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JJCC 1065 1–9 Journal of Cardiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Review
Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy Mashio Nakamura (MD, PhD, FJCC)a,b,*, Norikazu Yamada (MD, PhD)a, Masaaki Ito (MD, PhD)a a b
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan Center for Pulmonary Embolism and Venous Thrombosis, Murase Hospital, Suzuka, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 March 2015 Accepted 20 March 2015 Available online xxx
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. ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Anticoagulation Deep vein thrombosis Nonvitamin K antagonist oral anticoagulant Venous thromboembolism Pulmonary embolism
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence of venous thromboembolism in Japan . . . . . . . . . . . . . . . . . . . . . Risk factors for venous thromboembolism in Japan. . . . . . . . . . . . . . . . . . . Management and outcome of venous thromboembolism in Japan . . . . . . . Future direction of nonvitamin K antagonist oral anticoagulants in Japan . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Venous thromboembolism (VTE), manifesting as either deep vein thrombosis (DVT) or pulmonary embolism (PE), is common and results in long-term morbidity and mortality affecting >1–2 per
* Corresponding author at: Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu 514-8507, Japan. Tel.: +81 59 231 5015; fax: +81 59 231 5201. E-mail address: [email protected] (M. Nakamura).
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1000 individuals each year in the USA and Europe [1–3]. Patients with VTE have a high and persistent risk of recurrence, including nonfatal and fatal PE. The cumulative incidence of recurrent VTE is estimated to be at least 10% at 1 year and 30% at 5 years following withdrawal of anticoagulant therapy [4]. Several clinical guidelines for VTE have been published in the USA and Europe including the ‘‘2014 ESC (European Society of Cardiology) Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism’’ [5], ‘‘Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012)’’
http://dx.doi.org/10.1016/j.jjcc.2015.03.012 0914-5087/ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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M. Nakamura et al. / Journal of Cardiology xxx (2015) xxx–xxx
parenteral and oral anticoagulant therapies overcome some limitations of standard therapy, including the need for injection and regular dose adjustments resulting from laboratory monitoring [9–13]. Recently, fondaparinux and edoxaban have been approved as alternative therapeutic options to UFH and warfarin in Japan and are expected to improve the prognosis of VTE. The objective of this review is to discuss current VTE epidemiology and advances in anticoagulant therapy in Japan to provide a perspective on the clinical management of VTE. Incidence of venous thromboembolism in Japan
Fig. 1. Changes in the number of clinically diagnosed cases of pulmonary embolism in Japan over time. Information compiled from Refs. [14–18].
[6], and ‘‘Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association (2012)’’ [7]. Concurrently, because of increased prevalence of venous thromboembolic risk factors through continued westernization of Japanese life and an aging society, the medical and social impacts of VTE have recently received increased attention. The first Japanese guidelines for the treatment of VTE were published in 2004 and revised in 2009 [8]. However, several recommendations were not supported by clinical evidence from Japanese patients, and data regarding real-world practice and guideline compliance are lacking. Anticoagulant therapy is the cornerstone of VTE treatment. Standard anticoagulation treatment in Japan involves the use of unfractionated heparin (UFH), overlapped and followed by warfarin. Because of the need for frequent monitoring to assess bleeding risk, the efficacy of UFH and warfarin is often questioned, despite limited data on VTE treatment in Japanese patients. New
Fig. 1 shows the number of clinically diagnosed PE cases in Japan measured by questionnaire surveys [14–18]. The number of patients with PE has increased 4.6-fold in the past 15 years with the annual incidence estimated to be 126 per 1,000,000 people in Japan in 2011. In contrast, as shown in Fig. 2, survey results from the Japanese Society of Anesthesiologists demonstrate that the incidence of postoperative PE significantly decreased from 2004 when Japanese VTE prophylaxis guidelines were published [19]. The proportions of PE occurring in hospital were 51% and 30% in 2000–2003 and 2011, respectively (Fig. 3A) [18,20]. Submassive and nonmassive severity types of PE were the most frequently diagnosed in 2000–2003 and 2011, respectively (Fig. 3B) [18,20]. In addition, an isolated calf vein thrombosis was recently found to be the most common diagnosed form of DVT (Fig. 3C) [18]. These results indicate that the number of VTE diagnoses occurring out-of-hospital and milder severities of VTE appear to be rapidly increasing in Japan. This change may be because of improved diagnostic accuracy resulting from rising awareness among medical staff, increased recognition of VTE, and advances in imaging modalities. Risk factors for venous thromboembolism in Japan Multiple risk factors, including genetic and acquired, or environmental, risk factors, are involved in the development of VTE. The Japan VTE Treatment Registry (JAVA) study is a nationwide, observational, multicenter, Japanese cohort study of consecutive patients with objectively-confirmed symptomatic PE,
Fig. 2. Relative risk of perioperative symptomatic pulmonary embolism based on the 2002 incidence in Japan. Error bars represent 95% confidential intervals. **p < 0.01 vs. 2002, yp < 0.01 vs. 2006. From Kuroiwa et al. [19] with permission.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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JJCC 1065 1–9 M. Nakamura et al. / Journal of Cardiology xxx (2015) xxx–xxx
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Fig. 3. Clinical images of venous thromboembolism in Japan. (A) Site of pulmonary embolism development (in-hospital or out-of-hospital). Information for the years 2000– 2003 and 2011 was compiled from Nakamura et al. [20] and Ota et al. [18], respectively. (B) Distribution of pulmonary embolism severity. Information for the years 2000– 2003 and 2011 was compiled from Nakamura et al. [20] and Ota et al. [18], respectively. (C) Graph representing proximal venous thrombus development. Information was compiled from Ota et al. [18]. There was distribution of deep vein thrombosis severity.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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JJCC 1065 1–9 M. Nakamura et al. / Journal of Cardiology xxx (2015) xxx–xxx
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symptomatic DVT, or asymptomatic proximal DVT treated between April 2009 and March 2010 that retrospectively identified 1076 patients with VTE [21]. This registry revealed recent trends in risk factor prevalence in Japan (Table 1). A history of recent surgery was reported in 17.8% of VTE cases. Postoperative VTE has been significantly decreased as a result of in-hospital thromboprophylaxis. Among risk factors for VTE, a medical history of cancer was found to be the most prevalent at 27.0% in VTE patients. An increased mortality rate was observed in patients with cancer (30.3% per patient-year) than in those without cancer (3.7% per patient-year). These cancer patients were found to be more likely to have received subtherapeutic durations or levels of anticoagulation because of concerns regarding bleeding complications and the association between warfarin initiation and improved prognosis in cancer patients. Approximately three-quarters of the deaths occurred in patients with a history of cancer at the time of VTE diagnosis. Consequently, improving VTE management in patients with cancer may lead to an overall decrease in all-cause mortality in patients diagnosed with VTE. One of the most notable findings of the JAVA study was the observation that 43.2% of all registered VTEs were considered ‘‘idiopathic’’ or ‘‘unprovoked’’ without an associated trigger or an identified chronic risk factor. The major inheritable risk factors in the Japanese population are the K196E mutation of protein S (protein S Tokushima) and deficiencies in protein C, protein S, and antithrombin [22,23]. Factor V Leiden and prothrombin G20210A gene mutation associated with VTE are highly prevalent in Caucasian populations but virtually nonexistent in the Japanese population [24]. Conversely, protein S Tokushima is observed exclusively in Japanese populations [25]. These genetic differences may be one explanation for ethnic variability in the observed incidence of VTE. Indefinite anticoagulation may be required in cancer patients with VTE, patients with unprovoked VTE, and VTE patients with inheritable risk factors. Management and outcome of venous thromboembolism in Japan Fig. 4 shows an example of a treatment algorithm for PE from the second Japanese guidelines for the diagnosis, treatment, and Table 1 Risk factors of venous thromboembolism. Risk factor
Obesity (BMI 30) Recent surgery (within 3 months) Cancer Heart disease Respiratory disease Severe infection Severe injury Fracture Cesarean delivery (within 14 days) History of VTE Thrombophilia Lower limb paresis Varicosis Estrogen and/or HRT Central venous catheter Immobilization
Overall n = 1076 (100%)
PE with or without DVT n = 338 (31.4%)
DVT alone n = 738 (68.6%)
59 (5.5) 192 (17.8)
23 (6.8) 56 (16.6)
36 (4.9) 136 (18.4)
290 72 49 30 7 49 3
(27.0) (6.7) (4.6) (2.8) (0.7) (4.6) (0.3)
78 22 19 8 3 14 3
(23.1) (6.5) (5.6) (2.4) (0.9) (4.1) (0.9)
212 50 30 22 4 35 0
(28.7) (6.8) (4.1) (3.0) (0.5) (4.7) (0.0)
66 44 32 45 28 43 225
(6.1) (4.1) (3.0) (4.2) (2.6) (4.0) (20.9)
21 12 10 11 8 8 65
(6.2) (3.6) (3.0) (3.3) (2.4) (2.4) (19.2)
45 32 22 34 20 35 160
(6.1) (4.3) (3.0) (4.6) (2.7) (4.7) (21.7)
From Ref. [21] with permission. Data given as n (%). BMI, body mass index; DVT, deep vein thrombosis; PE, pulmonary embolism; HRT, hormone replacement therapy; VTE, venous thromboembolism.
prevention of pulmonary embolism and deep vein thrombosis issued in 2009 [8]. Anticoagulation is recommended as first-line therapy for treating VTE as in the USA and Europe. In addition, thrombolysis or vena cava filter insertion is performed depending on hemodynamic state and extent of venous thrombus. Fig. 5 shows changes in treatment approaches for PE in Japan [20,26–28]. PE management in Japan frequently involves thrombolysis with a high rate of vena cava filter insertion, despite low recommendation levels for these treatment procedures in the USA and Europe. Until the spring of 2011, the standard anticoagulation treatment in Japan for the acute phase of VTE involved intravenous UFH, with routine monitoring of activated partial thromboplastin time (aPTT) for dose adjustment followed by long-term administration of warfarin. One downside of UFH is the necessity for aPTT monitoring by frequent blood sampling. For this reason, dose adjustments based on aPTT were subtherapeutic (aPTT 1.5) in almost 40% of cases in Japanese clinical practice (Table 2). The use of low-molecular-weight heparin (LMWH) to overcome the limitations of UFH was already a standard practice in the USA and Europe 20 years ago, whereas LMWH has yet to be approved for the treatment of VTE in Japan [29]. Fondaparinux [30], a synthetic inhibitor of the coagulation factor Xa, was approved as an alternative to UFH for the treatment of acute VTE in spring of 2011 in Japan, despite being approved in the USA and Europe in 2004. Fondaparinux acts by selectively inhibiting factor Xa activity by specifically binding to antithrombin. Unlike UFH, fondaparinux does not inhibit thrombin activity. The selective inhibition of factor Xa upstream of thrombin enables efficient inhibition of the coagulation response without increasing bleeding risk. Fondaparinux is subcutaneously administered once daily and does not require dose adjustments or monitoring of coagulation parameters. Two large randomized clinical trials of fondaparinux in the USA and Europe, MATISSE PE [9], an open-labeled trial involving patients with PE, and MATISSE DVT [31], a double-blind trial involving those with DVT, demonstrated noninferiority of fondaparinux to UFH and LMWH, respectively. The safety and efficacy of fondaparinux has also been examined in a small number of Japanese patients. This study suggested that once-daily, subcutaneous fondaparinux without monitoring was as effective and safe as adjusted-dose intravenous UFH for the initial treatment of VTE in Japanese patients [32]. To prevent recurrent VTE, warfarin therapy after parenteral anticoagulant therapy was recommended in the 2009 Japanese guidelines [8]. The duration of warfarin therapy is recommended to be 3 months in patients with reversible risk factors and at least 3 months in patients with congenital coagulopathy and those with idiopathic VTE. Furthermore, warfarin should be administered for an increased duration in patients with cancer and those with recurrent VTE. The recommended target prothrombin time–international normalized ratio (PT–INR) for VTE based on the Japanese guidelines is 2.0 (range, 1.5–2.5), lower than the target value (PT–INR, 2.5; range, 2.0–3.0) used in the USA and Europe [33]. In the JAVA study [21] described above, Japanese clinicians used warfarin for an average of 6–7 months, despite the 2004 Japanese guidelines recommending at least 6 months of warfarin usage, with a target PT–INR in the range of 1.5–2.5 in most cases (Table 2). The estimated annual incidence of recurrent VTE was 3.6% and the incidence rate was 4.0 per 100 patient-years in Kaplan–Meier analyses reported for the JAVA study. However, the incidence rate was 8.1 per 100 patient-years following completion of warfarin therapy, while the incidence rate was 2.8 per 100 patient-years during warfarin therapy (Fig. 6) [34]. The subsequent incidence rates for all types of bleeding and major bleeding were 8.2% and 3.3% per patient-year, respectively, in this registry. Therefore, the continued use of warfarin for prolonged periods becomes difficult to justify when considering the benefit–risk ratio.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Fig. 4. An example treatment algorithm for pulmonary embolism from the second Japanese guidelines for the diagnosis, treatment, and prevention of pulmonary embolism and deep vein thrombosis. *1 When risk of bleeding is high. *2 Treat complications appropriately with available methods. *3 Unstable hemodynamics consistent with shock or prolonged hypotension. *4 Condition requiring cardiopulmonary resuscitation or prolonged severe shock. *5 Consider PCPS according to hospital equipment and patient condition. *6 Select appropriate treatment according to hospital equipment and patient condition. *7 Evaluate based on right ventricular enlargement on echocardiography and severity of pulmonary hypertension. *8 Presence/absence of DVT, which may have serious effects upon release of emboli causing recurrent embolism. The above algorithm is an example. Each institution should select appropriate methods according to its healthcare resources. DVT, deep vein thrombosis; PCPS, percutaneous cardiopulmonary support; IVC, inferior vena cava. From JCS Joint Working Group [8] with permission.
The limitations of warfarin have stimulated the development of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of VTE [10–13] among other indications. NOACs directly inhibit either Factor Xa or thrombin. In contrast to conventional warfarin, these agents have a rapid onset of action, shorter half-life, and fewer drug interactions with no necessity for routine monitoring when administered in fixed doses. For these reasons, NOACs can be used as replacements of parenteral anticoagulants and warfarin for initial, long-term, and extended VTE treatment.
In Japan, edoxaban, a once-daily, oral, direct factor Xa inhibitor, was approved in September 2014 for the treatment of VTE based on the result of the Hokusai–VTE trial [13]. The Hokusai–VTE trial was a randomized, multinational, double-blind, noninferiority study that evaluated the efficacy and safety of heparin followed by edoxaban 60 mg once daily or edoxaban 30 mg once daily in patients with a creatinine clearance of 30–50 ml per minute, body weight of 60 kg, or in patients who were receiving concomitant treatment with potent P-glycoprotein inhibitors against heparin overlapped with and followed by warfarin. Hokusai–VTE demonstrated that
Fig. 5. Changes in pulmonary embolism management in Japan over time. Information from 94.01-06.08 compiled from Refs. [20,26–28]. Information for the year 2011 compiled from Ref. [18].
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Table 2 Antithrombotic management (acute and chronic phases). Overall n = 1076 Thrombolytic Urokinase tPA Parenteral anticoagulant UFH aPTT 3 LMWH Warfarin Duration (months) Target INR 2.5 NA
225 163 63 908 864
(20.9) (71.8) (27.8) (84.4) (80.3)
PE with or without DVT n = 338 87 41 47 302 293
(25.7) (47.1) (54.0) (89.3) (86.7)
Future direction of nonvitamin K antagonist oral anticoagulants in Japan DVT alone n = 738 138 122 16 606 571
(18.7) (87.1) (11.4) (82.1) (77.4)
268 (37.6) 438 (61.4) 7 (1.0) 45 (4.2) 956 (88.8) 7 4.8
91 (35.4) 166 (64.6) 0 (0.0) 10 (3.0) 305 (90.2) 6.4 5.0
177 (38.8) 272 (59.6) 7 (1.5) 35 (4.7) 651 (88.2) 7.3 4.7
65 812 49 30
19 253 22 11
46 559 27 19
(6.8) (84.9) (5.1) (3.1)
(6.2) (83.0) (7.2) (3.7)
(7.1) (85.9) (4.1) (2.9)
From Ref. [21] with permission. Data given as n (%) or mean SD. DVT, deep vein thrombosis; PE, pulmonary embolism; aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecularweight heparin; NA, not available (INR performed but unknown or not measured); tPA, tissue plasminogen activator; UFH, unfractionated heparin.
edoxaban following initial heparin treatment was noninferior to the standard of care; heparin overlapped with and was followed by warfarin, and was associated with significantly fewer bleeding events in a broad spectrum of patients with VTE (Fig. 7). The results of a regional subanalysis of Hokusai–VTE examining East Asia, including the Japanese population, were consistent with the overall study [35]. There have been concerns regarding the use of NOACs causing a higher risk of bleeding among patients with renal impairment and low body weight. Japanese VTE patients appeared to be older with impaired creatinine clearance and a lower body weight (2-fold more likely to experience a recurrent event compared with those with isolated DVT (Fig. 8) [21]. Half of these events occurred within 3 months and became rarer after 6 months. However, the 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism state that patients with low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided [5]. More data are required to evaluate the efficacy and safety of NOACs for the initial treatment of PE. Despite this, transition and maintenance on NOACs may be more effective than with warfarin, when patients are initially treated with UFH or fondaparinux. Initial treatment of DVT without a heparin lead-in for outpatient therapy is thought to be a valid indication for the use of NOACs. However, there is currently a lack of data available to accurately determine the efficacy and safety of initiating edoxaban immediately at VTE presentation. A number of trials have indicated that home treatment is not associated with an increase in mortality, recurrent VTE, or major bleeding and may be associated
with improved outcomes [37,38]. From these data, the 2012 ACCP guidelines state that in patients with DVT of the leg and whose home circumstances are adequate, initial treatment at home is recommended over in-hospital treatment [6]. As noted above, the management of isolated distal DVT remains controversial, despite being a common occurrence [39,40]. Guidelines [6] suggest that in patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, serial imaging of the deep veins should be conducted over 2 weeks from initial anticoagulation. NOACs are safer than warfarin; therefore, their use in the management of isolated distal DVT may prove beneficial, despite the majority of isolated distal DVTs not requiring anticoagulation. Finally, the suitability of NOACs for the treatment of VTE in fragile patients, including those with very low body weight, pregnant women, and those with serious thrombophilia, has not been established. There are no validated tests allowing assessment of the antithrombotic effect of NOACs. The management of bleeding complications resulting from the use of NOACs requires a rapid and safe reversal agent for factor Xa or thrombin inhibition.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Fig. 8. Cumulative incidence of recurrent venous thromboembolism according to entry diagnosis in the JAVA study. Symptomatic PE with or without DVT (red line) or DVT alone (blue line). The risk of recurrence was significantly higher in patients with an initial diagnosis of PE (with or without DVT) than in those with isolated DVT (Cox proportional hazard analysis). DVT, deep vein thrombosis; PE, pulmonary embolism; JAVA, Japan VTE Treatment Registry. From Ref. [21] with permission.
Therefore, further studies are required to increase the utility of NOACs in the treatment of VTE. [5]
Conclusions This review summarizes the current status of VTE management in Japan with a focus on current epidemiology and advances in anticoagulant therapy. The number of clinically diagnosed cases of VTE continues to increase, with the majority cases of mild severity where decisions regarding treatment options are most controversial. The largest risk factor for VTE is cancer; however, unprovoked VTE is much more prevalent. Prolonged warfarin therapy is challenging in patients with cancer and unprovoked VTE. Recently, novel anticoagulant agents fondaparinux and edoxaban have been approved in Japan. These agents have the potential to provide more convenient and beneficial treatment options for VTE because they are both safer and more effective than current therapies. Although further randomized studies are required to fully validate the utility of these agents, they are expected to improve the quality of life of patients with VTE.
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Disclosures [10]
M. Nakamura has received remuneration from Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited. N. Yamada has received remuneration from Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited. M. Ito has received remuneration from Daiichi Sankyo Company, Limited, Mochida Pharmaceutical Co., Ltd., and scholarship funds from Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Pfizer Inc. References [1] Anderson FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol 2007;82:777–82. [2] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M, VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98:756–64. [3] Liao S, Woulfe T, Hyder S, Merriman E, Simpson D, Chunilal S. Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb Haemost 2014;12:214–9. [4] Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A. The risk of recurrent venous thromboembolism
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JJCC 1065 1–9 M. Nakamura et al. / Journal of Cardiology xxx (2015) xxx–xxx [18] Ota M, Yamada N, Matsuda A, Ogiwara Y, Ishikura K, Nakamura M, Ito M. The feature of deep vein thrombosis causing pulmonary thromboembolism – national survey in Japan. In: 78th annual scientific meeting of Japanese Circulation Society; 2014. OE-397. [19] Kuroiwa M, Morimatsu H, Tsuzaki K, Irita K, Sanuki M, Nakatsuka H, Nakamura M. 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. J Anesth 2014 [Epub ahead of print]. [20] Nakamura M, Fujioka H, Yamada N, Sakuma M, Okada O, Nakanishi N, Miyahara Y, Kuriyama T, Kunieda T, Sugimoto T, Nakano T. Clinical characteristics of acute pulmonary thromboembolism in Japan: results of a multicenter registry in the Japanese Society of Pulmonary Embolism Research. Clin Cardiol 2001;24:132–8. [21] Nakamura M, Miyata T, Ozeki Y, Takayama M, Komori K, Yamada N, Origasa H, Satokawa H, Maeda H, Tanabe N, Unno N, Shibuya T, Tanemoto K, Kondo K, Kojima T. Current venous thromboembolism management and outcomes in Japan. Circ J 2014;78:708–17. [22] Kinoshita S, Iida H, Inoue S, Watanabe K, Kurihara M, Wada Y, Tsuda H, Kang D, Hamasaki N. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem 2005;38:908–15. [23] Miyata T, Kimura R, Kokubo Y, Sakata T. Genetic risk factors for deep vein thrombosis among Japanese: importance of protein S K196E mutation. Int J Hematol 2006;83:217–23. [24] Ro A, Hara M, Takada A. The factor V Leiden mutation and the prothrombin G20210A mutation was not found in Japanese patients with pulmonary thromboembolism. Thromb Haemost 1999;82:1769. [25] Liu W, Yin T, Okuda H, Harada KH, Li Y, Xu B, Yang J, Wang H, Fan X, Koizumi A, Miyata T. Protein S K196E mutation, a genetic risk factor for venous thromboembolism, is limited to Japanese. Thromb Res 2013;132:314–5. [26] Sakuma M, Nakamura M, Nakanishi N, Miyahara Y, Tanabe N, Yamada N, Kuriyama T, Kunieda T, Sugimoto T, Nakano T, Shirato K. Inferior vena cava filter is a new additional therapeutic option to reduce mortality from acute pulmonary embolism. Circ J 2004;68:816–21. [27] Sakuma M, Nakamura M, Nakanishi N, Miyahara Y, Tanabe N, Yamada N, Kuriyama T, Kunieda T, Sugimoto T, Nakano T, Shirato K. Clinical characteristics, diagnosis and management of patients with pulmonary thromboembolism who are not diagnosed in the acute phase and not classified as chronic thromboembolic pulmonary hypertension. Circ J 2005;69:1009–15. [28] Sakuma M, Nakamura M, Nakanishi N, Miyahara Y, Tanabe N, Yamada N, Kuriyama T, Kunieda T, Sugimoto T, Nakano T, Shirato K. Kyuseihaisokusensho no shindan to chiryo Diagnosis and therapy of acute pulmonary embolism Ther Res 2007;28:130–1. [29] Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2010;(9). CD001100.
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JJCC 1065 1–9 Journal of Cardiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
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Review
Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy Mashio Nakamura (MD, PhD, FJCC)a,b,*, Norikazu Yamada (MD, PhD)a, Masaaki Ito (MD, PhD)a a b
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan Center for Pulmonary Embolism and Venous Thrombosis, Murase Hospital, Suzuka, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 March 2015 Accepted 20 March 2015 Available online xxx
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. ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Anticoagulation Deep vein thrombosis Nonvitamin K antagonist oral anticoagulant Venous thromboembolism Pulmonary embolism
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence of venous thromboembolism in Japan . . . . . . . . . . . . . . . . . . . . . Risk factors for venous thromboembolism in Japan. . . . . . . . . . . . . . . . . . . Management and outcome of venous thromboembolism in Japan . . . . . . . Future direction of nonvitamin K antagonist oral anticoagulants in Japan . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Venous thromboembolism (VTE), manifesting as either deep vein thrombosis (DVT) or pulmonary embolism (PE), is common and results in long-term morbidity and mortality affecting >1–2 per
* Corresponding author at: Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu 514-8507, Japan. Tel.: +81 59 231 5015; fax: +81 59 231 5201. E-mail address: [email protected] (M. Nakamura).
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1000 individuals each year in the USA and Europe [1–3]. Patients with VTE have a high and persistent risk of recurrence, including nonfatal and fatal PE. The cumulative incidence of recurrent VTE is estimated to be at least 10% at 1 year and 30% at 5 years following withdrawal of anticoagulant therapy [4]. Several clinical guidelines for VTE have been published in the USA and Europe including the ‘‘2014 ESC (European Society of Cardiology) Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism’’ [5], ‘‘Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012)’’
http://dx.doi.org/10.1016/j.jjcc.2015.03.012 0914-5087/ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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parenteral and oral anticoagulant therapies overcome some limitations of standard therapy, including the need for injection and regular dose adjustments resulting from laboratory monitoring [9–13]. Recently, fondaparinux and edoxaban have been approved as alternative therapeutic options to UFH and warfarin in Japan and are expected to improve the prognosis of VTE. The objective of this review is to discuss current VTE epidemiology and advances in anticoagulant therapy in Japan to provide a perspective on the clinical management of VTE. Incidence of venous thromboembolism in Japan
Fig. 1. Changes in the number of clinically diagnosed cases of pulmonary embolism in Japan over time. Information compiled from Refs. [14–18].
[6], and ‘‘Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association (2012)’’ [7]. Concurrently, because of increased prevalence of venous thromboembolic risk factors through continued westernization of Japanese life and an aging society, the medical and social impacts of VTE have recently received increased attention. The first Japanese guidelines for the treatment of VTE were published in 2004 and revised in 2009 [8]. However, several recommendations were not supported by clinical evidence from Japanese patients, and data regarding real-world practice and guideline compliance are lacking. Anticoagulant therapy is the cornerstone of VTE treatment. Standard anticoagulation treatment in Japan involves the use of unfractionated heparin (UFH), overlapped and followed by warfarin. Because of the need for frequent monitoring to assess bleeding risk, the efficacy of UFH and warfarin is often questioned, despite limited data on VTE treatment in Japanese patients. New
Fig. 1 shows the number of clinically diagnosed PE cases in Japan measured by questionnaire surveys [14–18]. The number of patients with PE has increased 4.6-fold in the past 15 years with the annual incidence estimated to be 126 per 1,000,000 people in Japan in 2011. In contrast, as shown in Fig. 2, survey results from the Japanese Society of Anesthesiologists demonstrate that the incidence of postoperative PE significantly decreased from 2004 when Japanese VTE prophylaxis guidelines were published [19]. The proportions of PE occurring in hospital were 51% and 30% in 2000–2003 and 2011, respectively (Fig. 3A) [18,20]. Submassive and nonmassive severity types of PE were the most frequently diagnosed in 2000–2003 and 2011, respectively (Fig. 3B) [18,20]. In addition, an isolated calf vein thrombosis was recently found to be the most common diagnosed form of DVT (Fig. 3C) [18]. These results indicate that the number of VTE diagnoses occurring out-of-hospital and milder severities of VTE appear to be rapidly increasing in Japan. This change may be because of improved diagnostic accuracy resulting from rising awareness among medical staff, increased recognition of VTE, and advances in imaging modalities. Risk factors for venous thromboembolism in Japan Multiple risk factors, including genetic and acquired, or environmental, risk factors, are involved in the development of VTE. The Japan VTE Treatment Registry (JAVA) study is a nationwide, observational, multicenter, Japanese cohort study of consecutive patients with objectively-confirmed symptomatic PE,
Fig. 2. Relative risk of perioperative symptomatic pulmonary embolism based on the 2002 incidence in Japan. Error bars represent 95% confidential intervals. **p < 0.01 vs. 2002, yp < 0.01 vs. 2006. From Kuroiwa et al. [19] with permission.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Fig. 3. Clinical images of venous thromboembolism in Japan. (A) Site of pulmonary embolism development (in-hospital or out-of-hospital). Information for the years 2000– 2003 and 2011 was compiled from Nakamura et al. [20] and Ota et al. [18], respectively. (B) Distribution of pulmonary embolism severity. Information for the years 2000– 2003 and 2011 was compiled from Nakamura et al. [20] and Ota et al. [18], respectively. (C) Graph representing proximal venous thrombus development. Information was compiled from Ota et al. [18]. There was distribution of deep vein thrombosis severity.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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symptomatic DVT, or asymptomatic proximal DVT treated between April 2009 and March 2010 that retrospectively identified 1076 patients with VTE [21]. This registry revealed recent trends in risk factor prevalence in Japan (Table 1). A history of recent surgery was reported in 17.8% of VTE cases. Postoperative VTE has been significantly decreased as a result of in-hospital thromboprophylaxis. Among risk factors for VTE, a medical history of cancer was found to be the most prevalent at 27.0% in VTE patients. An increased mortality rate was observed in patients with cancer (30.3% per patient-year) than in those without cancer (3.7% per patient-year). These cancer patients were found to be more likely to have received subtherapeutic durations or levels of anticoagulation because of concerns regarding bleeding complications and the association between warfarin initiation and improved prognosis in cancer patients. Approximately three-quarters of the deaths occurred in patients with a history of cancer at the time of VTE diagnosis. Consequently, improving VTE management in patients with cancer may lead to an overall decrease in all-cause mortality in patients diagnosed with VTE. One of the most notable findings of the JAVA study was the observation that 43.2% of all registered VTEs were considered ‘‘idiopathic’’ or ‘‘unprovoked’’ without an associated trigger or an identified chronic risk factor. The major inheritable risk factors in the Japanese population are the K196E mutation of protein S (protein S Tokushima) and deficiencies in protein C, protein S, and antithrombin [22,23]. Factor V Leiden and prothrombin G20210A gene mutation associated with VTE are highly prevalent in Caucasian populations but virtually nonexistent in the Japanese population [24]. Conversely, protein S Tokushima is observed exclusively in Japanese populations [25]. These genetic differences may be one explanation for ethnic variability in the observed incidence of VTE. Indefinite anticoagulation may be required in cancer patients with VTE, patients with unprovoked VTE, and VTE patients with inheritable risk factors. Management and outcome of venous thromboembolism in Japan Fig. 4 shows an example of a treatment algorithm for PE from the second Japanese guidelines for the diagnosis, treatment, and Table 1 Risk factors of venous thromboembolism. Risk factor
Obesity (BMI 30) Recent surgery (within 3 months) Cancer Heart disease Respiratory disease Severe infection Severe injury Fracture Cesarean delivery (within 14 days) History of VTE Thrombophilia Lower limb paresis Varicosis Estrogen and/or HRT Central venous catheter Immobilization
Overall n = 1076 (100%)
PE with or without DVT n = 338 (31.4%)
DVT alone n = 738 (68.6%)
59 (5.5) 192 (17.8)
23 (6.8) 56 (16.6)
36 (4.9) 136 (18.4)
290 72 49 30 7 49 3
(27.0) (6.7) (4.6) (2.8) (0.7) (4.6) (0.3)
78 22 19 8 3 14 3
(23.1) (6.5) (5.6) (2.4) (0.9) (4.1) (0.9)
212 50 30 22 4 35 0
(28.7) (6.8) (4.1) (3.0) (0.5) (4.7) (0.0)
66 44 32 45 28 43 225
(6.1) (4.1) (3.0) (4.2) (2.6) (4.0) (20.9)
21 12 10 11 8 8 65
(6.2) (3.6) (3.0) (3.3) (2.4) (2.4) (19.2)
45 32 22 34 20 35 160
(6.1) (4.3) (3.0) (4.6) (2.7) (4.7) (21.7)
From Ref. [21] with permission. Data given as n (%). BMI, body mass index; DVT, deep vein thrombosis; PE, pulmonary embolism; HRT, hormone replacement therapy; VTE, venous thromboembolism.
prevention of pulmonary embolism and deep vein thrombosis issued in 2009 [8]. Anticoagulation is recommended as first-line therapy for treating VTE as in the USA and Europe. In addition, thrombolysis or vena cava filter insertion is performed depending on hemodynamic state and extent of venous thrombus. Fig. 5 shows changes in treatment approaches for PE in Japan [20,26–28]. PE management in Japan frequently involves thrombolysis with a high rate of vena cava filter insertion, despite low recommendation levels for these treatment procedures in the USA and Europe. Until the spring of 2011, the standard anticoagulation treatment in Japan for the acute phase of VTE involved intravenous UFH, with routine monitoring of activated partial thromboplastin time (aPTT) for dose adjustment followed by long-term administration of warfarin. One downside of UFH is the necessity for aPTT monitoring by frequent blood sampling. For this reason, dose adjustments based on aPTT were subtherapeutic (aPTT 1.5) in almost 40% of cases in Japanese clinical practice (Table 2). The use of low-molecular-weight heparin (LMWH) to overcome the limitations of UFH was already a standard practice in the USA and Europe 20 years ago, whereas LMWH has yet to be approved for the treatment of VTE in Japan [29]. Fondaparinux [30], a synthetic inhibitor of the coagulation factor Xa, was approved as an alternative to UFH for the treatment of acute VTE in spring of 2011 in Japan, despite being approved in the USA and Europe in 2004. Fondaparinux acts by selectively inhibiting factor Xa activity by specifically binding to antithrombin. Unlike UFH, fondaparinux does not inhibit thrombin activity. The selective inhibition of factor Xa upstream of thrombin enables efficient inhibition of the coagulation response without increasing bleeding risk. Fondaparinux is subcutaneously administered once daily and does not require dose adjustments or monitoring of coagulation parameters. Two large randomized clinical trials of fondaparinux in the USA and Europe, MATISSE PE [9], an open-labeled trial involving patients with PE, and MATISSE DVT [31], a double-blind trial involving those with DVT, demonstrated noninferiority of fondaparinux to UFH and LMWH, respectively. The safety and efficacy of fondaparinux has also been examined in a small number of Japanese patients. This study suggested that once-daily, subcutaneous fondaparinux without monitoring was as effective and safe as adjusted-dose intravenous UFH for the initial treatment of VTE in Japanese patients [32]. To prevent recurrent VTE, warfarin therapy after parenteral anticoagulant therapy was recommended in the 2009 Japanese guidelines [8]. The duration of warfarin therapy is recommended to be 3 months in patients with reversible risk factors and at least 3 months in patients with congenital coagulopathy and those with idiopathic VTE. Furthermore, warfarin should be administered for an increased duration in patients with cancer and those with recurrent VTE. The recommended target prothrombin time–international normalized ratio (PT–INR) for VTE based on the Japanese guidelines is 2.0 (range, 1.5–2.5), lower than the target value (PT–INR, 2.5; range, 2.0–3.0) used in the USA and Europe [33]. In the JAVA study [21] described above, Japanese clinicians used warfarin for an average of 6–7 months, despite the 2004 Japanese guidelines recommending at least 6 months of warfarin usage, with a target PT–INR in the range of 1.5–2.5 in most cases (Table 2). The estimated annual incidence of recurrent VTE was 3.6% and the incidence rate was 4.0 per 100 patient-years in Kaplan–Meier analyses reported for the JAVA study. However, the incidence rate was 8.1 per 100 patient-years following completion of warfarin therapy, while the incidence rate was 2.8 per 100 patient-years during warfarin therapy (Fig. 6) [34]. The subsequent incidence rates for all types of bleeding and major bleeding were 8.2% and 3.3% per patient-year, respectively, in this registry. Therefore, the continued use of warfarin for prolonged periods becomes difficult to justify when considering the benefit–risk ratio.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Fig. 4. An example treatment algorithm for pulmonary embolism from the second Japanese guidelines for the diagnosis, treatment, and prevention of pulmonary embolism and deep vein thrombosis. *1 When risk of bleeding is high. *2 Treat complications appropriately with available methods. *3 Unstable hemodynamics consistent with shock or prolonged hypotension. *4 Condition requiring cardiopulmonary resuscitation or prolonged severe shock. *5 Consider PCPS according to hospital equipment and patient condition. *6 Select appropriate treatment according to hospital equipment and patient condition. *7 Evaluate based on right ventricular enlargement on echocardiography and severity of pulmonary hypertension. *8 Presence/absence of DVT, which may have serious effects upon release of emboli causing recurrent embolism. The above algorithm is an example. Each institution should select appropriate methods according to its healthcare resources. DVT, deep vein thrombosis; PCPS, percutaneous cardiopulmonary support; IVC, inferior vena cava. From JCS Joint Working Group [8] with permission.
The limitations of warfarin have stimulated the development of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of VTE [10–13] among other indications. NOACs directly inhibit either Factor Xa or thrombin. In contrast to conventional warfarin, these agents have a rapid onset of action, shorter half-life, and fewer drug interactions with no necessity for routine monitoring when administered in fixed doses. For these reasons, NOACs can be used as replacements of parenteral anticoagulants and warfarin for initial, long-term, and extended VTE treatment.
In Japan, edoxaban, a once-daily, oral, direct factor Xa inhibitor, was approved in September 2014 for the treatment of VTE based on the result of the Hokusai–VTE trial [13]. The Hokusai–VTE trial was a randomized, multinational, double-blind, noninferiority study that evaluated the efficacy and safety of heparin followed by edoxaban 60 mg once daily or edoxaban 30 mg once daily in patients with a creatinine clearance of 30–50 ml per minute, body weight of 60 kg, or in patients who were receiving concomitant treatment with potent P-glycoprotein inhibitors against heparin overlapped with and followed by warfarin. Hokusai–VTE demonstrated that
Fig. 5. Changes in pulmonary embolism management in Japan over time. Information from 94.01-06.08 compiled from Refs. [20,26–28]. Information for the year 2011 compiled from Ref. [18].
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Table 2 Antithrombotic management (acute and chronic phases). Overall n = 1076 Thrombolytic Urokinase tPA Parenteral anticoagulant UFH aPTT 3 LMWH Warfarin Duration (months) Target INR 2.5 NA
225 163 63 908 864
(20.9) (71.8) (27.8) (84.4) (80.3)
PE with or without DVT n = 338 87 41 47 302 293
(25.7) (47.1) (54.0) (89.3) (86.7)
Future direction of nonvitamin K antagonist oral anticoagulants in Japan DVT alone n = 738 138 122 16 606 571
(18.7) (87.1) (11.4) (82.1) (77.4)
268 (37.6) 438 (61.4) 7 (1.0) 45 (4.2) 956 (88.8) 7 4.8
91 (35.4) 166 (64.6) 0 (0.0) 10 (3.0) 305 (90.2) 6.4 5.0
177 (38.8) 272 (59.6) 7 (1.5) 35 (4.7) 651 (88.2) 7.3 4.7
65 812 49 30
19 253 22 11
46 559 27 19
(6.8) (84.9) (5.1) (3.1)
(6.2) (83.0) (7.2) (3.7)
(7.1) (85.9) (4.1) (2.9)
From Ref. [21] with permission. Data given as n (%) or mean SD. DVT, deep vein thrombosis; PE, pulmonary embolism; aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecularweight heparin; NA, not available (INR performed but unknown or not measured); tPA, tissue plasminogen activator; UFH, unfractionated heparin.
edoxaban following initial heparin treatment was noninferior to the standard of care; heparin overlapped with and was followed by warfarin, and was associated with significantly fewer bleeding events in a broad spectrum of patients with VTE (Fig. 7). The results of a regional subanalysis of Hokusai–VTE examining East Asia, including the Japanese population, were consistent with the overall study [35]. There have been concerns regarding the use of NOACs causing a higher risk of bleeding among patients with renal impairment and low body weight. Japanese VTE patients appeared to be older with impaired creatinine clearance and a lower body weight (2-fold more likely to experience a recurrent event compared with those with isolated DVT (Fig. 8) [21]. Half of these events occurred within 3 months and became rarer after 6 months. However, the 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism state that patients with low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided [5]. More data are required to evaluate the efficacy and safety of NOACs for the initial treatment of PE. Despite this, transition and maintenance on NOACs may be more effective than with warfarin, when patients are initially treated with UFH or fondaparinux. Initial treatment of DVT without a heparin lead-in for outpatient therapy is thought to be a valid indication for the use of NOACs. However, there is currently a lack of data available to accurately determine the efficacy and safety of initiating edoxaban immediately at VTE presentation. A number of trials have indicated that home treatment is not associated with an increase in mortality, recurrent VTE, or major bleeding and may be associated
with improved outcomes [37,38]. From these data, the 2012 ACCP guidelines state that in patients with DVT of the leg and whose home circumstances are adequate, initial treatment at home is recommended over in-hospital treatment [6]. As noted above, the management of isolated distal DVT remains controversial, despite being a common occurrence [39,40]. Guidelines [6] suggest that in patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, serial imaging of the deep veins should be conducted over 2 weeks from initial anticoagulation. NOACs are safer than warfarin; therefore, their use in the management of isolated distal DVT may prove beneficial, despite the majority of isolated distal DVTs not requiring anticoagulation. Finally, the suitability of NOACs for the treatment of VTE in fragile patients, including those with very low body weight, pregnant women, and those with serious thrombophilia, has not been established. There are no validated tests allowing assessment of the antithrombotic effect of NOACs. The management of bleeding complications resulting from the use of NOACs requires a rapid and safe reversal agent for factor Xa or thrombin inhibition.
Please cite this article in press as: Nakamura M, et al. Current management of venous thromboembolism in Japan: Current epidemiology and advances in anticoagulant therapy. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.03.012
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Fig. 8. Cumulative incidence of recurrent venous thromboembolism according to entry diagnosis in the JAVA study. Symptomatic PE with or without DVT (red line) or DVT alone (blue line). The risk of recurrence was significantly higher in patients with an initial diagnosis of PE (with or without DVT) than in those with isolated DVT (Cox proportional hazard analysis). DVT, deep vein thrombosis; PE, pulmonary embolism; JAVA, Japan VTE Treatment Registry. From Ref. [21] with permission.
Therefore, further studies are required to increase the utility of NOACs in the treatment of VTE. [5]
Conclusions This review summarizes the current status of VTE management in Japan with a focus on current epidemiology and advances in anticoagulant therapy. The number of clinically diagnosed cases of VTE continues to increase, with the majority cases of mild severity where decisions regarding treatment options are most controversial. The largest risk factor for VTE is cancer; however, unprovoked VTE is much more prevalent. Prolonged warfarin therapy is challenging in patients with cancer and unprovoked VTE. Recently, novel anticoagulant agents fondaparinux and edoxaban have been approved in Japan. These agents have the potential to provide more convenient and beneficial treatment options for VTE because they are both safer and more effective than current therapies. Although further randomized studies are required to fully validate the utility of these agents, they are expected to improve the quality of life of patients with VTE.
[6]
[7]
[8]
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Disclosures [10]
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