Mashio Nakamura

Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V.

BackgroundIn the absence of thromboprophylaxis, patients undergoing total hip arthroplasty (THA) are at increased risk for venous thromboembolism (VTE). The objective of this study was to compare the efficacy and safety of edoxaban with enoxaparin for the prevention of VTE after THA in Japan.MethodsThis was a phase 3, double-blind, double-dummy, noninferiority study. Patients undergoing elective, unilateral primary THA were randomized to receive edoxaban 30xa0mg once daily (nu2009=u2009307) or enoxaparin 2000xa0IU (equivalent to 20xa0mg) twice daily (nu2009=u2009303) for 11 to 14xa0days. The primary efficacy endpoint was the incidence of VTE. Safety endpoints included the incidence of major or clinically relevant nonmajor (CRNM) bleeding.ResultsThe incidence of VTE, based on venography and clinical surveillance, was 2.4xa0% in the edoxaban group and 6.9xa0% in the enoxaparin group (P <0.001). The absolute difference in the incidence of VTE was −4.5xa0% (95xa0% confidence interval [CI]: −8.6, −0.9), which was within the noninferiority margin set at 8xa0% for the difference and established the noninferiority of edoxaban to enoxaparin. Since the upper limit of the 95xa0% CI of the absolute difference was less than 0xa0%, the superiority of edoxaban over enoxaparin was demonstrated. The incidence of major or CRNM bleeding was 2.6xa0% in the edoxaban group and 3.7xa0% in the enoxaparin group (Pu2009=u20090.475).ConclusionsOral edoxaban 30xa0mg once daily was superior to subcutaneous enoxaparin 2000xa0IU twice daily in the prevention of VTE following THA without increasing the risk for major or CRNM bleeding.

Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy

Venous thromboembolism (VTE), manifesting as either deep vein thrombosis or pulmonary embolism, is common worldwide including in Japan. The number of patients clinically diagnosed with VTE is increasing with the majority of cases occurring out-of-hospital and of milder severity. Cancer is the largest risk factor for VTE and VTE in cancer patients confers an increased 1-year mortality rate. However, the majority of VTE cases are considered idiopathic or unprovoked. The limited efficacies of unfractionated heparin and warfarin have stimulated the development of new anticoagulant therapies. Recently, parenteral and oral administration of the Xa inhibitors fondaparinux and edoxaban, respectively, was approved in Japan. These agents have the potential to provide safer and more efficacious treatment options for VTE. Although further randomized studies are required to validate the utility of these agents, they are expected to substantially improve quality of life in VTE patients. This review summarizes the current status of VTE management in Japan focusing on current epidemiology and recent advances in anticoagulant therapy.

Venous thromboembolism after total joint arthroplasty: results from a Japanese multicenter cohort study

IntroductionReal-world evidence of the effectiveness of pharmacological thromboprophylaxis for venous thromboembolism (VTE) is limited. Our objective was to assess the effectiveness and safety of thromboprophylactic regimens in Japanese patients undergoing joint replacement in a real-world setting.MethodOverall, 1,294 patients (1,073 females and 221 males) who underwent total knee arthroplasty (TKA) and 868 patients (740 females and 128 males) who underwent total hip arthroplasty (THA) in 34 Japanese national hospital organization (NHO) hospitals were enrolled. The primary efficacy outcome was the incidence of deep vein thrombosis (DVT) detected by mandatory bilateral ultrasonography up to post-operative day (POD) 10 and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding (major or minor) and death from any cause up to POD28.ResultsPatients undergoing TKA (nu2009=u20091,294) received fondaparinux (nu2009=u2009360), enoxaparin (nu2009=u2009223), unfractionated heparin (nu2009=u200972), anti-platelet agents (nu2009=u200945), or no medication (nu2009=u2009594). Patients undergoing THA (nu2009=u2009868) received fondaparinux (nu2009=u2009261), enoxaparin (nu2009=u2009148), unfractionated heparin (nu2009=u200932), anti-platelet agents (nu2009=u200944), or no medication (nu2009=u2009383). The incidence rates of sonographically diagnosed DVTs up to POD10 were 24.3% in patients undergoing TKA and 12.6% in patients undergoing THA, and the incidence rates of major bleeding up to POD28 were 1.2% and 2.3%, respectively. Neither fatal bleeding nor fatal pulmonary embolism occurred. Significant risk factors for postoperative VTE identified by multivariate analysis included gender (female) in both TKA and THA groups and use of a foot pump in the TKA group. Only prophylaxis with fondaparinux reduced the occurrence of VTE significantly in both groups. Propensity score matching analysis (fondaparinux versus enoxaparin) showed that the incidence of DVT was lower (relative risk 0.70, 95% confidence interval (CI) 0.58 to 0.85, Pu2009=u20090.002 in TKA and relative risk 0.73, 95% CI 0.53 to 0.99, Pu2009=u20090.134 in THA) but that the incidence of major bleeding was higher in the fondaparinux than in the enoxaparin group (3.4% versus 0.5%, Pu2009=u20090.062 in TKA and 4.9% versus 0%, Pu2009=u20090.022 in THA).ConclusionsThese findings indicate that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of DVT but increases bleeding tendency in patients undergoing TKA and THA.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry: UMIN000001366. Registered 11 September 2008.

Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4/heparin antibody formation after orthopedic surgery

Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.

Risk of Venous Thromboembolism after Total Knee Arthroplasty in Patients with Rheumatoid Arthritis

Objective. To compare the incidence of venous thromboembolism (VTE) following total knee arthroplasty (TKA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA). Methods. The subjects were composed of 1084 Japanese patients with OA and 204 with RA. Primary effectiveness outcomes were any deep vein thrombosis (DVT) as detected by bilateral ultrasonography up to postoperative Day 10 (POD10) and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding and death from any cause up to POD28. Plasma D-dimer levels were measured before and at POD10 after TKA. Results. The study cohort was composed of 1288 patients from 34 hospitals. There was no death up to POD28. PE occurred in 2 patients with OA and in no patients with RA. The incidence of primary effectiveness outcome was 24.3% and 24.0% in patients with OA and RA, respectively. The incidence of major bleeding up to POD28 was 1.3% and 0.5% in patients with OA and RA, respectively. No differences in the incidence of VTE (symptomatic/asymptomatic DVT plus PE) or bleeding were noted between patients with RA and OA. D-dimer levels on POD10 were significantly higher in patients with OA compared with those with RA. Also, D-dimer levels on POD10 were significantly lower in patients receiving fondaparinux than in patients without pharmacological prophylaxis. Conclusion. Despite some differences in demographic data, patients with RA and OA have equivalent risks of VTE and bleeding following TKA.

Changes in the incidence, case fatality rate, and characteristics of symptomatic perioperative pulmonary thromboembolism in Japan: Results of the 2002-2011 Japanese Society of Anesthesiologists Perioperative Pulmonary Thromboembolism (JSA-PTE) Study.

PurposeThis study aimed to examine the incidence, case fatality rate, and characteristics of perioperative symptomatic pulmonary thromboembolism (PS-PTE) throughout Japan.MethodsFrom 2002 to 2011, confidential questionnaires were mailed annually to all Japanese Society of Anesthesiologists-certified training hospitals for data collection to determine the incidence and case fatality rate of PS-PTE patients. Data from 10,537 institutions in which a total of 11,786,489 surgeries had been performed were analyzed using the Mann–Whitney and Chi-square tests.ResultsIn total, 3,667 PS-PTE cases were identified. The average incidence of PS-PTE was 3.1 (2.2–4.8) per 10,000 surgeries, and the average case fatality rate was 17.9xa0% (12.9–28.8xa0%). The incidence of PS-PTE began to significantly decrease in 2004 compared with that of 2002 (0.0036 vs. 0.0044xa0%: pxa0<xa00.01). The case fatality rate temporarily increased toward 2005 (17.9 to 28.8xa0%); however, it gradually decreased since 2008 (15.7xa0%) and was the lowest (12.9xa0%) in 2011. Regarding the trends in prophylaxis, the rate of mechanical prophylaxis increased significantly in 2003 compared with that of 2002 (59.5 vs. 35.0xa0%: pxa0<xa00.01), and almost plateaued (73.1–83.1xa0%) after 2004. Furthermore, the rate of pharmacological prophylaxis started increasing in 2008 (17.6xa0%) and reached around 30xa0% after 2009 (28.8–30.2xa0%).ConclusionsThe results of our 10-year survey study show that the incidence of PS-PTE decreased significantly since 2004, and the case fatality rate seemed to show a downward trend since 2008. Major changes in the distribution of prophylaxis in PS-PTE patients were observed.

Spinal anesthesia increases the risk of venous thromboembolism in total arthroplasty: Secondary analysis of a J-PSVT cohort study on anesthesia

Abstract Clinical guidance on the choice of anesthetic modality vis-à-vis the risk of perioperative venous thromboembolism (VTE) is largely lacking because of a paucity of recent evidence. A comparative effect of general anesthesia and neuraxial blockade on the perioperative incidence of VTE has not been well-investigated. We compared the effects of different types of anesthetic modalities on the risk of VTE after total hip arthroplasty (THA) and total knee arthroplasty (TKA). This is a secondary analysis of the Japanese Study of Prevention and Actual Situation of Venous Thromboembolism after Total Arthroplasty (J-PSVT). Data pertaining to a total of 2162 patients who underwent THA and TKA at 34 hospitals were included in this analysis. We compared the different anesthetic modalities with respect to the incidence of VTE. The composite end-point was asymptomatic/symptomatic deep vein thrombosis detected using scheduled bilateral ultrasonography up to postoperative day (POD) 10 and fatal/non-fatal pulmonary embolism up to POD 10. The study groups were as follows: general anesthesia (nu200a=u200a646), combined epidural/general anesthesia (nu200a=u200a1004), epidural anesthesia (nu200a=u200a87), and spinal anesthesia (nu200a=u200a425). On multivariate analysis, only spinal anesthesia was associated with a significant increase in the risk of VTE as compared with that associated with general anesthesia. Propensity score-matched analysis for “combined epidural/general anesthesia group” versus “spinal anesthesia group” demonstrated a 48% higher incidence of VTE (relative risku200a=u200a1.48, 95% confidence interval [CI] 1.18–1.85) in the latter. Spinal anesthesia was associated with a higher risk of postoperative VTE, as compared with that associated with combined epidural/general anesthesia, in patients undergoing total arthroplasty.

Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Japan

Direct oral anticoagulants (DOACs) were developed to compensate for the demerits of warfarin. In Japan, three factor Xa inhibitors are used for the treatment of venous thromboembolism (VTE): edoxaban, rivaroxaban, and apixaban. Despite problems, such as the inability to monitor their effect and the lack of an antidote, these inhibitors have the same efficacy as conventional treatment with warfarin, and they are associated with a significantly high degree of safety in relation to hemorrhagic complications. East Asians, including Japanese, suffer from hemorrhage more frequently; therefore, DOACs are considered to be highly effective. Although there is no evidence to date, DOACs may be effective in a wide variety of ways, including the possibility that they prevent recurrence over the long term, reduce the length of hospitalization, allow treatment to be started on an outpatient basis, and be effective in cancer patients.