Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis.

BACKGROUND: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). METHODS: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. RESULTS: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02-1.03) per 1.0-µg/mL increase in baseline D-dimer level. CONCLUSIONS: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Rivaroxaban treatment for asymptomatic venous thromboembolism: insights from the J'xactly study.

BACKGROUND: An established treatment strategy for asymptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) remains uncertain in Japan; therefore, in this study, we clarify the characteristics and outcomes of symptomatic compared to asymptomatic patients with PE or DVT. METHODS: This prospective, multicenter sub-analysis of the J'xactly study in Japan included 1,016 patients (mean age, 68; 41% male) with venous thromboembolism (VTE) treated with rivaroxaban. RESULTS: Asymptomatic PE patients (47% of PE patients) were more likely to have active cancer and asymptomatic proximal DVT at lower severity than symptomatic PE patients, despite no differences in age, sex, or the proportion receiving intensive 30 mg/day-rivaroxaban. Patients with asymptomatic DVT (34% of DVT patients) were older, had higher rates of female sex, active cancer, and distal DVT, and received shorter, less intense rivaroxaban treatment. Incidences did not differ between asymptomatic and symptomatic PE patients for recurrent symptomatic VTE (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.22-1.62; P = 0.31) or major bleeding (HR, 0.68; 95% CI, 0.20-2.33; P = 0.58), nor between asymptomatic and symptomatic DVT patients for recurrent symptomatic VTE (HR, 0.56; 95% CI, 0.23-1.40; P = 0.21) and major bleeding (HR, 1.47; 95% CI, 0.54-3.97; P = 0.45). CONCLUSIONS: The real-world composite adverse event rate for treatment with rivaroxaban, as physician-adjusted for dose and duration, was similar for asymptomatic and symptomatic patients regardless of the presence of PE or DVT, suggesting a favorable safety profile for potential rivaroxaban treatment for asymptomatic VTE.

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan　- Results From Post-Marketing Surveillance (XASSENT).

BACKGROUND: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. CONCLUSIONS: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Effectiveness and safety of rivaroxaban in patients with venous thromboembolism and active cancer: A subanalysis of the J'xactly study.

BACKGROUND: Data on the effectiveness and safety of rivaroxaban for the treatment of patients with venous thromboembolism (VTE) and active cancer are limited in the Japanese real-world setting. METHODS: In this subanalysis of the J'xactly study, which was a multicenter, prospective, observational study, we evaluated the effectiveness and safety of rivaroxaban in patients with acute VTE and active cancer (n = 193) versus those without active cancer (n = 823). RESULTS: Compared with patients without active cancer, those with active cancer demonstrated a significantly different age distribution, with fewer aged <65 and ≥75 years; a lower proportion of women; a lower mean body mass index; and a lower proportion of physical inactivity, injury, thrombophilia, and heart failure. There was no difference in the initial dose distribution of rivaroxaban between patients with and without active cancer. The incidences of recurrence or aggravation of symptomatic VTE and major bleeding were not significantly different [VTE: 1.44 % vs. 2.80 % per patient-year, hazard ratio (HR) 0.50, 95 % confidence interval (CI) 0.18-1.39, p = 0.172; major bleeding: 4.49 % vs. 2.55 % per patient-year, HR 1.80, 95 % CI 0.82-3.95, p = 0.137]. Approximately 10 % of patients with active cancer died at 6 months, with a significantly higher cumulative all-cause mortality rate than those without active cancer (23.29 % vs. 2.03 % per patient-year, HR 11.31, 95 % CI 7.30-17.53, p < 0.001). CONCLUSIONS: In patients with VTE and active cancer, rivaroxaban showed acceptable effectiveness, although clinically significant bleeding remains a concern. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000025072.

Clinical Outcome After Discontinuation of Anticoagulation Therapy in Japanese Patients With Venous Thromboembolism　- Insights From the J'xactly Study.

Background: Rivaroxaban, a direct oral anticoagulant, is used as first-line treatment to prevent venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). However, the frequency of rivaroxaban discontinuation and the subsequent clinical outcomes remain unclear. Methods and Results: The study was a subanalysis of the prospective, multicenter, observational J'xactly study, conducted in Japan, and included patients who underwent anticoagulant discontinuation without major bleeding and recurrent VTE. The modified intention-to-treat population (n=1,016) included 579 patients (57%) who underwent anticoagulant discontinuation during a mean follow-up period of 20.2 months (mean [±SD] anticoagulation period 6.9±6.2 months). Patients were divided into 3 groups: those with active cancer, those without active cancer and a transient risk factor for VTE, and those without active cancer or a transient risk factor and/or with previous VTE (unprovoked group). After discontinuation, VTE recurrence occurred in 4.1% of patients, with an annual incidence of 4.6%/year and an increased tendency in the unprovoked group; major bleeding occurred in 8 patients (1.4%; annual incidence 1.1%/year), of whom half were in the cancer group. Conclusions: This analysis of a real-world observational study provides data on VTE recurrence after rivaroxaban discontinuation, which will facilitate anticoagulant discontinuation according to individual risk-benefit considerations.

One-year incidence of venous thromboembolism, bleeding, and death in patients with solid tumors newly initiating cancer treatment: Results from the Cancer-VTE Registry.

INTRODUCTION: Although many publications have reported the incidence of venous thromboembolism (VTE) in patients with cancer from Western countries, to date, no prospective East Asian studies have been published, and potential racial differences remain unclear. The multicenter, prospective, observational Cancer-VTE Registry aimed to clarify the incidence of VTE and bleeding and identify risk factors in Japanese patients with solid tumors after one year of follow-up. MATERIALS AND METHODS: Patients with colorectal, lung, stomach, pancreatic, breast, or gynecologic cancer were enrolled after VTE screening and before starting cancer treatment. The follow-up period was one year. The main outcomes were the incidences of symptomatic VTE, bleeding events (major or clinically relevant non-major), and all-cause death, evaluated according to VTE presence/absence at baseline. Multivariate analyses were conducted to identify risk factors for events. RESULTS: Among 9630 patients, the one-year cumulative incidences of symptomatic VTE, bleeding events, and all-cause death were 0.5%, 1.4%, and 12.2%, respectively. The majority of VTEs identified at baseline were asymptomatic distal deep vein thromboses; however, affected patients had higher event rates during the follow-up period. The most important independent risk factor for developing symptomatic VTE, bleeding events, and death during the follow-up period was the presence of symptomatic or asymptomatic VTE at baseline. CONCLUSIONS: These data have revealed the incidence of symptomatic VTE in Japanese patients with solid tumors during one year of follow-up. The presence of any VTE before initiating cancer treatment was an independent risk factor for symptomatic VTE, bleeding events, and death during subsequent treatment.

Real-World Insurance Claims Analysis of Venous Thromboembolism in Japanese Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD), which encompasses both ulcerative colitis (UC) and Crohn's disease (CD), is a risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). AIM: To investigate the incidence of, and risk factors for, VTE in patients with IBD in Japan. METHODS: This was a retrospective, non-interventional study in patients with IBD from the Japan Medical Data Center claims database. Incidence rates (IRs; unique patients with events per 100 patient-years) were calculated for VTE, DVT, and PE among the IBD, UC, and CD cohorts. Odds ratios of potential risk factors were calculated by univariate and multivariate analyses in a nested case-control design. RESULTS: Overall, 16 273 patients with IBD were included: 13 585 with UC and 3443 with CD. VTE events occurred in 1.3%, 1.2%, and 1.9% of patients with IBD, UC, and CD, respectively. In patients with IBD, UC, and CD, IRs of VTE were 0.45, 0.40, and 0.64, respectively, IRs of DVT were 0.42, 0.38, and 0.61, respectively, and IRs of PE were 0.07, 0.07, and 0.11, respectively. In patients with IBD, treatment history (immunomodulators), cardiovascular risk (hypertension, high-density lipoprotein or diabetes mellitus, and history of coronary artery disease or heart failure), malignancy, and undergoing major surgery were identified as potential risk factors for VTE in the multivariate analysis, with similar risk factors reported for patients with UC and CD. CONCLUSIONS: This large study provides insight into the incidence and risk factors for VTE in patients with IBD from Japan.

Safety and Effectiveness of Apixaban in Japanese Patients With Venous Thromboembolism in Clinical Practice　- A Post-Marketing Surveillance.

BACKGROUND: A post-marketing surveillance study (STANDARD-VTE) evaluated the real-world safety and effectiveness of apixaban in Japanese patients prescribed for either the treatment of venous thromboembolism (VTE) or prevention of recurrent VTE.Methods and Results:Patients newly initiated on apixaban were followed up for 52 weeks or 28 days post-discontinuation. Subgroup analysis was performed on patients with and without active cancer, and on patients with provoked VTE and with unprovoked VTE. A total of 1,119 patients were enrolled. Of these, 43.1% were aged ≥75 years, 46.4% had body weight ≤60 kg, and 21.3% had active cancer; mean serum creatinine was 0.76 mg/dL. The incidence of adverse drug reactions (ADRs) was 8.85%, and that of severe ADRs was 3.22%. Incidence of any bleeding, major bleeding, and recurrent VTE was 6.70%, 3.40%, and 0.80%, respectively. In patients starting apixaban 10 mg twice daily, THE incidence of any bleeding and major bleeding was 7.72% and 3.86%, respectively. In patients with active cancer, THE incidence of any bleeding and major bleeding was 16.81% and 9.24%, respectively. CONCLUSIONS: No new safety signals of apixaban were identified in Japanese patients with VTE. In this study, the safety and effectiveness of apixaban in real-world practice was consistent with the results of the apixaban phase III trial.

A Multicenter Prospective Observational Cohort Study to Investigate the Effectiveness and Safety of Rivaroxaban in Japanese Venous Thromboembolism Patients (The J'xactly Study).

BACKGROUND: There is insufficient real-world data on the current status of Japanese patients with venous thromboembolism (VTE) or its treatment and prevention with rivaroxaban.Methods and Results:In this multicenter, prospective, observational study conducted in Japan, 1,039 patients with acute symptomatic/asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) with or without DVT prescribed rivaroxaban were enrolled at 152 institutions and observed for a median of 21.3 months. Mean age was 68.0±14.7 years, mean body weight was 60.3±14.1 kg, 59.0% were females, and 19.0% had active cancer. Incidences of recurrence or aggravation of symptomatic VTE (primary effectiveness outcome) and major bleeding (principal safety outcome) were 2.6% and 2.9% per patient-year, respectively. These outcomes did not differ between patients with DVT and those with PE (primary effectiveness outcome: 2.6% vs. 2.5% per patient-year, P=0.810; principal safety outcome: 3.5% vs. 2.4% per patient-year, P=0.394). The incidence of composite clinically relevant events, including recurrence or aggravation of symptomatic VTE, acute coronary syndrome, ischemic stroke, all-cause death, or major bleeding events, was 9.2% per patient-year. Multivariate analysis revealed that male sex, being underweight, having active cancer, chronic heart and lung disease, and previous stroke were independent determinants for composite clinically relevant events. CONCLUSIONS: In Japanese clinical practice, a single-drug approach with rivaroxaban was demonstrated to be a valuable treatment for a broad range of VTE patients.

Venous thromboembolism in cancer patients: report of baseline data from the multicentre, prospective Cancer-VTE Registry.

BACKGROUND: The Cancer-VTE Registry evaluates the occurrence and management of venous thromboembolism in Japanese participants with major solid tumors. Using Registry data, we evaluated the frequency of concurrent venous thromboembolism in cancer patients prior to treatment initiation by cancer type. METHODS: The Cancer-VTE Registry is an ongoing (March 2017-September 2020) prospective cohort study using a nationwide, multicentre clinical registry. Participants aged ≥20 years with colorectal, lung, stomach, pancreatic, breast or gynecologic cancer, confirmed staging, ≥6 months life expectancy post-registration and who had undergone venous thromboembolism screening were managed with routine clinical care. Venous thromboembolism frequency at registration was evaluated. RESULTS: Of 9735 participants, 571 (5.9%) had venous thromboembolism at baseline, including asymptomatic [5.5% (n = 540)] and symptomatic venous thromboembolism [0.3% (n = 31)]. Most participants with venous thromboembolism (n = 506, 5.2%) had deep vein thrombosis only; 65 (0.7%) had pulmonary embolism with/without deep vein thrombosis. The prevalence of distal and proximal deep vein thrombosis was 4.8% (n = 466) and 0.9% (n = 83), respectively. The highest prevalence of venous thromboembolism was for pancreatic cancer (8.5%) and the lowest for breast cancer (2.0%). Venous thromboembolism prevalence increased as cancer stage advanced. CONCLUSIONS: Although there was a marked difference in venous thromboembolism by cancer type, the data suggest that cancer stage is an important risk factor for venous thromboembolism. Thus, metastasis seems a critical risk factor for venous thromboembolism. This is the first demonstration of venous thromboembolism prevalence and risk factors in Japanese cancer patients prior to treatment. TRIAL REGISTRATION: UMIN000024942.

Safety and Effectiveness of Edoxaban in Japanese Venous Thromboembolism Patients　- Final Analysis of One-Year Follow-up Data From a Japanese Postmarketing Observational Study (ETNA-VTE-Japan).

Background: ETNA-VTE-Japan is a prospective, observational study conducted as part of a postmarketing study regarding the safety and effectiveness of edoxaban in Japanese patients with venous thromboembolism (VTE). The results of the final analysis of data collected at 1 year are presented. Methods and Results: A total of 1,732 patients were included in this study. The safety and effectiveness were evaluated in 1,702 patients (safety analysis set; SAS) and in 1,698 patients (effectiveness analysis set). In the SAS, 39.4% of patients were aged ≥75 years, 58.2% had body weight ≤60 kg, and 22.2% had creatinine clearance <50 mL/min. Approximately 90% of patients received a dose recommended on the package insert. A total of 46.1% of patients continued treatment for 1 year, with mean and median treatment periods of 235.8 and 263.0 days, respectively. The incidence of bleeding adverse events (AE) was 10.3%; major bleeding, 2.6%; and VTE recurrence, 1.8%. The risk factor commonly associated with bleeding AE and VTE recurrence was cancer. The safety and effectiveness profiles of edoxaban in patients receiving the appropriate low dose (30 mg/day), generally used in patients with high bleeding risk, were similar to those for the appropriate standard dose (60 mg/day). Conclusions: At 1 year of treatment, there were no major concerns regarding the safety and effectiveness of edoxaban in Japanese patients with VTE.

Venous thromboembolism in patients with cancer: design and rationale of a multicentre, prospective registry (Cancer-VTE Registry).

INTRODUCTION: Patients with cancer are at higher risk of venous thromboembolism (VTE) than the general population as the malignancy itself and treatment modalities, including medication and surgery, contribute to the risk of developing VTE. Furthermore, patients with cancer developing VTE have a worse prognosis than those without cancer. There are no multicentre prospective data on the occurrence and treatment of VTE in patients with cancer in Japan, and data on the outcomes, complications and incidence of VTE in these patients have not been reported. In addition, Japanese patients with cancer are traditionally treated with unfractionated heparin or warfarin; however, the use of direct oral anticoagulants, which became available in 2014, has not been sufficiently examined in this patient group. Therefore, this multicentre, prospective registry has been designed to capture VTE data from Japanese patients presenting with six cancer types. METHODS AND ANALYSIS: This registry will enrol 10 000 patients with colorectal, lung, stomach, breast, gynaecological (including endometrial, cervical, ovarian, fallopian tube and peritoneal) or pancreatic cancer between March 2017 and March 2019 and follow them for 1 year. We plan to collect data on the incidences of symptomatic VTE, bleeding events, stroke, systemic embolic events, incidental VTE requiring treatment in patients, overall survival and symptomatic VTE event-free survival. ETHICS AND DISSEMINATION: All patients will provide written informed consent. Data will remain anonymous and will be collected using an online electronic data capture system. Study protocol, amendments and informed consent forms will be approved by the institutional review board/independent ethics committee at each site prior to study commencement. Results will be disseminated at national meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000024942.

Novel Anticoagulant Therapy of Venous Thromboembolism: Current Status and Future Directions.

The first-line treatment of venous thromboembolisms (VTE) is anticoagulant therapy, and unfractionated heparin and warfarin are used in Japan. However, as both drugs require dosage adjustments that are difficult, VTE recurrences occur relatively frequently, and hemorrhagic complications are extremely common. The parenteral factor Xa inhibitor fondaparinux and the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and apixaban have recently become available as treatments for VTE in Japan. These novel anticoagulants have more stable effects than traditional therapies and are thus considered safer and more effective than the traditional agents. Especially, DOACs offer improved long-term prevention of recurrence in patients with unprovoked VTE. The initiation of DOAC monotherapy soon after VTE onset leads to shorter hospital stays than required with the older therapies and allows for outpatient treatment. DOACs have additional benefits, such as safer anticoagulant therapy for cancer patients. These novel anticoagulants are extremely promising, but there is a current lack of evidence in areas such as dosing regimens for highly vulnerable patients and dosing for long-term use, and alternative regimens for each DOAC.

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.

Predictors of venous thromboembolism recurrence and the bleeding events identified using a Japanese healthcare database.

BACKGROUND: Treatment to prevent the recurrence of venous thromboembolism (VTE) and prevent bleeding events should be given to patients with VTE in an appropriate balance in relation to relevant predictors. We elucidated the current medical care in a real world setting and quantified predictors using a Japanese healthcare database. METHODS: The study included 3578 patients who were diagnosed with VTE between April 2008 and September 2013 at a Japanese acute-care hospital and included in the hospital database. Twenty-four patients who had a VTE event during the 180-day period after enrollment were excluded. We analyzed the incidence of recurrent VTE, incidence of bleeding events, and predictors in VTE patients. Events were defined by disease, medication, imaging, and laboratory testing, among other factors. RESULTS: The rate of recurrence of VTE events was 7.2 per 100 patient-years. The incidence rate of bleeding events was 8.3 per 100 patient-years. The presence of malignant disease, antipsychotic drugs, and nonsteroidal anti-inflammatory drugs increased the risk for recurrent VTE. The predictors for bleeding events were malignant disease, central venous catheterization, cancer chemotherapy, stroke, and diabetes. CONCLUSIONS: These findings obtained from healthcare database suggest predictors either for recurrent VTE and bleeding that should be considered when selecting treatment to reduce the risk of recurrent VTE and mitigate bleeding.

Clinical benefit of graduated compression stockings for prevention of venous thromboembolism after total knee arthroplasty: post hoc analysis of a phase 3 clinical study of edoxaban.

BACKGROUND: Guidelines from the Japanese Circulation Society recommend prophylaxis with anticoagulation plus intermittent pneumatic compression or graduated compression stockings (GCS) among patients at the highest risk for developing venous thromboembolism (VTE). However, the benefits of concomitant GCS use for patients undergoing total knee arthroplasty (TKA) and receiving anticoagulation remain unknown. In this study, the efficacy of GCS plus anticoagulation compared with anticoagulation alone was evaluated among patients undergoing TKA. METHODS: This study is a post hoc analysis of a previously reported phase 3 trial involving patients undergoing TKA. In the primary study, which permitted the use of GCS for mechanical prophylaxis, patients were randomized to receive edoxaban 30 mg once daily or enoxaparin 20 mg twice daily for 11 to 14 days following TKA. The primary endpoint was the incidence of VTE, a composite of symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), and asymptomatic DVT. Treatment comparisons were performed using the chi-square test, and the 95 % confidence intervals were calculated. RESULTS: Among patients receiving edoxaban, the incidence of VTE was 3.8 and 5.8 % for patients with and without GCS, respectively. For patients receiving enoxaparin, VTE incidence was 8.4 and 20.8 % among those with and without GCS, respectively. Overall, VTE incidence was 6.0 and 13.0 % for anticoagulated patients with and without GCS mechanical prophylaxis, respectively. No deaths or symptomatic PE were reported during this study. CONCLUSIONS: Although the incidence of VTE was >2-fold lower among patients receiving anticoagulation plus GCS compared with those receiving anticoagulation alone, statistical significance was not achieved. Further studies are required to confirm the findings of this preliminary analysis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01181102.

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.

Occurrence of Deep Vein Thrombosis among Hospitalized Non-Surgical Japanese Patients.

OBJECTIVE: To estimate the frequency of deep vein thrombosis (DVT) among non-surgical inpatients, and to evaluate the D-dimer assay as a screening tool for DVT. METHODS: Subjects were non-surgical inpatients aged 20 years or older who had been bedridden for at least 24 hours and had moderate-to-high risk factors for DVT. We assessed the presence of DVT by venous ultrasonography. Patients who received a diagnosis of venous thromboembolism (VTE) before admission, who had symptoms or findings of VTE at admission, or who had surgery or trauma within the past 3 months before admission were excluded. RESULTS: DVT was confirmed in 96 of 525 patients (18.3%). In a logistic regression analysis, longer duration of hospitalization, higher D-dimer value, and history of cancer surgery were significantly associated with the occurrence of DVT. The D-dimer assay showed high sensitivity (96.1%) and high negative predictive value (97.6%). CONCLUSION: Non-surgical inpatients with a long-term hospitalization or history of cancer surgery have a risk for DVT, and need to be considered for added DVT preventive measures as recommended in the prevention guidelines. In addition, the D-dimer assay is beneficial for the screening of DVT in medical practice.