Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism ― The Primary Results From the K … (2024)

Abstract

Background: Direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulation therapy in the acute phase of venous thromboembolism (VTE). However, there is limited real-world data for Japanese VTE patients.

Methods and Results: The KUROSIO study (UMIN000023747) was a prospective long-term observational study comprising 1,017 patients with concurrent acute symptomatic pulmonary thromboembolism and proximal deep vein thrombosis (DVT) or isolated calf DVT initially treated with DOACs. After excluding 24 patients, 993 (mean age, 66.3±15.1 years; 58.6% females) were analyzed. The incidences of recurrent symptomatic VTE and major bleeding for up to 52 weeks after diagnosis were 3.2% and 2.2%, respectively. Multivariate analyses revealed chemotherapy and anemia as significant risk factors associated with recurrent symptomatic VTE and major bleeding, respectively.

Conclusions: The efficacy and safety of DOACs in Japanese patients with VTE were determined in this real-world observational study.

Many large randomized controlled trials have shown that direct oral anticoagulants (DOACs), also known as non-vitamin K antagonist oral anticoagulants, are effective and safe, leading to worldwide approval for treating acute venous thromboembolism (VTE).15 In Japan, edoxaban, rivaroxaban, and apixaban are the available drugs for treating acute pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), and are strongly recommended as first-line anticoagulants for VTE in several guidelines.68 DOACs are applicable in the acute and chronic phases of VTE as they do not require routine coagulation monitoring and dose adjustment, have fewer side effects, and have less interaction with drugs and food compared with warfarin.9,10 In contrast, the therapeutic effects of unfractionated heparin and warfarin are monitored using the activated partial thromboplastin time and prothrombin time-international normalized ratio (PT-INR), respectively; however, the therapeutic effect and bleeding risk of DOACs using blood sampling are not established. DOACs are pivotal for anticoagulant therapy for VTE in Japan, although real-world data on their efficacy and safety in the Japanese population and on the optimal administration period and long-term treatment status are limited. Therefore, we conducted this multicenter prospective study to clarify the current status of both DOAC treatment and long-term prognosis in Japanese patients with VTE.

Methods

Study Design

The prospective study of non-vitaminKantagonist oral anticoagUlants management in Japanese patients with deep vein thROmboSIs and pulmOnary embolism (the KUROSIO study) was a multicenter, prospective, observational cohort study designed to obtain real-world evidence of clinical outcomes in Japanese patients with acute symptomatic/asymptomatic VTE (DVT, PE, or both) treated with DOACs in real-world clinical practice and followed up for 1 year after diagnosis. The target patient population was 1,000.

Eligible Patients

Eligible patients were those diagnosed with acute symptomatic PE and symptomatic/asymptomatic DVT, including isolated distal DVT, through imaging techniques and prescription of DOACs. Patients were excluded if warfarin was administered during the initial treatment period. All patients provided written informed consent before registration.

Variables

The survey variables comprised patients’ background characteristics, including risk factors for VTE and clinical characteristics; medication status and drugs used concomitantly; nonpharmacological therapy for VTE; invasive treatment, including minor surgery other than therapy for VTE; clinical course; clinical laboratory test results; adverse events (AEs), including bleeding; clinical events, including the recurrence of symptomatic VTE, according to established imaging techniques. Bleeding AEs were classified by attending physicians based on the criteria of the International Society on Thrombosis and Hemostasis, with slight modifications. Data were collected from each patient’s case report at 12 months after participation in the study.

Outcome Assessments

Data on the survey variables were used to evaluate the safety and efficacy of DOACs in clinical practice. The primary efficacy outcome was the recurrence of symptomatic VTE during treatment. The principal safety outcome measure was major bleeding during treatment. Blinded adjudication of the outcomes was conducted by an independent clinical event committee.

Patients were divided into 3 groups according to their risk factors: provoked, unprovoked, and cancer. Patients with transient risk factors, including surgery within 3 months, prolonged bed rest, a central venous catheter, pregnancy or puerperium, trauma/fracture, burns, infections, and hormone replacement therapy, were classified into the provoked group.

Patients in whom the index episode occurred without provoked risk factors or active cancer were classified into the unprovoked group. Patients with active cancer were classified into the cancer group.

Statistical Analysis

All analyses were performed after excluding the missing data. Categorical variables are summarized as frequencies and proportions. For continuous variables, summary statistics (mean and standard deviation) were summarized. To identify risk factors for recurrence and bleeding, a multivariate Cox proportional hazards model with a stepwise variable selection method (significance level, 5%) was used. The variables used in the multivariate analysis for recurrence and bleeding were patients’ background characteristics. The incidence rates of recurrence and bleeding were calculated as the cumulative incidence and person-time (events/100 patient-years), respectively. The Kaplan-Meier method was used to investigate the characteristics of recurrence and bleeding. Statistical analysis was performed using SAS version 9.4 (SAS Institute Japan, Tokyo, Japan), and statistical significance was set at P<0.05 (two-tailed). The target sample size was calculated using the width of the 95% confidence interval (CI). For acute symptomatic PE and proximal DVT, regarding the incidence of bleeding for DOACs and based on previous studies on VTE, the incidences of recurrence and bleeding at 12 months with edoxaban were 3.16% and 1.36%, respectively.3 The incidences of recurrence and bleeding at 12 months with rivaroxaban were 2.07% and 0.97%, respectively.1 The incidences of recurrence and bleeding at 6 months with apixaban were 2.26% and 0.56%, respectively.2 The 12-month incidence was twice that of the 6-month, and the incidences of recurrence and bleeding were 4.52% and 1.12%, respectively. Considering that the bias in the proportion of DOACs used by the enrolled participants was small and using the average value for each drug, the incidences of recurrence and bleeding at 52 weeks were 3.25% and 1.15%, respectively. We aimed to estimate the 95% CI for recurrence and bleeding within ±1.70% and ±1.00%, respectively. Sample sizes required for recurrence and bleeding were 418 and 437, respectively. The target sample size was 500, assuming that approximately 12% of the participants would drop out, be censored, or be missing.

For acute isolated distal DVT in the lower leg, the incidences of recurrence and bleeding were estimated to be similar to those of acute symptomatic PE and proximal DVT.9 Therefore, the target sample size was 500.

Ethics Statement

This study was conducted following the principles of the Declaration of Helsinki, the Ethical Guidelines for Clinical Studies from the Japanese Ministry of Health, Labor and Welfare, and all applicable laws in Japan. The protocol of the present study was reviewed and approved by the Clinical Research Ethics Review Committee of Mie University Hospital (reference number: 2942) and the institutional review boards of all participating institutions. The data were reviewed by an independent data and safety monitoring committee.

The KUROSIO trial is registered with the UMIN Clinical Trials Registry (UMIN000023747).

Results

Between September 2016 and November 2019, 1,017 patients were enrolled from 66 institutions (Appendix) within 4 weeks of VTE diagnosis and were monitored until the end of the follow-up period.

Figure 1 is a flow diagram of the final patient population enrolled in the study. The patients were followed up until November 2021, and the median follow-up period was 367.0 days (interquartile range, 349.0–392.0 days). Data from 24 of these 1,017 patients were excluded from the analysis for the following reasons: treatment without DOACs (2 patients), chronic thrombus (5 patients), duplicate registration (2 patients), upper limb thrombus not covered in this study (2 patients), withdrawal of consent (1 patient), and inadequate procedure according to the ethics review board (9 patients). Therefore, the full analysis set comprised data from 993 patients.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism ― The Primary Results From the K … (1)

Figure 1.

Flowchart of the study. VTE, venous thromboembolism.

Baseline Patient Characteristics

The baseline characteristics of the patients in this study (n=993) are summarized in Table 1. The number of observation data points for the continuous variables is listed in Table 1. In the study population, the mean age was 66.3±15.1 years, 58.6% were female, the mean body weight was 60.8±14.5 kg, and the mean creatinine level was 0.79±0.29 mg/dL. The number (proportion) of patients diagnosed with symptomatic PE, proximal DVT, and isolated distal DVT was 490 (49.3%), 296 (29.8%), and 207 (20.8%), respectively. The provoked, unprovoked, and cancer groups comprised 259 (26.1%), 499 (50.2%), and 235 (23.7%) patients, respectively.

Table 1.

Demographic and Clinical Characteristics of the Patients

All patients (n=993)
Age (years), mean±SD66.3±15.1
 ≥75 years, n (%)336 (33.8%)
Male sex, n (%)411 (41.4%)
Body weight (kg)60.8±14.5
Body mass index23.8±4.4
Body weight ≤60 kg, n (%)520 (52.4%)
CrCL, mL/min, n (%)
 ≥50784 (79.0%)
 30≤CrCL<50171 (17.2%)
 15≤CrCL<3023 (2.3%)
 <153 (0.3%)
Qualifying diagnosis, n (%)
  PE490 (49.3%)
  Proximal DVT296 (29.8%)
  Distal DVT207 (20.8%)
Severity classification of PE, n (%)
  Cardiac arrest or collapse5 (1.0%)
  Massive27 (5.5%)
  Sub-massive201 (41.0%)
  Non-massive257 (52.4%)
Cause of DVT or PE, n (%)
  Provoked259 (26.1%)
  Unprovoked499 (50.2%)
  Cancer235 (23.7%)
Risk factors of VTE
 Hormone replacement therapy65 (6.5%)
 Thrombophilia70 (7.0%)
  Protein C deficiency20 (2.0%)
  Protein S deficiency30 (3.0%)
  Antithrombin deficiency8 (0.8%)
Concomitant medications
 Aspirin61 (6.2%)
Treated with reduced dose
 Rivaroxaban
  25 mg/day1 (0.1%)
  20 mg/day8 (0.8%)
  15 mg/day87 (8.8%)
  10 mg/day6 (0.6%)
 Apixaban
  10 mg/day87 (8.8%)
  5 mg/day15 (1.5%)
  2.5 mg/day1 (0.1%)
 Edoxaban
  30 mg/day217 (21.9%)
  15 mg/day10 (1.0%)
  10 mg/day3 (0.3%)

Provoked risk factors included recent surgery within 3 months, prolonged immobilization, central venous catheter indwelling, pregnancy/postpartum period, trauma, bone fracture, burns, infection, or hormone replacement therapy. CrCL, creatinine clearance; DVT, deep vein thrombosis; PE, pulmonary thromboembolism.

Efficacy and Safety of DOAC Therapy

The number of patients treated with rivaroxaban, edoxaban, and apixaban was 374, 367, and 252, respectively. The mean administration period was 227.0±181.0 days.

In the full analysis set, the primary efficacy outcome occurred in 32 patients (3.2%), corresponding to an incidence rate of 3.7% per patient-year (95% CI, 2.4–5.0%; Figure 2A). Details of the recurrent events included acute symptomatic PE in 13 patients (1.3%), acute symptomatic proximal DVT in 15 (1.5%), and acute symptomatic distal DVT in 4 (0.4%). No fatalities were observed.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism ― The Primary Results From the K … (2)

Figure 2.

(A) Kaplan-Meier cumulative event rates for the primary efficacy outcome (recurrent venous thromboembolism). (B) Kaplan-Meier cumulative event rates for the principal safety outcome (major bleeding).

The principal safety outcome, major bleeding, occurred in 22 patients (2.2%), corresponding to an incidence rate of 2.6% per patient-year (95% CI, 1.5–3.7%). The bleeding incidences included intracranial bleeding in six patients (0.6%), gastrointestinal in nine (0.9%), others (including uterine bleeding, hematuria, and bleeding from the procedural site) in seven (0.7%), and non-fatal (Figure 2B).

The multivariate analyses of patients who received DOACs revealed chemotherapy and height as a risk factor associated with recurrent VTE (Table 2) and anemia at enrollment as that associated with bleeding complications (Table 3).

Table 2.

Difference in Recurrence of Symptomatic VTE Among Background Factors According to the Cox Proportional Hazard Model (52 Weeks)

Overall
Univariate analysisMultivariate analysis
HR95% CIP valueHR95% CIP value
LowerUpperLowerUpper
Patient characteristics
 Age, years1.0060.9831.0300.613
 Male, yes2.5771.2765.2080.008
 Height, cm1.0401.0061.0760.0211.0431.0071.0790.019
 Weight, kg1.0160.9941.0380.148
 Body mass index1.0080.9291.0930.853
 Smoking, yes1.8250.7064.7150.214
 In-hospital onset, yes0.9950.4502.1970.990
Risk factors of VTE
 Active cancer, yes1.4260.6653.0550.362
 Chemotherapy, yes2.9521.3366.5220.0073.2251.4457.1960.004
 Surgery, yes0.3390.0811.4130.137
 Hormone replacement therapy, yes1.8620.6565.2850.243
 Varicosis, yes0.5610.0774.1050.570
 CKD, yes0.5230.0723.8240.523
 Congenital thrombophilia, yes0.6970.1672.9180.621
Treatment
 Unfractionated heparin, yes0.9850.4871.9900.966
 Thrombolytic therapy, yes1.1370.3483.7190.832
 Inferior vena cava filter, yes0.6690.1602.7940.582
 Aspirin, yes1.2600.3015.2730.751

CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; VTE, venous thromboembolism.

Table 3.

Difference in Bleeding Complications Among Background Factors According to the Cox Proportional Hazard Model (52 Weeks)

Overall
Univariate analysisMultivariate analysis
HR95% CIP valueHR95% CIP value
LowerUpperLowerUpper
Patient characteristics
 Age, year1.0150.9851.0470.329
 Male, yes0.9630.4122.2520.930
 Height, cm0.9770.9381.0180.265
 Weight, kg0.9420.9080.9780.002
 Smoking, yes1.0480.2454.4870.949
Risk factors of VTE
 Active cancer, yes2.6891.1466.3080.023
 Trauma/Fracture, yes0.5880.0794.3730.604
 Lower limb paralysis, yes1.7170.23112.7710.598
 Recent surgery (within 3 months), yes0.5580.1302.3890.432
 Chemotherapy, yes0.8880.2073.8000.873
 Inflammation, yes2.2280.6597.5280.197
 Hormone replacement therapy, yes2.2730.6737.6830.186
Baseline laboratory tests
 Hemoglobin, g/mL0.6860.5690.828<0.0010.6970.5650.8600.001
 Platelet, ×104/μL1.0030.9991.0060.158
 Serum creatinine, mg/dL0.3840.0582.5390.321
 SBP, mmHg1.0000.9811.0200.985
 DBP, mmHg0.9760.9461.0070.132
Drug treatment for VTE
 Unfractionated heparin, yes0.8470.3452.0780.717
 Thrombolytics, yes0.5550.0754.1290.565
Treatment for VTE other than drugs
 Inferior vena cava filter, yes0.5090.0683.7860.509
 Aspirin, yes1.4980.3506.4100.586
 Clopidogrel, yes6.0231.40725.7840.016
 NSAIDs, yes3.8701.14513.0790.029

DBP, diastolic blood pressure; NSAIDs, nonsteroidal anti-inflammatory drugs; SBP, systolic blood pressure. Other abbreviations as in Table 2.

Discussion

DOACs, which have been judged as effective and safe according to many randomized controlled trials, are fast-acting anticoagulants not requiring blood tests to adjust doses, and have become pivotal in the treatment of VTE.68 Based on the results of large-scale randomized overseas studies in which DOACs were compared with the conventional anticoagulants heparin and warfarin,15 and the clinical trials with limited cases conducted in Japan,11,12 3 DOACs, edoxaban, rivaroxaban, and apixaban, have been approved for VTE treatment in Japan. However, there is limited real-world data, from patients with various backgrounds, that verify the efficacy and safety of DOACs in Japan. Therefore, in this prospective registry study, we investigated the efficacy and safety of DOACs for Japanese patients with VTE. Results from the KUROSIO study showed a VTE recurrence rate of 3.7/100 person-years and major bleeding rate of 2.6/100 person-years. The average age of the patients enrolled in this study was 66.3 years, and the proportion of those with cancer was 23.7%.

The JAVA study, a prospective registry study in the era of conventional treatment centered on unfractionated heparin and warfarin before the introduction of DOACs in Japan, comprised 1,076 patients with VTE. In that study, 338 patients had PE with or without DVT, and 738 had DVT alone, of whom 290 (27.0%) had cancer. The mean follow-up period was 252.2 days, and the annual recurrence rate of VTE was 3.6%. The incidence of major bleeding was 3.3/100 person-years, 6.0/100 person-years in patients with PE, and 2.2/100 person-years in those with DVT alone. Patients with PE experienced recurrence more frequently than those with DVT alone.13

In previous large-scale clinical trials, the VTE recurrence and major bleeding rates were 2.1% and 1.0%, respectively, in the EINSTEIN trial investigating the efficacy and safety of rivaroxaban;1 2.3% and 0.6%, respectively in the AMPLIFY trial of apixaban;2 and 3.2% and 1.4%, respectively, in the HOKUSAI trial of edoxaban.3 Considering that the enrolled patients were in their 50 s and that the rate of active cancer was <10% in these randomized controlled trials, there was no significant deviation from the results of the KUROSIO study, which focused on Japanese patients with VTE, thus demonstrating the efficacy and safety of DOACs.

The results of post-marketing surveillance (PMS) for each DOAC in Japan were recently reported. In the PMS of apixaban, the STANDARD-VTE study, 1,119 VTE patients (21.3% with active cancer) were observed for 52 weeks, and the frequencies of VTE recurrence and major bleeding were 0.8% and 3.4%, respectively.14 The ETNA-VTE-Japan study, a PMS study of edoxaban, included 1,732 VTE patients (28.1% with cancer), and the frequencies of VTE recurrence and major bleeding were 1.8% and 2.6%, respectively.15 In the prospective cohort J’xactly study of rivaroxaban, the frequencies of VTE recurrence and major bleeding were 2.6% and 2.9%, respectively, in 1,039 patients with VTE (19.0% with active disease).16 The present study (KUROSIO) also showed efficacy and safety similar to those of the PMS surveys.

In KUROSIO, chemotherapy was a significant risk factor for recurrent symptomatic VTE, but the relationship of chemotherapy with VTE recurrence remains unclear. Endothelial injury associated with chemotherapy may be a cause of VTE recurrence, as reported previously.17 Additionally, the interaction between anticancer drugs and DOACs may attenuate anticoagulant effects. There is limited evidence on the clinical outcomes of concurrent DOACs and anticancer therapies with potential drug-drug interactions.18,19 Further investigation is required to clarify the cause.

Although cancer was a significant risk factor for recurrence and bleeding in patients with VTE in previous studies,13,20 this was not a finding in the present study. The reason for these discrepant results may be the prospective design of KUROSIO. The annual all-cause mortality rate of patients in the previous retrospective studies was relatively high,13,20 whereas it was low in this prospective study because patients with poor prognoses are unlikely to be enrolled in prospective studies.

Study Limitations

This was a prospective observational study, and the type, dose, and duration of DOACs to be administered were decided by the attending physicians. The results cannot be compared between DOACs because of the small number of cases in each group and the different patient backgrounds. In addition, because patient enrollment into this prospective observational study was based on the evaluation of the attending physicians, patients with extremely poor prognoses may have been excluded, thereby potentially influencing the interpretation of the results.

This study of the efficacy and safety of DOAC treatment for patients with VTE under real-world clinical conditions in Japan revealed that the recurrence rate of VTE was similar to that of conventional heparin and warfarin treatments in Japan. The incidence of major bleeding was lower than with conventional heparin and warfarin treatments in Japan. Compared with the large-scale clinical trials of DOACs in Western countries, the recurrence rate of VTE and the incidence of major bleeding in this Japanese study were considered similar, considering the age of the enrolled patients and the proportion of those with cancer. Therefore, the efficacy and safety of DOAC treatment in Japanese patients with VTE in clinical practice were determined.

Acknowledgments

The authors appreciate the support and collaboration of the coinvestigators who participated in the KUROSIO study. The authors thank Editage (www.editage.com) for the English language editing. The authors also acknowledge the members of the KUROSIO Study Group (see Appendix).

Sources of Funding

This study was funded by Daiichi Sankyo Co., Ltd., Tokyo, Japan. The sponsor had no role in the study design, conduct, data collection and analysis, decision to publish, or manuscript preparation.

Disclosures

N.Y. received lecture fees from Bayer Yakuhin, Ltd., and Pfizer Japan Inc. K.T. is a member of Circulation Journal’s Editorial Team. K.T. received grant fees from PPD-Shin Nippon Biomedical Laboratories K.K., Alexion Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Abbott Medical Japan LLC., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., and ITI Co., Ltd.; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational event fees from Abbott Medical Japan LLC., Amgen K.K., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., Kowa Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan, Inc., and Janssen Pharmaceutical K.K.; and has other financial or non-financial interests with Abbott Japan LLC., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Corp., Nipro Corp., Terumo Corp., Abbott Medical Japan LLC., Boston Scientific Japan K.K., Cardinal Health K.K., Fides-one, Inc., FUKUDA DENSHI Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., and Medtronic Japan Co., Ltd. Masato N. reports receiving lecture fees from Daiichi Sankyo Co., Ltd., and Bayer Yakuhin, Ltd., and grant fee from Daiichi Sankyo Co., Ltd; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational event fees from Daiichi Sankyo Co., Ltd. The other authors have nothing to disclose.

IRB Information

This study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (reference no. 2942) and the institutional review boards of all participating institutions.

Data Availability

The deidentified participant data will not be shared.

Appendix

Members of the KUROSIO Study Group are listed.

Principal Investigator: Hidamarinooka Nakamura Medical Clinic: Mashio Nakamura

Research Office: Department of Cardiology, Kuwana City Medical Center: Norikazu Yamada

Steering Committee: Division of Cardiovascular Intensive Care, Nippon Medical School Hospital: Takeshi Yamamoto; Department of Cardiovascular Surgery, Fukushima Medical University Hospital, Fukushima (Japanese Red Cross Society Fukushima Hospital): Hirono Satokawa; Department of Cardiology, Musashino Red Cross Hospital: Toru Obayashi

Study Sites Recruiting at Least 1 Patient: Tohoku University Graduate School of Medicine: Michihisa Umetsu, Kumamoto University Hospital: Kenichi Tsujita, Toho University Ohashi Medical Center: Masato Nakamura, Okayama Medical Center: Atsuyuki Watanabe, Saiseikai Wakayama Hospital: Mitsuru Yuzaki, Tokushima University Hospital: Masataka Sata, Yokohama Rosai Hospital: Kazuhiko Yumoto, Nippon Medical School Hospital: Wataru Shimizu, Nagasaki University Graduate School of Biomedical Sciences: Koji Maemura, Mie University Graduate School of Medicine: Yoshito Ogihara, Saku Central Hospital Advanced Care Center: Yazaki Yoshikazu, Saiseikai Yahata General Hospital: Shinsuke Mii, National Cerebral and Cardiovascular Center: Akihiro Tsuji, Kyorin University Faculty of Medicine: Takumi Inami, International University of Health and Welfare Mita Hospital: Yuichi Tamura, Saiseikai Yokohamashi Nanbu Hospital: Tsutomu Endo, Japanese Red Cross Musashino Hospital: Toshihiro Nozato, Tokyo Metropolitan Tama Medical Center: Tomonori Miyabe, Fujisawa City Hospital: Kengo Tsukahara, Tokyo Medical University Hospital: Jun Yamashita, Kakogawa Central City Hospital: Takahiro Sawada, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai: Moriaki Inoko, Nihon University School of Medicine: Yasuo Okumura, Kansai Medical University Medical Center: Hiroyoshi Komai, Osaka Prefectural Hospital Organization Osaka International Cancer Institute: Mikio Mukai, Kokura Memorial Hospital: Kenji Ando, Medical Corporation JR Hiroshima Hospital: Hiroki Teragawa, Iwate Prefectural Central Hospital: Masanori Kanazawa, IMS Fujimi General Hospital: Takayuki Tohara, Ohara Healthcare Foundation, Kurashiki Central Hospital: Kazushige Kadota, Hamamatsu Medical Center: Naoto Yamamoto, Graduate School of Medicine, Kyoto University: Takeshi Kimura, Showa University Fujigaoka Hospital: Hiroshi I Suzuki, Hokkaido University Hospital: Takashi Yokota, Hamamatsu University School of Medicine: Naoki Unno, Fujita Health University, School of Medicine, Cardiovascular Surgery: Masayoshi Kobayashi, Saiseikai Senri Hospital: Keiji Hirooka, Yamagata Prefectural Central Hospital: Motoyuki Matsui, Toyonaka Municipal Hospital: Hironobu Fujimura, University of Tsukuba Hospital: Kazuko Tajiri, Chiba Cerebral and Cardiovascular Center: Naoki Hayashida, Kurume University School of Medicine: Shinichi Hiromatsu, Yokohama City University Medical Center: Kazuo Kimura, Aichi Medical University: Hiroyuki Ishibashi, Gifu Prefectural General Medical Center: Toshiyuki Noda, Kochi Medical School: Tatsuya Noguchi, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital: Yasuhiro Ogura, Nishinomiya Municipal Central Hospital: Tetsuya Kurimoto, National Hospital Organization Kyoto Medical Center: Masaharu Akao, Tokai University Hospital: Koichiro Asano, Jichi Medical University Hospital: Masahisa Shimpo, Kamiichi General Hospital: Masahiro Toshima, Fukushima Medical University Hospital: Hirono Satokawa, Tokai University Hachioji Hospital: Fumio Sakamaki, Nagasaki Medical Center: Kenji Kumagai, Tokyo Women’s Medical University: Nobuhisa Hagiwara, NHO Yokohama Medical Center: Fumiaki Mori, Kurume University School of Medicine: Yoshihiro Fukumoto, Tomei Atsugi Hospital Social Medical Corporation Sanshikai: Atsuo Kojima, Hirosaki University Hospital: Hirofumi Tomita, Murase Hospital: Mashio Nakamura, International University of Health and Welfare Hospital: Atsubumi Murakami, Dokkyo Medical University Nikko Medical Center: Takanori Yasu, University of Fukui Hospital: Hiroshi Tada, Nara Medical University: Masanori Yoshikawa, Toho University: Kazuhiro Shimizu, National Hospital Organization Osaka National Hospital: Tatsuhisa Ozaki.

Event Adjudication Committee: Miharadai Hospital: Yoshiyuki Miyahara; Hitachi Memorial Hospital: Shigetsugu Ohgi; Kinki Health Administration Center, Mie Division: Masakatsu Nishikawa; Mie Prefectural General Medical Center: Hideo Wada

Clinical Research Support: Clinical Research Support Center, Mie University Hospital: Satoshi Tamaru

Biostatistician: Clinical Research Support Center, Mie University Hospital: Toru Ogura

Data Management: Clinical Research Support Center, Mie University Hospital: Yuki Nishimura, Chieko Fujimoto

Audit: NPO Mie Chiken Iryo Net: Yoko Uhira

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Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism ― The Primary Results From the K … (2024)
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