The Efficacy and Safety of Rivaroxaban for Venous Thromboembolism Prophylaxis after Total Hip and Total Knee Arthroplasty
ABSTRACT 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.
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ABSTRACT: There have been no comprehensive studies that have compared the incidence of symptomatic VTE over a spectrum of different urgent or elective surgical procedures. In this study we determined the incidence of symptomatic venous thromboembolic events (VTE) within a 3 month period after 76 different surgical procedures. Using a large administrative data-base, we analyzed 1,653,275 cases that underwent one of 76 selected surgical procedures between January 1, 1992 and September 30, 1996. The principal outcomes were venous thrombosis or pulmonary embolism, during either the initial hospitalization or a re-hospitalization for VTE within 91 days of the date of surgery. Predictors of VTE were analyzed using logistic regression. Overall, VTE was diagnosed in 13,533 cases (0.8%, 95% CI = 0.7-0.9%) and of these, 5049 (37%, 95% CI = 36-38%) had pulmonary embolism. Predictors of VTE included: advancing age (OR=1.1 per 5 year increment in age, 95% CI =1.1-1.1), Latino ethnicity (OR = 0.9, 95% CI = 0.8-0.9), Asian/Pacific Islander ethnicity (OR = 0.5, 95% CI = 0.4-0.6), presence of a malignancy (OR = 1.7, 95% CI = 1.6-1.8) and prior VTE (OR = 6.2, 95% CI = 5.5-7.0). High-risk procedures that had an incidence of symptomatic VTE of approximately 2 to 3% included invasive neurosurgery, total hip arthroplasty, major vascular surgery and radical cystectomy. Fifty-six percent of all VTE events diagnosed within 91 days of surgery occurred after discharge. The findings of this study provide a basis for categorizing different surgical procedures as low, intermediate, high and very high risk for VTE. Because of the high incidence of VTE diagnosed after hospital discharge, further studies of extended thromboprophylaxis appear warranted.Thrombosis and Haemostasis 10/2003; 90(3):446-55. · 5.76 Impact Factor
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ABSTRACT: Over a 13-year period we studied all patients who underwent major hip and knee surgery and were diagnosed with objectively confirmed symptomatic venous thromboembolism, either deep venous thrombosis or non-fatal pulmonary embolism, within six months after surgery. Low-molecular-weight heparin had been given while the patients were in hospital. There were 5607 patients. The cumulative incidence of symptomatic venous thromboembolism was 2.7% (150 of 5607), of which 1.1% had developed pulmonary embolism, 1.5% had deep venous thrombosis and 0.6% had both. Patients presented with deep venous thrombosis at a median of 24 days and pulmonary embolism at 17 days after surgery for hip fracture. After total hip replacement, deep venous thrombosis and pulmonary embolism occurred at a median of 21 and 34 days respectively. After total knee replacement, the median time to the presentation of deep venous thrombosis and pulmonary embolism was 20 and 12 days respectively. The cumulative risk of venous thromboembolism lasted for up to three months after hip surgery and for one month after total knee replacement. Venous thromboembolism was diagnosed after discharge from hospital in 70% of patients who developed this complication. Despite hospital-based thromboprophylaxis, most cases of clinical venous thromboembolism occur after discharge and at different times according to the operation performed.The Bone & Joint Journal 04/2006; 88(3):386-91. · 2.80 Impact Factor
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ABSTRACT: The optimal strategy for thromboprophylaxis after major joint replacement has not been established. Low-molecular-weight heparins such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use. In a double-blind, double-dummy study, we randomly assigned patients undergoing total knee replacement to receive 2.5 mg of apixaban orally twice daily or 30 mg of enoxaparin subcutaneously every 12 hours. Both medications were started 12 to 24 hours after surgery and continued for 10 to 14 days. Bilateral venography was then performed. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, and death from any cause during treatment. Patients were followed for 60 days after anticoagulation therapy was stopped. A total of 3195 patients underwent randomization, with 1599 assigned to the apixaban group and 1596 to the enoxaparin group; 908 subjects were not eligible for the efficacy analysis. The overall rate of primary events was much lower than anticipated. The rate of the primary efficacy outcome was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02; 95% confidence interval, 0.78 to 1.32). The composite incidence of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P=0.03). As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. (ClinicalTrials.gov number, NCT00371683.)New England Journal of Medicine 09/2009; 361(6):594-604. · 54.42 Impact Factor
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.
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