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

for Thromboprophylaxis Evidence-based Synthesis Program

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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Comparative Effectiveness of New Oral Anticoagulants

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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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Comparative Effectiveness of New Oral Anticoagulants

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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, 
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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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Comparative Effectiveness of New Oral Anticoagulants

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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