Economic Evaluation of Rivaroxaban Versus Enoxaparin for Prevention of Venous Thromboembolism After Total Knee Replacement and Total Hip Replacement: A Systematic Review

Abstract

Background
Deep vein thrombosis (DVT) and pulmonary embolism (PE) together are called venous thromboembolism (VTE) and impose a high economic burden on healthcare systems. Thousands of people are hospitalized annually due to benign and treatable diseases but die due to PE; with the adoption of appropriate prevention, these deaths can be prevented.Objective
To investigate the cost-effectiveness of using rivaroxaban versus enoxaparin in published economic analyses for prevention of VTE after total knee (TKR) or hip replacement (THR).Method
In a systematic review electronic searches were performed on various online databases, including PubMed, Web of science, Embase, Scopus, Health Economic Evaluations Database (HEED), and ProQuest. The inclusion criteria were: studies that were conducted on the cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of VTE after TKR and THR; cost-effectiveness studies conducted using decision analysis models based on the economic evaluation approach; studies with available full-text papers; and studies written in English and published between 2007 and 2019. The exclusion criteria were: studies with partial cost effectiveness (such as effectiveness assessment, cost assessment, quality-of-life assessment); studies written in languages other than English; and all protocols, conference abstracts, and letters to the editor. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist was used to qualitatively evaluate the studies.ResultsOf a total of 537 initial studies, nine papers met the inclusion criteria. The time scope of studies ranged from 3 months to 5 years. Among the selected studies, some studies had included discount rates (n = 4) and the other studies did not utilize discount rates and were set to zero percent by default (n = 5). In all studies, direct medical costs, including costs related to the prevention, diagnosis, and treatment of VTE and PE, and management and monitoring of treatment costs were reviewed.Conclusion
The results of this systematic review showed that using rivaroxaban in patients undergoing total knee or hip replacement reduced costs and increased quality of life. However, since most of the studies had been conducted in developed countries, it is not possible to generalize the results to developing countries. Nonetheless, given that rivaroxaban is administered orally and does not require continuous monitoring, it will be less costly for patients and health systems and is more appropriate to administer it as a thromboprophylactic drug following total knee or hip replacement surgery.

Full text

Vol.:(0123456789)
Clinical Drug Investigation
https://doi.org/10.1007/s40261-020-00940-4
SYSTEMATIC REVIEW
Economic Evaluation ofRivaroxaban Versus Enoxaparin forPrevention
ofVenous Thromboembolism After Total Knee Replacement andTotal
Hip Replacement: ASystematic Review
AsmaRashkiKemmak1· AliAbutorabi2· VahidAlipour2
© Springer Nature Switzerland AG 2020
Abstract
Background Deep vein thrombosis (DVT) and pulmonary embolism (PE) together are called venous thromboembolism
(VTE) and impose a high economic burden on healthcare systems. Thousands of people are hospitalized annually due to
benign and treatable diseases but die due to PE; with the adoption of appropriate prevention, these deaths can be prevented.
Objective To investigate the cost-effectiveness of using rivaroxaban versus enoxaparin in published economic analyses for
prevention of VTE after total knee (TKR) or hip replacement (THR).
Method In a systematic review electronic searches were performed on various online databases, including PubMed, Web of
science, Embase, Scopus, Health Economic Evaluations Database (HEED), and ProQuest. The inclusion criteria were: stud-
ies that were conducted on the cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of VTE after TKR and
THR; cost-effectiveness studies conducted using decision analysis models based on the economic evaluation approach; studies
with available full-text papers; and studies written in English and published between 2007 and 2019. The exclusion criteria
were: studies with partial cost effectiveness (such as effectiveness assessment, cost assessment, quality-of-life assessment);
studies written in languages other than English; and all protocols, conference abstracts, and letters to the editor. The Consoli-
dated Health Economic Evaluation Reporting Standards (CHEERS) checklist was used to qualitatively evaluate the studies.
Results Of a total of 537 initial studies, nine papers met the inclusion criteria. The time scope of studies ranged from
3months to 5years. Among the selected studies, some studies had included discount rates (n = 4) and the other studies did
not utilize discount rates and were set to zero percent by default (n = 5). In all studies, direct medical costs, including costs
related to the prevention, diagnosis, and treatment of VTE and PE, and management and monitoring of treatment costs were
reviewed.
Conclusion The results of this systematic review showed that using rivaroxaban in patients undergoing total knee or hip
replacement reduced costs and increased quality of life. However, since most of the studies had been conducted in developed
countries, it is not possible to generalize the results to developing countries. Nonetheless, given that rivaroxaban is admin-
istered orally and does not require continuous monitoring, it will be less costly for patients and health systems and is more
appropriate to administer it as a thromboprophylactic drug following total knee or hip replacement surgery.
* Ali Abutorabi
Abutorabi.a@iums.ac.ir
Asma Rashki Kemmak
rashki.a@iums.ac.ir
1 Department ofHealth Economics, School ofHealth
Management andInformation Sciences, Iran University
ofMedical Sciences, Tehran, Iran
2 Health Management andEconomics Research Center, School
ofHealth Management andInformation Sciences, Iran
University ofMedical Sciences, Tehran, Iran
Key Points
Rivaroxaban versus enoxaparin is cost-effective for the
prevention of VTE after total knee or hip replacement
surgery.
The studies did not mention indirect costs, and these
costs could play a major role in increasing the costs of
the disease.
The generalization of economic evaluation studies
should be approached with caution due to the limitations
of these studies.

A.Rashki Kemmak et al.
1 Introduction
Ranked after coronary artery disease and stroke, venous
thromboembolism (VTE) is the third most common car-
diovascular disease, and is experienced by 2–5% of people
throughout their lives [1]. VTE is a major cause of mortality
in hospitals, while being highly preventable [2]. The annual
incidence of VTE in the world is about 1 million cases per
year [3]. In Europe, the annual incidence of VTE is esti-
mated at around 100–200 cases per 100,000 people [4]. It
is estimated that the incidence of VTE will increase with
the aging of the population [5]. The annual incidence of
hospital-based VTE is 32,000 cases in the UK [6], 540,000
cases in the USA [7], and 30,000 cases in Australia [6].
Every year, about 100,000–300,000 deaths due to VTE
occur in the USA [8]. The incidence of deaths from venous
thromboembolism in Europe in 2004 was estimated at 700
cases per million, of which only 7% had been correctly diag-
nosed with VTE before death [5].
Complications and side effects of VTE include the fol-
lowing: delayed discharge from hospitals, relapses and re-
hospitalization, complications caused by the use of antico-
agulants, and relapse of thromboembolism [9]. Up to 70%
of cases of VTE can be asymptomatic. In addition, about 6%
of cases of DVT and 12% of cases of pulmonary embolism
(PE) result in death within 1month after diagnosis [10]. In
the USA and Europe, the number of people dying of VTE
is higher than the number of people dying of AIDS, breast
cancer, prostate cancer, and traffic accidents [11]. Up to 60%
of cases of VTE occur during or after hospitalization, and it
is the most important preventable cause of hospital deaths
[3]. The risk of VTE is significantly increased during sur-
gery, especially orthopedic surgery, major vascular surgery,
neurosurgery, and in cases of cancer. Half of patients with
VTE may develop long-term complications such as swelling,
pain, and discoloration; in addition, 33% of patients suffer
from disease recurrence within 10years [12]. Studies have
shown that thromboembolic problems occur in more than
half of major orthopedic surgeries [13].
Total hip replacement (THR) and total knee replace-
ment (TKR) are being performed with increasing regular-
ity, driven by aging populations. Furthermore, due to the
increasing prevalence of obesity, the demand for TKR has
outpaced that for THR in the USA [14]. Despite being well
established and generally safe procedures, both THR and
TKR are associated with a high risk of developing a VTE
with either DVT or PE. The current rate of symptomatic
VTE events within 35days following orthopedic surgery
has been estimated at 4.3% in patients who have not received
anticoagulant prophylaxis [15].
The highest number of cases of venous thrombosis
occur on the fourth day after surgery, which indicates the
significance and the need for prevention measures in the
first few days [16]. Without prophylaxis, the risk of VTE
in patients undergoing major surgery, such as gynecologic,
urologic, or neurosurgery, is estimated at 15–40%. Patients
undergoing major orthopedic procedures such as THR or
TKR surgery are at even greater risk, with an incidence of
any (including asymptomatic) DVT without prophylaxis in
the order of 40–60% [17].
For more than 20years, pharmacological prophylaxis
for VTE has been available to patients undergoing THR
or TKR surgeries and is recommended in current clinical
guidelines. The most commonly used anticoagulants for
VTE prophylaxis in Europe are low-molecular-weight hep-
arins (LMWHs), such as enoxaparin or dalteparin, which
are administered by subcutaneous injection. Multivariate
analysis of results from a Spanish study identified receiv-
ing thromboprophylaxis with LMWH for less than 3weeks
and chronic lung disease as the only two factors that were
independently associated with a higher risk for VTE [17]. At
the time of its introduction, several studies showed enoxa-
parin to be cost-effective compared with unfractionated
heparin and warfarin as prophylaxis after orthopedic sur-
gery. Since 2008, several new oral anticoagulants (NOACs)
have received marketing authorization, including dabigatran,
rivaroxaban, apixaban, and edoxaban [15].
Rivaroxaban is a novel, once-daily, orally administered
thromboprophylactic agent. It is a direct factor Xa inhibitor
that demonstrates activity against both clot-associated and
free factor Xa, as well as inhibiting prothrombinase activ-
ity and reducing thrombin generation. In addition to being
orally administered, unlike warfarin, rivaroxaban does not
require any monitoring during administration. Phase III
clinical trials have demonstrated that rivaroxaban has supe-
rior efficacy compared with enoxaparin in terms of reduc-
ing VTE events, and a similar safety profile, after THR and
TKR [18].
However, although rivaroxaban may represent an effec-
tive and safe alternative for VTE treatment, it may also
impose a tangible cost to the healthcare system and pay-
ers, and a key question now is whether or not these clinical
advantages of rivaroxaban are associated with any signifi-
cant health economic outcome. On the other hand, due to
the prevalence of VTE, the need for evidence of which drug
is useful for the prevention of this disease is essential. The
objective of this systematic review was to investigate the
published cost-effectiveness evidence of rivaroxaban versus
enoxaparin for the prevention of VTE after TKR and total
hip replacement THR.

Economic Evaluation of Rivaroxaban Vs. Enoxaparin for Prevention of VTE
2 Method
2.1 Search Strategy
This study reviewed studies involving a full economic eval-
uation to compare rivaroxaban and enoxaparin in patients
undergoing TKR and THR from 2007 to 2019. This start-
ing point was chosen because rivaroxaban was approved in
2007 [19].To find suitable studies for analysis, several data-
bases including PubMed, Web of science, Embase, Scopus,
Health Economic Evaluations Database (HEED), and Pro-
Quest were searched using the keywords Cost benefit analy-
sis, Venous thromboembolism, Rivaroxaban, Enoxaparin,
Arthroplasty replacement knee, and Arthroplasty replace-
ment hip. The search strategy was designed by combining
keywords. Databases were explored using search keywords,
synonyms, and their combination with OR and AND opera-
tors to increase search sensitivity. The search strategy for
PubMed database was as follows:
(“Cost benefit analysis” [Title/Abstract] OR “Cost effec-
tiveness” [Title/Abstract] OR “Economic evaluation” [Title/
Abstract] OR “Cost utility” [Title/Abstract] AND (“Venous
Thromboembolism” [Title/Abstract] OR “Thromboembo-
lism” [Title/Abstract] OR “Pulmonary Embolism” [Title/
Abstract]) AND (“Rivaroxaban” [Title/Abstract]) AND
(“Enoxaparin” [Title/Abstract]) AND (“Arthroplasty,
Replacement, Knee” [Title/Abstract]) AND (“Arthroplasty,
Replacement, Hip” [Title/Abstract]”)
2.1.1 Inclusion andExclusion Criteria
In this systematic review inclusion criteria were: studies that
conducted cost-effectiveness analyses of rivaroxaban versus
enoxaparin for the prevention of VTE (the result of a venous
blood clot formation that may manifest itself as DVT or PE)
[20]; cost-effectiveness studies conducted using decision
analysis models based on the economic evaluation approach;
studies with available full-text papers; and studies written in
English and published between 2007 and 2019.
This systematic review excluded papers that did not meet
the following criteria: studies with partial cost-effectiveness
analysis (such as effectiveness assessment, cost assessment,
quality-of-life assessment); studies with a low score in the
CHEERS checklist; studies written in languages other than
English; and all protocols, conference abstracts, and letters
to the editor.
2.1.2 Quality Assessment ofMethodology oftheStudies
The reporting quality of the identified studies was measured
against the CHEERS checklist for assessing economic evalu-
ations. This checklist contains five questions with 24 criteria
that assess the quality of each economic evaluation study in
terms of title and abstract, introduction and problem state-
ment, methodology, results, and discussion and conclusion
[21]. A study was deemed to be of excellent reporting qual-
ity if it scored 85% or higher, 70– < 85% very good quality,
55– < 70% good quality, and studies scoring below 55% were
classified as poor quality.
2.2 Data Analysis
After searching different databases, all the recovered stud-
ies were imported into EndNote software and the duplicates
were removed. The remaining papers were independently
studied by two researchers specializing in this field. At this
stage, PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) principles were followed
to retrieve the final studies. In the first stage, the title and
abstract of the studies were reviewed and the relevant papers
were selected according to inclusion and exclusion criteria.
In the next step, if the full text of a selected study was avail-
able, it was carefully reviewed and the final studies were
selected. In each of these stages, if there was disagreement
between the two researchers, the studies were reviewed by a
third researcher. For each study entering into the final step, a
sheet in Excel software was generated to extract the primary
data, including author(s) name, year of publication, country
of origin, studied population, cost-effectiveness, interven-
tion, comparator, basis of cost calculation, basis of cost-
effectiveness analysis, and cost savings.
3 Results
3.1 Search Results
After the initial search in the databases, a total of 533
studies were detected. After removing the duplicates, 419
papers remained. Of the remaining 419 studies, 280 were
found to be not relevant based on the title. A review of the
abstracts of the remaining 102 articles identified a total
of 37 relevant studies. After reviewing the full text of 37
studies, 28 papers were removed based on the inclusion
and exclusion criteria. Finally, nine studies were selected
for further assessment and review (Fig.1).
The review of the references of the selected papers did
not result in detection of new and relevant studies. The
CHEERS checklist was used to evaluate the quality of the
nine studies (Table1). To avoid bias when evaluating the
quality of the research papers, the reviewers were blinded
to primary information of the studies, such as author(s)
name, country, and year of publication. The results of the
quality assessment of the studies were acceptable and no
study was excluded based on the quality criteria. After the

A.Rashki Kemmak et al.
quality assessment, the data of the selected studies were
extracted using a form and extracted in a table (Table2).
3.2 Results ofAssessment oftheQuality
oftheStudies
The quality of the nine studies was assessed vising the 24
items of CHEERS checklist. Items that were completely met
in the studies received a score of 1 and marked with the
symbol of ✓; items that were partially met in of the studies
received a score of 0.5 and marked with the symbol of #, and
items that were not fulfilled at all received a score of zero
and marked with the symbol of × . All studies were found
to be of excellent reporting quality (scoring 85% or higher).
3.3 Study Characteristics
The selected studies included the cost-effectiveness analy-
sis of rivaroxaban in some countries. Most of the studies
had been conducted in high-income countries. The World
Bank defines a high-income country as one that has a
gross national income per capita exceeding $12,376 or
more [29]. The gross national income (GNI) is calculated
by adding gross domestic product to factor incomes from
foreign residents, then subtracting income earned by non-
residents. The studies had been carried out in the USA,
Germany, Canada, Ireland, China, Portugal, and Sweden,
and one study was jointly conducted in France, Italy, and
Spain. Among the selected studies, three studies were
conducted from the payer perspective [17, 22, 24], two
from the national and health sector perspective [18, 26],
one from the social perspective [27], one study from the
hospital and health insurers’ perspective [25], and one
from the perspective of healthcare providers [28]; all of
them examined the costs and benefits of the interventions.
The perspective of one study was unclear [23]. In all the
studies, the intervention was performed using rivaroxa-
ban, which was used to prevent VTE, and it was compared
Idenficaon
Screenin
g
Eli
g
ibilit
y
Included
Records idenfied through database
searching
n = 533
Duplicate records removed
n = 114
Records aer duplicates removed
n = 419
Records excluded at tle and
abstract level
n = 382
Full-text arcles assessed for eligibility
n= 37
Full-text arcles excluded
n = 28
Full-text arcles included in qualitave
synthesis
n = 9
Studies represented in qualitave
synthesis
n = 9
Fig. 1 Results of the systematic literature search

Economic Evaluation of Rivaroxaban Vs. Enoxaparin for Prevention of VTE
Table 1 Quality assessment of studies with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist
Question/
Author
Title Abstract Back-
ground
Popu-
lation
char-
acter-
istic
Set-
ting
and
loca-
tion
Per-
spec-
tive
Com-
parators
described
Time
hori-
zon
Dis-
count
rate
Out-
comes
and
rel-
evance
Meas-
ure-
ment
of
effec-
tive-
ness
Prefer-
ence
based
out-
comes
Estimating
resources
and costs
Cur-
rency,
date
Model
choice
described
Assump-
tions
Anal-
ysis
meth-
ods
Param-
eters of
values
Incre-
mental
costs
sensi-
tivity
anal-
yses
Het-
erogeneity
explained
Find-
ings
and
lim-
ita-
tions
Fund-
ing
source
Poten-
tial
con-
flict of
interest
Total Percent
satisfied
(%)
McCul-
laghet
al.
[22]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ #✓ ✓ ✓ ✓ ✓ 22.5 93
Diaman-
topou-
loset
al.
[18]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 23 95
Rytt-
berget
al.
[23]
✓ ✓ ✓ ✓ ✓ ×✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 22 91
Duranet
al.
[24]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ × 22 91
Zindelet
al.
[25]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ 22 91
McDon-
aldet
al.
[26]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 23 95
Mon-
realet
al.
[17]
✓×✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ×✓ ✓ ✓ ✓ ✓ 22 91
Neveset
al.
[27]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ #✓ ✓ # × × 21 87
Yanet al.
[28]
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ #✓ ✓ ✓ ✓ ✓ 23.5 97

A.Rashki Kemmak et al.
Table 2 Summary ofcharacteristics and results of included studies
Author, year, country Patients, study perspective Comparators/effectiveness
measure
Model, time horizon Discount
rate/sensi-
tivity
analysis
Included cost ICER
McCullagh etal. (2009),
Ireland [22]
Patients undergoing THR
and TKR, health-payer
Enoxaparin/QALYs and
LYG, distal DVT, proxi-
mal DVT, symptomatic,
MB, stroke
Decision Tree Model,
180days post-surgery
No/yes Direct costs include: (1)
orthopedic procedure
(2) Prevention of VTE
events
(3) Diagnosis and treat-
ment of VTE events and
prophylaxis-related major
bleeding
ICER ($/QALY): Rivaroxa-
ban dominated
Diamantopoulos
et al. (2010), Canada [18]
Patients undergoing THR
and TKR, healthcare
system.
Enoxaparin/VTE, symp-
tomatic VTE, asympto-
matic VTE, non-fatal PE,
MB, symptomatic DVT,
QALY
Markov model, decision
analytic model, 5year
No/yes Medication and direct cost For TKR, the cost per
QALY was approximately
C$24,977, which is well
below the frequently-ref-
erenced cost-effectiveness
threshold of C$50,000/
QALY
For THR the incremental
cost saving is increased to
approximately C$379 and
the incremental quality
of life benefit to 0.0033
QALYs. rivaroxaban
remains the
dominant intervention
Ryttberg etal. (2011),
Sweden [23]
Patients undergoing THR
and TKR, NA
Enoxaparin, warfarin,
dalteparin/QALY, VTE,
symptomatic VTE, nonfa-
tal PE, Fatal PE, MB
Markov model, 1year No/yes Monitoring or administra-
tion cost
The incremental cost per
additional quality-adjusted
life-year of extended proph-
ylaxis for 35days with
rivaroxaban vs. 14days of
prophylaxis with enoxapa-
rin or dalteparin was SEK
29,400 and SEK 35,400

Economic Evaluation of Rivaroxaban Vs. Enoxaparin for Prevention of VTE
Table 2 (continued)
Author, year, country Patients, study perspective Comparators/effectiveness
measure
Model, time horizon Discount
rate/sensi-
tivity
analysis
Included cost ICER
Duran etal. (2012), USA
[24]
Patients undergoing THR
and TKR, payer’s per-
spective
Enoxaparin/QALY, VTE,
symptomatic VTE,
asymptomatic
VTE, fatal PE, non-fatal
PE, symptomatic DVT
and prophylaxis related
MB
Decision analytic model,
over 1year and 5years
time
Yes 3%/yes (1) Prophylaxis drugs
(2) Administration, moni-
toring diagnosis
(3) Treatment of VTE
(4) Treatment of PTS
(5) Recurrent VTE
In terms of the cost-utility
analysis, in the THR
population
Rivaroxaban was associated
with an additional 0.0019
QALYs, while saving
$US511.93 per patient. In
the TKR population, rivar-
oxaban was associated with
additional 0.0024 QALYs
gained, as well as average
cost savings of $US465.74
per patient
Zindel etal. (2012), Ger-
many [25]
Patients undergoing THR
and TKR, hospital per-
spective and social health
insurance
Enoxaparin/QALY, MB,
VTE, DVT, symptomatic
DVT, asymptomatic
DVT, non-fatal PE, distal
DVT
Decision Tree, 3months
after surgery
No/yes Prophylaxis, diagnosis and
treatment of VTE events
From the SHI perspective,
prophylaxis with rivar-
oxaban after TKR is cost
saving (€27.3 saving per
patient treated). The cost-
effectiveness after THR
(€17.8 cost per person)
remains unclear because
of stochastic uncertainty.
From the hospital perspec-
tive, for given DRGs, the
hospital profit will decrease
through the use of rivaroxa-
ban by €20.6 (TKR) and
€31.8 (THR) per case
McDonald etal. (2012),
Canada [26]
Patients undergoing THR
and TKR, Ontario Minis-
try of Health Perspective
Enoxaparin/QALY, VTE,
symptomatic VTE, non-
fatal PE, MB
Decision analytic model,
5year
No/yes Medication and direct cost Incremental cost per QALY
gained: of C$6741.96
Monreal etal. (2013),
France, Italy, and Spain
[17]
Patients undergoing THR
and TKR, healthcare
providers and payers
Enoxaparin, dabigatran/
health-related quality of
life, VTE, symptomatic
VTE, asymptomatic VTE,
non-fatal PE, sympto-
matic DVT, MB
Decision analytic model,
5year
Yes 3%/yes (1) Prophylactic drug costs
(acquisition, administra-
tion and monitoring)
(2) Treatment of prophy-
laxis-related bleeding
(3) VTE diagnosis and
treatment; LTCs, includ-
ing diagnosis
(4) Treatment of recurrent
VTE, PTS and CTPH
Rivaroxaban associated
with fewer events and cost
savings in the range of €30
to €160 in THR and €8 to
€137 in TKR

A.Rashki Kemmak et al.
with enoxaparin in all studies. In addition, in three studies
it was compared with dabigatran, warfarin, and dalteparin
[17, 23]. In cost-effectiveness, it is necessary to identify
intervention and complications and the implications and
costs at a given time horizon. Most studies were conducted
over a 5-year period. One of the studies was conducted
over a 3-month period [25], one study a 6-month period
[22], and one other study over a 1-year period [23]. Among
the final studies, three investigated cost-saving [17, 24,
25] and the other studies analyzed cost-effectiveness. Four
studies included discount rates in their study [17, 24, 27,
28] and the other studies did not utilize discount rates and
were set to zero percent by default. In all studies, direct
medical costs, including costs related to the prevention,
diagnosis, and treatment of VTE and PTS, and manage-
ment and monitoring of treatment costs were reviewed.
Quality of life as well as the effectiveness of interven-
tions in PE, VTE, deep vein thrombosis, chronic throm-
boembolic pulmonary hypertension, and post-thrombosis
syndrome were also calculated in all the studies. Cost per
QALY was determined in some of the selected studies
(n = 4) [18, 23, 24, 26]. The incremental cost-effectiveness
ratios (ICERs) of the included studies were converted into
2019 US dollars at an annual rate of 3% [30] (based on the
gross domestic product purchasing power parity in 2019).
The highest and lowest costs per QALY rate were $24,977
for Canada and $466 for the USA, respectively (Fig.2)
The majority of studies (seven out of nine studies), showed
that rivaroxaban, prescribed for the prevention of VTE,
was cost-effective in both TKR and THR. In all studies,
the use of rivaroxaban resulted in less bleeding and less
VTE events. In Zindel’s study (2012), rivaroxaban was
cost-effective in preventing VTE compared to enoxaparin
in TKR and THR; however, its cost-effectiveness was not
clear in hip replacement surgery [25]. Only in Yan etal.’s
study [28] was enoxaparin dominant.
4 Discussion
VTE is one of the major concerns of surgeons. In addition,
as the average age of the community increases with the
improvement in health services, there is an increase in the
number of people who need major surgeries such as heart
surgery or TKR and THR. Nevertheless, a high percentage
of patients are not satisfied with the outcome of their sur-
gery. This dissatisfaction is mainly due to the complications
associated with surgery and greatly affects the quality of life
of patients. VTE is considered as the most important factor
in decreasing the quality of life after surgery [31] and it has
increasingly become important and necessary to optimize
surgeries to reduce related complications.
Table 2 (continued)
Author, year, country Patients, study perspective Comparators/effectiveness
measure
Model, time horizon Discount
rate/sensi-
tivity
analysis
Included cost ICER
Neves etal. (2014) Portugal
[27]
Patients undergoing THR
and TKR, societal
Enoxaparin/QALY, VTE,
DVT with PE event,
(CTPH)
Decision analytic model,
5year
Yes 5%/yes Included costs related: (1)
Prophylaxis
(2) VTE treatment and
bleedings
Cost-effectiveness analysis
for rivaroxaban in THR and
TKR show that rivaroxaban
dominates
Yan etal. (2017) China [28] Patients after THR, health-
care system
Enoxaparin/QALY, DVT,
PE, VTE CTEPH, MB,
PTS
Decision model, 5year Yes 5%/yes Direct medical costs
included: (1) Retail prices
of drugs
(2) Management costs
associated with VTE or
bleeding
ICER ($/QALY): Enoxaparin
dominated
VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, CTPH chronic thromboembolic pulmonary hypertension, PTS post-thrombotic syndrome, MB major
bleeding, QALY quality of life, TKR total knee replacement, THR total hip replacement, LYG life-years gained, ICER incremental cost-effectiveness ratio, DRG diagnosis-related group, SHI
social health insurance, LTCs low transverse Cesarean section, SE swedish Krona

Economic Evaluation of Rivaroxaban Vs. Enoxaparin for Prevention of VTE
The latest guideline of the National Institute for Health
and Care Excellence (NICE) for the Prevention of VTE in
Patients Aged over 16 Years Old has been released recently.
In this guideline, there have been major changes to the NICE
recommendations for specific subgroups of patients. How-
ever, there is weak evidence in this field; consequently NICE
has introduced the development of evidence for the preven-
tion of VTE as one of its priorities [32].
The results of this systematic review showed that the use
of rivaroxaban significantly improves the long-term health
of patients undergoing THR and TKR. As a result, it leads
to significant savings in the community by significantly
reducing the burden of cardiovascular disease and the costs
associated with treating it. Only in the Yan etal. [28] study
was rivaroxaban not cost-effective. In the Yan etal. study,
which compared apixaban, rivaroxaban, and enoxaparin, the
results showed that rivaroxaban had higher costs and lower
QALY as compared with the other two drugs. According to
this study, one of the reasons for the increase in QALY after
the administration of enoxaparin was the lower incidence of
PE events that had resulted in a lower rate of mortality. The
economic burden of PE in China has been reported to be
extremely high, and this reduction in mortality rate had led
to a significant reduction in costs. According to this study,
the higher cost of new oral anticoagulants and lower costs of
enoxaparin and management of VTE events in China were
the other reasons for the cost-effectiveness of enoxaparin,
as compared with rivaroxaban. Finally, the study concluded
that enoxaparin was more cost-effective than the other two
drugs [28].
In a study by Duran etal., when a longer (5-year) time
horizon was considered in sensitivity analysis, the cost-
effectiveness of rivaroxaban improved more than when it
was evaluated at a 1-year time horizon, indicating that in a
longer time horizon, rivaroxaban caused a decrease in the
incidence of VTE through preventing its recurrence and
relapse [24]. In the Ryttberg study, the reduction in VTE
prevention costs was reported as one of the most impor-
tant outcomes of using rivaroxaban, and although it did not
significantly affect the cost of VTE treatment, as compared
with enoxaparin, rivaroxaban was more effective in saving
costs and increasing QALY, thus it was recognized as a more
cost-effective option [23].
In a study by Monreal etal. that was conducted in three
countries, including France, Italy and Spain, despite their
different healthcare systems, the results were similar.
According to the results, as compared with enoxaparin,
rivaroxaban resulted in greater cost savings and an increase
in the quality of life of individuals, indicating that these
results could be generalized to other European countries
[17]. In their study, Donald etal. showed that rivaroxaban
was superior to enoxaparin in preventing VTE because it
had a lower cost over the course of treatment [26]. In the
study of McCullagh etal., rivaroxaban and dabigatran were
less costly and effective than enoxaparin. Furthermore, rivar-
oxaban was also less costly and effective than dabigatran
[22]. In the Diamantopoulos study, rivaroxaban as compared
with enoxaparin was a cost-effective option for preventing
VTE [18]. In a study by Neves etal., rivaroxaban resulted
in lower costs and higher QALY in patients compared to
enoxaparin [27].
In the study of Zindel etal. prophylaxis with rivaroxaban
reduced VTE events compared with enoxaparin. From the
social health insurance perspective, prophylaxis with rivar-
oxaban after TKR is cost saving [25]. Findings from a review
study demonstrated rivaroxaban was superior to enoxaparin,
with a greater reduction in the occurrence of symptomatic
VTE and symptomatic death, which is consistent with the
Fig. 2 The cost per quality-
adjusted life-year (QALY)
(ICER (incremental cost-
effectiveness ratio) inflated to
2019 US dollars at an annual
rate of 3%)
0
5000
10000
15000
20000
25000
30000
Canada Sweden USACanada
Cost per QALY (USD 2019)

A.Rashki Kemmak et al.
findings of our review on the efficacy of rivaroxaban [33].
Huang etal. identified advantages of rivaroxaban over
enoxaparin in their meta-analysis, especially that DVT and
PE rates were lower in the rivaroxaban group, though the
number of studies that were based on those conclusions were
low [34].
Prophylaxis for VTE in orthopedic surgery, particularly in
arthroplasties, continues to cause considerable debate among
healthcare professionals. On the one hand, one should avoid
VTE and its repercussions and, on the other, minimize the
risks of operative bleeding [33].
In this systematic review, economic evaluations of these
two drugs have been carried out in high-income countries.
One of the limitations of cost-effectiveness studies is the
generalization of study results to other countries because
one technology or drug in one country can be cost-effective
while in another country it is not cost-effective. It is difficult
to generalize the results of this study to low-income coun-
tries because these countries have different epidemiological
conditions than high-income countries due to their different
lifestyles, income, and demographics.
Also, heterogeneity of the study population, the follow-up
time, the discount rate, and the different thresholds between
studies make it difficult to generalize the results.
In this study we tried to avoid any bias through conduct-
ing a comprehensive and systematic search. One of the limi-
tations of this study was only review of published articles
in English and failure to follow a standard cost-detection
approach in the selected studies. The failure to follow a
standard cost-detection approach in the selected studies
reduced the consistency of the reported results.
5 Conclusion
The results of our systematic review showed that rivaroxa-
ban reduced costs and increased quality of life in people
undergoing surgery. However, since most studies had been
conducted in developed countries, there are limitations
in generalization of the results to developing countries.
Nevertheless, given that rivaroxaban is orally administered
and does not require continuous monitoring, it will be less
costly for the patient and health systems, and its use as a
thromboprophylactic drug following surgery is preferable.
Compliance with Ethical Standards
This article does not contain clinical studies or patient data.
Conflict of interest The authors declare that they have no conflicts of
interest.
Funding This study was part of a PhD thesis supported by the Iran
University of Medical Sciences (IUMS/SHMIS with Grant no: 98-2-
37-15593 and with ethical code IR.IUMS.REC.1398.534).
References
1. Aslan A, Khorami R, Rezaii J, Godarzi M, Abbasi DZ. Drug
updates for prevention and treatment of venous thromboem-
bolism in orthopedic surgeries. Iranian J Cardiovasc Nurs.
2017;6(2):66–73.
2. Beckman MG, Abe K, Barnes K, Bartman B, Brady PJ,
Hooper WC. Strategies and partnerships toward prevention of
healthcare-associated venous thromboembolism. J Hosp Med.
2016;11(Suppl 2):S5.
3. Jha AK, Larizgoitia I, Audera-Lopez C, Prasopa-Plaizier N,
Waters H, Bates DW. The global burden of unsafe medical
care: analytic modelling of observational studies. BMJ Qual
Saf. 2013;22(10):809–15.
4. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitz-
maurice D, Galiè N, etal. 2014 ESC Guidelines on the Diag-
nosis and Management of Acute Pulmonary Embolism: The
Task Force for the Diagnosis and Management of Acute Pulmo-
nary Embolism of the European Society of Cardiology (ESC)
Endorsed by the European Respiratory Society (ERS). Eur
Heart J Cardiovasc Pharmacother. 2014;35(43):3033–73.
5. Heisen M, Treur MJ, Heemstra HE, Giesen EB, Postma MJ.
Cost-effectiveness analysis of rivaroxaban for treatment and
secondary prevention of venous thromboembolism in the Neth-
erlands. J Med Econ. 2017;20(8):813–24.
6. Health Select Committee. The prevention of venous throm-
boembolism in hospitalised patients. London: The Stationery
Office Limited; 2005.
7. Centers for Disease Control and Prevention (CDC). Venous
thromboembolism in adult hospitalizations-United States,
2007–2009.
8. Rathbun S. The surgeon general’s call to action to prevent
deep vein thrombosis and pulmonary embolism. Circulation.
2009;119(15):e480–2.
9. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Col-
well CW, etal. Prevention of venous thromboembolism: the
seventh ACCP conference on antithrombotic and thrombolytic
therapy. Chest. 2004;126(3):338–400.
10. Ruppert A, Lees M, Steinle T. Clinical burden of venous throm-
boembolism. Curr Med Res Opin. 2010;26(10):2465–73.
11. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D,
Brecht JG, etal. Venous thromboembolism (VTE) in Europe.
Thromb Haemost. 2007;98(10):756–64.
12. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous
thromboembolism: a public health concern. Am J Prev Med.
2010;38(4):S495–501.
13. Habibzadeh H, Mohammadi A, Safari MB, Khalkhali HR,
Rezaeipour N. The effect of care plan based on nutrition and exer-
cise on deep vein thrombosis in patients undergoing lower limb
orthopedic surgery in Urmia Imam Khomeini Hospital in 1391. J
Urmia Nurs Midwifery Fac. 2013;11(9):680–7.
14. Derman PB, Fabricant PD, David G. The role of overweight and
obesity in relation to the more rapid growth of total knee arthro-
plasty volume compared with total hip arthroplasty. J Bone Jt
Surg. 2014;96(11):922–8.
15. Brockbank J, Wolowacz S. Economic evaluations of new oral anti-
coagulants for the prevention of venous thromboembolism after

Economic Evaluation of Rivaroxaban Vs. Enoxaparin for Prevention of VTE
total hip or knee replacement: a systematic review. Pharmacoeco-
nomics. 2017;35(5):517–35.
16. Moghtadaee M, Shahhoseini GH, Farahini H, Yegane A, Rajab-
pour S. Dabigatran etexilate, a novel oral direct thrombin inhibi-
tor, for preventing thromboembolic events after knee replacement
arthroplasty. Tehran Univ Med J. 2012;69(11):725–9.
17. Monreal M, Folkerts K, Diamantopoulos A, Imberti D, Brosa M.
Cost-effectiveness impact of rivaroxaban versus new and existing
prophylaxis for the prevention of venous thromboembolism after
total hip or knee replacement surgery in France, Italy and Spain.
Thromb Haemost. 2013;110(11):987–94.
18. Diamantopoulos A, Lees M, Wells PS, Forster F, Ananthapavan J,
McDonald H. Cost-effectiveness of rivaroxaban versus enoxaparin
for the prevention of postsurgical venous thromboembolism in
Canada. J Thromb Haemost. 2010;104(10):760–70.
19. National Center for Biotechnology Information. PubChem Data-
base. Rivaroxaban, CID = 9875401, https ://pubch em.ncbi.nlm.nih.
gov/compo und/Rivar oxaba n. Accessed 15 May 2020.
20. Schellack G, Modau T, Schellack N. Clinical overview of venous
thromboembolism. S Afr Fam Pract. 2016;58(1):39–45.
21. Husereau D, Drummond M, Petrou S, Carswell C, Moher D,
Greenberg D, etal. Consolidated health economic evaluation
reporting standards (CHEERS) statement. Int J Technol Assess
Health Care. 2013;29(2):117–22.
22. McCullagh L, Tilson L, Walsh C, Barry M. A cost-effectiveness
model comparing rivaroxaban and dabigatran etexilate with
enoxaparin sodium as thromboprophylaxis after total hip and total
knee replacement in the Irish healthcare setting. Pharmacoeco-
nomics. 2009;27(10):829–46.
23. Ryttberg L, Diamantopoulos A, Forster F, Lees M, Fraschke A,
Björholt I. Cost-effectiveness of rivaroxaban versus heparins for
prevention of venous thromboembolism after total hip or knee
surgery in Sweden. Expert Rev Pharmacoecon Outcomes Res.
2011;11(5):601–15.
24. Duran A, Sengupta N, Diamantopoulos A, Forster F, Kwong L,
Lees M. Cost effectiveness of rivaroxaban versus enoxaparin for
prevention of post-surgical venous thromboembolism from a US
Payer’s perspective. Pharmacoecon Open. 2012;30(2):87–101.
25. Zindel S, Stock S, Müller D, Stollenwerk B. A multi-perspec-
tive cost-effectiveness analysis comparing rivaroxaban with
enoxaparin sodium for thromboprophylaxis after total hip and
knee replacement in the German Healthcare Setting. BMC Health
Serv Res. 2012;12(1):192.
26. McDonald H, Diamantopoulos A, Wells P, Lees M, Folkerts
K, Forster F, etal. Cost-effectiveness of rivaroxaban in the
prevention of venous thromboembolism: a Canadian analysis
using the Ontario Ministry of Health perspective. J Med Econ.
2012;15(5):817–28.
27. Neves JR, Folkerts K, Umbelino S, Santos IF. Cost-effectiveness
of rivaroxaban compared with enoxaparin for the prevention of
venous thromboembolism in adult patients undergoing elective
hip or knee replacement surgery in Portugal. Rev Port Farmacoter.
2014;6:16–23.
28. Yan X, Gu X, Xu Z, Lin H, Wu B. Cost-effectiveness of different
strategies for the prevention of venous thromboembolism after
total hip replacement in China. Adv Ther. 2017;34(2):466–80.
29. Fantom JN, Umar S. The World Bank’s classification of countries
by income (English). Policy Research working paper; no. WPS
7528. Washington, D.C; 2016: World Bank Group
30. Haacker M, Hallett TB, Atun R. On discount rates for eco-
nomic evaluations in global health. Health Policy Plan.
2020;35(1):107–14.
31. van Korlaar IM, Vossen CY, Rosendaal FR, Bovill EG, Cushman
M, Naud S, Kaptein AA. The impact of venous thrombosis on
quality of life. Thromb Res. 2004;114(1):11–8.
32. Griffin XL, McBride D, Nnadi C, Reed MR, Rossiter ND. “Don’t
shoot the messengers…..”: the new NICE guidance for the pre-
vention of venous thromboembolism in adults–fake news or a real
opportunity? Bone Jt J. 2018;1136–1137.
33. Rodarte RR, Guimarães JA, Franco JS, Fonseca L, Nascimento V,
Aramburu JP, etal. Systematic review of prophylaxis for venous
thromboembolism after knee arthroplasty: enoxaparin versus
rivaroxaban. Rev Col Bras Cir. 2019;46(2):e2075.
34. Huang HF, Li SS, Yang XT, Xie Q, Tian XB. Rivaroxaban versus
enoxaparin for the prevention of venous thromboembolism after
total knee arthroplasty: a meta-analysis. Medicine. 2018; 97(48).