J Thromb Thrombolysis DOI 10.1007/s11239-013-1046-1
Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures Anhua Long • Lihai Zhang • Yingze Zhang • Baoguo Jiang • Zhi Mao • Hongda Li • Shanbao Zhang • Zongyan Xie • Peifu Tang
Ó Springer Science+Business Media New York 2014
Abstract Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6 % in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7 %, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6 %), but the difference between the groups was not statistically
A. Long L. Zhang Z. Mao P. Tang (&) Department of Orthopedics, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China e-mail: [email protected] A. Long H. Li S. Zhang Z. Xie School of Medicine, Nankai University, TianJing 300071, People’s Republic of China Y. Zhang Department of Orthopedics, Hospital 1, Hebei Medical University, Shijiazhuang 050031, Hebei Province, People’s Republic of China B. Jiang Peoples Hospital, Peking University, Beijing 100871, People’s Republic of China
significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45 % without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings. Keywords Deep vein thrombosis Venous thromboembolism Major bleeding events Thromboprophylaxis Rivaroxaban Low-molecularweight heparin
Introduction The risk of venous thromboembolism (VTE) is extremely high in patients with trauma. Venography studies have shown that in patients with trauma who do not receive prophylactic anticoagulant therapy, the incidence of VTE is as high as 58 % [1]. Although it has been reported that the incidence of VTE in Asian populations is lower than in European and US populations, a recent meta-analysis of 22 studies showed that the incidence of postoperative VTE in Asian patients who underwent major orthopedic surgery was as high as 31.7 % [2]. Consequently, current guidelines all recommend that thrombosis prevention should be routinely performed in trauma patients at high risk of thrombosis, and that chemoprophylaxis is the most effective way to prevent VTE [3, 4]. Low-molecular-weight heparins (LMWHs) have been recommended as the first choice therapy for prevention of
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thrombosis in patients undergoing major orthopedic surgery for the past two decades [4]. Recently, the oral direct factor Xa inhibitor rivaroxaban was developed and has been found be a safe, effective and convenient method to prevent VTE. Four large-scale, phase III clinical trials all showed that rivaroxaban has superior efficacy to enoxaparin in reducing the incidence of VTE after hip and knee replacement surgery [5–8]. In comparison with enoxaparin, rivaroxaban significantly reduced the incidence of VTE (RR 0.41; 95 % CI 0.20–0.83) without increasing the risk of bleeding (RR 1.73; 95 % CI 0.94–3.17) [4]. Rivaroxaban is currently recommended for thromboprophylaxis after hip and knee replacement surgery [3, 4, 9], for which it is started at 6–10 h after surgery and administered continuously until up to 35 days after surgery. Thus far, all phase III clinical trials of rivaroxaban have been conducted in patients undergoing hip and knee replacement and none has been carried out in trauma patients. Evidence-based medicine studies of rivaroxaban, such as efficacy and safety trials, have not been performed in trauma patients, especially those with lower extremity fractures. Consequently, there is no strong evidence supporting the use of rivaroxaban in these patients. This study summarizes our clinical experience with rivaroxaban thromboprophylaxis in patients with lower extremity fractures treated at the Department of Orthopedics and Trauma at our hospital. As part of the study, a comparison of the efficacy and safety of LMWH and rivaroxaban for thromboprophylaxis was undertaken. The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital. Due to its retrospective nature and the fact that the patient data were anonymous, informed consent was not requested from patients.
Methods Patients The study was a retrospective cohort investigation. Data were obtained on patients with lower extremity fractures who were admitted to the Department of Orthopedics and Trauma at the PLA General Hospital between January 2009 and December 2012. Eligible patients were those aged 18 years or older who had lower extremity fractures, including proximal femoral fractures, femoral shaft fractures, distal femur fractures, patella fractures, proximal tibial fractures, tibia and fibula fractures, distal tibial fractures, and ankle and foot fractures. Patients who were admitted but did not undergo surgery for various reasons or who were diagnosed with any type of VTE at admission were excluded from the study.
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Diagnosis After admission to hospital, laboratory investigations such as routine blood tests, biochemistry and coagulation tests, and compression ultrasound (CUS) were performed. Laboratory parameters were routinely re-measured at Day 1, Day 3 and Day 7 postoperatively. Lower extremity vascular ultrasound or angiography examinations were repeated in patients who suffered from symptoms of suspected deep vein thrombosis (DVT) such as lower limb swelling, local tenderness and unexplained fever. A diagnosis of DVT was made based on the results of ultrasound and angiography. Lung ventilation/perfusion scanning or spiral CT was performed in patients with chest pain, breathing difficulties and other symptoms of suspected pulmonary embolism (PE). A diagnosis of PE was based on the results of the examinations. Thromboprophylaxis regimens All patients admitted to hospital received routine drug and/ or physical preventive measures according to current guidelines. From January 2009 to October 2010, a LMWH (nadroparin; FraxiparineÒ, GlaxoSmithKline) was used as the first choice for thromboprophylaxis and was administered subcutaneously once daily at a dose volume of 0.2–0.4 mL from the evening of the day the patients were admitted to hospital to the evening of the day before surgery. Subsequently, the LMWH regimen was resumed at least 8 h after surgery and continued until up to 35 days after surgery. Since November 2010, oral administration of 10 mg rivaroxaban (XareltoÒ, Bayer) once daily has been recommended in patients with lower extremity fractures at our hospital. Rivaroxaban was administered from the evening of the day the patients were admitted to hospital to the evening of the day before surgery. Thereafter, it was resumed at least 8 h after surgery and continued until up to 35 days after surgery. Both agents were used during the period November 2010 to December 2012. Therefore, two large cohorts of unselected, consecutive patients receiving thromboprophylaxis with either LMWH or rivaroxaban were investigated in our study. Based on the different regimens for prevention of thrombosis, the patients were divided into three groups: rivaroxaban group, LMWH group, and a nondrug prevention group. Efficacy and safety outcomes The primary efficacy outcome was all VTE events that occurred in patients within 3 months after surgery. Secondary outcomes included the incidences of DVT, PE, and
Patients with lower limb fractures
proximal thrombosis (thrombosis in the popliteal vein and above), and the incidence of single distal embolization within 3 months after surgery. The primary safety outcome was the incidence of major bleeding events occurring from the day thromboprophylaxis was commenced to 2 days after withdrawal of the drug. Major bleeding events were defined as fatal bleeding, bleeding in critical sites such as retroperitoneal, intracranial and spinal cord bleeding, bleeding leading to reoperation, significant bleeding in extra-surgical sites leading to a 20 g/L or greater fall in hemoglobin, or a transfusion requirement of more than two units of whole blood/ red blood cells. The secondary safety outcome was the incidence of minor bleeding events, which were defined as incision hematomas, gastrointestinal bleeding, and other bleeding events that were not major events and required clinical treatment. Other outcomes evaluated included the average duration of hospitalization, and the transfusion of more or less than three units of blood during hospitalization. Statistical analysis Student’s t test was used to analyze continuous data for comparisons of the baseline characteristics of the various patients groups. Pearson’s Chi square test, Fisher’s exact test and analysis of variance (ANOVA) were used for intergroup or inner-group comparisons of constituent ratios. Logistic regression analysis was used for 2-category data. Multivariate analysis was performed by the stepwise maximum likelihood method, and 95 % confidence intervals (CIs) and odds ratio (OR) values were used to describe the hazard ratio. A p value less than 0.05 was considered statistically significant. All statistical procedures were accomplished with SPSS 19.0.
Results From January 2009 to December 2012, 2,050 patients met the inclusion criteria; 608 patients (29.7 %) received rivaroxaban as the primary drug for prevention of thrombosis, 717 (35.0 %) received LMWH, and 725 (35.3 %) did not receive any drugs. All patients were followed until 3 months postoperatively, except for 106 (5.2 %) with whom contact was lost during the follow-up period. Although the median age of the patients and the numbers with multiple fractures were lower in the rivaroxaban group than in the LMWH group, and these differences and the types of anesthesia and surgery performed were significantly different between the two groups, there were no significant differences between the groups in terms of gender, body mass index (BMI), number of cases with open
fractures, VTE history, fracture type, and ASA score (Table 1). However, the mean duration of thromboprophylaxis was significantly longer in the rivaroxaban group (15.5 days, 95 % CI 14.29–16.71 vs 10.8 days, 95 % CI 10.08–11.44; p \ 0.001; Table 1). Efficacy outcomes The incidences of all VTEs in the rivaroxaban and LMWH groups were 4.9 % (30/608) and 8.6 % (62/717), respectively, and the difference between the groups was statistically significant (p = 0.008). No patient in the rivaroxaban group experienced PE, but two patients (0.3 %) in LMWH group had postoperative PE; however, the difference between the two groups for this endpoint was not statistically significant (p = 0.192). The median times for diagnosis of VTE after surgery were 18 days in rivaroxaban group and 21 days in LMWH group; this difference was not statistically significant (p = 0.432; Table 2). The incidence of DVT in the rivaroxaban group was significantly lower than in LMWH group (4.9 vs 8.6 %; p = 0.008). Although the incidences of proximal thrombosis in the two groups were not significantly different (0.9 vs 2.9 %; p = 0.123), the incidences of single distal venous thrombosis were significantly different (1.8 vs 5.7 %; p = 0.036) suggesting that rivaroxaban reduced the incidence of DVT mainly by reducing the occurrence of single distal venous thrombosis (Table 2). Safety outcomes The incidences of both major and minor bleeding events in the two groups were not significantly different. Only one case of major bleeding occurred in the rivaroxaban group and this patient died of gastrointestinal bleeding at Day 7 postoperatively. In the LMWH group, four patients developed major bleeding events that resulted in a reduction of hemoglobin of 20 g/L or more, all whom recovered after symptomatic treatment such as red blood cell transfusions. In the rivaroxaban group, five patients suffered from postoperative wound hematomas and one suffered from gastrointestinal bleeding. In comparison, there were 12 cases of postoperative wound hematomas and three of gastrointestinal bleeding in the LMWH group. However, there were no significant differences in the incidence of either major bleeding events or minor bleeding events between the two groups (Table 2). Of the patients in the rivaroxaban group, 144 (23.7 %) received transfusions of more than three units of red blood cells during the perioperative period, as compared with 172 (24.0 %) in the LMWH group, but this difference was not statistically significant (p = 0.897). The average lengths of hospital stays in the rivaroxaban and LMWH groups were
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A. Long et al. Table 1 Patients characteristics and type of VTE prophylaxis in all patients admitted for lower extremity fractures between January 2009 and December 2012 Rivaroxaban (n = 608)
LMWH (n = 717)
p value
Non-prophylaxis (n = 725)
Age
60.2 ± 20.3
63.6 ± 19.1
0.023
Gender (male/female)
309/299
336/381
0.151
42.2 ± 17.2 505/220
History of VTE Fracture site
3 (0.5 %)
3 (0.4 %)
0.577 0.263
1 (0.1 %)
Proximal femur
370 (60.9 %)
455 (63.5 %)
100 (13.8 %)
Shaft of femur
40 (6.6 %)
54 (7.5 %)
83 (11.4 %)
Distal femur
14 (2.3 %)
20 (2.8 %)
26 (3.6 %)
Patella
32 (5.3 %)
48 (6.7 %)
89 (12.3 %)
Proximal tibiofibula
46 (7.6 %)
30 (4.2 %)
73 (10.1 %)
Shaft of tibiofibula
42 (6.9 %)
40 (5.6 %)
140 (19.3 %)
Distal tibiofibula
22 (3.6 %)
22 (3.1 %)
57 (7.9 %)
Ankle
25 (4.1 %)
28 (3.9 %)
72 (9.9 %)
Foot
17 (2.8 %)
20 (2.8 %)
Open fracture
39 (6.4 %)
46 (6.4 %)
0.999
154 (21.2 %)
Multi-fracture
28 (4.6 %)
69 (9.6 %)
\0.001
119 (16.4 %)
Anesthesia method
–
–
\0.001
General
173 (28.5 %)
255 (35.6 %)
164 (22.6 %)
Epidural Nerve block
257 (42.3 %) 178 (29.3 %)
365 (50.9 %) 97 (13.5 %)
517 (71.3 %) 44 (6.1 %)
I and II
374 (61.5 %)
419 (58.4 %)
565 (77.9 %)
III and IV
161 (26.5 %)
220 (30.7 %)
48 (6.6 %)
Intramedullary
201 (33.1 %)
239 (33.3 %)
129 (17.8 %)
Extramedullary
128 (21.1 %)
110 (15.3 %)
258 (35.6 %)
ASA score
85 (11.7 %)
0.114
\0.001
Type of surgery
Arthoplasty
188 (30.9 %)
207 (28.9 %)
17 (2.3 %)
External fixation
20 (3.3 %)
22 (3.1 %)
75 (10.3 %)
Cannulated screws
66 (10.9 %)
138 (19.2 %)
23.7 ± 4.0
23.5 ± 4.0
Mean (95 % CI)
15.5 (14.29–16.71)
10.8 (10.08–11.44)
\0.001
Median (25th and 75th percentiles)
10 (7, 16)
10 (5, 12)
\0.001
BMI (kg/m2)
231 (31.9 %) 0.528
23.6 ± 3.6
Duration of prophylaxis (days)
ASA American Society of Anesthesiologists, BMI body mass index, LMWH low-molecular-weight heparin, VTE venous thromboembolism
12.2 and 13.1 days, respectively, and this difference was statistically significant (p = 0.016) (Table 2). Univariate and multivariate analyses Univariate analysis of the risk of VTE showed that advanced age, female sex, a prior history of VTE, fractures of the proximal hip, ASA scores of grade III–IV, the use of general anesthesia, and intramedullary fixation were all risk factors for VTE, and that treatment with rivaroxaban could significantly reduce the risk of VTE (OR 0.55, 95 % CI 0.35–0.86; p = 0.009). However, multivariate analysis showed that only the proximal hip joint fracture site was an
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independent risk factor for VTE (OR 1.19, 95 % CI 1.04–1.35; p = 0.008), the risk of which could be significantly reduced by rivaroxaban treatment (OR 0.56, 95 % CI 0.34–0.91; p = 0.009) (Table 3).
Discussion The results of this retrospective cohort study in patients with lower extremity fractures indicate that rivaroxaban reduced the incidence of VTE by 45 % in comparison with LMWH therapy. These results are consistent with the results of 2 phase III clinical trials of patients who
Patients with lower limb fractures Table 2 Efficacy outcomes and safety outcomes in all patients receiving rivaroxaban or LMWH for thromboprophylaxis after lower limb fracture (n = 1,325)
All venous thromboembolism
Rivaroxaban n (%)
LMWH n (%)
p value
OR
95 % CI
30 (4.9 %)
62 (8.6 %)
0.008
0.55
0.35–0.86
24.3 (14.1–38.8) 18 (11, 31)
28.4 (15.6–41.3) 21 (13, 33)
0.357 0.432 0.35–0.86
VTE diagnosed after surgery (days) Mean (95 % CI) Median (25th and 75th percentiles) Pulmonary embolism
0
2 (0.3 %)
0.192
Deep venous thrombosis
30 (4.9 %)
62 (8.6 %)
0.008
0.55
Proximal
10 (0.9 %)
21 (2.9 %)
0.123
0.55
0.26–1.19
Distal only
20 (1.8 %)
41 (5.7 %)
0.036
0.56
0.32–0.97
1 (0.2 %)
4 (0.6 %)
0.244
0.29
0.03–2.63
Fatal bleeding
1 (0.2 %)
0
Bleeding into a critical organ
0
0
Bleeding leading to re-operation
0
0
Clinically overt extra-surgical site bleeding leading to a fall in hemoglobin of C20 g/L
0
4 (0.6 %)
Clinically overt extra-surgical site bleeding leading to transfusion of C2 units of blood
0
0
Major bleeding events
Non-major bleeding events:
6 (1.0 %)
13 (1.8 %)
0.207
0.54
0.20–1.43
Wound hematoma
5 (0.8 %)
12 (1.7 %)
0.170
0.49
0.17–1.39
Gastrointestinal bleeding
1 (0.2 %)
3 (0.4 %)
0.376
0.39
0.04–3.77
Patients receiving blood transfusions C3 units
144 (23.7 %)
172 (24.0 %)
0.897
0.98
0.76–1.27
Length of hospital stay (days)
12.2 ± 5.1
13.1 ± 7.4
0.016
CI confidence interval, LMWH low-molecular-weight heparin, OR odds ratio
Table 3 Univariate and multivariate analysis using logistic regression models to evaluate potential risk factors for the occurrence of VTE in patients receiving rivaroxaban or LMWH for thromboprophylaxis after lower limb fracture (n = 1,325) OR
95 % CI
p value
0.009
Univariate analysis Use of rivaroxaban
0.55
0.35–0.86
Female sex
1.53
1.05–2.22
0.026
BMI ([30 kg/m2)
0.72
0.29–1.79
0.478
Age (per 10 years)
1.37
1.24–1.51
0.000
15.12
4.00–57.06
0.000
Proximal femur fracture
1.32
1.19–1.45
0.000
Open fracture
1.47
0.76–2.84
0.256
Multi-fracture
0.67
0.33–1.33
0.250
General anesthesia
1.47
1.09–1.96
0.011
ASA score III and IV
1.91
1.47–2.48
0.000
Intramedullary fixation
1.19
1.06–1.32
0.002
0.56 1.19
0.34–0.91 1.04–1.35
0.020 0.008
Previous VTE
Multivariate analysis Use of rivaroxaban Proximal femur fracture
LMWH low-molecular-weight heparin, VTE venous thromboembolism
underwent total hip or knee replacement. In these trials, comparisons of rivaroxaban and enoxaparin showed that after knee replacement, rivaroxaban was associated with a more than 50 % reduction in the incidence of VTE [5, 6]. Currently, there are no large-scale, comparative studies of rivaroxaban and LMWHs in trauma patients. Therefore, we can only horizontally compare the results of our study with the results of studies in patients who underwent total hip or knee replacement. In our study, rivaroxaban reduced the incidence of VTE versus LMWH mainly by reducing the incidence of single distal venous thrombosis, as the incidences of proximal vein thrombosis in the rivaroxaban and LMWH groups were not statistically different. Since single distal venous thrombosis has a significantly lower risk of PE than proximal vein thrombosis, the benefit for patients of lowering the incidence of single distal venous thrombosis is currently controversial [10–12]. In the multivariate regression analysis, factors such as age, gender, BMI, prior VTE history, fracture site, ASA classification, anesthesia and surgery type, and the drug used for thromboprophylaxis were comprehensively analyzed. The results showed that rivaroxaban significantly reduced the incidence of VTE versus LMWH with a risk
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ratio of 0.56 (95 % CI 0.34–0.91; p = 0.020), and in this regard, our results were similar to those of the studies conducted in patients who underwent total hip and knee replacement. While our retrospective cohort study compared the efficacy and safety of rivaroxaban with LMWH in patients with lower extremity fractures, further prospective, large-scale, multicenter, randomized, controlled studies will be needed to provide a higher level evidence. In our study, the incidences of VTE in patients treated with rivaroxaban and LMWH for thromboprophylaxis were significantly higher than in patients who did not receive any drug for prophylaxis (7.1 vs 1.1 %; p = 0.000). This reason for this is that the risk of VTE varies between patients with lower extremity fractures, and factors such as age, gender, surgery type, and anesthesia type affect the clinician’s choice of anticoagulant measures [13]. Thus, our results suggest that routine thromboprophylaxis for all patients with lower extremity fractures is inappropriate, and is only applicable for patients with lower extremity fractures who are at high risk of thrombosis. Multivariate analysis showed that the fracture site was an independent risk factor of VTE in patients with lower extremity fractures. Therefore, prophylactic measures for patients with lower extremity fractures should differ according to the fracture site. The incidences of major bleeding events were very low in all groups in our study. Only one patient in the rivaroxaban group and four patients in the LMWH group suffered from major bleeding events. Because this was an observational study, specific interventions for patients were not pre-determined. The clinicians chose the appropriate anticoagulant drug (or no anticoagulant drug) according to the patients’ specific conditions, and decided whether or not to use hemostatics in those with bleeding. Therefore, the incidence of major bleeding events in our study was less than that reported in similar studies [8]. In addition, the incidence of minor bleeding events was also lower. However, the incidences of total bleeding events, major bleeding events, and minor bleeding events in the rivaroxaban group were not statistically different from those in LMWH group, which suggests that the safety of rivaroxaban in patients with lower extremity fractures is comparable to that of LMWHs widely used in clinical practice. Whereas LMWHs need to be injected subcutaneously due to their pharmaceutical properties, which may result in poor compliance by patients after discharge and difficulty in achieving the full course of anticoagulation [14], rivaroxaban is administered orally. Its greater convenience and the fact that laboratory monitoring and dose adjustments for the elderly are not required, may lead to improved compliance with long-term anticoagulant therapy after discharge. Therefore, patients may be more likely to continue to taking rivaroxaban to prevent VTE in accordance
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with their clinician’s instructions, and may be able to be discharged earlier. In the present study, the mean duration of hospital stay was significantly shorter in the rivaroxaban group than in the LMWH group (12.2 vs 13.1 days, respectively; p = 0.016). And we observed that the duration of thromboprophylaxis in rivaroxaban group was clearly longer than in LMWH group, this result reflected oral medication may improve the compliance of thromboprophylaxis after discharge. Our study has several limitations. Firstly, its retrospective nature limited the randomization and control of patients. Consequently, patients in the rivaroxaban and LMWH groups exhibited some significant differences in baseline demographic characteristics. The median age of the patients and the number with multiple fractures in the rivaroxaban group were lower than for patients in the LMWH group, and patients in the two groups were also significantly different in terms of the types of anesthesia and surgery. Therefore, a multivariate analysis of all these factors was performed which indicated that the fracture site was an independent risk factor for the occurrence of VTE in this study and that the risk could be significantly reduced by rivaroxaban administration. Secondly, although the longest duration of follow-up in this study was 3 months after surgery, the patients did not undergo routine venous ultrasonography or venography after discharge and only underwent ultrasound examination of the veins of the lower extremities for suspected VTE at follow-up visits. Therefore, our results might have underestimated the real incidence of VTE. Thirdly, we could not determine whether the VTEs were symptomatic or asymptomatic because this information had not been correctly recorded. In addition, due to the limitations of the retrospective design, the medication compliance of patients en rolled in the study was not able to be assessed, and we could not control for the use of mechanical thromboprophylaxis measures after discharge. Despite these shortcomings, our study is the first to report the results of a large-scale investigation of the efficacy and safety of rivaroxaban in patients with lower extremity fractures. Our postoperative follow-up data over a period of up to 3 months indicated that rivaroxaban had superior efficacy to LMWH in preventing VTE without increasing the risk of bleeding.
Conclusion This non-randomized, retrospective cohort study is the first large-scale investigation of the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE incidence by 45 % without increasing the risk of bleeding.
Patients with lower limb fractures Acknowledgments Editorial assistance with the manuscript was provided by Content Ed Net Shanghai, Co. Ltd. Conflict of interest
None.
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Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures Anhua Long • Lihai Zhang • Yingze Zhang • Baoguo Jiang • Zhi Mao • Hongda Li • Shanbao Zhang • Zongyan Xie • Peifu Tang
Ó Springer Science+Business Media New York 2014
Abstract Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6 % in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7 %, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6 %), but the difference between the groups was not statistically
A. Long L. Zhang Z. Mao P. Tang (&) Department of Orthopedics, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China e-mail: [email protected] A. Long H. Li S. Zhang Z. Xie School of Medicine, Nankai University, TianJing 300071, People’s Republic of China Y. Zhang Department of Orthopedics, Hospital 1, Hebei Medical University, Shijiazhuang 050031, Hebei Province, People’s Republic of China B. Jiang Peoples Hospital, Peking University, Beijing 100871, People’s Republic of China
significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45 % without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings. Keywords Deep vein thrombosis Venous thromboembolism Major bleeding events Thromboprophylaxis Rivaroxaban Low-molecularweight heparin
Introduction The risk of venous thromboembolism (VTE) is extremely high in patients with trauma. Venography studies have shown that in patients with trauma who do not receive prophylactic anticoagulant therapy, the incidence of VTE is as high as 58 % [1]. Although it has been reported that the incidence of VTE in Asian populations is lower than in European and US populations, a recent meta-analysis of 22 studies showed that the incidence of postoperative VTE in Asian patients who underwent major orthopedic surgery was as high as 31.7 % [2]. Consequently, current guidelines all recommend that thrombosis prevention should be routinely performed in trauma patients at high risk of thrombosis, and that chemoprophylaxis is the most effective way to prevent VTE [3, 4]. Low-molecular-weight heparins (LMWHs) have been recommended as the first choice therapy for prevention of
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thrombosis in patients undergoing major orthopedic surgery for the past two decades [4]. Recently, the oral direct factor Xa inhibitor rivaroxaban was developed and has been found be a safe, effective and convenient method to prevent VTE. Four large-scale, phase III clinical trials all showed that rivaroxaban has superior efficacy to enoxaparin in reducing the incidence of VTE after hip and knee replacement surgery [5–8]. In comparison with enoxaparin, rivaroxaban significantly reduced the incidence of VTE (RR 0.41; 95 % CI 0.20–0.83) without increasing the risk of bleeding (RR 1.73; 95 % CI 0.94–3.17) [4]. Rivaroxaban is currently recommended for thromboprophylaxis after hip and knee replacement surgery [3, 4, 9], for which it is started at 6–10 h after surgery and administered continuously until up to 35 days after surgery. Thus far, all phase III clinical trials of rivaroxaban have been conducted in patients undergoing hip and knee replacement and none has been carried out in trauma patients. Evidence-based medicine studies of rivaroxaban, such as efficacy and safety trials, have not been performed in trauma patients, especially those with lower extremity fractures. Consequently, there is no strong evidence supporting the use of rivaroxaban in these patients. This study summarizes our clinical experience with rivaroxaban thromboprophylaxis in patients with lower extremity fractures treated at the Department of Orthopedics and Trauma at our hospital. As part of the study, a comparison of the efficacy and safety of LMWH and rivaroxaban for thromboprophylaxis was undertaken. The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital. Due to its retrospective nature and the fact that the patient data were anonymous, informed consent was not requested from patients.
Methods Patients The study was a retrospective cohort investigation. Data were obtained on patients with lower extremity fractures who were admitted to the Department of Orthopedics and Trauma at the PLA General Hospital between January 2009 and December 2012. Eligible patients were those aged 18 years or older who had lower extremity fractures, including proximal femoral fractures, femoral shaft fractures, distal femur fractures, patella fractures, proximal tibial fractures, tibia and fibula fractures, distal tibial fractures, and ankle and foot fractures. Patients who were admitted but did not undergo surgery for various reasons or who were diagnosed with any type of VTE at admission were excluded from the study.
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Diagnosis After admission to hospital, laboratory investigations such as routine blood tests, biochemistry and coagulation tests, and compression ultrasound (CUS) were performed. Laboratory parameters were routinely re-measured at Day 1, Day 3 and Day 7 postoperatively. Lower extremity vascular ultrasound or angiography examinations were repeated in patients who suffered from symptoms of suspected deep vein thrombosis (DVT) such as lower limb swelling, local tenderness and unexplained fever. A diagnosis of DVT was made based on the results of ultrasound and angiography. Lung ventilation/perfusion scanning or spiral CT was performed in patients with chest pain, breathing difficulties and other symptoms of suspected pulmonary embolism (PE). A diagnosis of PE was based on the results of the examinations. Thromboprophylaxis regimens All patients admitted to hospital received routine drug and/ or physical preventive measures according to current guidelines. From January 2009 to October 2010, a LMWH (nadroparin; FraxiparineÒ, GlaxoSmithKline) was used as the first choice for thromboprophylaxis and was administered subcutaneously once daily at a dose volume of 0.2–0.4 mL from the evening of the day the patients were admitted to hospital to the evening of the day before surgery. Subsequently, the LMWH regimen was resumed at least 8 h after surgery and continued until up to 35 days after surgery. Since November 2010, oral administration of 10 mg rivaroxaban (XareltoÒ, Bayer) once daily has been recommended in patients with lower extremity fractures at our hospital. Rivaroxaban was administered from the evening of the day the patients were admitted to hospital to the evening of the day before surgery. Thereafter, it was resumed at least 8 h after surgery and continued until up to 35 days after surgery. Both agents were used during the period November 2010 to December 2012. Therefore, two large cohorts of unselected, consecutive patients receiving thromboprophylaxis with either LMWH or rivaroxaban were investigated in our study. Based on the different regimens for prevention of thrombosis, the patients were divided into three groups: rivaroxaban group, LMWH group, and a nondrug prevention group. Efficacy and safety outcomes The primary efficacy outcome was all VTE events that occurred in patients within 3 months after surgery. Secondary outcomes included the incidences of DVT, PE, and
Patients with lower limb fractures
proximal thrombosis (thrombosis in the popliteal vein and above), and the incidence of single distal embolization within 3 months after surgery. The primary safety outcome was the incidence of major bleeding events occurring from the day thromboprophylaxis was commenced to 2 days after withdrawal of the drug. Major bleeding events were defined as fatal bleeding, bleeding in critical sites such as retroperitoneal, intracranial and spinal cord bleeding, bleeding leading to reoperation, significant bleeding in extra-surgical sites leading to a 20 g/L or greater fall in hemoglobin, or a transfusion requirement of more than two units of whole blood/ red blood cells. The secondary safety outcome was the incidence of minor bleeding events, which were defined as incision hematomas, gastrointestinal bleeding, and other bleeding events that were not major events and required clinical treatment. Other outcomes evaluated included the average duration of hospitalization, and the transfusion of more or less than three units of blood during hospitalization. Statistical analysis Student’s t test was used to analyze continuous data for comparisons of the baseline characteristics of the various patients groups. Pearson’s Chi square test, Fisher’s exact test and analysis of variance (ANOVA) were used for intergroup or inner-group comparisons of constituent ratios. Logistic regression analysis was used for 2-category data. Multivariate analysis was performed by the stepwise maximum likelihood method, and 95 % confidence intervals (CIs) and odds ratio (OR) values were used to describe the hazard ratio. A p value less than 0.05 was considered statistically significant. All statistical procedures were accomplished with SPSS 19.0.
Results From January 2009 to December 2012, 2,050 patients met the inclusion criteria; 608 patients (29.7 %) received rivaroxaban as the primary drug for prevention of thrombosis, 717 (35.0 %) received LMWH, and 725 (35.3 %) did not receive any drugs. All patients were followed until 3 months postoperatively, except for 106 (5.2 %) with whom contact was lost during the follow-up period. Although the median age of the patients and the numbers with multiple fractures were lower in the rivaroxaban group than in the LMWH group, and these differences and the types of anesthesia and surgery performed were significantly different between the two groups, there were no significant differences between the groups in terms of gender, body mass index (BMI), number of cases with open
fractures, VTE history, fracture type, and ASA score (Table 1). However, the mean duration of thromboprophylaxis was significantly longer in the rivaroxaban group (15.5 days, 95 % CI 14.29–16.71 vs 10.8 days, 95 % CI 10.08–11.44; p \ 0.001; Table 1). Efficacy outcomes The incidences of all VTEs in the rivaroxaban and LMWH groups were 4.9 % (30/608) and 8.6 % (62/717), respectively, and the difference between the groups was statistically significant (p = 0.008). No patient in the rivaroxaban group experienced PE, but two patients (0.3 %) in LMWH group had postoperative PE; however, the difference between the two groups for this endpoint was not statistically significant (p = 0.192). The median times for diagnosis of VTE after surgery were 18 days in rivaroxaban group and 21 days in LMWH group; this difference was not statistically significant (p = 0.432; Table 2). The incidence of DVT in the rivaroxaban group was significantly lower than in LMWH group (4.9 vs 8.6 %; p = 0.008). Although the incidences of proximal thrombosis in the two groups were not significantly different (0.9 vs 2.9 %; p = 0.123), the incidences of single distal venous thrombosis were significantly different (1.8 vs 5.7 %; p = 0.036) suggesting that rivaroxaban reduced the incidence of DVT mainly by reducing the occurrence of single distal venous thrombosis (Table 2). Safety outcomes The incidences of both major and minor bleeding events in the two groups were not significantly different. Only one case of major bleeding occurred in the rivaroxaban group and this patient died of gastrointestinal bleeding at Day 7 postoperatively. In the LMWH group, four patients developed major bleeding events that resulted in a reduction of hemoglobin of 20 g/L or more, all whom recovered after symptomatic treatment such as red blood cell transfusions. In the rivaroxaban group, five patients suffered from postoperative wound hematomas and one suffered from gastrointestinal bleeding. In comparison, there were 12 cases of postoperative wound hematomas and three of gastrointestinal bleeding in the LMWH group. However, there were no significant differences in the incidence of either major bleeding events or minor bleeding events between the two groups (Table 2). Of the patients in the rivaroxaban group, 144 (23.7 %) received transfusions of more than three units of red blood cells during the perioperative period, as compared with 172 (24.0 %) in the LMWH group, but this difference was not statistically significant (p = 0.897). The average lengths of hospital stays in the rivaroxaban and LMWH groups were
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A. Long et al. Table 1 Patients characteristics and type of VTE prophylaxis in all patients admitted for lower extremity fractures between January 2009 and December 2012 Rivaroxaban (n = 608)
LMWH (n = 717)
p value
Non-prophylaxis (n = 725)
Age
60.2 ± 20.3
63.6 ± 19.1
0.023
Gender (male/female)
309/299
336/381
0.151
42.2 ± 17.2 505/220
History of VTE Fracture site
3 (0.5 %)
3 (0.4 %)
0.577 0.263
1 (0.1 %)
Proximal femur
370 (60.9 %)
455 (63.5 %)
100 (13.8 %)
Shaft of femur
40 (6.6 %)
54 (7.5 %)
83 (11.4 %)
Distal femur
14 (2.3 %)
20 (2.8 %)
26 (3.6 %)
Patella
32 (5.3 %)
48 (6.7 %)
89 (12.3 %)
Proximal tibiofibula
46 (7.6 %)
30 (4.2 %)
73 (10.1 %)
Shaft of tibiofibula
42 (6.9 %)
40 (5.6 %)
140 (19.3 %)
Distal tibiofibula
22 (3.6 %)
22 (3.1 %)
57 (7.9 %)
Ankle
25 (4.1 %)
28 (3.9 %)
72 (9.9 %)
Foot
17 (2.8 %)
20 (2.8 %)
Open fracture
39 (6.4 %)
46 (6.4 %)
0.999
154 (21.2 %)
Multi-fracture
28 (4.6 %)
69 (9.6 %)
\0.001
119 (16.4 %)
Anesthesia method
–
–
\0.001
General
173 (28.5 %)
255 (35.6 %)
164 (22.6 %)
Epidural Nerve block
257 (42.3 %) 178 (29.3 %)
365 (50.9 %) 97 (13.5 %)
517 (71.3 %) 44 (6.1 %)
I and II
374 (61.5 %)
419 (58.4 %)
565 (77.9 %)
III and IV
161 (26.5 %)
220 (30.7 %)
48 (6.6 %)
Intramedullary
201 (33.1 %)
239 (33.3 %)
129 (17.8 %)
Extramedullary
128 (21.1 %)
110 (15.3 %)
258 (35.6 %)
ASA score
85 (11.7 %)
0.114
\0.001
Type of surgery
Arthoplasty
188 (30.9 %)
207 (28.9 %)
17 (2.3 %)
External fixation
20 (3.3 %)
22 (3.1 %)
75 (10.3 %)
Cannulated screws
66 (10.9 %)
138 (19.2 %)
23.7 ± 4.0
23.5 ± 4.0
Mean (95 % CI)
15.5 (14.29–16.71)
10.8 (10.08–11.44)
\0.001
Median (25th and 75th percentiles)
10 (7, 16)
10 (5, 12)
\0.001
BMI (kg/m2)
231 (31.9 %) 0.528
23.6 ± 3.6
Duration of prophylaxis (days)
ASA American Society of Anesthesiologists, BMI body mass index, LMWH low-molecular-weight heparin, VTE venous thromboembolism
12.2 and 13.1 days, respectively, and this difference was statistically significant (p = 0.016) (Table 2). Univariate and multivariate analyses Univariate analysis of the risk of VTE showed that advanced age, female sex, a prior history of VTE, fractures of the proximal hip, ASA scores of grade III–IV, the use of general anesthesia, and intramedullary fixation were all risk factors for VTE, and that treatment with rivaroxaban could significantly reduce the risk of VTE (OR 0.55, 95 % CI 0.35–0.86; p = 0.009). However, multivariate analysis showed that only the proximal hip joint fracture site was an
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independent risk factor for VTE (OR 1.19, 95 % CI 1.04–1.35; p = 0.008), the risk of which could be significantly reduced by rivaroxaban treatment (OR 0.56, 95 % CI 0.34–0.91; p = 0.009) (Table 3).
Discussion The results of this retrospective cohort study in patients with lower extremity fractures indicate that rivaroxaban reduced the incidence of VTE by 45 % in comparison with LMWH therapy. These results are consistent with the results of 2 phase III clinical trials of patients who
Patients with lower limb fractures Table 2 Efficacy outcomes and safety outcomes in all patients receiving rivaroxaban or LMWH for thromboprophylaxis after lower limb fracture (n = 1,325)
All venous thromboembolism
Rivaroxaban n (%)
LMWH n (%)
p value
OR
95 % CI
30 (4.9 %)
62 (8.6 %)
0.008
0.55
0.35–0.86
24.3 (14.1–38.8) 18 (11, 31)
28.4 (15.6–41.3) 21 (13, 33)
0.357 0.432 0.35–0.86
VTE diagnosed after surgery (days) Mean (95 % CI) Median (25th and 75th percentiles) Pulmonary embolism
0
2 (0.3 %)
0.192
Deep venous thrombosis
30 (4.9 %)
62 (8.6 %)
0.008
0.55
Proximal
10 (0.9 %)
21 (2.9 %)
0.123
0.55
0.26–1.19
Distal only
20 (1.8 %)
41 (5.7 %)
0.036
0.56
0.32–0.97
1 (0.2 %)
4 (0.6 %)
0.244
0.29
0.03–2.63
Fatal bleeding
1 (0.2 %)
0
Bleeding into a critical organ
0
0
Bleeding leading to re-operation
0
0
Clinically overt extra-surgical site bleeding leading to a fall in hemoglobin of C20 g/L
0
4 (0.6 %)
Clinically overt extra-surgical site bleeding leading to transfusion of C2 units of blood
0
0
Major bleeding events
Non-major bleeding events:
6 (1.0 %)
13 (1.8 %)
0.207
0.54
0.20–1.43
Wound hematoma
5 (0.8 %)
12 (1.7 %)
0.170
0.49
0.17–1.39
Gastrointestinal bleeding
1 (0.2 %)
3 (0.4 %)
0.376
0.39
0.04–3.77
Patients receiving blood transfusions C3 units
144 (23.7 %)
172 (24.0 %)
0.897
0.98
0.76–1.27
Length of hospital stay (days)
12.2 ± 5.1
13.1 ± 7.4
0.016
CI confidence interval, LMWH low-molecular-weight heparin, OR odds ratio
Table 3 Univariate and multivariate analysis using logistic regression models to evaluate potential risk factors for the occurrence of VTE in patients receiving rivaroxaban or LMWH for thromboprophylaxis after lower limb fracture (n = 1,325) OR
95 % CI
p value
0.009
Univariate analysis Use of rivaroxaban
0.55
0.35–0.86
Female sex
1.53
1.05–2.22
0.026
BMI ([30 kg/m2)
0.72
0.29–1.79
0.478
Age (per 10 years)
1.37
1.24–1.51
0.000
15.12
4.00–57.06
0.000
Proximal femur fracture
1.32
1.19–1.45
0.000
Open fracture
1.47
0.76–2.84
0.256
Multi-fracture
0.67
0.33–1.33
0.250
General anesthesia
1.47
1.09–1.96
0.011
ASA score III and IV
1.91
1.47–2.48
0.000
Intramedullary fixation
1.19
1.06–1.32
0.002
0.56 1.19
0.34–0.91 1.04–1.35
0.020 0.008
Previous VTE
Multivariate analysis Use of rivaroxaban Proximal femur fracture
LMWH low-molecular-weight heparin, VTE venous thromboembolism
underwent total hip or knee replacement. In these trials, comparisons of rivaroxaban and enoxaparin showed that after knee replacement, rivaroxaban was associated with a more than 50 % reduction in the incidence of VTE [5, 6]. Currently, there are no large-scale, comparative studies of rivaroxaban and LMWHs in trauma patients. Therefore, we can only horizontally compare the results of our study with the results of studies in patients who underwent total hip or knee replacement. In our study, rivaroxaban reduced the incidence of VTE versus LMWH mainly by reducing the incidence of single distal venous thrombosis, as the incidences of proximal vein thrombosis in the rivaroxaban and LMWH groups were not statistically different. Since single distal venous thrombosis has a significantly lower risk of PE than proximal vein thrombosis, the benefit for patients of lowering the incidence of single distal venous thrombosis is currently controversial [10–12]. In the multivariate regression analysis, factors such as age, gender, BMI, prior VTE history, fracture site, ASA classification, anesthesia and surgery type, and the drug used for thromboprophylaxis were comprehensively analyzed. The results showed that rivaroxaban significantly reduced the incidence of VTE versus LMWH with a risk
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ratio of 0.56 (95 % CI 0.34–0.91; p = 0.020), and in this regard, our results were similar to those of the studies conducted in patients who underwent total hip and knee replacement. While our retrospective cohort study compared the efficacy and safety of rivaroxaban with LMWH in patients with lower extremity fractures, further prospective, large-scale, multicenter, randomized, controlled studies will be needed to provide a higher level evidence. In our study, the incidences of VTE in patients treated with rivaroxaban and LMWH for thromboprophylaxis were significantly higher than in patients who did not receive any drug for prophylaxis (7.1 vs 1.1 %; p = 0.000). This reason for this is that the risk of VTE varies between patients with lower extremity fractures, and factors such as age, gender, surgery type, and anesthesia type affect the clinician’s choice of anticoagulant measures [13]. Thus, our results suggest that routine thromboprophylaxis for all patients with lower extremity fractures is inappropriate, and is only applicable for patients with lower extremity fractures who are at high risk of thrombosis. Multivariate analysis showed that the fracture site was an independent risk factor of VTE in patients with lower extremity fractures. Therefore, prophylactic measures for patients with lower extremity fractures should differ according to the fracture site. The incidences of major bleeding events were very low in all groups in our study. Only one patient in the rivaroxaban group and four patients in the LMWH group suffered from major bleeding events. Because this was an observational study, specific interventions for patients were not pre-determined. The clinicians chose the appropriate anticoagulant drug (or no anticoagulant drug) according to the patients’ specific conditions, and decided whether or not to use hemostatics in those with bleeding. Therefore, the incidence of major bleeding events in our study was less than that reported in similar studies [8]. In addition, the incidence of minor bleeding events was also lower. However, the incidences of total bleeding events, major bleeding events, and minor bleeding events in the rivaroxaban group were not statistically different from those in LMWH group, which suggests that the safety of rivaroxaban in patients with lower extremity fractures is comparable to that of LMWHs widely used in clinical practice. Whereas LMWHs need to be injected subcutaneously due to their pharmaceutical properties, which may result in poor compliance by patients after discharge and difficulty in achieving the full course of anticoagulation [14], rivaroxaban is administered orally. Its greater convenience and the fact that laboratory monitoring and dose adjustments for the elderly are not required, may lead to improved compliance with long-term anticoagulant therapy after discharge. Therefore, patients may be more likely to continue to taking rivaroxaban to prevent VTE in accordance
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with their clinician’s instructions, and may be able to be discharged earlier. In the present study, the mean duration of hospital stay was significantly shorter in the rivaroxaban group than in the LMWH group (12.2 vs 13.1 days, respectively; p = 0.016). And we observed that the duration of thromboprophylaxis in rivaroxaban group was clearly longer than in LMWH group, this result reflected oral medication may improve the compliance of thromboprophylaxis after discharge. Our study has several limitations. Firstly, its retrospective nature limited the randomization and control of patients. Consequently, patients in the rivaroxaban and LMWH groups exhibited some significant differences in baseline demographic characteristics. The median age of the patients and the number with multiple fractures in the rivaroxaban group were lower than for patients in the LMWH group, and patients in the two groups were also significantly different in terms of the types of anesthesia and surgery. Therefore, a multivariate analysis of all these factors was performed which indicated that the fracture site was an independent risk factor for the occurrence of VTE in this study and that the risk could be significantly reduced by rivaroxaban administration. Secondly, although the longest duration of follow-up in this study was 3 months after surgery, the patients did not undergo routine venous ultrasonography or venography after discharge and only underwent ultrasound examination of the veins of the lower extremities for suspected VTE at follow-up visits. Therefore, our results might have underestimated the real incidence of VTE. Thirdly, we could not determine whether the VTEs were symptomatic or asymptomatic because this information had not been correctly recorded. In addition, due to the limitations of the retrospective design, the medication compliance of patients en rolled in the study was not able to be assessed, and we could not control for the use of mechanical thromboprophylaxis measures after discharge. Despite these shortcomings, our study is the first to report the results of a large-scale investigation of the efficacy and safety of rivaroxaban in patients with lower extremity fractures. Our postoperative follow-up data over a period of up to 3 months indicated that rivaroxaban had superior efficacy to LMWH in preventing VTE without increasing the risk of bleeding.
Conclusion This non-randomized, retrospective cohort study is the first large-scale investigation of the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE incidence by 45 % without increasing the risk of bleeding.
Patients with lower limb fractures Acknowledgments Editorial assistance with the manuscript was provided by Content Ed Net Shanghai, Co. Ltd. Conflict of interest
None.
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