Chinese Medical Journal 2014;127(12):2201-2205:10.3760/cma.j.issn.0366-6999.20132175
Aspirin combined with mechanical measures to prevent venous thromboembolism after total knee arthroplasty: a randomized controlled trial

Jiang Yi, Du Hui, Liu Jian and Zhou Yixin

Keywords
aspirin; venous thromboembolism; prevention; arthroplasty; replacement; knee
Abstract
Background Venous thromboembolism (VTE) is an important complication after major orthopedic surgery. Pharmaceutical methods represent the main strategy of VTE prevention. The use of aspirin in VTE prevention is still controversial worldwide, especially in China. The purpose of this study was to evaluate the role of aspirin combined with mechanical measures in the prevention of VTE after total knee arthroplasty (TKA).
Methods Between January 2012 and May 2013 and in accordance with the inclusion criteria, 120 patients undergoing TKA were randomly allocated to two groups. To prevent VTE, patients in group A received aspirin combined with mechanical measures postoperatively, while patients in group B received low-molecular-weight heparin (LMWH) sodium and rivaroxaban sequentially in combination with mechanical measures postoperatively. All surgeries were performed by one surgeon using a posterior-stabilized cemented prosthesis. The two groups were followed up and compared for the incidence of deep vein thrombosis (DVT) by duplex ultrasound scan and clinical VTE events. The adverse events, the blood loss index, and the cost of VTE prevention were also compared.
Results DVT was detected in 10 of 60 patients in group A (16.7%, 95% CI: 7.3%−26.1%) compared with 11 of 60 in group B (18.3%, 95% CI: 8.5%−27.8%) (P=0.500). There is no statistical evidence supporting the inferior effect of aspirin in preventing DVT as compared with the other medications. There were no cases of symptomatic VTE or death during the follow-up period. Area of ecchymosis was lower in group A than in group B, and the differences were statistically significant. Patients in group A had the lower blood loss index as compared with patients in group B. No transfusion cases were found in both groups. The differences were statistically significant. The cost of VTE prevention analysis indicated a cost reduction using aspirin in group A compared with using LMWH and rivaroxaban in group B.
Conclusion Aspirin combined with mechanical measures had a good effect on prevention of VTE after TKA and resulted in lower cost, less blood loss, and less subcutaneous ecchymosis.
Total knee arthroplasty (TKA) is the main treatment for advanced knee osteoarthritis.In recent years, there is a fast-growing trend of joint replacement surgeries in China. Venous thromboembolism (VTE) is an important complication after TKA and may be associated with deep vein thrombosis (DVT) and pulmonary embolism (PE). Fatal PE is one of the main causes of perioperative mortality.1Preventive measures after TKA can effectively reduce the incidence of VTE, thereby reducing perioperative mortality. If prophylaxis is not used, DVT will develop in 40%-60% of these patients and a fatal PE in 0.5%-
2%.2Drug prevention is the main measure of VTE prevention. The incidence of DVT was estimated in a systematic review to be 11%-35% following hip and knee arthroplasty, while patients were treated with low-molecular-weight heparin (LMWH) for VTE.3Aspirin has advantages because it is cheaper, more convenient, and safer than warfarin, LMWH, and coagulation Xafactor inhibitors. Aspirin was chosen for use as a VTE prophylaxis drug after hip and knee arthroplasty in the latest editions of the American College of Chest Physicians (ACCP) and American Academy of Orthopaedic Surgeons (AAOS) guidelines.4In China, however, aspirin is not recommended for use as a sole pharmaceutical agent for VTE prevention because of the lack of sufficient evidence in the VTE prevention guidelines for Chinese major orthopedic surgeries, which was released by the Chinese Orthopedic Association (COA) in 2009.5Although Chinese orthopedic surgeons are concerned about that prophylactic anticoagulation can increase the potential risk of hemorrhagic complications, there is no evidence that aspirin has its role in VTE prevention for Chinese patients.
This randomized controlled study was designed to compare the effect of aspirin with that of other medications in VTE prevention after TKA. It can be viewed as a first attempt in comparative effectiveness research in preventing VTE using aspirin after major orthopedic surgery in China. The results of our study provide an important insight to guide future larger scale studies and ultimately improve clinical practice.
METHODS
Study design
This is a prospective randomized comparative study comparing postoperative administration of aspirin combined with mechanical measures (group A) versus postoperative administration of LMWH and rivaroxaban sequentially combined with mechanical measures (group B) for the prevention of DVT. The objective is to test whether group A has significantly higher incidence rate of DVT than group B. Patients and doctors were not blinded since the objective is to evaluate the effectiveness of the two treatment regiments in real world. Patients are randomized to one of the two groups in a 1:1 ratio using random number table before operation. The study was approved by the Institutional Review Board of Beijing Jishuitan Hospital.
Patients
All patients were enrolled in this study from January 2012 to May 2013 according to the inclusion criteria: patients undergoing primary unilateral TKA for degenerative arthritis at Beijing Jishuitan Hospital. Patients with hepatic or renal dysfunction, coagulation abnormalities, anemia, anticoagulant use that presented a contraindication to surgery, a history of digestive tract ulcers, a previous history of VTE, nonsteroidal anti-inflammatory drug allergies, diabetes, and preoperative arterial abnormalities in the lower extremity as detected by ultrasound were excluded. A total of 132 patients underwent primary unilateral TKA by the same surgeon during the study period and were screened. Twelve patients were dropped after screening. Eligible and willing patients gave written informed consent before participation in the study. One hundred and twenty patients were randomized to one of the two treatment groups: 60 in group A (the aspirin group) and 60 in group B (the LMWH and rivaroxaban group), and no patients dropped after randomization (Figure 1).
Surgical technique and postoperative care
All operations were performed by the same surgeon under general anesthesia with use of a laryngeal mask airway combined with regional anesthesia. A posterior-stabilized cemented knee prosthesis was used in each case. A pneumatic tourniquet was applied during the operation. A wound drain was not placed after the operation, and elastic limb bandages were used for up to 48 hours after the operation.
Active and passive motions of the knee joint and straight-leg-raising exercises were performed on postoperative day 1. At the same time, a walking frame was used to help patients walk. After finishing the operation, thromboembolic deterrent stockings and intermittent pneumatic compression (IPC) devices would be used as soon as possible to prevent VTE. After using the IPC devices for up to 5 days after surgery, the patients would be discharged. The stockings were used for up to 2 weeks postoperatively.
Patients in group A received aspirin orally at 100 mg/d from postoperative days 1 to 14. Patients in group B received LMWH subcutaneously at 5 000 U/day from postoperative days 1 to 5, then received rivaroxaban (Xafactor inhibitor) orally at 10 mg/d until postoperative day 14.
Outcome
The primary outcome measure was the incidence of DVT as determined by duplex ultrasound scan performed on both limbs on 4th and 5th postoperative days; in addition, patients were followed for 6 weeks postoperatively for clinical VTE events. The thrombi were categorized and scaled according to the Marder’s classification,6which permits the assessment of the following 11 deep veins: common iliac, external iliac, common femoral, superficial femoral, and popliteal veins, and the six deep veins of the calf.
The secondary outcome measures were adverse events, the blood loss index, and the cost of VTE prevention. Adverse events were assessed and documented each day until discharge. They were wound complications (exudation, hematoma formation, and infection), area of ecchymosis on postoperative day 5 (patient’s palm area was considered to represent 1% of the body surface area), and others. The blood loss index was calculated using the following equation: blood loss index = preoperative hemoglobin level – hemoglobin level before discharge + number of units transfused. The cost of VTE prevention included the cost of aspirin in group A, the cost of LMWH and rivaroxaban in group B, and the cost of IPC devices used in both groups.
Statistical analysis
Sample size calculation is based on a one-sided test of the null hypothesis that group A has equal or less DVT incidence rate as compared with group B versus the alternative hypothesis that group A has higher DVT incidence rate than group B. Existing literature suggests that the incidence rate of DVT is 11%-35% for group B and 40%-60% without prophylactic treatment. Assuming group B has 20% incidence rate, with 60 patients in each group, we will have 81% power to detect a 21% increase in DVT incidence rate in group A (i.e., 41% in group A) with one-sided type I error controlled at 0.05. Baseline characteristics of the two groups are tabulated for potential imbalance in variables. Continuous variables are summarized by typical parameters such as mean, standard deviation, and range and compared using two-sampleTtest (if the normality assumption holds) or Wilcoxon rank-sum test (if the normality assumption does not hold). Normality of distribution is determined using the Kolmogorov-Smirnov goodness-of-fit test. Categorical data are summarized by frequency and percentage and analyzed using the χ2or Fisher’s exact test, as appropriate. Endpoints are compared using the same strategy. 95% confidence intervals of the means/proportions for endpoints are constructed using normal approximation. A two-sidedPvalue of 0.05 or less is considered statistically significant except for primary endpoints where one-sidedPvalue of 0.05 or less is considered statistically significant.
RESULTS
Between January 2012 and May 2013, 132 patients were screened and 120 patients were randomized. All randomized patients completed the study from each group: 60 in group A treated by aspirin and 60 in group B treated by LMWH and rivaroxaban. All 12 dropouts were screened for diabetes.
The two groups were comparable in terms of baseline characteristics of the patient and operative time. There were no statistically significant differences between the two groups in age, gender, body mass index, and operative time (Table 1).
DVT was detected in 10 of 60 patients in the aspirin group (16.7%, 95%CI: 7.3%-26.1%) compared with 11 of 60 in the LMWH and rivaroxaban group (18.3%, 95%CI: 8.5%-27.8%) (P=0.500). Thus, there is no statistical evidence supporting the inferior effect of aspirin in preventing DVT as compared with the other medications. Most of DVT cases were found in the veins of the calf, and no extra treatment was provided to them except the prophylaxis in the protocol. While one popliteal vein thrombosis case was found in each group, we stopped the mechanical measures and immobilized the limb for two weeks. All the DVT cases were asymptomatic. No patient died and no symptomatic VTE was found during the follow-up period (Table 2).
Adverse events were recorded on a daily basis. Wound complications and area of ecchymosis were probably related to the treatment in both groups. Area of ecchymosis was lower in the aspirin group than in the LMWH and rivaroxaban group, and the differences were statistically significant. Patients in the aspirin group had the lower blood loss index as compared with patients in the LMWH and rivaroxaban group. No transfusion cases were found in both groups. The differences were statistically significant.
The cost of VTE prevention analysis was on the basis of current costs of aspirin, LMWH, and rivaroxaban in Beijing Jishuitan Hospital. The pricing of IPC devices and thromboembolic deterrent stockings was calculated according to the manufacturer’s price list in Beijing Jishuitan Hospital. The analysis indicated a cost reduction using aspirin in group A compared with using LMWH and rivaroxaban in group B. Saving per patient was found to be 772.37 RMB Yuan (Table 3).
DISCUSSION
VTE is a very severe complication after total hip and knee arthroplasty, and fatal PE is one of the main causes of perioperative mortality. VTE prevention after TKA can effectively avoid serious complications and is widely approved and valued by clinicians and researchers. However, the most optimal preventive measures, particularly medications, remain controversial. Increasingly, more clinicians are being faced with the same problems that accompany rapid growth in the number of joint replacement surgeries.
In this study, all cases of DVT were asymptomatic VTE. The incidence rate of VTE is as high as 60% after knee arthroplasty in the literature, but most cases are asymptomatic VTE; the incidence rates of symptomatic VTE and fatal PE are reportedly 1.8% and 0.15%, respectively.7,8Parvizi et al found that the correlation between DVT and PE is low; thus, the importance of asymptomatic DVT is debatable.9A reduction in the incidence of PE secondary to a reduction in the incidence of DVT is also worthy of discussion. VTE prevention is very important after knee arthroplasty, but medication side effects, especially severe bleeding events, must be given more attention.
The ACCP and AAOS guidelines are internationally accepted reference standards for VTE prevention. There was a substantial difference between the guidelines of these two organizations before 2011. For pharmaceutical VTE prevention, the ACCP guidelines strongly recommended the use of LMWH and not aspirin, while aspirin was suggested by the AAOS guidelines as an effective prevention method. This difference was mainly due to different research endpoints. Both symptomatic and asymptomatic VTEs were included as endpoints in an ACCP study. However, only symptomatic VTE was included in the AAOS research. Thus, the AAOS research found aspirin to be effective because no significant difference in the incidence of symptomatic VTE was found between aspirin and LMWH. However, the AAOS paid more attention to potential bleeding problems secondary to anticoagulants. The ACCP guidelines more strongly emphasized the prevention of VTE after orthopedic surgery while ignoring complications of pharmaceutical prevention. Aspirin is not recommended for use as a sole pharmaceutical agent in the VTE prevention guidelines for Chinese major orthopedic procedures, which was released by COA in 2009. This situation has resulted in confusion among clinicians, especially orthopedic surgeons, in terms of choosing the most appropriate VTE prevention measures. Our study demonstrated that aspirin alone is an effective VTE prophylaxis drug in Chinese patients undergoing TKA.
Aspirin achieves its antithrombotic function by inhibiting platelet aggregation. Anticoagulant drugs have a greater impact on thrombosis than do antiplatelet drugs because of slow blood flow in the venous system, but many clinicians use aspirin for VTE prevention because of its convenience, low cost, and few side effects. A randomized controlled study published inThe Lancetin 2000 showed that the incidences of DVT and PE were reduced by 36% and 58%, respectively, compared with the low-dose aspirin placebo in VTE prevention after hip fracture.10Jameson et al retrospectively studied the use of aspirin or LMWH for VTE prevention after knee arthroplasty among 156 800 cases in the UK from 2003 to 2008. This study showed that the incidence of PE was 0.49% with the use of aspirin and 0.45% with the use of LMWH. There was no difference in the incidence of VTE, 90-day mortality, or major hemorrhage between the two groups.11Other randomized controlled studies and large-scale retrospective studies in the past 2 years have also shown that aspirin does not differ from other drugs in the prevention of VTE after major orthopedic surgery.12-14In the present study, aspirin reduced the amount of blood loss and postoperative subcutaneous ecchymosis formation in addition to showing the same results as described above; however, no large-scale randomized controlled trials or meta-analyses have shown that aspirin is associated with a lower incidence of severe bleeding complications than other VTE prevention drugs.
In addition to drugs, mechanical measures play an indispensable role in VTE prevention after TKA. A multicenter randomized controlled study by Colwell showed that there is no difference between LMWH and a single session of IPC in terms of reducing the incidence of VTE, but fewer bleeding complications are associated with IPC.15However, IPC is recommended for using combined with pharmaceutical agent by COA for VTE prevention. Similarly, gentle and fine surgical techniques and early postoperative functional exercises are the basic VTE prevention measures used among joint surgeons after performing TKA.
The study endpoint was changed to symptomatic VTE or fatal PE in the latest edition of the ACCP guidelines (2012). The study endpoint was defined as only symptomatic or fatal PE in the 2011 AAOS guidelines. These definitions not only avoid biases in evaluating studies of indicators between anticoagulation and bleeding, but also achieve a better balance between effective prevention and reductions in complications. Accordingly, aspirin was recommended as the most effective VTE prevention drug in both guidelines, graded 1B. IPC was recommended as grade 1C prevention. In China, the official VTE prevention guidelines published by COA have not yet been updated. Aspirin is not a widely accepted VTE prevention strategy among Chinese surgeons. Our study is the first randomized trial to support the use of aspirin as a sole pharmaceutical prevention method in Chinese patients.
The results of this study suggest that aspirin is not inferior to other preventive medications in preventing incidence of VTE after TKA and that aspirin has some level of advantages in the reduction of postoperative blood loss and saving treatment costs. We recognize that given the relatively small sample size, we are not powered to detect small increase in DVT incidence rate with aspirin. However, as the point estimate of the difference in DVT incidence rates between the two groups is very close to zero, we feel that the detrimental effect of aspirin, if exists, is likely to be small. Given the potential financial and physiological benefits of aspirin over alternative medications, our study underscores the need for a larger scale study to investigate the cost-effectiveness of aspirin in reducing VTE. In our study, ultrasonography was used for DVT detection, but angiography (the gold standard) would have been more accurate. We hope that this study may lead to larger, more rigorously designed clinical studies on pharmaceutical VTE prevention, allowing for the identification of a suitable integratedVTE prevention measure for Chinese patients.
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(Received August 15, 2013)
Edited by Hao Xiuyuan

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Figure 1. Flowchart of patients.
Table 1.Demographic characteristics and operative times of group A (aspirin) and group B (LMWH and rivaroxaban)
Indices Group A
(n=60)
Group B
(n=60)
t-or χ2-values Pvalues
Sex (male/female,n) 5/55 4/56 0.100 0.752
Age (years) 65.1±7.5 63.8±6.7 0.956 0.343
BMI (kg/m2) 24.2±3.3 24.6±3.6 –1.537 0.130
Operative time (min) 82.5±4.7 83.0±4.3 –0.845 0.401
LMWH: low-molecular-weight heparin; BMI: body mass index.
Table 2. Incidence of DVT in both groups
Indices Group A (n=60) Group B
(n=60)
t-or χ2-values Pvalue
Percentage of DVT (%)
DVT cases (n)
16.67 18.33 0.058 0.500
Veins of the calf 9 10    
Popliteal vein 1 1    
Symptomatic VTE and death
within 6 weeks (n)
0 0    
DVT: deep vein thrombosis; VTE: venous thromboembolism.
Table 3. Clinical data and cost analysis in both groups
Indices Group A
(n=60)
Group B
(n=60)
t-or
χ2-values
Pvalues
Blood loss index (g/L)
Wound complications (n)
33.4±3.7 38.1±3.8 –6.777 0.000
Effusion 1 2 0.342 0.559
Hematoma 0 0    
Infection
Area of ecchymosis (%)
Total cost of VTE prevention
(RMB Yuan)
Saving per patient (RMB Yuan)
0
1.6±1.6
710.93
772.37
0
3.1±2.0
1483.3
 
 
–6.858
 
 
0.000
 
VTE: venous thromboembolism.