effectiveness Reviews.

29 In brief, this approach requires assessment of four domains: risk of 

bias, consistency, directness, and precision. For risk of bias, we considered basic (e.g., RCT) 

and detailed study design (e.g., adequate randomization) using the quality assessments of the 

primary literature reported in the systematic reviews. We used results from meta-analyses when 

evaluating consistency (forest plots, tests for heterogeneity), precision (confidence intervals), 

strength of association (odds ratio), and whether publication bias was detected (e.g., funnel plots 

or Begg’s test). Optimal information size and consideration of whether the confidence interval 

crossed the clinical decision threshold for a therapy were also used when evaluating precision.30

These domains were considered qualitatively, and a summary rating of high, moderate, low, or 

insufficient strength of evidence was assigned after discussion by two reviewers. This four-level 

rating scale consists of the following definitions:

•	 High—Further research is very unlikely to change our confidence on the estimate of 

effect.

•	 Moderate—Further research is likely to have an important impact on our confidence in 

the estimate of effect and may change the estimate.

•	 Low—Further research is very likely to have an important impact on our confidence in 

the estimate of effect and is likely to change the estimate.
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Comparative Effectiveness of New Oral Anticoagulants

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•	 Insufficient—Evidence on an outcome is absent or too weak, sparse, or inconsistent to 

estimate an effect.

When a rating of high, moderate, or low was not possible or was imprudent to make, a grade of 

insufficient was assigned.31

PEER REVIEW

A draft version of the report was reviewed by technical experts and clinical leadership. A 

transcript of their comments can be found in Appendix E, which elucidates how each comment 

was considered in the final report.
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Comparative Effectiveness of New Oral Anticoagulants

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RESULTS

LITERATURE SEARCH

The flow of articles through the literature search and screening process is illustrated in Figure 2. 

Our search for systematic reviews (SRs) identified 162 unique citations from a combined search 

of MEDLINE via PubMed (n=117), Embase (n=42), and the Cochrane Database of Systematic 

Reviews (n=3). Manual searching of included study bibliographies and review articles added 20 

more citations for a total of 182 unique citations. After applying inclusion and exclusion criteria 

at the title-and-abstract level, 47 full-text articles were retrieved and screened. Of these, 38 were 

excluded at the full-text screening stage, leaving 9 articles (representing 9 unique studies) for 

data abstraction. After further review, we excluded three systematic reviews32-34 because they 

reviewed only one drug of interest and all of the primary studies included in these systematic 

reviews were already represented in another, more comprehensive included review. Thus, the 

final set of articles used in this evidence report comprises six systematic reviews.

Appendix B provides a complete listing of published articles excluded at the full-text screening 

stage, with reasons for exclusion. We did not search www.clinicaltrials.gov for randomized 

controlled trials (RCTs) currently underway, as we relied on methods in the included systematic 

reviews to ascertain publication bias. We grouped the studies by key question (Figure 2). 

Figure 2. Literature flow diagram

Search results:

182 referencesa

Excluded: 135 references at the 

title/abstract level

Retrieved for full-text review:

47 references

Excluded: 38 references

Not a systematic review: 32

Poor-quality systematic review: 1

Did not address KQs: 5

Note: 20 of these 38 were flagged

for background.

Potential for abstraction: 

9 references

Excluded: 3 references that examined a 

single drug and all primary studies were 

represented in other reviewsb

Abstracted:

6 systematic reviews (SRs)

KQ 1: New oral 

anticoagulants 

vs. comparator

(6 SRs)

KQ 2: Mechanical 

interventions

(1 SR)

KQ 3: Within-class 

comparisons

(2 SRs)

a

Search results for systematic reviews from PubMed (117), Embase (42), Cochrane (3), previous database (14), and manual (6) 

were combined.

b

Cao, 2010; Huang, 2011; and Turun, 2011. 

Note: The reference list of this report includes additional references cited for background and methods plus Web sites relevant to 

the key questions.

Abbreviations: KQ=key question; SR=systematic review
20

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STUDY CHARACTERISTICS

We identified six recent, good-quality SRs9,20-23,35 that were relevant to our KQs (Table 5). 

All of the SRs compared newer oral anticoagulants with other drug classes used for 

thromboprophylaxis in THR or TKR (KQ 1), although one considered only safety outcomes such 

as major bleeding.35 Two of the six SRs compared one newer oral anticoagulant with another 

(KQ 3) though all results were based on indirect comparisons; i.e., through common comparison 

with enoxaparin.21,23 Only one SR9 compared a pharmacological agent plus mechanical modality 

versus mechanical modality alone (KQ 2). Five of the six SRs included trials examining 

thromboprophylaxis for both THR and TKR, while one also included hip fracture surgery.9

Characteristics of the SRs are summarized in Table 5; detailed quality assessments are presented 

in Appendix D.

Search dates ranged from May 2009 to December 2011. All literature search strategies included 

MEDLINE, and all but one21 included some aspect of the Cochrane Library. Other databases or 

sources of information were meeting abstracts (5), Embase (3), regulatory Web sites (4), clinical 

trial registries (3), and the Center for Reviews and Dissemination (1). Four studies9,20-22 also 

involved a manual search of the bibliographies of exemplary primary articles. The searches were 

limited only to RCTs in four of the SRs. One included SRs,22 and one included observational 

studies of more than 750 subjects9 in addition to RCTs. Language limits were used in only two of 

the studies. 

All reviews assessed the quality of included trials. Overall trial quality was judged to be good, 

with the most common quality problems being unclear allocation concealment and incomplete 

reporting of outcome data. Publication bias was assessed most commonly with funnel plots, 

which did not indicate any publication bias that would favor newer oral anticoagulants. All 

studies conducted random-effects meta-analyses, but specific strategies varied. Two SRs 

compared drug classes as a whole (for example, FXa inhibitors versus LMWH9,20), while the 

other four SRs compared individual drugs, some analyzing THR and TKR studies separately. All 

of the SRs performed meta-analysis using direct comparisons, and two also provided indirect 

comparisons.21,23 Every SR except one21 evaluated major bleeding using the same definition: 

bleeding that was fatal, involved a critical organ, required reoperation, or where bleeding was 

associated with a fall in hemoglobin level of at least 2 g/dL or required infusion of 2 or more 

units of whole blood or packed cells. Our other prespecified primary outcomes—all-cause 

mortality, symptomatic DVT, and nonfatal PE—were reported in three of the SRs.9,20,22 It was 

difficult to evaluate the other SRs21,23,35 due to the individuality of the definitions given for the 

outcomes reported, many of which were composite outcomes. For example, in the study by 

Loke et al.,21 the authors state the composite primary outcome as “total VTE” and define it as 

“DVT, non-fatal PE and all-cause mortality” (emphasis added). The study also reports bleeding 

as a combination of major bleeding (using the standard definition given above) and “clinically 

relevant non-major bleeding.”

Three of the SRs were unfunded and reported no conflicts of interest.21,23,35 One SR was unfunded 

but did report a conflict of interest for one author.20 Two SRs were funded by government 

agencies.9,22
21

ew Oral Anticoagulants for Thromboprophylaxis Evidence-based Synthesis Program

uded systematic reviews

mann, 201220 Sobieraj, 20129 Gómez-Outes, 201223 Loke, 201121 Ringerike, 201122 Alves, 201135

Good Good Good Good Good

KQs 1, 2 KQs 1, 3 KQs 1, 3 KQ 1 KQ 1 (safety only)

KR THR, TKR, HFS THR, TKR THR, TKR THR, TKR THR, TKR

g classes:

s. LMWH 

H/warfarin in one 

tudies)

As drug classes:- FXa vs. LMWH- DTI vs. LMWH- DTI vs. UFH

As individual drugs vs. LMWH:- Apixaban- Dabigatran- Rivaroxaban

As individual drugs vs. LMWH:- Dabigatran- Rivaroxaban

As individual drugs vs. LMWH:- Dabigatran- Rivaroxaban

As individual drugs vs. LMWH:- Apixaban- Rivaroxaban

NE, Embase, 

T, meeting 

cts

MEDLINE, CCRCT, Scopus, clinical trial registries, meeting abstracts, regulatory Web sites

MEDLINE, CCRCT, clinical trial registries, meeting abstracts, regulatory Web sites

MEDLINE, Embase, clinical trial registries, regulatory Web sites

MEDLINE, Embase, Cochrane Library and Center for Reviews and Dissemination

MEDLINE, Cochrane Library; meeting abstracts, regulatory Web sites

ber 2011 May 2011 April 2011 May 2009 September 2010 June 2011

None None None English, Scandinavian NoneRCTs, observational if more than 750 subjects RCTs RCTs RCTs, SRs RCTs

nalysis, direct, 

up by dosage

Meta-analysis, direct, indirect,network MA

Meta-analysis, direct, indirect,subgroup by surgery type

Meta-analysis, direct, indirect,subgroup by protocol

Meta-analysis, subgroup by type of surgery

Meta-analysis, direct, subgroup by surgery type

ty, symptomatic 

onfatal PE, 

bleeding

Mortality, symptomatic DVT, nonfatal PE, major bleeding

Symptomatic DVT, nonfatal PE, major bleeding

None included Mortality, symptomatic 

DVT, nonfatal PE, major bleeding

Major bleeding 

anial bleeding, 

g leading to 

ation

Symptomatic VTE, major VTE,PE, surgical site bleeding, readmission

Total VTE or mortality, symptomatic VTE, clinically relevant bleeding

Total VTE (mortality + DVT + nonfatal PE), bleeding (major + clinically relevant nonmajor)

None Safety variables:

Other types of bleeding, adverse events

Government None None Government None

sclosed No No No NR No

 2=combined pharmacological and mechanical vs. pharmacological monotherapy; KQ 3=within-class comparisons of newer oral anticoagulants, all of which 

tral Registry of Controlled Trials; CINAHL=Cumulative Index of Nursing and Allied Health Literature; COI=conflict of interest; DTI=direct thrombin inhibitor; 

r Xa inhibitor; HFS=hip fracture surgery; KQ=key question; LMWH=low molecular weight heparin; MA=meta-analysis; NR=not reported; PE=pulmonary em

al; SR=systematic review; THR=total hip replacement; TKR=total knee replacement; UFH=unfractionated heparin; VTE=venous thromboembolism
22

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PARTICIPANT CHARACTERISTICS

Information on the populations studied was very limited in all of the included SRs (Table 6). The 

number of primary articles included ranged from 5 to 45; total sample size ranged from just over 

19,000 to almost 240,000, but two articles did not report the total number of subjects. Females 

made up approximately 50 to 75 percent of the population when reported. Mean age ranged 

from 55 to 68 years in the 5 studies reporting age. Weight or body mass index was reported in 

four studies and indicated most subjects were moderately overweight to slightly obese. Risk 

factors for VTE were limited to a prior history of VTE (two studies) or history of cancer (one 

study); only a small proportion of patients had one of these risk factors. No other risk profiles 

or population characteristics were reported, and no study reported whether or not Veterans 

were included in the sample. However, our review of the primary studies found that no studies 

specifically included Veterans or were conducted at VA medical centers.

Table 6. Characteristics of patient samples

Study Neumann, 

201220

Sobieraj, 

20129

GómezOutes, 201223 Loke, 201121 Ringerike, 

201122 Alves, 201135

Studies

(N patients)a 22 (32,159) 45 (36,152) 16 (38,747) 9 (19,218) 5 (NR) 12 (28,483)

Female

(% range) 44.6 to 72.5

RCTs

36.05–84.1% 

observational

63–65% 

50 to 74 55 to 70 NRb 51 to 71

Mean age

(range) 57.8 to 67.6

RCTs

52.4 to 78.3;

observational

66.4 to 71

61 to 68 63.2 to 67.7 NRb 60.6 to 67.6

Weight

(kg range)

26.5 to 32.7c 

RCTs

64.2 to 89 kg; 

observational 

NR

75 to 89 76 to 89 NR NR

Veterans? No No No No No No

Risk factors:

History of VTE

History of 

cancer

NR

 0 to 14.5%

 0 to 12.4%

1 to 4% 

(9 studies) NR NR NR

Risk factorsd NR NR NR NR NR NR

a

Numbers are for RCTs, with the exception of Ringerike et al., which reviewed three RCTs and two SRs. Sobieraj et al. also 

reviewed three observational studies including over 239,000 participants.

b

Ringerike et al. did not give demographics on study populations but did give national statistics on who had these surgeries 

performed in Sweden: average age is 69.1 and 69.4 yrs and % female is 68.4 and 67.4% on average for THR and TKR, 

respectively.

c

Value is in BMI units (kg/m2). d

Risk factors sought were prior gastrointestinal bleeding, anemia, chronic kidney disease, and diabetes mellitus. 

Abbreviations: kg=kilogram; NR=not reported; RCT=randomized controlled trial; VTE=venous thromboembolism
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Comparative Effectiveness of New Oral Anticoagulants

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KEY QUESTION 1. For patients undergoing total hip or total knee 

replacement, what is the comparative effectiveness of newer oral 

anticoagulants and standard drug classes (low molecular weight 

heparin, injectable FXa inhibitors, unfractionated heparin, warfarin, 

aspirin) on the incidence of symptomatic, objectively confirmed 

venous thromboembolism (VTE), other VTE events, total mortality, 

and bleeding outcomes?

Key Points 

• For all-cause mortality and nonfatal PE, there were no important differences between 

oral FXa inhibitors and LMWH (high strength of evidence). Using a base rate of 9 events 

per 1000 patients with LMWH, FXa inhibitors were associated with lower symptomatic 

DVT (4 fewer events per 1000 patients; 95% CI, 3 to 6). Overall, FXa inhibitors were 

associated with an increased risk of major bleeding, but major bleeding did not differ 

importantly at low to moderate doses (moderate strength of evidence). Based on subgroup 

analyses, there was not a consistent pattern of differences in treatment effects for THR 

and TKR.

• There were fewer studies evaluating oral DTIs than oral FXa inhibitors; all trials 

compared dabigatran with enoxaparin. Although estimates of effect were often imprecise, 

there were no significant differences between oral DTIs and enoxaparin for any major 

outcome.

• Neither oral FXa inhibitors nor DTIs have been compared directly with adjusted-dose 

warfarin, oral antiplatelet drugs, or unfractionated heparin in existing SRs.

We identified six good-quality SRs9,20-23,35 that evaluated thromboprophylaxis using newer oral 

anticoagulants versus LMWH. For each comparison, we focus our discussion on the review 

having the most recent search date and comprehensive analysis, and which reported our 

prespecified outcomes of interest. Other reviews are described briefly when findings differed 

importantly or additional analyses provided relevant results. 

Effects of Oral FXa Inhibitors Compared With Low Molecular Weight Heparin

A good-quality SR20 (search date December 2011) included 22 RCTs and a total of 32,159 

patients that compared FXa inhibitors with LMWH for surgical thromboprophylaxis. Eleven of 

the included studies were on hip replacement, 10 were on knee replacement, and 1 was on either 

procedure. FXa inhibitors included apixaban (four studies), rivaroxaban (eight studies), edoxaban 

(four studies), YM150 (two studies), and LY1517717, TAK442, razaxaban, and betrixaban (one 

study each). Of these drugs, only rivaroxaban is currently available in the United States. In the 

majority of trials, the European-approved dose of enoxaparin, 40 mg daily, was the comparator 

instead of the U.S.-approved dose, 30 mg twice daily. The duration of thromboprophylaxis was 

14 days or less in all but 4 trials. Patients were followed for less than 14 days in 9 trials, 30 to 70 

days in 12 trials, and up to 90 days in one trial. In addition to a random-effects meta-analysis of 

drug class comparisons, this sophisticated review performed a multiple-treatment-comparison 

meta-analysis to evaluate effects of FXa dose, and sensitivity analyses to examine the effects 

of missing outcomes. Pooled estimates of effect were presented as summary odds ratios and 
24

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for Thromboprophylaxis Evidence-based Synthesis Program

summary risk differences. In addition, risk differences were estimated by applying the relative 

risk reduction from meta-analysis to the baseline risk estimated from a large cohort study. 

This SR by Neumann et al.20 found high strength of evidence suggesting no important difference 

between oral FXa inhibitors and LMWH for all-cause mortality (OR 0.95; 95% CI, 0.55 to 

1.63; I2=43%) and nonfatal PE (OR 1.07; CI, 0.65 to 1.73; I2=35%) in patients undergoing THR 

or TKR. However, high strength of evidence indicated that the risk of symptomatic DVT is 

decreased by 4 events for every 1000 patients treated using FXa thromboprophylaxis compared 

with LMWH (OR 0.46; CI, 0.30 to 0.70; I2=0%). There was moderate strength of evidence 

because of inconsistency, suggesting that the risk of major bleeding may be increased with 

oral FXa inhibitors compared with LMWH (OR 1.27; CI, 0.98 to 1.65; I2=55%). This finding 

represents an increase of 2 major bleeding events per 1000 patients treated with FXa, for 1 to 

5 weeks compared with LMWH. The pooled effect estimate of bleeding that led to reoperation 

also was increased (OR 1.62; CI, 0.82 to 3.19; I2=1%), but the confidence interval included the 

possibility of a chance association. 

In a subgroup analysis, higher doses of FXa inhibitors, but not intermediate or lower doses, 

were associated with increased risk of bleeding (OR 2.50; 95% CI, 1.38 to 4.53; p=0.02). The 

authors did not report the drug doses used for this subgroup analysis. Total daily doses were 

reported for the primary studies and ranged from 5 to 20 mg for apixaban and 5 to 60 mg for 

rivaroxaban. In an analysis that adjusted for FXa dose, there was no significant difference in 

thrombotic or bleeding outcomes for different FXa inhibitors. Sensitivity analyses that accounted 

for missing outcomes did not differ appreciably from the main analyses. Thus this SR concluded 

that while there is no important difference between low-dose oral FXa inhibitors and LMWH for 

the outcomes of all-cause mortality, nonfatal PE, and major bleeding, there is a small absolute 

reduction in symptomatic DVT events (4 fewer events per 1000 patients treated). However, 

most studies included in this SR reported bleeding as a composite outcome and did not include 

details; this introduces uncertainty about the importance of the reported bleeding events. Other 

limitations of the included trials in this SR were (1) missing outcomes for 3 to 41 percent of 

randomized patients, (2) the short duration of followup in many trials, (3) the nonstandard dosing 

of enoxaparin, and (4) the short duration of prophylaxis in patients undergoing THR. 

The other SRs9,21-23,35 were generally in agreement with the results and conclusions of Neumann 

et al. Where disagreements occurred, they were mainly due to different outcomes (e.g., 

composite outcomes), differences in approach to data analysis (separate analyses for each drug), 

and fewer included studies due to earlier search dates and more restrictive inclusion criteria 

(e.g., only FDA-approved drugs). Also, most SRs reported on outcomes by individual new oral 

anticoagulants, whereas those by Neumann et al. and Sobieraj et al. reported on outcomes by 

drug class. 

We summarize below the notable findings from these other SRs:

• In a good-quality review23 that separately analyzed the effects of apixaban (4 trials) and 

rivaroxaban (8 trials), both drugs were associated with lower symptomatic DVT than 

enoxaparin (apixaban, RR 0.41; 95% CI, 0.18 to 0.95, and rivaroxaban, RR 0.40; CI, 

0.22 to 0.72). Symptomatic VTE (DVT or PE) was decreased with rivaroxaban (RR 0.48; 

CI, 0.31 to 0.75; I2

=5%) but not apixaban (RR 0.82; CI, 0.41 to 1.64; I2=40%). All-cause 
25

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mortality was not reported as a separate outcome. Symptomatic PE and major bleeding 

did not differ significantly from LMWH, but confidence intervals for these estimates were 

wide and included the potential for clinically important differences. Notably, to increase 

the consistency of outcome definitions and results, major bleeding rates for the RECORD 

studies of rivaroxaban36-39 were analyzed using data reported to the FDA—a definition that 

included wound bleeding. Subgroup analyses showed no differences in treatment effect by 

type of surgery (THR vs. TKR) for symptomatic VTE or clinically relevant bleeding. 

• In a review limited by the exclusion of rivaroxaban,9 the pooled effect from four RCTs 

comparing LMWH with FXa inhibitors did not show a significant difference in major 

bleeding leading to reoperation (OR 0.67; 95% CI, 0.28 to 1.61). 

• In a review limited by the exclusion of apixaban,21 the risk of hemorrhage (major and 

clinically relevant nonmajor bleeding) did not differ significantly for rivaroxaban 

compared with LMWH (RR 1.26; 95% CI, 0.94 to 1.69; I2=28%). Hemorrhage was 

defined as major bleeding leading to death, reoperation, blood transfusion of two or more 

units, a drop in hemoglobin level of more than two g/dL, or bleeding into a critical organ. 

In contrast to the review by Gómez-Outes et al., published rates of bleeding rather than 

rates reported to the FDA (that included wound bleeding) were used for these analyses.

• A report on adverse outcomes by type of surgery compared two oral FXa inhibitors with 

enoxaparin.35 There was a lower risk of major bleeding with apixaban compared with 

LMWH in TKR (RR 0.56; 95% CI, 0.32 to 0.96) but not in THR (RR 1.22; 95% CI, 0.65 

to 2.26). Major bleeding events were not different with rivaroxaban treatment compared 

with LMWH in both types of surgeries. Subgroup analysis showed an increased risk of 

bleeding with the 30-mg twice-daily dosing regimen of LMWH compared with the 40-

mg once-daily dose.

Effects of Direct Thrombin Inhibitors Compared with Low Molecular Weight Heparin

Only four SRs9,21-23 included comparisons of dabigatran—the only available DTI—with standard 

thromboprophylaxis using LMWH. A good-quality SR (search date April 2011) included 4 trials 

involving 12,897 patients that compared dabigatran with enoxaparin for thromboprophylaxis of 

THR or TKR.23 The surgical procedure was THR and TKR in two trials each. In three trials, the 

comparator was enoxaparin at 40 mg daily, and in one trial the dose was 30 mg twice daily. The 

duration of thromboprophylaxis was 15 days or less in the two TKR studies and 28 to 35 days in 

the two THR studies. The duration of followup was approximately 3 months. Three studies used 

a three-arm design; the dabigatran 150 mg and dabigatran 220 mg treatment arms were combined 

for meta-analysis. The two-arm trial evaluated dabigatran 220 mg, a dose that is not approved by 

the FDA. All-cause mortality was not reported as a separate outcome.

In a random-effects meta-analysis, the risk of symptomatic PE (RR 0.69; 95% CI, 0.31 to 

1.54; I2=NR) and symptomatic DVT (RR 0.82; CI, 0.17 to 3.99; I2=NR) did not differ between 

dabigatran and enoxaparin.23 Similarly, there was no statistically significant difference in 

symptomatic VTE (DVT and PE), but treatment effects differed substantially across studies 

(I2

=73%). Clinically relevant bleeding events (major bleeding and clinically relevant nonmajor 

bleeding) were not different with dabigatran treatment (RR 0.94; CI, 0.58 to 1.52; p=0.79). In 

subgroup analyses, there was no statistically significant interaction between type of surgery and 

effects on symptomatic VTE or clinically relevant bleeding.
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Three other SRs9,21,22 reported additional outcomes, including mortality, major bleeding, and 

bleeding leading to rehospitalization, summarized below:

• The SR by Ringerike et al.22 included an additional study (BISTRO-II)40 of patients 

undergoing either THR or TKR, but anticoagulation was given for 7 days only. The SR 

by Sobieraj et al.9 evaluated an injectable DTI (desirudin) but did not include the most 

recent trial of oral DTI,40 which was also omitted in the SR by Loke et al.21 Despite these 

differences in approach, mortality did not differ significantly for DTIs compared with 

enoxaparin in any of these analyses. Consistent with the findings by Gómez-Outes et al.23

for clinically relevant bleeding, major bleeding did not differ between drug classes when 

analyzed by surgical procedure22 or in aggregate.9,21

• Sobieraj et al.9 found no significant difference between LMWH and dabigatran for 

bleeding leading to rehospitalization (RR 1.27; 95% CI, 0.43 to 3.75; moderate strength 

of evidence).

Other Comparisons of Interest

Only one good-quality SR by Sobieraj et al.9

 (search date May 2011) addressed drug class 

comparisons between older antithrombotics. We summarize results for key drug class 

comparisons and outcomes below.

Low molecular weight heparin versus vitamin K antagonists. Sobieraj et al.9 reported 

on the comparative effects of LMWH thromboprophylaxis versus adjusted-dose warfarin. 

LMWHs included enoxaparin (30 mg every 12 hours) and logiparin. Other details such as 

duration of treatment and duration of followup were not reported uniformly for the included 

trials. Depending on outcomes, 3 to 7 trials were included in the meta-analyses. There was no 

significant difference in mortality (OR 0.79; 95% CI, 0.42 to 1.50; I2=0%), nonfatal PE (OR 

1.00; CI, 0.20 to 4.95; I2=NR), or symptomatic DVT (OR 0.87; CI, 0.61 to 1.24; I2=28.4%). The 

risk of major bleeding was significantly higher in the LMWH treatment group (OR 1.92; CI, 1.27 

to 2.91; I2=0; high strength of evidence).

Oral FXa inhibitors versus unfractionated heparin. Sobieraj et al.9 reported on the 

comparative effects of oral FXa inhibitors versus unfractionated heparin. There were no RCTs 

comparing oral or injectable FXa inhibitors with unfractionated heparin. One observational study 

compared an injectable FXa inhibitor (fondaparinux) with unfractionated heparin; drug doses 

were not reported. The injectable FXa inhibitor was associated with lower mortality compared 

with unfractionated heparin. The risk of major bleeding was found to be increased in the 

unfractionated heparin treatment group compared with the injectable FXa inhibitor group (OR 

1.27; 95% CI, 1.06 to 1.52). Effects on symptomatic DVT and nonfatal PE were not reported. 

Low molecular weight heparin versus oral antiplatelet agents. Sobieraj et al.9

 reported on the 

comparative effects of LMWH versus oral antiplatelet agents but identified no studies comparing 

these drug classes.

Antiplatelet agents versus vitamin K antagonists. Sobieraj et al.9 reported on the comparative 

effects of antiplatelet agents versus vitamin K antagonists, identifying a single RCT. Among 

patients undergoing hip fracture surgery, the risk of mortality was similar in both treatment 

arms (RR 0.98; 95% CI, 0.32 to 3.05). Nonfatal PE was evaluated, but there were no events 
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for Thromboprophylaxis Evidence-based Synthesis Program

in either treatment arm. The risk of major bleeding was also reported in this trial and did not 

show a statistically significant difference (RR 0.20; CI 0.03 to 1.23). In addition to this RCT, 

two observational studies compared aspirin prophylaxis with vitamin K antagonists in patients 

undergoing THR or TKR. One study showed higher mortality with aspirin prophylaxis (0.3 

percent vs. 0 percent; p=0.013); the other study found no significant difference in mortality. 

There were no reports on symptomatic DVT or symptomatic VTE. 

KEY QUESTION 2. For patients undergoing total hip or total knee 

replacement, what are the effects of combined pharmacological and 

mechanical modalities versus pharmacological treatment alone on 

the incidence of symptomatic, objectively confirmed VTE, other VTE 

events, total mortality, and bleeding outcomes?

Key Points

• In the included SRs, no studies were identified that compared the combination of newer 

oral anticoagulants and mechanical thromboprophylaxis with pharmacological treatment 

alone.

• Few studies have compared older antithrombotics (LMWH, oral antiplatelet agents, or 

unfractionated heparin) combined with mechanical prophylaxis to pharmacological or 

mechanical prophylaxis alone. 

• The strength of evidence is insufficient to determine the comparative effectiveness for 

combined pharmacological and mechanical prophylaxis compared with pharmacological 

prophylaxis alone for all major outcomes prioritized for this report. 

One good-quality SR9

 (search date May 2011) included 6 trials and a total of 995 patients 

that compared a combined-modality thromboprophylaxis (pharmacological and mechanical 

agents) with a single modality and found a paucity of data. Four of the included studies were 

on hip replacement, one was on knee replacement, and one included both surgeries. No trial 

evaluated the combination of a newer oral anticoagulant together with mechanical prophylaxis. 

Combination treatments included LMWH, aspirin, or unfractionated heparin together with 

mechanical prophylaxis. Of the six trials, the comparator was pharmacologic prophylaxis alone 

(4 trials), mechanical prophylaxis alone (1 trial), and both pharmacological and mechanical 

comparators (1 trial). Duration of followup ranged from the postoperative period to 90 days. 

Three trials reported effects on mortality, but treatment effects were not pooled. Two of 

these trials had no mortality events; the third trial comparing the combination of aspirin plus 

pneumatic compression to aspirin alone found no effects on mortality (OR 7.72; 95% CI, 0.15 

to 389.59), but the trial was underpowered for clinically significant differences. Two trials 

evaluated the effects on nonfatal PE, but there were no events in either trial. A single older 

trial evaluated the effects of sequential unfractionated heparin for 3 days, then aspirin together 

with a venous foot pump versus sequential pharmacologic prophylaxis alone or a venous foot 

pump alone. The combined modality had a lower risk of symptomatic DVT compared with 

pharmacologic prophylaxis only (RR 0.14; 95% CI, 0.01 to 1.42), but there were few events, 

and the confidence interval included no effect. Only one trial reported the effects of combined 
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for Thromboprophylaxis Evidence-based Synthesis Program

thromboprophylaxis (aspirin plus venous foot pump) compared with aspirin alone for major 

bleeding. However, there were no major bleeding events in either treatment arm. The authors 

concluded that there was insufficient evidence for all outcomes when comparing pharmacologic 

plus mechanical prophylaxis to pharmacologic prophylaxis alone, with the exception of overall 

DVT (including asymptomatic DVT). For overall DVT, combined treatment was more effective 

than pharmacologic prophylaxis alone. 

KEY QUESTION 3. For patients undergoing total hip or total knee 

replacement, what is the comparative efficacy of individual newer 

oral anticoagulants on the incidence of symptomatic, objectively 

confirmed VTE, other VTE events, total mortality, and bleeding 

outcomes?

Key Points

• No clinical trials directly compared newer oral anticoagulants with each other for 

thromboprophylaxis of TKR or THR.

• The included SRs did not estimate the comparative efficacy of newer oral anticoagulants 

for symptomatic DVT, nonfatal PE, all-cause mortality, or surgical site bleeding.

• Based on indirect comparisons, there were few differences between newer oral 

anticoagulants for the outcomes examined. Rivaroxaban was associated with more 

major bleeding than apixaban (RR 1.59; 95% CI, 0.84 to 3.02). In contrast, the risk of 

symptomatic VTE was lower for rivaroxaban than apixaban or dabigatran, but confidence 

intervals included the possibility of a chance association.

In the absence of direct comparisons between the newer oral anticoagulants, two good-quality 

SRs used indirect comparisons21,23 to analyze these drugs. 

A good-quality comprehensive review23 (search date April 2011) evaluated apixaban (4 trials), 

dabigatran (4 trials), and rivaroxaban (8 trials) against a common comparator (enoxaparin). 

These indirect comparisons utilized pooled risk ratios and yielded an unbiased estimate of effect 

“when there is no interaction between covariates defining subgroups of patients (reflected, for 

instance, in different inclusion criteria in different studies) and the magnitude of the treatment 

effect.”41 Of the 16 trials (total of 38,747 patients), 8 were of total hip replacement and 8 of 

total knee replacement. Outcomes reported in the indirect comparisons included symptomatic 

venous thromboembolism (DVT or PE), clinically relevant bleeding (major bleeding or clinically 

relevant nonmajor bleeding), major bleeding, and a net clinical endpoint—defined as a composite 

of symptomatic VTE, major bleeding, and all-cause death. Overall, the primary trials were rated 

low risk of bias. Individual drug comparisons across these 4 outcomes (12 comparisons) showed 

only one statistically significant difference: rivaroxaban resulted in more clinically relevant 

bleeding compared with apixaban (RR 1.52; 95% CI, 1.19 to 1.95). The risk of major bleeding 

was also increased with rivaroxaban compared with apixaban (RR 1.59; CI, 0.84 to 3.02), but 

the difference was not statistically significant. Rivaroxaban was associated with lowest risk of 

symptomatic VTE compared with dabigatran (RR 0.68; CI, 0.21 to 2.23) and apixaban (RR 0.59; 

CI, 0.26 to 1.33), but neither comparison was statistically significant. Overall, differences in the 
29

Comparative Effectiveness of New Oral Anticoagulants

for Thromboprophylaxis Evidence-based Synthesis Program

number of VTE events were offset by the number of major bleeding episodes. Thus, there was no 

difference on the net clinical endpoint among apixaban, dabigatran, and rivaroxaban. The review 

concluded that “higher efficacy of new anticoagulants was generally associated with higher 

bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety.”23

The other SR provided few additional relevant findings. Similar to the review described above, 

Loke et al.21 (search date May 2009) used indirect analysis methods but excluded studies of 

apixaban, yielding a less informative analysis. In addition, a dabigatran trial published after 2009 

and three rivaroxaban studies were excluded due to more restrictive eligibility criteria. Despite 

these differences, findings regarding rivaroxaban compared with dabigatran were generally 

similar. The authors concluded that rivaroxaban was superior to dabigatran in preventing VTE 

(RR 0.50; 95% CI, 0.37 to 0.68) although with an increased risk of bleeding (RR 1.14; CI, 0.80 

to 1.64). The decreased risk of VTE with rivaroxaban was consistent across different doses of 

dabigatran (150 mg vs. 220 mg), different dosing regimens of enoxaparin in the control groups 

(30 mg twice daily vs. 40 mg once daily), and the type of surgery (THR vs. TKR).
30

Comparative Effectiveness of New Oral Anticoagulants

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SUMMARY AND DISCUSSION

We identified six good-quality SRs that evaluated thromboprophylaxis using newer oral 

anticoagulants versus LMWH. One SR evaluated additional drug classes, including 

unfractionated heparin, aspirin, and vitamin K antagonists. Although we identified no direct 

comparisons of newer oral anticoagulants, two good-quality SRs indirectly compared one newer 

oral anticoagulant with another through common comparison to enoxaparin.21,23 Only one SR 

compared combined pharmacologic and mechanical thromboprophylaxis to either method 

alone.9 FXa inhibitors have been studied more extensively than DTIs. In the absence of head-tohead comparisons between newer oral anticoagulants, it is difficult to draw strong conclusions 

on inter- or intra-drug class differences. The main findings and strength of evidence from our 

literature synthesis are summarized by key question in the section that follows. 

SUMMARY OF EVIDENCE BY KEY QUESTION

KQ 1: Newer Oral Anticoagulants Versus Standard Treatments

FXa inhibitors. Rivaroxaban and apixaban are the most commonly studied FXa inhibitors. 

The risk of symptomatic DVT was reduced with FXa inhibitors thromboprophylaxis compared 

with LMWH, while the risk of nonfatal PE and mortality was not significantly different (all 

high strength of evidence). The estimated absolute risk difference was 4 fewer symptomatic 

DVT events for each 1000 patients receiving thromboprophylaxis with FXa inhibitors over 5 

weeks compared with LMWH. However, these benefits were offset by an increase in major 

bleeding (moderate strength of evidence). The absolute risk difference was 2 more major 

bleeding events per 1000 patients on FXa thromboprophylaxis over a period of 5 weeks. Higher 

doses of FXa inhibitors but not intermediate or low doses were associated with increased major 

bleeding.20 Subgroup analysis by specific drug and type of surgery showed a reduced risk of 

bleeding with apixaban compared with LMWH in TKR but not in THR; risk of major bleeding 

with rivaroxaban did not differ significantly for either surgery.35 No reviews identified trials 

comparing oral FXa inhibitors with warfarin, UFH, or oral antiplatelet agents.

Direct thrombin inhibitors. Dabigatran is the only FDA-approved oral DTI, and the only 

DTI evaluated in existing SRs. Compared with LMWH, dabigatran was not associated with 

significant differences for any outcome examined. The strength of evidence was low for 

most outcomes due to few events and imprecise estimates of effect; also, effects on mortality 

varied substantially across studies. In addition to the major outcomes, a subgroup analysis in 

one SR found no significant difference between both treatment groups on bleeding requiring 

rehospitalization.9

 No reviews identified trials comparing oral DTIs with warfarin, unfractionated 

heparin, or oral antiplatelet agents. 

Table 7 summarizes the findings and strength of evidence for the effects of newer oral 

anticoagulant drug classes compared with enoxaparin in patients undergoing THR or TKR 

surgery.
31

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gth of evidence for KQ 1 

Domains Pertaining to SOE

Effect Estimate (95% CI) SOE 

mber 

tudies 

bjects)

Study Design/ 

Quality

Consistency

Directness

Precision

Publication Bias

38) RCT/Good Consistent

Direct

PreciseNone detected

OR=0.95 (0.55 to 1.63)RD=0 (2 fewer to 1 more) deaths/1000 patients

High

77) RCT/Good Consistent

Direct

PreciseNone detected

OR=0.46 (0.30 to 0.70)RD=4 fewer (3 to 6 fewer) events/1000 patients

High

98) RCT/Good Consistent

Direct

PreciseNone detected

OR=1.07 (0.65 to 1.73)RD=0 (1 fewer to 2 more) events/1000 patients

High

24) RCT/Good Inconsistent

Direct

PreciseNone detected

OR=1.27 (0.98 to 1.65)RD=2 more (0 to 4 more) events/1000 patients

Moderate

0) RCT/Good Inconsistent

Direct

ImpreciseNone detected

TKR  RR=1.06 (0.36 to 3.12) RD=0 (2 fewer to 6 more) events/1000 patientsTHR  RR=1.17 (0.04 to 36.52) RD=0 (3 fewer to 107 more) events/1000 

patients

Low

4) RCT/Good Consistent

Direct

ImpreciseNone detected

RR=0.82 (0.17 to 3.99)RD=2 fewer (7 fewer to 27 more) events/1000 

patients

Low

4) RCT/Good Consistent

Direct

ImpreciseNone detected

OR=0.69 (0.31 to 1.54)RD=1 fewer (2 fewer to 2 more) events/1000 

patients

Low

4) RCT/Good Consistent

Direct

ImpreciseNone detected

RR=0.94 (0.58 to 1.52)RD=0 (3 fewer to 3 more) events/1000 patients

Moderate

otics

NA NA NA Not estimable Insufficient

nd Gómez-Outes, 2012; risk difference calculated; SOE ratings from Sobieraj, 2012.

may be some differences for hip versus knee replacement (different baseline risk and different duration of anticoagulation in existing studies); there is some 

oses increase risk of bleeding.

DVT=deep vein thrombosis; DTI=direct thrombin inhibitor; FXa=factor X inhibitor; LMWH=low molecular weight heparin; NA=not applicable; OR=odds 

andomized controlled trial; RD=risk difference; RR=risk ratio; SOE=strength of evidence; THR=total hip replacement; TKR=total knee replacement
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KQ 2: Combined Pharmacological and Mechanical Prophylaxis

No reviews identified trials comparing newer oral anticoagulants combined with mechanical 

prophylaxis to pharmacological prophylaxis alone. Even when considering standard treatments, 

very little data are available comparing combined-modality thromboprophylaxis and 

pharmacologic prophylaxis only. One SR found moderate strength of evidence that combinedmodality thromboprophylaxis was associated with a decreased risk of overall DVT (including 

asymptomatic events) compared with pharmacologic prophylaxis only.9

 The evidence was 

insufficient for all other outcomes.

KQ 3: Comparisons of Individual Newer Oral Anticoagulants

Only indirect comparisons of rivaroxaban, apixaban, and dabigatran were performed through 

common comparison with LMWH.23,35 These comparisons were made for only two of our major 

outcomes—symptomatic VTE (DVT or PE) and major bleeding. There were no significant 

differences in treatment effect for symptomatic VTE or major bleeding. Because these indirect 

comparisons are subject to confounding and the treatment effects were imprecise, we considered 

the strength of evidence low. Other outcomes reported included clinically relevant bleeding 

and net clinical endpoints. Rivaroxaban was found to be associated with an increased risk of 

clinically relevant bleeding, but there was no significant difference in net clinical endpoints 

(symptomatic VTE, major bleeding and death). Table 8 summarizes the findings and strength 

of evidence for between-drug comparisons of newer oral anticoagulants in patients undergoing 

THR or TKR.
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gth of evidence for KQ 3

Domains Pertaining to SOE

Effect Estimate (95% CI) SOE 

er 

dies 

cts)

Study Design/ 

Quality

Consistency

Directness

Precision

Publication Bias

ana

NA NA NA Outcome not reported Insufficient

NA NA NA Outcome not reported Insufficient

NA NA NA Outcome not reported Insufficient

RCT/Good NA

Indirect

Imprecise None detected

Rivaroxaban vs. dabigatran RR=0.68 (0.21 to 2.23)  RD=3 fewer (11 fewer to 4 more) events/1000 patientsRivaroxaban vs. apixaban RR=0.59 (0.26 to 1.33) RD=4 fewer (9 fewer to 1 more)/1000 patientsApixaban vs. dabigatran RR=1.16 (0.31 to 4.28) RD=1 more (7 fewer to 8 more)/1000 patients

LowLowLow

RCT/Good NA

Indirect

Imprecise None detected

Rivaroxaban vs. dabigatran

 RR=1.37 (0.21 to 2.23); 

 RD=4 more (2 fewer to 11 more) events/1000 patientsRivaroxaban vs. apixaban RR=1.59 (0.84 to 3.02); RD=5 more (2 fewer to 12 more)/1000 patientsApixaban vs. dabigatran RR=1.16 (0.31 to 4.28); RD=0 (8 fewer to 7 more)/1000 patients

LowLowLow

osis; NA=not applicable; NR=not reported; PE=pulmonary embolism; RD=risk difference; RR=risk ratio; SOE=strength of evidence; VTE=venous thrombo34

Comparative Effectiveness of New Oral Anticoagulants

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CLINICAL AND POLICY IMPLICATIONS

Patients undergoing total knee replacement or total hip replacement are at a significant 

risk for VTE. The precise risk for VTE in contemporary orthopedic surgery is difficult to 

estimate because of changes in surgical management, the paucity of recent trials comparing 

thromboprophylaxis to placebo, and the high frequency of thromboprophylaxis in routine 

practice, making observational studies of natural history difficult to conduct. A recent, 

careful analysis estimated the prevalence of symptomatic VTE without thromboprophylaxis 

at 2.8 percent for the initial 14 days and 4.3 percent at 35 days following major orthopedic 

surgery.1

 Appropriate use of perioperative thromboprophylaxis significantly reduces the risk of 

postoperative proximal VTE, but the evidence is much more limited for effects on symptomatic 

DVT, PE, and mortality.1,9

Our evidence synthesis primarily addresses the comparative effectiveness of newer oral 

anticoagulants compared with standard antithrombotic agents for VTE prophylaxis. These newer 

drugs have been compared only to LMWH and show similar effects on most major clinical 

outcomes, although the strength of evidence varies by drug class and specific drug. In evaluating 

whether to add these newer agents to the VA formulary and whether to promote a specific 

thromboprophylaxis strategy, consideration should be given to the evidence of effectiveness 

and the importance and variability of patient values and preferences, costs, and health care 

system resources for successfully implementing competing strategies. In the following section, 

we summarize recommendations from the two major U.S. clinical guideline panels that have 

addressed this issue.

Guidelines

Both the American College of Chest Physicians (ACCP) and the American Academy of 

Orthopaedic Surgeons (AAOS) have recently issued guidelines on thromboprophylaxis in 

patients undergoing TKR or THR.1,2,24 The ACCP recommends antithrombotic prophylaxis over 

no prophylaxis for patients undergoing TKR or THR. The AAOS guidelines suggest individual 

assessment of patients for thromboprophylaxis. For patients at average risk, the guidelines do 

not include a recommendation for a specific thromboprophylactic strategy, considering the 

evidence for comparative effectiveness to be inconclusive. In contrast, the ACCP guidelines make 

recommendations for specific strategies and include the following options: LMWH, fondaparinux, 

apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose vitamin K 

antagonists, aspirin, or an intermittent pneumatic compression device. However, in the absence of 

elevated bleeding risk, LMWH is recommended in preference to other agents. Factors identified as 

increasing the risk of bleeding include previous major bleeding, severe renal failure, concomitant 

antiplatelet use, and a history of or difficult-to-control surgical bleeding during the current operative 

procedure, extensive surgical dissection, and revision surgery.1

 For patients with increased bleeding 

risk, ACCP recommends intermittent pneumatic compression device or no prophylaxis.

In making recommendations, both guideline panels considered benefits and potential harms but 

had different approaches to considering costs. The AAOS did not conduct cost analyses and 

instructed guideline members to consider costs only when the impact was likely to be substantial. 

The ACCP process considered costs when it was plausible that resource use might change 
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the direction or strength of recommendation and when high-quality economic analyses were 

available; it is not stated whether costs were considered in the recommendations pertaining to 

major orthopedic surgery. Guideline recommendations regarding choice of thromboprophylaxis 

are summarized in Table 9. Finally, we note that these guidelines address other clinical 

management issues, including duration and timing of thromboprophylaxis and use of routine 

DVT screening, which are not summarized here since they are not directly germane to our key 

questions.

Table 9. U.S. guideline recommendations related to specific thromboprophylaxis strategies

ACCP 2012a AAOS 2011b

In patients undergoing THR or TKR, we recommend 

use of one of the following for minimum of 10–14 days 

rather than no antithrombotic prophylaxis: LMWH, 

fondaparinux, apixaban, dabigatran, rivaroxaban lowdose unfractionated heparin (LDUH), adjusted-dose 

VKA, aspirin (all Grade 1B) or an intermittent pneumatic 

compression device (IPCD) (Grade 1C).

We suggest the use of pharmacologic agents and/or 

mechanical compressive devices for the prevention 

of VTE in patients undergoing elective hip or knee 

arthroplasty, and who are not at elevated risk beyond 

that of the surgery itself for venous thromboembolism 

or bleeding. 

Grade: Moderate

In patients undergoing THR or TKR, irrespective of the 

concomitant use of an IPCD or length of treatment, 

we suggest the use of LMWH in preference to the 

other agents we have recommended as alternatives: 

fondaparinux, apixaban, dabigatran, rivaroxaban lowdose unfractionated heparin (LDUH) (all Grade 1B), 

adjusted-dose VKA, aspirin (all Grade 2C).

Current evidence is unclear about which prophylactic 

strategy is optimal or suboptimal. Therefore, we 

are unable to recommend for or against specific 

prophylactics in these patients. 

Grade: Inconclusive

In patients undergoing major orthopedic surgery, we 

suggest using dual prophylaxis with an antithrombotic 

agent and an IPCD during the hospital stay (Grade 2C).

In the absence of reliable evidence, patients who have 

had a previous VTE should receive pharmacologic 

prophylaxis and mechanical compressive devices.

Grade: Consensus

In patients undergoing major orthopedic surgery and 

increased risk of bleeding, we suggest using an IPCD 

or no prophylaxis rather than pharmacologic treatment 

(Grade 2C).

In the absence of reliable evidence, patients with a 

known bleeding disorder and/or active liver disease 

should use mechanical compressive devices for 

preventing VTE.

Grade: Consensus

In patients undergoing major orthopedic surgery and 

who decline or are uncooperative with injections or an 

IPCD, we recommend using apixaban or dabigatran 

(alternatively, rivaroxaban or adjusted-dose VKA if 

apixaban or dabigatran are unavailable) rather than 

other forms of prophylaxis (Grade 1B).

In the absence of reliable evidence about how long to 

employ these prophylactic strategies, it is the opinion 

of this work group that patients discuss the duration of 

prophylaxis with their treating physicians.

Grade: Consensus

a

ACCP evidence grading of evidence was as follows: grade 1 recommendations are strong and indicate that the benefits do or 

do not outweigh risks, burden, and costs, while grade 2 suggestions imply that individual patient values may lead to different 

choices. Furthermore, level A indicates consistent results from RCTs or observational studies with very strong association and 

secure generalization (high), B indicates inconsistent results from RCTs or RCTs with methodological limitations (moderate), C 

indicates unbiased observational studies (low), and D indicates other observational studies (e.g. case series) (very low). 

b

AAOS grading was as follows: strong when good-quality evidence, moderate when fair-quality evidence, weak when poorquality evidence, inconclusive when insufficient or conflicting evidence, or consensus in the absence of reliable evidence. 

Abbreviations: IPCD=intermittent pneumatic compression device; LDUH=low-dose unfractionated heparin; LMWH=low 

molecular weight heparin; THR=total hip replacement; TKR=total knee replacement; VKA=vitamin K antagonist; VTE=venous 

thromboembolism
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Comparative Effectiveness of New Oral Anticoagulants

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APPLICABILITY

We think these results are likely to apply to Veteran populations, but recommend some caution 

when applying trial data to standard clinical practice. There were strict exclusion criteria for 

patients enrolled in these studies, including severe renal or hepatic impairment or high risk of 

bleeding. Patients enrolled in trials are often more adherent to treatment plans and are monitored 

more closely than patients in routine clinical care. As a result, treatment effects in standard 

clinical practice may differ from those observed in clinical trials. Furthermore, the definition of 

bleeding was not consistent across studies, and it did not always include surgical site bleeding,

which can lead to infection, dehiscence, and reoperation. Another limitation is the treatments 

compared. Newer anticoagulants were compared exclusively with LMWH, an appropriate 

and widely used comparator, but there were no direct comparisons to other treatment options 

recommended by guideline panels. Finally, none of these studies included patients from the VA 

health care system. Compared to patients with private sector insurance, VA patients on average 

have a greater burden of chronic disease, which would likely increase bleeding risk. If the 

comparative treatment effects vary by the presence of certain comorbid conditions, these results 

may not be reproducible in VA settings. 

STRENGTHS AND LIMITATIONS

Our study has a number of strengths, including a protocol-driven review, a comprehensive 

search, and careful quality assessment. Another strength is the opportunity for meta-synthesis 

from existing systematic reviews and the opportunity to carefully evaluate reasons for different 

findings or conclusions across published reviews. Limitations include the lack of head-to-head 

comparisons of the newer oral anticoagulants, which precludes strong conclusions on their 

comparative effectiveness. Further, the length of experience with these new anticoagulants is 

too short to allow identification of longer term adverse events that may only emerge with more 

widespread use.

RECOMMENDATIONS FOR FUTURE RESEARCH

We used the framework recommended by Robinson et al.42 to identify gaps in evidence and 

classify why these gaps exist (Table 10).

This approach considers PICOTS (population, intervention, comparator, outcomes, timing, and 

setting) to identify gaps and classifies them as due to: (1) insufficient or imprecise information, 

(2) biased information, (3) inconsistency or unknown consistency, and (4) not the right 

information. VA and other health care systems should consider their clinical and policy needs 

when deciding whether to invest in research to address gaps in evidence. Specific research 

questions can be evaluated quantitatively, using value-of-information analysis, which uses 

Bayesian methods to estimate the potential benefits of gathering further information through 

research.43
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Comparative Effectiveness of New Oral Anticoagulants

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Table 10. Evidence gaps and future research

Evidence Gap Reason Type of Studies to Consider

Absence of direct comparisons between 

newer anticoagulant drugs

Insufficient information Multicenter RCTs

High-quality network meta-analyses

Observational comparative 

effectiveness studies

Absence of direct comparisons between 

newer anticoagulants and agents other 

than LMWH

Insufficient information Multicenter RCTs 

Observational comparative 

effectiveness studies 

Absence of comparisons between 

combined treatment with newer 

anticoagulants and mechanical 

thromboprophylaxis to pharmacological 

thromboprophylaxis alone

Insufficient information Multicenter RCTs 

Observational comparative 

effectiveness studies 

Adverse effects with long-term use and 

in usual clinical practice

Insufficient information Observational studies

Abbreviations: LMWH=low molecular weight heparin; RCT=randomized controlled trial

CONCLUSION

For THR or TKR, the 35-day rate of symptomatic VTE without thromboprophylaxis is estimated 

to be 4.3 percent. Pharmacological thromboprophylaxis decreases VTE by approximately 50 

percent but with the tradeoff of increased bleeding. Newer oral anticoagulants have a more 

convenient route of administration compared with LMWH, and unlike adjusted dose warfarin, 

they do not require regular laboratory monitoring. Compared with LMWH, FXa inhibitors 

are associated with a reduced risk of symptomatic DVT, but mortality and nonfatal PE are not 

significantly different, and the risk of major bleeding episodes is increased. 

There are no available studies on head-to-head comparisons of these novel anticoagulants. 

Longer clinical experience and direct drug-drug comparisons are needed to better assess the 

risk-to-benefit ratio of newer oral anticoagulants for surgical thromboprophylaxis. Based on 

current evidence, newer anticoagulants—particularly FXa inhibitors—are a reasonable option for 

thromboprophylaxis in patients undergoing total hip replacement or total knee replacement.
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APPENDIX A. Search Strategies

Table A-1. Search strategy for PubMed (5/29/2012, updated 9/28/2012)

Set # Terms Results

1 Dabigatran[tiab] OR desirudin[tiab] OR edoxaban[tiab] OR rivaroxaban[tiab] OR 

apixaban[tiab] OR betrixaban[tiab] OR YM150[tiab] OR razaxaban[tiab] OR “dabigatran etexilate”[Supplementary Concept] OR “desirudin”[Supplementary Concept] OR 

“edoxaban”[Supplementary Concept] OR “rivaroxaban”[Supplementary Concept] OR 

“apixaban”[Supplementary Concept] OR “betrixaban”[Supplementary Concept] OR “razaxaban hydrochloride”[Supplementary Concept] OR “factor Xa, Glu-Gly-Arg-”[Supplementary 

Concept] OR “KFA1411”[Supplementary Concept]

1319

2 (((knee[tiab] OR hip[tiab] OR elbow[ti]) AND (replacement[tiab] OR Arthroplasty[tiab]))) OR 

(“Orthopedic Procedures”[Mesh])

194066

3 #1 AND #2 298

4 (“Review”[Publication Type] OR “Review Literature as Topic”[Mesh]) OR (“Meta-Analysis 

as Topic”[Mesh] OR “Meta-Analysis”[Publication Type]) OR systematic[sb]

1782948

5 #3 AND #4 117

Table A-2. Search strategy for Embase (5/30/2012, updated 9/28/2012)

Set # Terms Results

1 ‘dabigatran’/exp OR dabigatran OR ‘desirudin’/exp OR desirudin OR ‘edoxaban’/exp 

OR edoxaban OR ‘rivaroxaban’/exp OR rivaroxaban OR ‘apixaban’/exp OR apixaban 

OR’betrixaban’/exp OR betrixaban OR ‘ym150’/exp OR ym150 OR ‘razaxaban’/exp OR 

razaxaban OR ‘factor xa inhibitors’ OR ‘factor xa inhibitor’/exp OR ‘factor xa inhibitor’ OR 

‘fxa inhibitors’ OR ‘fxa inhibitor’ OR’direct thrombin inhibitor’ OR ‘direct thrombin inhibitors’ 

OR dtis OR ‘novel anticoagulants’ OR ‘new anticoagulants’ OR ‘novel anticoagulant’ OR 

‘new anticoagulant’

10942

2 ‘orthopedic surgery’/exp OR (hip:ab,ti OR knee:ab,ti OR elbow:ab,ti AND (replacement:ab,ti 

OR arthroplasty:ab,ti))

351,364

3 #1 AND #2 1522

4 #3 limited to Systematic reviews or meta –analysis AND (embase)/lim NOT (medline)/lim 43

Table A-3. Search strategy for Cochrane Database of Systematic Reviews (5/30/2012, updated 

9/28/2012)

Set # Term Results

1 dabigatran OR desirudin OR edoxaban OR rivaroxaban OR apixaban OR betrixaban OR 

YM150 OR razaxaban OR “factor Xa inhibitors” OR “factor Xa inhibitor” OR “fxa inhibitors” 

OR “fxa inhibitor” OR “direct thrombin inhibitor” OR “direct thrombin inhibitors” OR DTIs 

OR “novel anticoagulants” OR “new anticoagulants” OR “novel anticoagulant” OR “new 

anticoagulant”

472

2 MeSH descriptor Orthopedic Procedures explode all trees OR (knee):ti,ab,kw or 

(elbow):ti,ab,kw) AND (replacement):ti,ab,kw or (arthroplasty):ti,ab,kw

8138

3 #1 AND #2 117

4 #3 limited to Systematic reviews or meta-analysis 8
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Comparative Effectiveness of New Oral Anticoagulants

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APPENDIX B. Excluded Studies

All citations listed in Table B-1 were reviewed in their full-text version and excluded for the 

reason indicated. An alphabetical reference list follows the table.

Table B-1. Excluded studies with reasons

Reference Not a systematic review Does not address Key 

Questions

Cohen, 2012 Xa

Dahl, 2009 X

Dahl, 2010 X

Diamantopoulos, 2010 X

Duggan, 2009 X

Eriksson, 2011 X

Eriksson, 2009 X

Falck-Ytter, 2012 X

Friedman, 2011 X

Friedman, 2010 X

Friedman, 2011 X

Goff, 2011 X

Gomez-Outes, 2011 X

Gras, 2011 X

Holmes, 2009 X

Hull, 2010 X

Imberti, 2009 X

Jacobs, 2012 X

Kwong, 2011 X

Kwong, 2011 X

Lazo-Langner, 2009 X

Lee, 2012 X

Lereun, 2011 X

Mantha, 2011 X

Maratea, 2011 X

Melillo, 2010 X

Merli, 2009 X

Miller, 2012 X

Mont, 2011 X

Nieto, 2012 X

Poultsides, 2012 X

Prom, 2011 X

Raskob, 2012 X

Stevenson, 2009 X

Trkulja, 2010 X

Watkins, 2011 X

Wolowacz, 2011 X

Wolowacz, 2009 X

a

Rated as poor-quality systematic review and excluded.
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LIST OF EXCLUDED STUDIES

Cohen A, Drost P, Marchant N, et al. The efficacy 

and safety of pharmacological prophylaxis of venous 

thromboembolism following elective knee or hip 

replacement: systematic review and network metaanalysis. Clin Appl Thromb Hemost. 2012;18(6):611-

627.

Dahl OE. Dabigatran etexilate for the prophylaxis of 

venous thromboembolism after hip or knee replacement 

rationale for dose regimen. Clin Appl Thromb Hemost. 

2009;15 Suppl 1:17S-24S.

Dahl OE, Quinlan DJ, Bergqvist D, et al. A critical 

appraisal of bleeding events reported in venous 

thromboembolism prevention trials of patients 

undergoing hip and knee arthroplasty. J Thromb 

Haemost. 2010;8(9):1966-75.

Diamantopoulos A, Lees M, Wells PS, et al. Costeffectiveness of rivaroxaban versus enoxaparin for the 

prevention of postsurgical venous thromboembolism in 

Canada. Thromb Haemost. 2010;104(4):760-70.

Duggan ST, Scott LJ, Plosker GL. Rivaroxaban: 

a review of its use for the prevention of venous 

thromboembolism after total hip or knee replacement 

surgery. Drugs. 2009;69(13):1829-51.

Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran 

versus enoxaparin for thromboprophylaxis after primary 

total hip arthroplasty (RE-NOVATE II*). A randomised, 

double-blind, non-inferiority trial. Thromb Haemost. 

2011;105(4):721-9.

Eriksson BI, Friedman RJ. Dabigatran etexilate: pivotal 

trials for venous thromboembolism prophylaxis after 

hip or knee arthroplasty. Clin Appl Thromb Hemost. 

2009;15 Suppl 1:25S-31S.

Falck-Ytter Y, Francis CW, Johanson NA, et al. 

Prevention of VTE in orthopedic surgery patients: 

Antithrombotic Therapy and Prevention of Thrombosis, 

9th ed: American College of Chest Physicians 

Evidence-Based Clinical Practice Guidelines. Chest. 

2012;141(2 Suppl):e278S-325S.

Friedman RJ. Novel oral anticoagulants for VTE 

prevention in orthopedic surgery: overview of phase 3 

trials. Orthopedics. 2011;34(10):795-804.

Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran 

versus enoxaparin for prevention of venous 

thromboembolism after hip or knee arthroplasty: 

a pooled analysis of three trials. Thromb Res. 

2010;126(3):175-82.

Friedman RJ, Sengupta N, Lees M. Economic impact 

of venous thromboembolism after hip and knee 

arthroplasty: potential impact of rivaroxaban. Expert 

Rev Pharmacoecon Outcomes Res. 2011;11(3):299-306.

Goff T, Kontakis G, Giannoudis PV. Safety and efficacy 

of rivaroxaban for thromboprophylaxis following 

lower limb surgery: an update. Expert Opin Drug Saf. 

2011;10(5):687-96.

Gomez-Outes A, Terleira-Fernandez A, SuarezGea ML, et al. New oral anticoagulants for 

thromboprophylaxis after total hip or knee replacement: 

A meta-analysis and indirect treatment comparisons. 

Basic and Clinical Pharmacology and Toxicology. 

2011;109:34.

Gras J. Edoxaban for the prevention of thromboembolic 

events after surgery. Drugs Today (Barc). 

2011;47(10):753-61.

Holmes M, Carroll C, Papaioannou D. Dabigatran 

etexilate for the prevention of venous thromboembolism 

in patients undergoing elective hip and knee surgery: 

a single technology appraisal. Health Technol Assess. 

2009;13 Suppl 2:55-62.

Hull RD, Liang J, Brant R. Pooled analysis of trials may, 

in the presence of heterogeneity inadvertently lead to 

fragile conclusions due to the importance of clinically 

relevant variables being either hidden or lost when the 

findings are pooled. Thromb Res. 2010;126(3):164-5.

Imberti D, Dall’Asta C, Pierfranceschi MG. Oral 

factor Xa inhibitors for thromboprophylaxis in major 

orthopedic surgery: a review. Intern Emerg Med. 

2009;4(6):471-7.

Jacobs JJ, Mont MA, Bozic KJ, et al. American 

Academy of Orthopaedic Surgeons clinical practice 

guideline on: preventing venous thromboembolic 

disease in patients undergoing elective hip and knee 

arthroplasty. J Bone Joint Surg Am. 2012;94(8):746-7.

Kwong LM. Therapeutic potential of rivaroxaban in the 

prevention of venous thromboembolism following hip 

and knee replacement surgery: a review of clinical trial 

data. Vasc Health Risk Manag. 2011;7:461-6.

Kwong LM. Cost-effectiveness of rivaroxaban after 

total hip or total knee arthroplasty. Am J Manag Care. 

2011;17(1 Suppl):S22-6.
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Lazo-Langner A, Hawell J, Kovacs MJ, et al. A 

systematic review and meta-analysis of proportions of 

thrombosis and bleeding in patients receiving venous 

thromboembolism (VTE) prophylaxis after orthopedic 

surgery (OS). an update. Blood. 2009;114(22).

Lee S, White CM. Upcoming oral factor Xa inhibitors 

for venous thromboembolism prophylaxis in patients 

undergoing major orthopedic surgery: rivaroxaban 

(Xarelto) and apixaban (Eliquis) review. Conn Med. 

2012;76(1):39-42.

Lereun C, Wells P, Diamantopoulos A, et al. An 

indirect comparison, via enoxaparin, of rivaroxaban 

with dabigatran in the prevention of venous 

thromboembolism after hip or knee replacement. J Med 

Econ. 2011;14(2):238-44.

Mantha S. Oral factor Xa inhibitors vs. enoxaparin for 

thromboprophylaxis after joint replacement surgery: A 

meta-analysis. Journal of Thrombosis and Haemostasis. 

2011;9:189.

Maratea D, Fadda V, Trippoli S, et al. Prevention of 

venous thromboembolism after major orthopedic 

surgery: indirect comparison of three new oral 

anticoagulants. J Thromb Haemost. 2011;9(9):1868-70.

Melillo SN, Scanlon JV, Exter BP, et al. Rivaroxaban 

for thromboprophylaxis in patients undergoing 

major orthopedic surgery. Ann Pharmacother. 

2010;44(6):1061-71.

Merli G, Spyropoulos AC, Caprini JA. Use of 

emerging oral anticoagulants in clinical practice: 

translating results from clinical trials to orthopedic 

and general surgical patient populations. Ann Surg. 

2009;250(2):219-28.

Miller CS, Grandi SM, Shimony A, et al. MetaAnalysis of Efficacy and Safety of New Oral 

Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) 

Versus Warfarin in Patients With Atrial Fibrillation. Am 

J Cardiol. 2012.

Mont MA, Jacobs JJ, Boggio LN, et al. Preventing 

venous thromboembolic disease in patients undergoing 

elective hip and knee arthroplasty. J Am Acad Orthop 

Surg. 2011;19(12):768-76.

Nieto JA, Espada NG, Merino RG, et al. Dabigatran, 

Rivaroxaban and Apixaban versus Enoxaparin for 

thomboprophylaxis after total knee or hip arthroplasty: 

Pool-analysis of phase III randomized clinical trials. 

Thromb Res. 2012;130(2):183-91.

Poultsides LA, Gonzalez Della Valle A, Memtsoudis 

SG, et al. Meta-analysis of cause of death 

following total joint replacement using different 

thromboprophylaxis regimens. J Bone Joint Surg Br. 

2012;94(1):113-21.

Prom R, Spinler SA. The role of apixaban for 

venous and arterial thromboembolic disease. Ann 

Pharmacother. 2011;45(10):1262-83.

Raskob GE, Gallus AS, Pineo GF, et al. Apixaban 

versus enoxaparin for thromboprophylaxis after hip 

or knee replacement: pooled analysis of major venous 

thromboembolism and bleeding in 8464 patients from 

the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint 

Surg Br. 2012;94(2):257-64.

Stevenson M, Scope A, Holmes M, et al. Rivaroxaban 

for the prevention of venous thromboembolism: a single 

technology appraisal. Health Technol Assess. 2009;13 

Suppl 3:43-8.

Trkulja V, Kolundzic R. Rivaroxaban vs dabigatran for 

thromboprophylaxis after joint-replacement surgery: 

exploratory indirect comparison based on meta-analysis 

of pivotal clinical trials. Croat Med J. 2010;51(2):113-

23.

Watkins PB, Desai M, Berkowitz SD, et al. Evaluation 

of drug-induced serious hepatotoxicity (eDISH): 

application of this data organization approach to phase 

III clinical trials of rivaroxaban after total hip or knee 

replacement surgery. Drug Saf. 2011;34(3):243-52.

Wolowacz SE. Pharmacoeconomics of dabigatran 

etexilate for prevention of thromboembolism after 

joint replacement surgery. Expert Rev Pharmacoecon 

Outcomes Res. 2011;11(1):9-25.

Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy 

and safety of dabigatran etexilate for the prevention 

of venous thromboembolism following total hip or 

knee arthroplasty. A meta-analysis. Thromb Haemost. 

2009;101(1):77-85.
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APPENDIX C. Sample Data Abstraction Form

First author, year, Reference Library#

STATED OBJECTIVE OF PAPER: “ ”

METHODS:

Databases accessed for literature search: X, Y, Z... and abstracts of (meetings, Websites, etc.): 

Search date: 

Language limits for search: 

Inclusion criteria: Cut and paste from article AND ensure the following are addressed:

- Study design type:

- Patients: Any characteristic that would include or exclude (e.g., under 18 years)

- Intervention: Drugs of interest

- Comparator: What is considered a valid comparator for the drug of interest?

- Outcomes: Any of the following (also provide any definitions given by the authors): 

1. All-cause mortality

2. VTE-related mortality

3. VTE (only if DVT and PE not given separately)

4. Symptomatic DVT

5. Nonfatal PE

6. Serious AEs

7. Fatal bleeding

8. Major bleeding

9. Bleeding from the surgical site

10. Rehospitalization (includes bleeding that requires reoperation).

Exclusion criteria: Cut and paste from article

Summary of analysis approach: 

- System used (RevMan, Peto, CMA, etc.)

- Report statistic (OR, RR, RD, MD, combination?)

- Special procedures (double-checking, etc.)

- Heterogeneity addressed?

- Publication bias addressed? 

- Subgroup analyses?

- Sensitivity analyses?

-

Funding Source: Look carefully for pharma $

QUALITY: See separate quality rating form
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RESULTS: Number of key questions: XX (if multiple KQs, complete this section for each KQ)

A. Number of studies included (if numbers vary by KQ, give total and number for each KQ): 

XX met eligibility; XX analyzed (were any articles specific excluded, why?)

B. Patient characteristics (range across studies):

Type of surgery: Knee replacement (n=); hip replacement (n=); either knee or hip (n=)

Sex (female-n %): ---- to ---- (XX.X to XX.X%)

Sample size (n): YY to YY, YYY

Mean age (years): ZZ.Z to ZZ.Z

Mean BMI or weight: AA.A to AA.A 

Veteran settings, if given: 

Risk factors for bleeding (prior GI bleed, anemia, renal insufficiency, DM): 

Intervention drugs: (generic name, number of studies, notes about dosage)

1. KQ1 – newer oral anticoagulants (FXa or DTI)

2. KQ2 – combined pharmacological (any type) + mechanical modalities

3. KQ3 – new oral anticoagulant (FXa or DTI)

Comparator: 

1. KQ1 – LMWH, UFH, warfarin, aspirin

2. KQ2 – pharmacological treatment alone

3. KQ3 – other newer oral anticoagulant (FXa or DTI) – direct or indirect comparison

Concurrent other drug administration? (yes/no)

- Antiplatelet drugs: 

- Other

C. Outcomes: (FXa vs LMWH) 

Outcomes definition:

Were they objectively evaluated? 

Was there missing data? 

Other specifics mentioned about quality of results:

Duration of anticoagulation:

- Knee: e.g., 5–14 days (n=)

≥15 days (n=)

- Hip: e.g., < 28 days (n=)

≥ 28 days (n=)

Followup timing:

- e.g., <14 days (n=)

- 14–30 days (n=)

- > 30 days (n=)

-
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Risk of bias for primary studies: Any standard ratings given? Specific issues? (e.g., blinding? 

adjudication? poor completion rates?)

Quantitative summaries: Give # participants, # studies, summary estimate and 95% CI, I2

, RD 

(per 1,000), strength of evidence (SOE) if given. [For example: 22,838 participants, 11 studies; 

OR 0.95 (95% CI, 0.55 to 1.63); I2

=43%; RD=0 fewer events (CI, 2 fewer to 1 more) per 1,000; 

SOE=High]

Provide these data for the following outcomes, if given:

Mortality:

VTE-related mortality:

Total VTE:

Symptomatic DVT: 

Nonfatal PE: 

Serious AEs:

Major bleeding: 

Bleeding from the surgical site: 

Rehospitalization: (give reason if possible)

Other outcome of significance:

Did they measure publication bias? (via funnel plots, etc.)

Subgroup analyses: If presented, give type and outcome

Dose: 

Type of surgery:

Within drug class:

Multiple treatments:

Sensitivity analysis: If presented, give type and outcome

AUTHOR’S CONCLUSION: (take-home message): “ ”
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APPENDIX D. Criteria Used in Quality Assessment of

Systematic Reviews

For reviews, first determine whether it is a systematic review. To be a systematic review, it 

must include a methods section that describes (1) a search strategy and (2) an a priori approach 

to synthesizing the data. For reviews determined to meet the systematic review criteria, assess 

methodological quality.* 

General instructions: The purpose of this rating tool is to evaluate the scientific quality of

systematic reviews. It is not intended to measure the literary quality, importance, relevance,

originality, or other attributes of systematic reviews. 

Step 1: Grade each criterion listed below as “Yes,” “No,” “Can’t tell” or “Not Applicable.” 

Factors to consider when making an assessment are listed under each criterion. Where 

appropriate (particularly when assigning a “No,” or “Can’t tell” score), please provide a 

brief rationale for your decision (in parentheses).

1.	 Is a focused clinical question clearly stated?

At a minimum, the question should be developed a priori and should clearly identify 

population and outcomes. The study question does not have to be in PICO format 

(Population, Intervention, Comparisons, Outcomes.) 

[] Yes [] No [] Can’t tell [] N/A

2.	 Are the search methods used to identify relevant studies clearly described?

Search methods described in enough detail to permit replication (The report must include 

search date, databases used, and search terms (Key words and/or MESH terms must be stated 

and where feasible the search strategy should be provided.)

[] Yes [] No [] Can’t tell [] N/A 

3.	 Was a comprehensive literature search performed?

At least 2 electronic sources should be searched and electronic searches should be 

supplemented by consulting: reference lists from prior reviews, textbooks, or included 

studies; specialized registries (e.g., Cochrane registries); or queries to experts in the field.

[] Yes [] No [] Can’t tell [] N/A 

4.	 Was selection bias avoided?

Study reports the number of studies identified through searches, the numbers excluded, and 

gives appropriate reasons for excluding – based on explicit inclusion/exclusion criteria. 

[] Yes [] No [] Can’t tell [] N/A

5.	 Was there duplicate study selection and data extraction?

Did two or more raters make inclusion/exclusion decisions, abstract data, and assess study 

quality – either independently or with one rater over-reading the first raters result?

Was an appropriate method used to resolve disagreements (e.g., a consensus procedure)?

[] Yes [] No [] Can’t tell [] N/A 
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6.	 Were the characteristics of the included studies provided?

In an aggregated form such as a table, data from the original studies should be provided on 

the participants, interventions and outcomes. The ranges of characteristics in all the studies 

analyzed (e.g., age, race, sex, relevant socioeconomic data, disease status, duration, severity 

or other diseases) should be reported.

[] Yes [] No [] Can’t tell [] N/A 

7.	 Was the scientific quality of the included studies assessed and documented?

A priori methods of assessment should be provided and criteria used to assess study quality 

specified in enough detail to permit replication. 

[] Yes [] No [] Can’t tell [] N/A 

8.	 Were the methods used to combine the findings of studies appropriate?

For pooled results, an accepted quantitative method of pooling should be used (i.e., more 

than simple addition; e.g., random-effects or fixed-effect model). For pooled results, a 

qualitative and quantitative assessment of homogeneity (Cochran’s Q and/or I2

) should be 

performed. If only qualitative analyses are completed, the study should describe the reasons 

that quantitative analyses were not completed. 

[] Yes [] No [] Can’t tell [] N/A 

9.	 Was the scientific quality of the included studies used appropriately in formulating

conclusions?

The results of the methodological rigor and scientific quality should be considered in the 

analysis (e.g. subgroup analyses) and the conclusions of the review, and explicitly stated in 

formulating recommendations.

[] Yes [] No [] Can’t tell [] N/A 

10.	Was publication bias assessed?

Publication bias tested using funnel plots, test statistics (e.g., Egger’s regression test), and/or 

search of trials registry for unpublished studies. 

[] Yes [] No [] Can’t tell [] N/A 

11.	Was the conflict of interest stated?

Potential sources of support should be clearly acknowledged in both the systematic review 

and the included studies. 

[] Yes [] No [] Can’t tell [] N/A

12.	Are the stated conclusions supported by the data presented?

Were the conclusions made by the author(s) supported by the data and/or analyses reported in 

the systematic review?

[] Yes [] No [] Can’t tell [] N/A

Step 2: Rate the overall quality of the SR as “Good,” “Fair,” or “Poor” using the guidance

below. 

Good = After considering items 1-12, item 12 is rated “Yes” with no important limitations. 

This means that few of the items 1-12 are rated “No,” and none of the limitations are thought to 

decrease the validity of the conclusions. If items 3, 4, 7, or 8 are rated “No,” then the review is 

likely to have major flaws
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Fair = After considering items 1-12, item 12 is rated “Yes,” but with at least some important 

limitations. This means that enough of the items 1-12 are rated “No” to introduce some 

uncertainty about the validity of the conclusions.

Poor = After considering items 1-12, item 12 is rated “No.” This means that several of items 

1-12 are rated “No,” introducing serious uncertainty about the validity of the conclusions.

*Adapted from:

1. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool 

to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 

2007;7:10.

2. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses 

of randomised controlled trials: the QUOROM statement. Quality of Reporting of Metaanalyses. Lancet. 1999;354(9193):1896-900.

3. Marinopoulos SS, Dorman T, Ratanawongsa N, et al. Effectiveness of continuing medical 

education. Evid Rep Technol Assess (Full Rep). 2007(149):1-69.

Table D-1 shows the quality ratings for the systematic reviews included in this evidence report.

Table D-1. Quality assessment for included systematic reviews

Criteria for grading the quality of a 

systematic review (SR)

Neumann,

2012

Sobieraj, 

2012

GomezOutes, 

2012

Loke, 

2011

Ringerike, 

2011

Alves, 

2011

Q1. Is a focused clinical question clearly stated? Yes Yes Yes Yes Yes Yes

Q2. Are the search methods used to identify 

relevant studies clearly described?

Yes Yes Yes Yes Yes Yes

Q3. Was a comprehensive literature search 

performed?

Yes Yes Yes Yes Yes Yes

Q4. Was selection bias avoided? Yes Yes Yes Yes Yes Yes

Q5. Was there duplicate study selection and 

data extraction?

Yes Yes Yes Yes Yes Yes

Q6. Were the characteristics of the included 

studies provided?

Yes Yes Yes Yes No Yes

Q7. Was the scientific quality of the included 

studies assessed and documented?

Yes Yes Yes Yes Yes Can’t 

tell

Q8. Were the methods used to combine the 

findings of studies appropriate?

Yes Yes Yes Yes Yes Yes

Q9. Was the scientific quality of the included 

studies used appropriate in formulating 

conclusions?

Yes Yes Yes Yes Yes Yes

Q10. Was publication bias assessed? Yes Yes Yes Yes Yes Yes

Q11. Was the conflict of interest stated? Yes Yes Yes Yes Can’t tell Yes

Q12. Are the stated conclusions supported by 

the data presented?

Yes Yes Yes Yes Yes Yes

Overall quality Good Good Good Good Good Good
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eer Review Comments

Comment Response

 scope, and methods for this review clearly described?

 clear and KQs relevant to current clinical practice in VA. Scope as 

appropriate and clinically relevant. Methods are rigorous, transparent, and 

rding to latest accepted principles of evidence based medicine.

Thank you for your confidence in our process.

ents from reviewer 2. Thank you.ents from reviewer 3. Thank you.

tion of bias in our synthesis of the evidence?

ted. Transparency of methods allows for an open assessment of bias and 

ssess validity and accept results as valid for use in informing clinical 

Thank you again for your confidence in our process.

ents from reviewer 2. Thank you.

ted. Thank you.

ished or unpublished studies that we may have overlooked? 

 references to suggest. Thank you.

ents from reviewer 2. Thank you.

m aware of Thank you.

nal suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.

 transparency regarding conflict of interest

 report made by manufacturers Dr Ortel has potential conflicts of interest 

 and b. The sections Dr Ortel worked on were listed. Reader would be 

ss bias.

We added a description of Dr. Ortel’s role in the project.

e summary, 3rd paragraph, last sentence discussing ‘Disadvantages of newer 

s...’ From a clinical standpoint we are most concerned with veteran safety 

ecific antidote is a primary concern. Would edit that sentence to place this 

The recommended change has been made.

ary 35-day rate of symptomatic VTE w/o prophylaxis of 4.3% (page 1); 

mates for LMWH of 9 per 1000 symptomatic DVT, nonfatal PE 3 per 

per 1000 and major bleeding of 7 per 1000 (page 2) are extremely useful 

usy clinician to know for counseling patients, comparing with treatment 

4) and for making treatment decisions. Would include these numbers in the 

n on page 9. 

We added data on the rate of VTE to the conclusion section. We did not repeat the absolute risk reductions as this information is already contained in two locations: in the bullet points and in the summary of evidence table. We will be sure that this information is contained in the VA e-brief.
53

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Comment Response

ion section: a). first paragraph, as noted above in #3 would put in 

crease risk numbers and b). Last paragraph...‘Based on current 

nticoagulants—particularly Xa inhibitors—are a reasonable option 

ylaxis...’ Agree from this evidence synthesis that Xa inhibitors are a 

 Any suggested sequence of treatment? LMWH first then Xa? Or is Xa 

able as LMWH? Is there a way to assess the value of 4 per 1000 decrease 

VT vs an increase of 2 major bleeds per 1000 treated with a Xa?

Although there are formal methods to consider multiple outcomes to develop a rank order of interventions, none of these methods are robust. The decision whether to use thromboprophylaxis, and the particular mode, is one that involves tradeoffs between potential benefits and harms. Clinicians must consider the patient’s particular risks, values, and preferences when making this decision. Our data inform this decision. 

aragraph: ‘Dabigatran etexilate is an oral reversible DTI...’ Reversible seems 

n antidote for reversal and there is no antidote (other than stopping the 

ting it wear off). Recommend striking word ‘reversible’.

The recommended change has been made.

 Strategy first paragraph: Might be more explicit as why a synthesis of high 

ould be more effective approach to summarizing the evidence than a perhaps 

approach of searching the literature for RCTs and combining those in an 

s. Also, why limit the search only as far back as 1 Jan 2009. What is the 

earch timeframe?

We added a justification for this approach as follows: “This approach is particularly useful when different intervention options or outcomes are evaluated in multiple recent reviews and when the audience is policymakers.”

pant Characteristics: Discussion regarding no Veterans studied in the trials 

ts were predominantly female 50-75%. Given the available evidence is there 

ason(s) to believe Veterans would respond differently to these treatments or 

cable to Veterans patients? If so why? If not why not?

The applicability of the results to Veteran patients is discussion in the Applicability section of the Discussion.

a Inhibitors compared to LMWH: a reader might assume that all of these 

e in the US. While we are considering all the individual drugs, would 

ncy if drugs not available in the US were identified.

This detail has been added. Only rivaroxaban is currently available in the United States.

aph 3, first sentence “In subgroup analysis, higher doses of Xa inhibitors, but 

r lower doses, ...’ would list the doses considered high, intermediate or low 

 on page 32.

The authors did not report the doses categorized as high, intermediate, or low. However, they do give the doses studied in the individual trials and we have added the dosing ranges for apixaban and rivaroxaban, drugs approved in Canada and the United States, respectively.

 Comparisons of Interest section, 2nd paragraph ‘Low molecular weight 

n K antagonists, 3rd line, would put in dose regimen of enoxaparin (logiparin 

S, so could omit dose). Same page, section immediately below ‘Oral FXa 

ctionated heparin would list doses of fondaparinux and unfractionated 

We added the dose of enoxaparin (30 mg subcutaneously every 12 hours). Fondaparinux and unfractionated heparin were evaluated in an observational study that did not report doses.
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Comment Response

raph under ‘Key Points’ discussion of SRs and quality notes the industry 

k meta-analysis (Cohen 2012, ref 36) was rated fair quality. Then notes “The 

ot provide an adequate description or quality assessment of the included 

est the assumption of a constant treatment effect across different study 

ssumption inherent to network meta-analysis.” Page 32 same meta-analysis 

 and notes ‘the composite outcomes are suspect because they combine events 

ny DVT, PE, death] and major bleeding[major, clinically relevant and minor 

e very different clinical importance’. These seem to be fatal deficiencies 

ir. Appendix D pg 54 notes the quality rating scale and Pg 55 notes the 

essments. Item 12 for the study in question (Cohen 2012, ref 36) is answered 

hich there is no provision in the scoring system which notes if item 12 is 

ould be rated good or fair and if ‘No’ then Poor. A poor rating would have 

 trial from the analysis. The summary Table D-1 lists no answers for 6 of the 

s including critical items 7 and 8 which the text notes that the review is likely 

ws. Should the rating really be ‘poor’ and this analysis excluded?

We re-reviewed our quality rating for the Cohen study. We agree that it is poor quality and have excluded it from the final report.

elines’ section, First paragraph, end o paragraph notes ACCP recommends 

e of bleeding risk. Does ACCP suggest any sequence if there is an elevated 

We have added the ACCP recommendation for patients at increased bleeding risk: “For patients with increased bleeding risk, ACCP recommends intermittent pneumatic compression device or no prophylaxis.”

icability’. End of paragraph notes private sector vs VA patients potential 

comment #7 above). What should the reader conclude? This is a solid 

s but not applicable to VA patients? Or is applicable to VA patients?

We revised this section to state that the results likely apply to Veteran populations. We add a specific caution about higher comorbidities in Veterans, increasing the risk of bleeding.

clusion’: Same comments as #4 above as this section also appears on page 9 

ummary.

As stated above, we think these data should be used to make individualized decisions with patients about the choice and mode of thromboprophylaxis.

ndix D, item 8, 2nd to last line ‘...If only qualitative analyses are completed, 

scribe...’ Change ‘show’ to ‘should’.

Thank you for noting this error. It has been corrected.

tastic descriptions of confidence interval and statistical significance! Thank you.

urprised to see the evidence that newer anticoagulants did not offer much 

an ease of administration and less monitoring but also troubled to see the 

effects

Acknowledged
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ew Oral Anticoagulants for Thromboprophylaxis Evidence-based Synthesis Program

Comment Response

his review, but might note that earlier this month the FDA approved 

eatment of deep vein thrombosis or pulmonary embolism, and to reduce the 

VT and PE following initial treatment. These are 2 other important clinical 

The role of newer anticoagulants for treatment of DVT and PE was reviewed in an earlier VA ESP report.

linical performance measures, programs, quality improvement measures, patient care services, or conferences that will be 

 If so, please provide detail? 

e inpatient performance measure for DVT prophylaxis that could be 

nce measure Technical Manual would need to be checked

We will ask that this report be sent to the VA clinical guideline and performance measure groups.

f Thank you.

Thank you.

 recommendations on how this report can be revised to more directly address or assist implementation needs.

ed above. Thank you.

Thank you.

rom my perspective, that most VA providers are unaware of these reports, 

 take the time to read them. However, I find that they are a valuable 

ence tool. 

Thank you.

with contact details of any additional individuals/stakeholders who should be made aware of this report.

mD who is PBM contact for these medications. Lisa.longo@va.gov based 

Thank you; the report has been sent to Dr. Longo, and she is one of our stakeholders in the product.

Medicine; Chief Medical Officers; Chiefs of Staff Thank you.

Thank you.
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APPENDIX F. Glossary

Abstract screening

The stage in a systematic review during which titles and abstracts of articles identified in the 

literature search are screened for inclusion or exclusion based on established criteria. Articles 

that pass the abstract screening stage are promoted to the full-text review stage.

Anticoagulant agents

A class of medication that prevents coagulation (blood clotting).

ClinicalTrials.gov

A registry and results database of federally and privately supported clinical trials conducted in 

the United States and around the world. ClinicalTrials.gov provides information about a trial’s 

purpose, location, and participant characteristics among other details. 

Cochrane Database of Systematic Reviews

A bibliographic database of peer-reviewed systematic reviews and protocols prepared by the 

Cochrane Review Groups in The Cochrane Collaboration. 

Companion article

A publication from a trial that is not the article containing the main results of that trial. It may be 

a methods paper, a report of subgroup analyses, a report of combined analyses, or other auxiliary 

topic that adds information to the interpretation of the main publication.

Confidence interval (CI)

The range in which a particular result (such as a laboratory test) is likely to occur for everyone 

who has a disease. “Likely” usually means 95 percent of the time. Clinical research studies are 

conducted on only a certain number of people with a disease rather than all the people who have 

the disease. The study’s results are true for the people who were in the study but not necessarily 

for everyone who has the disease. The CI is a statistical estimate of how much the study findings 

would vary if other different people participated in the study. A CI is defined by two numbers, 

one lower than the result found in the study and the other higher than the study’s result. The size 

of the CI is the difference between these two numbers.

Data abstraction

The stage of a systematic review that involves a pair of trained researchers extracting reported 

findings specific to the research questions from the full-text articles that met the established 

inclusion criteria. These data form the basis of the evidence synthesis. 

Deep vein thrombosis (DVT)

A blood clot that develops in the deep veins of the legs.

Direct thrombin inhibitors (DTIs)

A new class of anticoagulants that bind directly to thrombin and block its interaction with its 

substrates.

DistillerSR

An online application designed specifically for the screening and data extraction phases of a 

systematic review.
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Embase

The Excerpta Medica database (EMBASE) produced by Elsevier, a major biomedical and 

pharmaceutical database indexing over 3500 international journals in the following fields: 

drug research, pharmacology, pharmaceutics, toxicology, clinical and experimental human 

medicine, health policy and management, public health, occupational health, environmental 

health, drug dependence and abuse, psychiatry, forensic medicine, and biomedical engineering 

or instrumentation. There is selective coverage for nursing, dentistry, veterinary medicine, 

psychology, and alternative medicine.

Exclusion criteria

The criteria, or standards, set out before a study or review. Exclusion criteria are used to 

determine whether a person should participate in a research study or whether an individual 

study should be excluded in a systematic review. Exclusion criteria may include age, previous 

treatments, and other medical conditions. 

Factor Xa (FXa) inhibitor

A new class of anticoagulants that bind directly to factor Xa and block its interaction with other 

substrates. 

Full-text review

The stage of a systematic review in which a pair of trained researches evaluates the full-text of 

study articles for potential inclusion in the review.

GRADE

Grading of Recommendations Assessment, Development, and Evaluation (GRADE), a system of 

assessing the quality of medical evidence and evaluating the strength of recommendations based 

on the evidence.

Inclusion criteria

The criteria, or standards, set out before the systematic review. Inclusion criteria are used 

to determine whether an individual study can be included in a systematic review. Inclusion 

criteria may include population, study design, sex, age, type of disease being treated, previous 

treatments, and other medical conditions. 

Low molecular weight heparin

A class of medication used to treat thrombosis or for prophylaxis in situations that lead to a 

high risk of thrombosis. These medications have a more predictable anticoagulant response than 

naturally occurring unfractionated heparin.

Optimal information size

The number of patients that need to be included in a pooled analysis (meta-analysis) to provide 

sufficient power to detect the smallest clinically important difference in treatment effect.

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses, an evidence-based 

minimum set of items for reporting in systematic reviews and meta-analyses. 
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Publication bias

The tendency of researchers to publish experimental findings that have a positive result, 

while not publishing the findings when the results are negative or inconclusive. The effect of 

publication bias is that published studies may be misleading. When information that differs 

from that of the published study is not known, people are able to draw conclusions using only 

information from the published studies.

PubMed®

A database of citations for biomedical literature from MEDLINE®, life science journals, and 

online books in the fields of medicine, nursing, dentistry, veterinary medicine, the health care 

system, and preclinical sciences.

Pulmonary embolism (PE)

Blocking of the pulmonary artery (lungs) or one of its branches by a clot.

Randomized controlled trial

A prospective, analytical, experimental study using primary data generated in the clinical 

environment. Individuals similar at the beginning of the trial are randomly allocated to two or 

more treatment groups and the outcomes the groups are compared after sufficient followup time. 

Properly executed, the RCT is the strongest evidence of the clinical efficacy of preventive and 

therapeutic procedures in the clinical setting. 

Risk

A way of expressing the chance that something will happen. It is a measure of the association 

between exposure to something and what happens (the outcome). Risk is the same as probability, 

but it usually is used to describe the probability of an adverse event. It is the rate of events (such 

as breast cancer) in the total population of people who could have the event (such as women of a 

certain age). 

Statistical significance

A mathematical technique to measure whether the results of a study are likely to be true. 

Statistical significance is calculated as the probability that an effect observed in a research study 

is occurring because of chance. Statistical significance is usually expressed as a P-value. The 

smaller the P-value, the less likely it is that the results are due to chance (and more likely that 

the results are true). Researchers generally believe the results are probably true if the statistical 

significance is a P-value less than 0.05 (p<.05).

Strength of evidence (SOE)

A measure of how confident reviewers are about decisions that may be made based on a body 

of evidence. SOE is evaluated using one of four grades: (1) High confidence that the evidence 

reflects the true effect; further research is very unlikely to change reviewer confidence in the 

estimate of effect; (2) moderate confidence that the evidence reflects the true effect; further 

research may change the confidence in the estimate of effect and may change the estimate; (3) 

low confidence that the evidence reflects the true effect; further research is likely to change the 

confidence in the estimate of effect and is likely to change the estimate; and (4) insufficient; the 

evidence either is unavailable or does not permit a conclusion.
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Comparative Effectiveness of New Oral Anticoagulants

for Thromboprophylaxis Evidence-based Synthesis Program

Systematic review

A summary of the clinical literature. A systematic review is a critical assessment and evaluation 

of all research studies that address a particular clinical issue. The researchers use an organized 

method of locating, assembling, and evaluating a body of literature on a particular topic using a 

set of specific criteria. A systematic review typically includes a description of the findings of the 

collection of research studies. The systematic review may also include a quantitative pooling of 

data, called a meta-analysis.

Venous thromboembolism (VTE)

Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the blood stream; 

includes deep vein thrombosis (DVT) and pulmonary embolism (PE).

Vitamin K antagonist (warfarin)

An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation 

factors; i.e., I, VII, IX and X.