Rivaroxaban in preventing venous thromboembolism after arthroplastic surgery in Taiwan
Abstract
Venous thromboembolism (VTE) is one of the severe complications of total hip arthroplasty (THA) and total knee arthroplasty (TKA). The incidence of VTE could be reduced if preventive antithrombotic medicines are used; however, the incidence of bleeding may increase. Rivaroxaban is a factor Xa inhibitor that prevents VTE after THA or TKA. This study is designed to confirm the efficacy and safety of rivaroxaban in Taiwan. This is a retrospective database study based on the data of 6996 patients provided by the Taiwan National Health Insurance Research Database from 2008 to 2012. The data included the number of prescription, the cost of prescription, and case number for patients treated with antithrombotic agents for the prevention or treatment of joint arthroplasty complications (including THA, TKA, partial hip arthroplasty, revision THA and TKA), and the incidence of thrombosis and hemorrhage from year 2008 to 2012. The overall postoperative VTE rate was 0.49%. Compared with other antithrombotic drugs, rivaroxaban and heparin analogs can reduce the percentage of thrombosis. We also found that the expenditure and hospitalization was less in the rivaroxaban group than in the heparin analogs group. Because some benefits of rivaroxaban were found in our study, further cost-effective and drug safety studies are warranted. It is important to consider the cost-effective principle for the use of antithrombotic drugs in preventing thromboembolic complications after total joint arthroplasty.
Introduction
Venous thromboembolism (VTE) frequently occurs after total joint replacement. The incidence of VTE may be reduced to 50% if antithrombotic drugs are used during total hip arthroplasty (THA) or total knee arthroplasty (TKA) [1]. In a large epidemiological study conducted in an Asian group, the incidence of deep vein thrombosis (DVT) was 41% if antithrombotic drugs were not used after THA or TKA surgery [2]. In another study in the United States including 250,000 THA patients and 600,000 TKA patients, it was found that 0.9% of THA patients and 0.7% of TKA patients had symptomatic DVT, and 0.3% of those patients developed serious pulmonary embolism and were subsequently readmitted for adverse medical problems [3]. According to the current therapeutic guidelines suggested by the American College of Chest Physicians, antithrombotic drugs should be regularly given for the prevention of DVT in patients who have undergone THA or TKA [4], [5]. The American Academy of Orthopedic Surgeons also suggested that the therapeutic rules should be based on individual case assessment to determine the best special preventive program in total joint arthroplasty patients with a minimum of 10 days [6]. It was also suggested by the National Institute for Clinical Excellence in 2010 that the updated guidelines for the prevention of DVT and pulmonary embolism after total joint arthroplasty should include the use of antithrombotic drugs such as unfractionated heparin, low molecular weight heparin, fondaparinux, and rivaroxaban [7].
One serious complication of frequently used antithrombotic drugs (such as aspirin, warfarin, or heparin) is hemorrhage. Clinicians should consider the possibility of hemorrhage if a patient receiving antithrombotic therapy develops any uncertain clinical problem. When a patient receives warfarin therapy, the status of hemorrhage may not only relate to the values of Prothrombin time/International ratio (PT/INR) but also the underlying disease. Careful consideration should be given when prescribing warfarin to DVT patients to avoid the possibility of heparin-induced thrombocytopenia. It may lead to amputation or even death when use of warfarin is initiated right before the termination of heparin owing to the occurrence of heparin-induced thrombocytopenia [8].
Rivaroxaban is an antithrombotic drug whose mechanism of action is direct inhibition of the coagulation factor Xa. The first dose of rivaroxaban (10 mg) is usually given about 6–10 hours after the surgery when the bleeding has stopped; then it is taken once daily. It is suggested to give a whole course of 14 days after TKA and 35 days after THA [6]. The best advantage of using rivaroxaban is that it is not necessary to monitor the coagulation status, such as PT and Partial prothrombin time (PTT). Moreover, the efficacy of rivaroxaban is not affected by meal intake, so it can be taken prior to or after meals. In a large research series, it has been found that the incidence of VTE was reduced to 49% in Europe and 31.4% in the United States, and the incidence is 70–79% lower than that recorded for enoxaparin and the incidence of bleeding is the same as that of enoxaparin [9]-[13].
Using the Taiwan National Health Insurance Research Database (NHIRD), a nationwide database with epidemiologic information on total joint arthroplasty, this study aimed to confirm the efficacy and the safety of antithrombotic agents, including the factor Xa inhibitor rivaroxaban, for the prevention of VTE after total joint arthroplasty in Taiwan.
Materials and methods
Data sources
Since 1995, Taiwan has implemented an only-payer National Health Insurance (NHI) Program to pay for the healthcare needs of all residents. All citizens have to participate in the NHI Program, so the coverage rate was more than 99.9% with more than 23.2 million individuals enrolled [14]. The National Health Research Institutes (NHRI) in Taiwan maintains the NHIRD. The database contains comprehensive information on insured persons: demographic data, diagnostic codes, dates of clinical visits and hospitalizations, length of hospital stay, details of prescriptions, procedures/surgeries, and expenditures, which were for research purposes only. This dataset was a randomized sampling distribution from about 23.2 million people, with comprehensive data covering all medications of 1 million people, and then all medical records were followed from 2008 to 2012.
Study population
The study was approved by the Institutional Review Board (KMUH-IRB-2013029). This study included 6996 patients who received arthroplasty from April 1, 2008 to September 30, 2012, including revision of THA, revision of TKA, partial hip arthroplasty, THA, and TKA in a database of 1 million people. Patients with thrombotic or hemorrhagic diseases within the past 90 days relating to arthroplasty and who have used antithrombotic drugs in clinics were excluded. The data include all medications up to 3 months after the surgery. The patients were grouped according to the anticoagulants they took. Group 1 patients took rivaroxaban. Group 2 patients took heparin analogs including heparin or enoxaparin. Group 3 consisted of patients who took anticoagulants other than rivaroxaban or heparin analogs. Patients in Group 4 did not take any anticoagulants at all.
Outcome measurement
Outcome measures included the efficacy and safety of antithrombotic drugs for total joint arthroplasty. The efficacy assessment included the analyses of total hospitalization days, costs of drugs, costs of medical care, and number of posthospitalization visits to orthopedic clinics, as well as refills of rivaroxaban posthospitalization visits to orthopedic clinics. The safety assessment focused on the incidence of thrombotic and hemorrhagic events based on their diagnostic codes. The thrombotic event codes were as follows: 433–436 cerebrovascular accident and acute cerebral vascular disease; 437.9 cerebrovascular disease; 453.8 deep vein thrombosis; 415.1x pulmonary embolism and 444–444.9 artery thrombosis disease. The hemorrhagic event codes were as follows: 430 subarachnoid hemorrhage; 431 intracerebral hemorrhage; cerebral hemorrhage; 432.1 subdural hemorrhage; 432.9 intracranial hemorrhage; 578.0 hematemesis; 578.9 upper gastrointestinal bleeding; 599.7 hematuria; 626.2 menorrhagia; 627.1 postmenopausal bleeding; 719.10 hemarthrosis; 786.3 hemoptysis; 784.7 epistaxis; 4590 unknown bleeding; 423 epicardium bleeding and 9981, 71910, 71916, 71917 surgical hemarthrosis or bleeding.
Statistical analysis
The categorical variables of operation diagnostic codes, disease codes, and types of antithrombotic drugs with single or combined use were expressed as case numbers and percentages. The continuous variables were expressed as means ± standard error. The Chi-square test was applied to analyze the differences in age, sex, and disease code, between the groups. Two-tailed t test and analysis of variance were used to analyze the differences in total hospitalization days and Charlson comorbidity index (CCI) [15] between groups. A value of p < 0.05 was considered statistically significant. The efficacy and safety of drugs were assessed with the total case numbers and incidences (percentages) of thrombosis and hemorrhage expressed as mean ± standard deviation, and the relative risks for the use of rivaroxaban and other antithrombotic drugs. The comparison between treatment with and without rivaroxaban, based on age, sex, hospitalization days, admission disease code, and CCI, were further analyzed with logistic regression if p < 0.05. The adjusted relative risks were used for the analysis of thrombosis and hemorrhage. All analyses were conducted using SAS version 9.1.3 and SPSS 20.
Results
Analysis during hospitalization
As shown in Table 1, the data for the treatment were compared in 2008 to 2012. It was found that age (Group 1: 67.3 ± 1.37 vs. Group 2: 72.7 ± 0.82 vs. Group 3: 71.4 ± 0.65 vs. Group 4: 70.5 ± 0.15, p < 0.01) and CCI (Group 1: 3.23 ± 0.123 vs. Group 2: 3.59 ± 0.084 vs. Group 3: 3.46 ± 0.055 vs. Group 4: 3.38 ± 0.013, p = 0.015) were significantly lower in Group 1 than in the other groups. Hospitalization days (Group 1: 8.5 ± 0.42 vs. Group 2: 11.4 ± 0.73 vs. Group 3: 8.8 ± 0.43 vs. Group 4: 8.3 ± 0.06, p < 0.01) and cost of medical care during hospitalization (Group 1: 120,927 ± 3798 vs. Group 2: 143,958 ± 6345 vs. Group 3: 121,049 ± 2870 vs. Group 4: 113,810 ± 612, p < 0.01) were significantly higher in Group 2. There was no significance in cost of drugs during hospitalization, admission during the same year, and readmission rate 90 days after discharge.
| Rivaroxaban | Heparin analogs | Others | None | p | |
|---|---|---|---|---|---|
| Number | 70 | 167 | 268 | 6491 | |
| Age (y) | 67.3 ± 1.37 | 72.7 ± 0.82 | 71.4 ± 0.65 | 70.5 ± 0.15 | <0.01 |
| Sex (M/F) | 11/59 | 61/106 | 75/193 | 2082/4409 | <0.01 |
| Charlson index | 3.23 ± 0.123 | 3.59 ± 0.084 | 3.46 ± 0.055 | 3.38 ± 0.013 | 0.015 |
| Cost of drugs during hospitalization (NTD) | 3467 ± 404 | 7068 ± 1371 | 3277 ± 406 | 2650 ± 432 | 0.375 |
| Cost of medical care during hospitalization (NTD) | 120,927 ± 3798 | 143,958 ± 6345 | 121,049 ± 2870 | 113,810 ± 612 | <0.01 |
| Hospitalization days | 8.5 ± 0.42 | 11.4 ± 0.73 | 8.8 ± 0.43 | 8.3 ± 0.06 | <0.01 |
| Admission during the same year | 1.12 ± 0.038 | 1.07 ± 0.019 | 1.05 ± 0.013 | 1.07 ± 0.003 | 0.258 |
| Readmission rate 90 d after discharge (rate) | 2 (2.86%) | 1 (0.60%) | 6 (2.24%) | 213 (3.28%) | 0.196 |
| Thrombosis event (rate) | 1 (1.43%) | 2 (1.20%) | 9 (3.36%) | 22 (0.34%) | <0.01 |
| Hemorrhage event(rate) | 3 (4.29%) | 10 (5.99%) | 4 (1.49%) | 121 (1.86%) | <0.01 |
- NTD = New Taiwanese dollar.
By contrast, the incidence of hemorrhage in Groups 1 and 2 was higher compared with that in Groups 3 and 4 (Group 1: 4.29% vs. Group 2: 5.99% vs. Group 3: 1.49% vs. Group 4: 1.86%, p < 0.01). The incidence of thrombosis in Group 3 was higher, but lower in Group 4 (Group 1: 1.45% vs. Group 2: 1.20% vs. Group 3: 3.36% vs. Group 4: 0.34%, p < 0.01).
Analysis at clinics after hospitalization
During the follow-up at clinics 14 days after discharge, most patients (91.9%) did not receive any coagulant. Only 459 patients took anticoagulants. In these patients, 430 patients took anticoagulants other than rivaroxaban and heparin analogs. Only seven patients took rivaroxaban, and 22 patients took heparin analogs (Table 2). It was found that age (Group 1: 67.9 ± 3.4 vs. Group 2: 67.7 ± 3.1 vs. Group 3: 74.6 ± 0.4, vs. Group 4: 70.5 ± 0.2, p < 0.01) and CCI (Group 1: 3.43 ± 0.3 vs. Group 2: 3.32 ± 0.24 vs. Group 3: 3.7 ± 0.03 vs. Group 4: 3.35 ± 0.01, p < 0.01) were significantly higher in Group 3 than in other groups. Drug expenditure (Group 1: 2579 ± 462 vs. Group 2: 9012 ± 3877 vs. Group 3: 2299 ± 124 vs. Group 4: 1201 ± 57, p < 0.01) was highest in Group 2 and lowest in Group 4. Medical expenditure (Group 1: 4422 ± 818 vs. Group 2: 17,877 ± 4021 vs. Group 3: 4190 ± 168 vs. Group 4: 2754 ± 65, p < 0.01) showed a similar trend to drug expenditure. The highest thrombosis ratio was found in the rivaroxaban group (42.9%), but there were no bleeding events in both rivaroxaban and heparin analog groups.
| Rivaroxaban | Heparin analogs | Others | None | p | |
|---|---|---|---|---|---|
| Age (y) | 67.9 ± 3.4 | 67.7 ± 3.1 | 74.6 ± 0.4 | 70.5 ± 0.2 | <0.01 |
| Charlson index | 3.43 ± 0.3 | 3.32 ± 0.24 | 3.7 ± 0.03 | 3.35 ± 0.01 | <0.01 |
| Drug expenditure (NTD) | 2579 ± 462 | 9012 ± 3877 | 2299 ± 124 | 1201 ± 57 | <0.01 |
| Medical expenditure (NTD) | 4422 ± 818 | 17,877 ± 4021 | 4190 ± 168 | 2754 ± 65 | <0.01 |
| Clinical visit (times) | 1.29 ± 0.18 | 1.32 ± 0.12 | 2.05 ± 0.06 | 1.68 ± 0.01 | <0.01 |
| Thrombosis event (yes/total) (ratio) | 3/7 (42.9%) | 1/22 (4.5%) | 70/430 (16.3%) | 337/5166 (6.5%) | <0.01 |
| Bleeding event (yes/total) (ratio) | 0/7 (0) | 0/22 (0) | 57/430 (13.3) | 523/5166 (10.1%) | 0.056 |
- NTD = New Taiwanese dollar.
We further analyzed the data at clinics from 2 weeks to 3 months after hospital discharge (Table 3). We found that age (Group 1: 69.4 ± 2.9 vs. Group 2: 69.1 ± 2.4 vs. Group 3: 74.7 ± 0.4, vs. Group 4: 70.7 ± 0.2, p < 0.01) was significantly higher in Group 3 than in other groups. CCI (Group 1: 3.8 ± 0.2 vs. Group 2: 3.43 ± 0.22 vs. Group 3: 3.73 ± 0.04 vs. Group 4: 3.37 ± 0.01, p < 0.01) was higher in Groups 1 and 3. Drug expenditure (Group 1: 2048 ± 192 vs. Group 2: 8653 ± 3722 vs. Group 3: 2377 ± 125 vs. Group 4: 1253 ± 59, p < 0.01) was highest in Group 2 and lowest in Group 4. Medical expenditure (Group 1: 3521 ± 822 vs. Group 2: 19,374 ± 3677 vs. Group 3: 4228 ± 167 vs. Group 4: 2819 ± 67, p < 0.01) showed the same trend as drug expenditure. The highest thrombosis ratio was also found in the rivaroxaban group (40%), but there were no bleeding events in both rivaroxaban and heparin analog groups.
| Rivaroxaban | Heparin analogs | Others | None | p | |
|---|---|---|---|---|---|
| Age (y) | 69.4 ± 2.9 | 69.1 ± 2.4 | 74.7 ± 0.4 | 70.7 ± 0.2 | <0.01 |
| Charlson index | 3.8 ± 0.2 | 3.43 ± 0.22 | 3.73 ± 0.04 | 3.37 ± 0.01 | <0.01 |
| Drug expenditure (NTD) | 2048 ± 192 | 8653 ± 3722 | 2377 ± 125 | 1253 ± 59 | <0.01 |
| Medical expenditure (NTD) | 3521 ± 822 | 19,374 ± 3677 | 4228 ± 167 | 2819 ± 67 | <0.01 |
| Clinical visit (times) | 6.2 ± 1.53 | 3.91 ± 0.54 | 5.11 ± 0.18 | 3.74 ± 0.04 | <0.01 |
| Thrombosis event (yes/total) (ratio) | 2/5 (40%) | 1/23 (4.3%) | 71/437 (16.2%) | 326/4938 (6.6%) | <0.01 |
| Bleeding event (yes/total) (ratio) | 0/5 (0) | 0/23 (0) | 58/437 (13.3%) | 519/4938 (10.5%) | 0.087 |
- NTD = New Taiwanese dollar.
Discussion
The current national insurance payment system for total joint arthroplasty in Taiwan is based on diagnosis-related groups (DRGs). Under DRGs, medical expenses paid to the hospital were fixed by the same diagnosis and procedure. Therefore, it is critical to reduce the total days of hospitalization and the costs of laboratory examinations [16]-[18]. As such, the diagnosis of VTE may be easily ignored. Furthermore, many orthopedic surgeons may worry about the complications of bleeding during surgery, and this may cause the possibility of wound complications [19], so that hospitalization days may be increased. Owing to the difficulty involved in diagnosing VTE in orthopedic departments, the confirmed diagnosis requires consultation with cardiologists or radiologists for further diagnostic tests. Therefore, the total number and dates of antithrombotic drug prescription are reduced if there is no adequate diagnosis. In a previous National Health Insurance database study, Wu et al. [20] reported that the occurrence rate of overall postoperative VTE was 0.44% during 2002 to 2006; a total of 114,026 patients underwent hip (N = 61,460) or knee (N = 52,566) replacement surgeries [20]. In this study, the overall postoperative VTE was 0.49% during 2008 to 2012. Our results were similar to the results of previous studies conducted in Taiwan even though the sample size and sampling methods used are not the same.
Hospital-acquired events were estimated by applying specific risk frequencies for developing VTE to the surgical and medical at-risk populations, according to whether or not they were receiving VTE prophylaxis [21]. In this study, we have found that prescription of antithrombotic drugs for total joint replacement was only 7.1% between 2008 and 2012. Once orthopedic surgeons have prescribed antithrombotic agents in thrombosis prevention after THA and TKA, they must add the diagnostic code of thrombosis for the reimbursement concerned. The likelihood of thrombosis diagnosis was greatly reduced among orthopedic surgeons who were not aware about DVT diagnosis and prevention, which may have led to the minimal use of antithrombotic drugs. The thrombosis code during hospitalization was checked by a code specialist according to the data found in the charts. This would lead to a significantly higher rate of thrombosis diagnosis in hospitalized patients treated with rivaroxaban, heparin analogs, or other antithrombotic drugs compared with those who did not receive antithrombotic drugs (Group 1: 1.45% vs. Group 2: 1.20% vs. Group 3: 3.36% vs. Group 4: 0.34%, p < 0.01). Theoretically, patients who did not receive antithrombotic drug treatment should have the highest incidence in thrombosis, but the results showed the opposite. Those who did not use antithrombotic medication may have been less likely to describe the symptoms and diagnosis of DVT, which in turn may have led to the very low incidence of thrombosis in the group that did not receive antithrombotic drugs. The phenomenon was more obvious in the follow-up data at clinics. There was an unreasonably high incidence of thrombosis incidence in the rivaroxaban group, which was recorded as 42.9% (3/7) and 40% (2/5). The incorrect diagnostic code is a detrimental drawback in the database study.
During hospitalization, heparin analogs led to high drug and hospitalization expenditure with longer hospitalization, but they had the least readmission rate 90 days after discharge. The drug and hospitalization expenditures were similar in rivaroxaban and other drug groups; however, the patients in the rivaroxaban group were younger compared with patients in the other groups, which translated to certain advantages: less drug and hospitalization expenditures and lower number of adverse events such as thrombosis and hemorrhage. Compared with other drug groups, rivaroxaban and heparin analog groups showed reduced thrombosis incidence with obviously more bleeding effects.
Regarding the follow-up results at clinics, heparin analogs led to high drug and medical expenditures compared with other groups, similar to the trend observed during hospitalization. In other drug groups, the patients were much older than their counterparts in all other groups with higher CCI values, which may have led to more visits to clinics. There was also a higher thrombosis incidence rate in other drug groups when compared with the heparin analog group. We therefore infer that heparin analogs had an effect in reducing thrombosis; we do not exactly know how age and higher CCI in other drug groups affected the incidence of thrombosis. Because the incidence of thrombosis in the rivaroxaban group was unreasonably high, we infer that the results may be somewhat misleading, because the use of rivaroxaban should have the code of thrombosis for reimbursement.
Rivaroxaban, a factor Xa inhibitor, has been paid for by national insurance reimbursement in Taiwan since 2012. In this study, we have demonstrated that the use of rivaroxaban and heparin analogs can reduce the incidence of thrombosis compared with other antithrombotic drugs after THA or TKA. The expenditure and hospitalization stay were lower in patients who took rivaroxaban compared with those who received heparin analogs. Regarding hemorrhage risk during hospitalization (Table 4), males had higher risks than females (odds ratio = 1.487). Use of any antithrombotic drug will increase the risk of hemorrhage. Therefore, we should pay more attention to male patients who received anticoagulants after undergoing total joint arthroplasty.
| Odds ratio | p | |
|---|---|---|
| Male (female = 1) | 1.487 | 0.025 |
| Antithrombotic drugs (no antithrombotic drugs = 1) | 1.868 | 0.018 |
| Rivaroxaban (other and no and antithrombotic drugs = 1) | 1.667 | 0.015 |
There are several limitations in this study. First, this study was randomized with millions sampling distribution and may have sampling bias within the actual population. Second, this study did not perform a chart review to determine the actual thrombosis rate. For DRG reimbursement applications, it is possible that the thrombosis code was not properly keyed in, resulting in a lower thrombosis rate in patients who did not use antithrombotic agents after THA and TKA. Third, this study was a retrospective data analysis; it could only find correlation but not the causality. Fourth, there might have been some errors in the NHI database. For example, the coding of diseases might have been added to the database for reimbursement reasons. Thus, the endpoints of thrombosis events might not have been correctly reflected.
Conclusion
In this study, we have demonstrated that the use of antithrombotic agents, particularly rivaroxaban, a factor Xa inhibitor, for preventing VTE can reduce the incidence of thrombosis after THA or TKA compared with other antithrombotic drugs (although it should be noted that those who received rivaroxaban were younger). We also found that the cost of medication was similar to other antithrombotic drugs, and the bleeding risk was similar to that of heparin analogs. However, further cost-effective and drug safety studies are required. It is important to consider the cost-effective principle for the use of antithrombotic drugs in preventing thromboembolic complications after total joint surgeries.
Acknowledgments
This study was supported in part by grants from the Kaohsiung Medical University Hospital (KMUH-2R36), Kaohsiung Medical University (KMU-TP103B06) and National Science Council (NSC 102-2314-B-037-021-MY2) of Taiwan. This study is based on part of the data in the “National Health Insurance Research Database” provided by the National Health Insurance Administration, Ministry of Health and Welfare and managed by National Health Insurance (Registered number NHIRD-103-038). The interpretation and conclusions contained herein do not represent of National Health Insurance Administration, Ministry of Health and Welfare or National Health Research Institutes.
