Hindawi Publishing Corporation
Volume 2013, Article ID 762310, 5 pages
The Efficacy and Safety of Rivaroxaban for
Venous Thromboembolism Prophylaxis after
Total Hip and Total Knee Arthroplasty
Robert D. Russell, William R. Hotchkiss, Justin R. Knight, and Michael H. Huo
Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, 1801 Inwood Road,
Dallas, TX 75390-8883, USA
Correspondence should be addressed to Michael H. Huo; email@example.com
Received 11 September 2012; Accepted 24 January 2013
Academic Editor: C. Arnold Spek
Copyright © 2013 Robert D. Russell et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Venous thromboembolism (VTE) is a common complication after total hip and total knee arthroplasty. Currently used methods
of VTE prophylaxis after these procedures have important limitations, including parenteral administration, and unpredictable
plasma levels requiring frequent monitoring and dose adjustment leading to decreased patient compliance with recommended
guidelines. New oral anticoagulants have been demonstrated in clinical trials to be equally efficacious to enoxaparin and allow for
fixed dosing without the need for monitoring. Rivaroxaban is one of the new oral anticoagulants and is a direct factor Xa inhibitor
that has demonstrated superior efficacy to that of enoxaparin. However, the data also suggest that rivaroxaban has an increased
risk of bleeding compared to enoxaparin. This paper reviews the available data on the efficacy and safety of rivaroxaban for VTE
prophylaxis after total hip and total knee arthroplasty.
(TKA). Without anticoagulant prophylaxis, symptomatic
deep venous thrombosis (DVT) occurs in approximately
15%–30% of the patients undergoing THA and TKA [1, 2].
Patients undergoing TKA are at higher risk for developing
DVT; however, the rate of symptomatic DVT is higher after
of preventing VTE, the rate of VTE has decreased over time
. Using currently accepted methods of VTE prophylaxis,
the rate of symptomatic DVT is approximately 1%–3%,
and the rate of pulmonary embolism (PE) is approximately
0.2%–1.1% [2, 5–8]. The efficacy of VTE prophylaxis must
be weighed against the risk of bleeding complications for
the patients. The most commonly used VTE chemoprophy-
laxes after THA and TKA are low-molecular-weight heparin
fondaparinux, or aspirin .
Current VTE prophylaxis regimens have significant
shortcomings. Warfarin has a slow onset of action and has a
narrow therapeutic window requiring frequent monitoring.
are frequently outside the targeted INR range increasing the
heparin (LMWH) and fondaparinux must be administered
parenterally, which requires time and cost. Patients are
less compliant with administration of these drugs due to
these barriers. One study reported only 75% continued the
medication after discharge . However, both warfarin and
LMWH have acceptable efficacy and safety profiles.
In addition to the type of VTE prophylaxis used, another
important consideration is the duration of prophylaxis. The
TKA is approximately 21 days and 10 days, respectively .
THA and TKA is 3 and 4 days, respectively . The current
recommendations for the duration of prophylaxis are a
Table 1: Description of RECORD trials comparing rivaroxaban to enoxaparin for VTE prophylaxis in patients undergoing THA and TKA.
Treatment duration (days) Enoxaparin 10–14, rivaroxaban 31–39
2509 Patients (푛)
undergoing THA . Thus, in addition to optimal efficacy
and safety profiles, the ideal VTE prophylaxis regimen must
be administered by the patient and requires no frequent
Three new oral anticoagulants have been developed.
Dabigatran is a direct factor IIa (thrombin) inhibitor. Riv-
aroxaban and apixaban both are direct factor Xa inhibitors.
Only rivaroxaban is currently approved in the United States
for VTE prophylaxis after THA and TKA . The results
for apixaban and dabigatran have demonstrated similar
efficacy and safety profiles when compared to enoxaparin,
in Europe [12–17]. Randomized-controlled trials comparing
rivaroxaban to enoxaparin for the prevention of VTE after
THA and TKA have demonstrated superior efficacy of
rivaroxaban to enoxaparin [18–21]. However, there is also
evidence suggesting that rivaroxaban has an increased risk
of bleeding complications compared to enoxaparin [22, 23].
While rivaroxaban appears to be a promising alternative to
LMWH or warfarin for VTE prophylaxis after THA and
TKA, the long-term safety of rivaroxaban remains to be
The purpose of this paper is to critically analyze the
current data on the efficacy and safety of rivaroxaban after
total hip and total knee arthroplasty.
2. Pharmacokinetics of Rivaroxaban
The recommended dose of rivaroxaban is 10mg daily for
10 to 35 days for VTE prophylaxis starting 6–10 hours
after THA or TKA . Rivaroxaban is a competitive,
direct factor Xa (FXa) inhibitor and acts by binding to the
active site of FXa preventing substrate binding. Factor Xa is
responsible for the conversion of prothrombin to thrombin
in the coagulation cascade . Rivaroxaban has a rapid
onset of action, reaching maximum plasma concentrations
after 2-3 hours and has a half-life of 8–10 hours [25, 26].
No increase in maximum plasma concentrations has been
demonstrated in the obese patients (>120kg). However, the
. Rivaroxaban is metabolized in the liver and primarily
excreted renally (66%), with the remainder excreted through
the gastrointestinal tract . In patients with impaired
renal function, the clearance of rivaroxaban is decreased
moderately, and its use is not recommendedforpatientswith
maximum plasma concentration has been demonstrated to
be up to 24% higher in patients weighing less than 50kg
severe renal impairment (creatinine clearance < 30mL/min)
3. Phase III Clinical Trials of Rivaroxaban
The safety and efficacy of rivaroxaban has been assessed in
two phase III trials each for patients undergoing THA and
TKA [18–21] (Table 1). All four were randomized, double-
blind, placebo-controlled studies. The study group respon-
sible for these trials is the Regulation of Coagulation in
Orthopedic Surgery to Prevent Deep Venous Thrombosis
and Pulmonary Embolism (RECORD). The primary effi-
cacy outcome for each study was DVT (symptomatic or
asymptomatic venographic), PE, or death, and the primary
safety outcome was major bleeding. Major bleeding was
defined as bleeding that was fatal, occurred in a critical
organ, requiring reoperation, or was clinically overt with a
drop in the hemoglobin level of at least 2g/dL or requiring
at least 2 units of blood transfusion. Major bleeding did
not include surgical site bleeding unless it led to reopera-
tion. Clinically relevant nonmajor bleeding was a secondary
safety outcome and was defined as multiple-source bleed-
wound hematoma, nose bleeding >5 minutes, gingivalbleed-
semen, intra-articular bleeding with trauma, or surgical site
The RECORD 1 trial included 4,541 patients undergoing
THA that were assigned to received either rivaroxaban 10mg
daily or enoxaparin 40mg daily, plus either a placebo tablet
or injection. Rivaroxaban was started after surgery, and
enoxaparin was started the evening prior to surgery. The
duration of treatment was 33 days on average in both groups.
The primary efficacy outcome occurred in 1.1% of patients
in the rivaroxaban group and in 3.7% of patients in the
patients in the enoxaparin group (푃 = 0.018). The combined
group, which was not statistically significant .
The RECORD 2 trial included 2,509 patients undergoing
THA that were assigned to receive either rivaroxaban 10mg
The primary efficacy outcome occurred in 2.0% of patients
in the rivaroxaban group and in 9.3% of patients in the
ing, spontaneous hematoma greater than 25cm2, excessive
ing >5 minutes, macroscopic hematuria, rectal bleeding,
coughing or vomiting blood, vaginal bleeding, blood in
enoxaparin group (푃 < 0.001). Major bleeding occurred in
rate of major and clinically relevant non-major bleeding was
3.2% in the rivaroxaban group and 2.5% in the enoxaparin
0.3% of patients in the rivaroxaban group and in 0.1% of
enoxaparin group (푃 < 0.0001). Major bleeding occurred in
only 1 patient in each group. However, the rate of clinically
relevant non-major bleeding occurred in 6.5% of patients in
the rivaroxaban group compared to 5.5% of patients in the
enoxaparin group .
The RECORD 3 trial included 2,531 patients undergoing
TKA that were assigned to receive either rivaroxaban 10mg
daily for or enoxaparin 40mg daily for 10–14 days. The
primary efficacy outcome occurred in 9.6% of patients in the
rivaroxaban group and in 18.9% of patients in the enoxaparin
group (푃 < 0.001). Major bleeding occurred in 0.6% of
and clinically relevant non-major bleeding was 3.3% in the
rivaroxaban group and 2.7% in the enoxaparin group, which
was not statistically significant .
The RECORD 4 trial included 3,148 patients undergoing
TKA that were assigned to receive either rivaroxaban 10mg
daily for or enoxaparin 30mg twice daily for 10–14 days. The
primary efficacy outcome occurred in 6.9% of patients in the
rivaroxaban group and in 10.1% of patients in the enoxaparin
enoxaparin group (푃 = 0.1096). The combined incidence of
patients in the rivaroxaban group and 0.5% of patients in
the enoxaparin group. The combined incidence of major
group (푃 = 0.0118). Major bleeding occurred in 0.7% of
patients in the rivaroxaban group and 0.3% of patients in the
4. Pooled Data from Clinical Trials
Pooled analyses of the data from the RECORD trials
have demonstrated similar findings of increased efficacy
of rivaroxaban at all time intervals [29, 30]. Moreover,
patients in the rivaroxaban groups had a reduced rate of
the composite of death, myocardial infarction, and stroke in
addition to symptomatic VTE . With data pooled from
all 4 RECORD trials, rivaroxaban significantly reduced the
rate of symptomatic VTE and death over the total study
duration (0.81% versus 1.63%, 푃 < 0.001; HR 0.42, 95%CI
days versus rivaroxaban given for 31–39 days), other authors
have excluded this study when pooling data. Despite this,
enoxaparin for the primary outcome (RR 0.5, 95%CI 0.34–
0.29–0.63) [29, 30]. Due to the discrepancy in treatment
duration of the RECORD 2 trial (enoxaparin given for 10–14
0.73, 푃 = 0.0003) .
although not statistically significant. Pooled data from all 4
trials demonstrated a trend of higher rates of major bleeding
in the rivaroxaban group for the treatment period (0.39%
However, in each of the RECORD trials, the rate of
bleeding complications was higher in the rivaroxaban group,
versus 0.21%, 푃 = 0.076). The combined endpoint of major
plus clinically relevant non-major bleeding was significantly
higher in the rivaroxaban group during the treatment period
(3.19% versus 2.55%, 푃
in patients under 65 years old (HR 1.44, 95%CI 1.02–2.04),
patients weighing greater than 90kg (HR 1.62, 95%CI 1.09–
=0.039; HR 1.25, 95%CI 1.01–
plus clinically relevant nonmajor bleeding were also seen
2.4) and patients with creatinine clearance >80mL/min (HR
1.5, 95%CI 1.12–2.00) [23, 29, 30] (Figure 1). Similarly, with
the RECORD 2 trial excluded, pooled analysis demonstrated
Weight >90 kg
Age less than
Hazard Ratio (HR)
Figure 1: Pooled incidence of major plus clinically relevant non-
major bleeding for RECORD trials 1–4. Patients taking rivaroxaban
rivaroxaban less than 65 years of age (푃 = 0.04), weighing less than
had more events than patients taking enoxaparin (푃 = 0.03).
In subgroup analysis, more events occurred in patients taking
(푃 = 0.005) .
ing in patients taking rivaroxaban (RR 1.29, 95%CI 1.03–1.63)
. Another study pooling data from the RECORD trials
90kg (푃 = 0.02), and with creatinine clearance over 80mL/min
group (OR 0.79, 95%CI 0.62–0.99, 푃 = 0.049) . The
In addition to bleeding, rivaroxaban was also associated
with increased risk for other adverse events. Pooled data
demonstrated that patients on rivaroxaban had a higher rate
1.49, 푃 = 0.05). Furthermore, patients in the rivaroxaban
number needed to harm by treating with rivaroxaban in this
study was 167 patients .
1.48, 푃 = 0.002) and also had a higher rate of treatment
group were more likely to have alanine aminotransferase
(ALT) levels more than 3x the upper limit of normal during
discontinuation due to adverse events (OR 1.22, 95%CI 1.00–
treatment (OR1.42, 95%CI 1.06–1.88, 푃 = 0.02) .
Venous thromboembolism is a common complication after
THA and TKA and creates a substantial burden to patients,
able anticoagulants have limitations that lead to decreased
compliance with VTE prophylaxis guidelines. Rivaroxaban
has superior efficacy compared to enoxaparin for the pre-
vention of symptomatic VTE for patients undergoing THA
and TKA. Although the patient compliance rate while taking
rivaroxaban remains unknown, rivaroxaban is administered
orally with fixed dosing and does not require monitoring
which makes it attractive. Furthermore, there is evidence to
support that the patients receiving rivaroxaban experience a
and stroke in addition to the reduction in symptomatic VTE.
However, the bleeding risk with rivaroxaban after THA and
TKA is not fully understood. Pooled data from the phase
III clinical trials indicate that patients taking rivaroxaban
experience more bleeding complications than those patients
taking Lovenox. Moreover, a retrospective cohort study of
that received thromboprophylaxis with rivaroxaban were
more likely to return to the operating room than those
Another large retrospective cohort study comparing rivarox-
aban to LMWH after THA and TKA found that patients
taking rivaroxaban were less likely to experience bleeding,
return to the operating room for wound complications, and
had a shorter hospital stay . Specific patient groups
at increased risk of bleeding complications include those
patients under 65 years old, patients weighing greater than
90kg, and patients with creatinine clearance >80mL/min.
diverse patient populations.
Postmarketing surveillance is critical to continue to monitor
 K. H. Xing, G. Morrison, W. Lim, J. Douketis, A. Odueyungbo,
and M. Crowther, “Has the incidence of deep vein thrombosis
time? A systematic review of randomized controlled trials,”
Thrombosis Research, vol. 123, no. 1, pp. 24–34, 2008.
 Y. Falck-Ytter, C. W. Francis, N. A. Johanson et al., “Prevention
and prevention of thrombosis, 9th ed: American College of
Chest Physicians evidence-based clinical practice guidelines,”
Chest, vol. 141, supplement, no. 2, pp. e278S–e325S, 2012.
 M. H. Huo, D. L. Spencer, B. J. Borah et al., “Post-discharge
venous thromboembolism and bleeding in a large cohort of
of Clinical Outcomes Management, vol. 19, no. 8, pp. 355–363,
 J.-M. Januel, G. Chen, C. Ruffieux et al., “Symptomatic in-
hospital deep vein thrombosis and pulmonary embolism fol-
lowing hip and knee arthroplasty among patients receiving
recommended prophylaxis: a systematic review,” Journal of the
 R. H. White, H. Zhou, and P. S. Romano, “Incidence of
symptomatic venous thromboembolism after different elective
or urgent surgical procedures,” Thrombosis and Haemostasis,
vol. 90, no. 3, pp. 446–455, 2003.
 M. Khatod, M. C. Inacio, S. A. Bini, and E. W. Paxton, “Prophy-
laxis against pulmonary embolism in patients undergoing total
hip arthroplasty,” Journal of Bone and Joint Surgery, vol. 93, no.
19, pp. 1767–1772, 2011.
 S. S. Jameson, S. C. Charman, P. J. Gregg, M. R. Reed, and J.
H. van der Meulen, “The effect of aspirin and low-molecular-
weight heparin on venous thromboembolism after hip replace-
ment: a non-randomised comparison from information in the
National Joint Registry,” Journal of Bone and Joint Surgery, vol.
93 B, no. 11, pp. 1465–1470, 2011.
 B. T. Bjørnar˚ a, T. E. Gudmundsen, and O. E. Dahl, “Frequency
and timing of clinical venous thromboembolism after major
joint surgery,” Journal of Bone and Joint Surgery, vol. 88, no. 3,
pp. 386–391, 2006.
 R. J. Friedman, A. S. Gallus, F. D. Cushner, G. FitzGerald,
and F. A. Anderson Jr., “Physician compliance with guidelines
for deep-vein thrombosis prevention in total hip and knee
1, pp. 87–97, 2008.
 P. Schuringa and D. Yen, “Home prophylactic warfarin antico-
agulation program after hip and knee arthroplasty,” Canadian
Journal of Surgery, vol. 42, no. 5, pp. 360–362, 1999.
 D. Warwick, R. J. Friedman, G. Agnelli et al., “Insufficient
duration of venous thromboembolism prophylaxis after total
thromboembolic events: findings from the Global Orthopaedic
Registry,” Journal of Bone and Joint Surgery B, vol. 89, no. 6, pp.
 M. R. Lassen, G. E. Raskob, A. Gallus, G. Pineo, D. Chen, and
after knee replacement,” The New England Journal of Medicine,
Journal of Medicine, vol. 361, no. 18, p.1814, 2009.
 M.R.Lassen,G.E.Raskob,A.Gallus, G.Pineo,D. Chen,andP.
Hornick, “Apixaban versus enoxaparin for thromboprophylaxis
after knee replacement (ADVANCE-2): a randomised double-
blind trial,” The Lancet, vol. 375, no. 9717, pp. 807–815, 2010.
 M. R. Lassen, A. Gallus, G. E. Raskob, G. Pineo, D. Chen, and
L. M. Ramirez, “Apixaban versus enoxaparin for thrombopro-
phylaxis after hip replacement,” The New England Journal of
Medicine, vol. 363, no. 26, pp. 2487–2498, 2010.
 B. I. Eriksson, O. E. Dahl, N. Rosencher et al., “Oral dabigatran
etexilate vs. subcutaneous enoxaparin for the prevention of
venous thromboembolism after total knee replacement: the
RE-MODEL randomized trial,” Journal of Thrombosis and
Haemostasis, vol. 5, no. 11, pp. 2178–2185, 2007.
 B. I. Eriksson, O. E. Dahl, N. Rosencher et al., “Dabigatran
etexilate versus enoxaparin for prevention of venous throm-
boembolism after total hip replacement: a randomised, double-
blind, non-inferiority trial,” The Lancet, vol. 370, no. 9591, pp.
949–956, 2007, Erratum in: The Lancet, vol. 370, no. 9604,
son et al., “Oral thrombin inhibitor dabigatran etexilate vs
North American enoxaparin regimen for prevention of venous
thromboembolism after knee arthroplasty surgery,” Journal of
Arthroplasty, vol. 24, no. 1, pp. 1–9, 2009.
 B. I. Eriksson, L. C. Borris, R. J. Friedman et al., “Rivaroxaban
versus enoxaparin for thromboprophylaxis after hip arthro-
plasty,” The New England Journal of Medicine, vol. 358, no. 26,
pp. 2765–2775, 2008.
 A. K. Kakkar, B. Brenner, O. E. Dahl et al., “Extended duration
blind, randomised controlled trial,” The Lancet, vol. 372, no.
9632, pp. 31–39, 2008.
 M. R. Lassen, W. Ageno, L. C. Borris et al., “Rivaroxaban
versus enoxaparin for thromboprophylaxis after total knee
26, pp. 2776–2786, 2008.
 A. G. Turpie, M. R. Lassen, B. L. Davidson et al., “Rivaroxaban
versus enoxaparin for thromboprophylaxis after total knee
arthroplasty (RECORD4): a randomised trial,” The Lancet, vol.
373, no. 9676, pp. 1673–1680, 2009.
 M. V. Huisman, D. J. Quinlan, O. E. Dahl, and S. Schulman,
“Enoxaparin versus Dabigatran or rivaroxaban for thrombo-
prophylaxis after hip or knee arthroplasty: results of separate
pooled analyses of phase III multicenter randomized trials,”
Circulation, vol. 3, no. 6, pp. 652–660, 2010.
 V. Trkulja and R. Kolundˇ zic, “Rivaroxaban vs dabigatran for
thromboprophylaxis after joint-replacement surgery: explor-
atory indirect comparison based on metaanalysis of pivotal
clinical trials,” Croatian Medical Journal, vol. 51, no. 2, pp. 113–
 “Xarelto Prescribing Information,” 2012, http://www.xarelto-
macodynamics and pharmacokinetics of oral direct thrombin
and factor Xa inhibitors in development,” Clinical Pharmacoki-
netics, vol. 48, no. 1, pp. 1–22, 2009.
 D. Kubitza, M. Becka, W. Mueck et al., “Effects of renal im-
pairment on the pharmacokinetics, pharmacodynamics and
Journal of Clinical Pharmacology, vol. 70, no. 5, pp. 703–712,
 D. Kubitza, M. Becka, M. Zuehlsdorf, and W. Mueck, “Body
weight has limited influence on the safety, tolerability, phar-
macokinetics, or pharmacodynamics of rivaroxaban (BAY 59-
7939) in healthy subjects,” Journal of Clinical Pharmacology,
vol. 47, no. 2, pp. 218–226, 2008, Erratum in:Journal of Clinical
Pharmacology, vol. 48, no. 11, p.1366–1367, 2008.
 R. J. Friedman, “Novel oral anticoagulants for VTE prevention
in orthopedic surgery: overview of phase 3 trials,” Orthopedics,
vol. 34, no. 10, pp. 795–804, 2011.
 A. G. Turpie, M. R. Lassen, A. K. Kakkar et al., “Pooled analysis
of four studies of rivaroxaban: effect on symptomatic events
and bleeding and the influence of clinically relevant patient
subgroups,” Chest, vol. 136, meeting abstracts, p. 144, 2009.
the prevention of venous thromboembolism after hip or knee
arthroplasty: pooled analysis of four studies,” Thrombosis and
Haemostasis, vol. 105, no. 3, pp. 444–453, 2011.
 N. G. Espada, R. G. Merino, and T. C. Gonz´ alez, “Dabigatran,
Rivaroxaban and Apixaban versus Enoxaparin for thombopro-
phylaxis after total knee or hip arthroplasty: pool-analysis of
phase III randomized clinical trials,” Thrombosis Research, vol.
130, no. 2, pp. 183–191, 2012.
 C. D. Jensen, A. Steval, P. F. Partington, M. R. Reed, and S.
D. Muller, “Return to theatre following total hip and knee
replacement, before and after the introduction of rivaroxaban:
a retrospective cohort study,” Journal of Bone and Joint Surgery
B, vol. 93, no. 1, pp. 91–95, 2011.
 J. L¨ utzner, L. Donath, L. Tittl et al., “Efficacy and safety
of thromboprophylaxis with low-molecular-weight heparin or
the ORTHO-TEP registry,” Thrombosis and Haemostasis, vol.
109, no. 1, pp. 154–163, 2013.