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Abstract

Propose:

Total hip arthroplasty (THA) is associated with a significant risk of venous thromboembolism (VTE). Different thromboprophylaxis strategies have been used to prevent VTE. The primary aim of this study was to report the incidence of VTE and compare the efficacy and safety of rivaroxaban to enoxaparin. The secondary outcome was to report the incidence of silent deep venous thrombosis (DVT) using computed tomography venography.

Methods:

One hundred sixty patients who underwent THA were enrolled in a prospective study. Patients were randomized into two groups as follows: those who received rivaroxaban 10 mg oral daily (group RXE) and those who received enoxaparin 40 IU/day subcutaneously for 14 days (group ENO).

Results:

Both groups were matched for age, sex, comorbidities, special habits and preoperative laboratory investigations. The overall incidence of DVT was 5% (n = 8), which included four patients clinically diagnosed as having DVT and four with silent DVT. All the DVT cases occurred in veins below the knee and in the group RXE; none of the cases occurred in group ENO (p = 0.04). The incidence of DVT was significantly higher in patients with high body mass indexes (p < 0.001), older age (p = 0.024) and medical comorbidities (p = 0.14). No mortality, pulmonary embolism, stroke, wound infection or major bleeding occurred in either group.

Conclusions:

Among the patients who underwent hip arthroplasty, rivaroxaban prophylaxis was found to be associated with lower efficacy and similar safety outcomes as compared with enoxaparin anticoagulants.

Keywords

deep venous thrombosis hip arthroplasty silent DVT thromboprophylaxis

Introduction

Total hip arthroplasty (THA) has a high success rate in the management of end-stage hip arthritis.¹ Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), remains one of the most common complications of THA.¹ Without prophylaxis, the reported incidence rates of DVT range from 40% to 60%. Meanwhile, VTE is one of the most preventable causes of death.²

Silent or asymptomatic DVT is the formation of a thrombus within the deep venous system with no overt clinical manifestations. Prevention of thrombus propagation is crucial, as it may eventually lead to serious venous thromboembolic events.³ In a Japanese prospective clinical trial, the risk of silent DVT reaches its peak on the fourth post-operative day after hip and knee replacement, reaching 27.1% and 58.3%, respectively.⁴

The classic symptoms of DVT include pain, swelling, calf and thigh tenderness, prominence of veins and positive Homans sign.⁵ However, the clinical diagnosis of DVT is unreliable, and laboratory screening tests such as D-dimer level are highly sensitive but have very low specificity. Ultrasonography (US) is widely used in the diagnosis of symptomatic DVT.^6
–8 However, computed tomography venography (CTV) is considered the reference standard for DVT imaging; it is more sensitive than US for detecting proximal DVT and asymptomatic DVT. CTV is recommended when other tests are unable to confirm the diagnosis.⁹ It offers high sensitivity (71–100%) and specificity (93–100%) in the diagnosis of proximal DVT and pelvic thrombi, which are difficult to assess on US.¹⁰ However, it is invasive and associated with contrast-related side effects.

The Ninth American College of Chest Physician (ACCP) Guidelines suggest the use of low-molecular-weight heparin (LMWH) and new oral anticoagulants for patients who had undergone THA.¹¹ DVT prophylaxis should be continued for at least 14 days after surgery and may be extended to 35 days in high-risk patients.¹¹

Many studies have compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for thromboprophylaxis in patients who had undergone THA.^12
–14 However, thromboprophylaxis after THA has been shown to be associated with a high incidence of clinically silent but venogram-positive DVT.¹⁵

The primary outcome of this study was to report the incidence of VTE and compare the efficacy of rivaroxaban and that of enoxaparin 14 days after THA. The secondary outcome was the incidence of silent DVT diagnosed using CTV in asymptomatic patients. In this study, we hypothesized that rivaroxaban and enoxaparin are similar in efficacy and safety.

Method

Study design

The study was performed between January 2019 and January 2020 at the University of Mansoura, Egypt. The study design and implementation followed the STROBE Statement Checklist. This was a prospective cohort study. In our institution, either rivaroxaban or enoxaparin is given to patients post-operatively on a surgeon preference basis.

On the basis of the ACCPs Evidence-based Clinical Practice Guidelines,¹⁶ the incidence of venographically detected silent DVT is up to 20.0%, while that of symptomatic VTE is 4.0% despite prophylaxis. With a power of 80% and α of 0.05, the sample size was estimated to be 64. However, we decided to increase the sample size to 80 for each group to overcome the small sample size calculated. A total of 160 patients were randomized into two groups.

Participants were enrolled in the study with an allocation ratio of 1:1 by using a permuted block randomization technique. The randomization process was performed by a research assistant who kept all the data in a secure computer. The intervention group assignment of the participants was performed by a research assistant, who informed the surgeons of the group assignments by phone after the end of the procedure.

Enrolment of the patients to the study was performed by an orthopaedic specialist after obtaining informed consent and discussing the procedure and details of the study.

Patients

The inclusion criterion was patients aged <70 years who underwent primary THA for the management of primary or secondary hip osteoarthritis. The exclusion criteria were patients with a history of VTE or who were receiving anticoagulation for any reason before the surgery and patients with decompensated hepatic or renal disease.

Half of the patients received rivaroxaban 10 mg oral daily for 14 days starting from 12 h after surgery (group RXE), and the other half received enoxaparin 40 IU/day subcutaneously for 14 days starting 12 h post-surgery (group ENO).

Data collection

The collected data included age, sex, body mass index (BMI), American Society of Anaesthesiologists level, medical comorbidities, previous surgeries, special habits and laboratory investigations such as complete blood count, international normalized ratio (INR), liver function test and renal function tests.

All the patients underwent a preoperative duplex US of the deep venous system of both lower limbs. All operative data were recorded, including the type of anaesthesia, surgical approach, type of prosthesis, volume of blood transfusion and surgical duration.

Surgical technique

Being the most commonly used approach for total hip replacement, the posterior approach was chosen for use in all the patients on the basis of Moore’s description.¹⁷

Four board-certified surgeons were involved in the study. They were divided into two groups, one led by the first author and the other by the last authors. Every 3 months, they exchanged groups to minimize the risk of performance bias.

Post-operative protocol

The post-operative protocol was the same in both groups. Mechanical prophylaxis was started in the recovery room, and the anticoagulant was started 12 h after surgery for 14 days. Post-operative laboratory investigations were repeated on the first 3 post-operative days.

Wound condition, blood transfusion and minor or major bleeding were documented. The patients were clinically evaluated using the Well score¹⁸ for clinical signs and symptoms of DVT (Table 1) by a blinded reviewer (orthopaedic arthroplasty fellow) on the basis of a retrospective chart review of clinical symptoms and patient history from the medical notes. The following cut-off Well scores were used: 1 for low probability, 2 for moderate probability and ≥3 for high probability.¹⁹

Table 1.

Well’s criteria for the prediction of DVT.^a

Clinical feature	Score
Malignancy (treatment ongoing, within 6 months or palliative)	1
Paralysis, paresis or recent plaster immobilization of the leg	1
Recently confined to bed for ≥3 days or major surgery within 12 weeks that requires general or regional anaesthesia	1
Localized tenderness along the distribution of the deep venous system	1
Entire leg swollen	1
Calf swelling at least 3 cm larger than that on the asymptomatic side	1
Pitting oedema confined to the symptomatic side	1
Collateral superficial veins (non-varicose)	1
Previously documented DVT	1
Alternative diagnosis at least as likely as deep vein thrombosis	−2

DVT: deep vein thrombosis.

^a Well’s scoring system for DVT: −2 to 0, low probability; 1 to 2, moderate probability; 3 to 8, high probability.

Direct CTV was performed on the seventh post-operative day, after measurement of the serum creatinine level. The patients received a high amount of intravenous fluid to prevent contrast-induced nephrotoxicity. A cannula was inserted in the dorsal foot vein followed by a dye injection; allergic reactions to the dye were observed.

The patients were discharged home if the CTV was negative for DVT. Patients diagnosed with DVT were treated with 3 months of anticoagulation for proximal DVT and a compression stocking without drug therapy for distal DVT, in accordance with the ACCP guidelines.²⁰

The patients were followed up in the outpatient clinic at 2 weeks, 6 weeks, 3 months and 1 year after operation. They were evaluated for DVT, PE, minor and major bleeding, stroke and unexplained death.

Statistical analyses

All the data were statistically analysed using IBM Statistical Package for Social Sciences (SPSS) version 20.0. Qualitative data were described using numbers and percentages.

Quantitative data were described as median values (range) for non-parametric data and as mean (standard deviation) for parametric data after testing for the normality of data using the Kolmogorov–Smirnov test.

The significance of the obtained results was judged at the 5% level. The tests used were the χ ², Fisher exact, Student t and Mann–Whitney tests.

Ethical consideration

Approval of the institutional review board of the Mansoura University, Egypt, to conduct the study was obtained (Ref. No. MS/15.06.06). Consent to participate was obtained from the participants. All the procedures performed in the study that involved human participants were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Results

In this study, 190 patients were enrolled, of whom 25 were excluded because they did not meet the inclusion criteria and 5 refused to participate in the study. The mean follow-up period was 15.6 ± 3.04 months (range = 12–22 months). None of the patients were lost to follow-up. The mean age of the patients was 41.53 ± 12.8 years (range = 19–63 years). The two groups were matched with no statistical significance for age, sex, BMI, special habits and preoperative laboratory test results. Among the participants, 32 patients had no medical comorbidities and 48 had ≥1 medical problems (Table 2).

Table 2.

Demographic analysis and group comparison of pre- and post-operative laboratory findings.^a,b

Categories	Total	Group RXE	Group ENO	Test of significance
	n = 160	n = 80	n = 80
	n (%)	n (%)	n (%)
Age (mean ± SD)	41.53 ± 12.8	42.95 ± 10.6	40.1 ± 14.7	t = 0.996 p = 0.3
Sex
Male	80 (50.0)	36 (45.0)	44 (55.0)	χ2 = 0.8 p = 0.4
Female	80 (50.0)	44 (55.0)	36 (45.0)	χ2 = 0.8 p = 0.4
Medical comorbidities
No	64 (40.0)	34 (42.5)	30 (37.5)
Yes	96 (60.0)	46 (47.5)	50 (62.5)
BMI (kg/m²)	29.13 ± 4.6	30.5 ± 4.8	29.8 ± 4.05	t = 2.7 p = 0.09
Special habits: smoking
No	148 (92.5)	76 (95.0)	72 (90.0)	χ ² = 0.72 p = 0.4
Yes	12 (7.5)	4 (5.0)	8 (10.0)	χ ² = 0.72 p = 0.4
Pre-operative laboratory investigation
Haemoglobin	12.16 ± 1.4	12.2 ± 1.3	12.1 ± 1.2	t = 0.13 p = 0.9
Platelets count	25,850.0 (150,000–483,000)	25,850.0 (150,000–483,000)	251,500.0 (150,000.0–470,000.0)	z = 0.44 p = 0.6
ALT	24.35 ± 7.09	23.5 ± 6.1	25.2 ± 7.9	t = 1.07 p = 0.2
AST	28.75 ± 7.6	26.8 ± 4.2	30.7 ± 9.5	t = 2.4 p = 0.09
Creatinine	0.83 ± 0.22	0.81 ± 0.15	0.86 ± 0.2	t = 0.9 p = 0.36
Albumin	4.25 ± 0.4	4.12 ± 0.4	4.39 ± 0.4	t = 3.05 p = 0.3
Bilirubin	0.78 ± 0.11	0.81 ± 0.13	0.75 ± 0.08	t = 2.6 p = 0.08
INR	1.03 ± 0.06	1.04 ± 0.06	1.02 ± 0.07	t = 0.79 p = 0.4
Pre-operative laboratory investigation
Haemoglobin	10.58 ± 1.03	10.2 ± 0.7	10.9 ± 1.2	t = 3.83 p < 0.001**
Platelet count	336,000 (135,000–670,000)	373,500.0 (135,000.0–670,000.0)	331,500.0 (165,000.0–531,000.0)	z = 1.02 p = 0.3
ALT	26.7 ± 10.8	23.6 ± 6.0	29.8 ± 13.5	t = 2.65 p = 0.4
AST	30.98 ± 13.4	27.9 ± 7.01	34.05 ± 17.2	t = 2.09 p = 0.3
Serum creatinine	0.89 ± 0.3	0.88 ± 0.2	0.91 ± 0.3	t = 0.54 p = 0.59
Serum albumin	3.8 ± 0.3	3.7 ± 0.3	3.89 ± 0.4	t = 2.3 p = 0.09
Serum bilirubin	0.8 ± 0.2	0.82 ± 0.2	0.79 ± 0.13	t = 0.62 p = 0.5
INR	1.04 ± 0.07	1.06 ± 0.07	1.03 ± 0.07	t = 2.02 p = 0.08

INR: international normalized ratio; BMI: body mass index; group RXE: those who received rivaroxaban 10 mg oral daily; group ENO: those who received enoxaparin 40 IU/day subcutaneously for 14 days.

^a T values were obtained using the Student t test and the z values using the Mann–Whitney U test.

^b All parameters are described as mean ± SD except for Platelet count, which is presented as median (range).

*p < 0.05.

Primary hip osteoarthritis was the main pathology in 96 patients (60%), avascular necrosis in 20 (12.5%), hip dysplasia in 20 (12.5%), post-traumatic arthritis in 12 (7.5%) and inflammatory arthritis in 12 (7.5%). A cementless prosthesis was used in 128 patients and a cemented prosthesis in 32. Spinal anaesthesia was used in 152 patients (95%) and general anaesthesia was used in 8 patients (5%). The mean surgical duration was 100 ± 6.96 minutes in group RXE and 101.25 ± 7.7 in group ENO, with no statistical significance between the groups (p = 0.82).

No cases of mortality, PE, stroke, wound infection or major bleeding were recorded in either group. The mean post-operative drain volume was 683.8 ± 27.66 mm, and no significant difference was found between the two groups (p = 0.39). Of the participants, 12 required post-operative blood transfusion, of whom 8 were in group RXE and 4 were in group ENO, with no statistically significant difference (p = 0.67). No statistically significant difference was found between the two groups in post-operative platelet count; serum creatinine or bilirubin, alanine transaminase (ALT), aspartate aminotransferase (AST) and serum albumin levels and the international normalized ratio (INR). The post-operative haemoglobin level was significantly lower in group RXE (p < 0.001).

The clinical assessment of the patients according to the Well score revealed that 76 and 4 patients in group RXE and 78 and 2 patients in group ENO had low and moderate probabilities of DVT, respectively.

CTV was performed on the seventh post-operative day for all the patients. None of the patients had an allergic reaction or increased serum creatinine level. In group RXE, eight patients (10%) had DVT in the popliteal veins and veins below the knee, whereas in group ENO, none of the patients had DVT. A significant difference was found between the two groups (p = 0.04).

The incidence of DVT was significantly higher in the patients with high BMIs (p < 0.001) and higher but without statistical significance in older patients and patients with medical comorbidities (p = 0.024 and 0.14, respectively). No significant differences were found in sex, laterality, type of anaesthesia, type of prosthesis or surgical duration (Table 3).

Table 3.

Demographic and surgical characteristics of the DVT and non-DVT cases.

Categories	Non-DVT	DVT	Test of significance
	n = 152	n = 8
	n (%)	n (%)
Age (years), mean ± SD	40.8 ± 12.7	55.5 ± 4.04	t = 2.3 p = 0.024*
Sex
Male	77 (50.6)	3 (37.5)
Female	75 (49.4)	5 (62.5)
BMI (kg/m²)	28.7 ± 4.3	36.95 ± 4.09	t = 3.73 p < 0.001**
Medical condition
No	64 (42.1)	0 (0.0)	FET p = 0.14
Yes	88 (57.9)	8 (100.0)	FET p = 0.14
Type of anaesthesia
Spinal	144 (94.7)	8 (100.0)	FET p = 1.0
General	8 (5.3)	0 (0.0)	FET p = 1.0
Duration of surgery (minutes), mean ±SD	107.8 ± 20.7	95.0 ± 5.8	t = 1.2 p = 0.2
Side of THA
Left	92 (60.5)	4 (50.0)	FET p = 1.0
Right	60 (39.5)	4 (50.0)	FET p = 1.0
Type of prosthesis
Cementless	124 (81.6)	4 (50.0)	FET p = 0.17
Cemented	28 (18.4)	4 (50.0)	FET p = 0.17
Post-operative drain (mL), mean ± SD	685.5 ± 283.5		t = 0.25 p = 0.8

DVT: deep vein thrombosis; BMI: body mass index; THA: total hip arthroplasty; FET: Fisher exact test.

Discussion

Patients who had undergone THA are at high risk of developing VTE in the post-operative period. Therefore, clinical guidelines recommend 14–35 days of thromboprophylaxis.¹¹ The ideal anticoagulant should be effective, safe and easy to administer. LMWH has been the gold standard for VTE prophylaxis for decades, with a significant relative risk reduction of VTE.¹¹ Rivaroxaban is an oral direct antithrombin factor Xa inhibitor used for thromboprophylaxis after hip and knee replacement.²¹ It does not need monitoring owing to its predictable pharmacodynamics and pharmacokinetics. However, no effective antidote has been developed yet.^22,23

Our study was a prospective comparison of the efficacy and safety of rivaroxaban and enoxaparin for thromboprophylaxis after total hip replacement. The patients were selected randomly and received anticoagulation for 14 days starting at 12 h after the procedure, in accordance with our hospital protocol.

The overall incidence of DVT in the study was 5%; all the cases occurred in the group RXE. Four cases (2.5%) were classified as clinically diagnosed DVT because they were diagnosed on the basis of a positive CTV finding and moderate probability for DVT according to the Well score. The other four cases (2.5%) were considered silent DVT because they were only diagnosed on the basis of a positive CTV finding and low probability according to the Well score. We found that a high BMI significantly increases the risk of DVT. In addition, older patients and patients with medical comorbidities were considered high-risk groups. The other factors such as sex, type of anaesthesia, surgical duration, medical comorbidities and type of prosthesis were insignificant.

Several studies have shown that rivaroxaban has a significant superiority to enoxaparin in the prevention of VTE and reduction of symptomatic VTE after joint replacement, with similar safety profiles and low incidence rates of major bleeding.^24
–26 Nevertheless, some studies also found no demonstrable differences between rivaroxaban and enoxaparin in the incidence rates of VTE, transfusion, reoperation, infection and major bleeding after hip and knee arthroplasty.^27
–29 Moreover, Chahal et al.³⁰ suggested that no consensus has been reached on the optimal form of VTE prophylactic treatment for patients who had undergone knee or hip arthroplasty or on the safety profile of the available chemical prophylactic modalities.

In our study, rivaroxaban and enoxaparin had comparable safety with no cases of major bleeding. Although the small sample size may have been insufficient to prove the superiority of one drug over the other, the risk of blood transfusion was higher in the patients who received rivaroxaban (group RXE), but not significantly. This can be explained by the lower post-operative haemoglobin level in these patients. This was also observed by the RECORD1 Study Group, which found that the two drugs had similar safety profiles in patients who underwent hip arthroplasty.¹²

Although LMWH remains a standard of care, its disadvantages include difficulty of administration and prolonged length of hospital stay, as many patients who undergo THA are often discharged within a few days. This is a considerable advantage for oral anticoagulation.

The main limitation of this study was the relatively short follow-up period and the small number of patients. Therefore, our results cannot be generalized, and further studies with larger numbers of patients are required. On the other hand, the patients were well matched with regards to all the demographics and preoperative medical comorbidities to eliminate confounding variables. In addition, we randomized the participants into two groups to minimize selection bias. Two surgeons, led by the first and last authors, were involved in each group and exchanged groups every 3 months to eliminate performance bias.

Furthermore, newer alternatives, including low-dose aspirin, are increasingly popularized. Aspirin was found to be safe to use as the main thromboprophylaxis in primary arthroplasty, as it was not associated with increased incidence rates of DVT, PE or mortality.³¹ Anderson et al. found that aspirin was not significantly different from rivaroxaban in terms of effectiveness for the prevention of VTE after THA.²¹ In addition, aspirin did not differ significantly from other anticoagulants used for VTE prophylaxis hip arthroplasty, as revealed by the systematic review and meta-analysis of randomized clinical trials by Matharu et al.³² On the basis of these studies, aspirin should be considered in future studies and applied in medical practise.

Moreover, assessments of the invasiveness of CTV and the accuracy of the Well score should be considered in future studies, based on which routine US should be performed as a less invasive test for screening patients with high Well scores. Likewise, the patients treated with THA for reasons other than osteoarthrits, such as the neck or femoral fractures³³ and ochronotic arthropathy,³⁴ should be included in future studies to examine the incidence of silent DVT and the effect of different anticoagulants.

Conclusion

In conclusion, although this was a prospective study, it failed to show any advantage of rivaroxaban over enoxaparin. The use of new oral anticoagulants is safe with reasonable efficacy; however, we still consider enoxaparin as the gold standard because of the lower rate of DVT specifically in asymptomatic cases, which can be a silent killer. Individuals with obesity, illnesses and old age are more susceptible to DVT; therefore, care should be taken in the management of these patients, use of multimodal thromboprophylaxis and close monitoring.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Wael A. Rahman

Omar A. Al-Mohrej

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Incidence of silent venous thromboembolism after total hip arthroplasty: A comparison of rivaroxaban and enoxaparin