Venous thromboembolism (VTE) is a general term used for deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE). Due to the lack of histological and clinical signs, early diagnosis of VTE is often difficult, although it can be detected by imaging methods such as venography or sonography. The onset of venous thrombus leading to a DVT is related to stagnation of blood flow; risk factors include lower limb orthopaedic surgical procedures, such as total knee arthroplasty (TKA), total hip arthroplasty (THA), and hip fracture surgery (HFS).1 Deep vein thromboses may begin to form during TKA and THA procedures, and immediately after a hip fracture. Although most resolve spontaneously without treatment,2 asymptomatic DVT sometimes advances into a proximal vein, and if not detected, it can lead to symptomatic PTE. Lethal PTE, without prophylaxis, occurs in 0.1% to 7.5% of patients who undergo lower limb orthopaedic surgery,3 making it one of the most serious surgical complications in orthopaedic surgery.
Pharmacological prophylaxis is one of the more effective prophylactic therapies, and many anticoagulants have been developed recently. This article reviews the recent studies on anticoagulants in Japan and provides an up-to-date status of anticoagulant treatment in orthopaedic surgery. The articles cited in this review mainly are clinical studies that are considered important in drug development and surveillance conducted in Japan.
INCIDENCE AND RISK FACTORS FOR VENOUS THROMBOEMBOLISM
The incidence of DVT after THA or TKA without prophylaxis has been reported for Western populations in the American College of Chest Physicians (ACCP) Guidelines3 and in an International Consensus Statement,4 and for Japan, in the Japanese Orthopaedic Association VTE Prophylactic Guidelines.5 The incidence of DVT without prophylaxis detected by venography in Japan was 22% to 33% after THA (1994 - 2001) and 51% to 61% after TKA (1999 - 2006), compared with 42% to 57% after THA and 41% to 85% after TKA in the West (1980 - 2002).3,5 In the United States, the median duration of VTE onset from the initial lower limb orthopaedic surgery to VTE diagnosis is 17 days after THA and 7 days after TKA.6
The occurrence of VTE after orthopaedic surgery significantly increases medical costs. Among patients in the US who underwent major orthopaedic surgery, the medical costs for those who experienced an in-hospital VTE were significantly higher (US $18,834; P<0.01) compared with those without VTE complication.7 Likewise, Japanese patients with VTE after major orthopaedic surgery compared with those who did not have a VTE complication, incur higher 90-day costs (¥864,153; P<0.001), require longer hospital stays (66 vs. 42 days; P=0.0041), and have consistently higher medical expenses during the 5 mo post-surgery.8
There are few reports on postoperative VTE risk factors in Japanese patients. A retrospective study of combination therapy using fondaparinux and mechanical prophylaxis for postoperative prevention of PTE by Nagase et al.9 identified age 70 yr or greater than, the presence of comorbidities, complications of rheumatoid arthritis, anesthetic type, and anesthetic duration as risk factors for postoperative PTE. Moreover, in a study reported by Migita et al.10 significant risk factors for postoperative VTE included female sex in TKA and THA, and the use of a foot pump in the TKA. These findings may be important to identify patients in need of VTE preventive therapy during the perioperative period of orthopaedic surgery.11 Among patients receiving VTE prophylaxis, TKA is associated with a higher risk for VTE than THA, as well as older age and a higher body mass index.12 In further support of the increased risk with TKA, Yamaguchi et al.13 reported that the incidence on day 4 of early postoperative asymptomatic DVT in Japanese patients receiving fondaparinux (for 14 days) was twice as high after TKA as that observed after THA.
HISTORICAL TRANSITION OF VENOUS THROMBOEMBOLISM PROPHYLAXIS
VTE has long been recognized as a serious orthopaedic surgical complication resulting in the recommendation of thromboprophylactic measures as early as 1970.11 Based on studies of patients who underwent surgery and received anticoagulant therapy, the clinical benefit of VTE thromboprophylaxis is widely recognized in the West.14,15 In Japan, as the number of surgeries and the examination frequency for VTE increased in the 1990s, reports of perioperative VTE also increased,16,17 leading to the publication of the first Japanese Guidelines for the Prevention of VTE in 2004.18 These initial guidelines recommended early ambulation, active exercise, and mechanical prophylaxis such as elastic stockings or intermittent pneumatic compression for patients at low to moderate risk for VTE; pharmacological prophylaxis using low-dose unfractionated heparin (UFH) was limited to the highest risk patients. In 2008, the Japanese guidelines were updated5 to more closely reflect ACCP Guidelines Version 7.19
ADVANCEMENT OF ANTICOAGULANT THERAPY
The efficacy and safety of fondaparinux20,21 and enoxaparin, a low-molecular-weight heparin (LMWH),22 were demonstrated in clinical studies, leading to their approval for use in clinical practice in Japan in 2007 and 2008, respectively. Their use for VTE prevention was then incorporated into the revised guidelines issued by the Japanese Orthopaedic Association in 2008.5 Additional guidelines, published by the Japanese Circulation Society in 2011,1 recommended pharmacological anticoagulation or intermittent pneumatic compression for patients undergoing THA, TKA, or HFS (considered high risk) and combination anticoagulation plus intermittent pneumatic compression or elastic stockings for patients undergoing THA, TKA, or HFS with a prior history of VTE. Although approved for VTE prophylaxis in Japan, the use of warfarin and low-dose UFH has been limited, as evidence regarding their efficacy and safety was limited to studies conducted in Europe and the US,23–25 with very few studies in Japanese patients.26,27 The anticoagulants indicated for VTE prophylaxis in Japan are listed in Table 1. Although not approved for VTE prophylaxis, there are reports that support administration of aspirin31 and mechanical prophylaxis32 without anticoagulants to aid VTE prevention after THA.
It is interesting to note that the frequency of VTE in control groups of recent placebo-controlled studies conducted in Japan appears to be decreasing slightly (Table 2);20,22,26,27,33,34 this decrease may be due to early postoperative ambulation. However, VTE frequency remains high in the placebo groups, thus the use of prophylaxis should be determined based on the risk of VTE and bleeding, a complication of anticoagulant therapy.1
The anticoagulant therapy status in Japan was revealed in a large-scale physician questionnaire conducted by the Japanese Society of Anesthesiologists in the Perioperative Pulmonary Thromboembolism (JSA-PTE) Study from 2002 to 2011, as reported by Kuroiwa et al.35 Migita et al.10 reported the prospective cohort study conducted by the National Hospital Organization from 2007 to 2010, and the Japanese study of Prevention and Actual situations of Venous Thromboembolism after Total Arthroplasty (J-PSVT). Perioperative symptomatic PTE (PS-PTE) was observed in 1359 cases in 2,261,899 surgeries, involving the hip and upper and lower limbs (incidence, 6.0 per 10,000 surgeries).35 In patients with PS-PTE, the use of pharmacological prophylaxis did not change much from 2002 to 2007 (7.9–10.8%), but it began to increase in 2008 (17.6%) and then maintained a level of approximately 30% usage from 2009 to 2011.35 The increased use of pharmacological prophylaxis in Japan reflects the approval of new drugs for perioperative thromboprophylaxis. The relative risk of PS-PTE increased slightly from 2006 to 2011,35 which was likely due to an improved diagnostic approach based on high compliance with ACCP Guidelines. In 2008, the rate of fatal PS-PTE began to decline,35 possibly the result of an increased use of pharmacological prophylaxis. In support of this, Kuroiwa et al.,35 noted an increasing percentage of pharmacological prophylaxis thought to be a reflection of compliance with the 2008 Japanese Orthopaedic Guidelines. In the J-PSVT study, the anticoagulant therapy status was reported separately for TKA and THA patients, with the highest use of fondaparinux in both TKA and THA patients, followed by enoxaparin, UFH, and others (Figure 1).10
In a 2012 study, the reported incidence of VTE and PTE associated with THA were 2.85% and 0.24%, respectively.36 For TKA, these rates were 2.28% and 0.20%, respectively, suggesting that the rates of VTE have declined since the publication of the Japanese Guidelines and widespread acceptance of the use of VTE prophylaxis; notably, 99% of patients in this study received VTE prophylaxis.36
THE NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANT, EDOXABAN
Non-vitamin K antagonist oral anticoagulants (NOAC) directly targeting factor Xa or factor IIa (thrombin), which play an important role in the coagulation cascade, were developed as alternative strategies for prophylaxis and treatment for thromboembolic disease (Figure 2).37 Studies on NOACs have shown consistent and convenient anticoagulation therapy compared with conventional anticoagulants, such as vitamin K antagonists (eg, warfarin), LMWH, and fondaparinux,3 with reduced medical cost after surgery and greater patient compliance.38,39 NOACs are administered orally, not parenterally, simplifying outpatient thromboprophylaxis and improving patient adherence to the regimen. In contrast to warfarin, the NOACs do not require routine monitoring and have predictable pharmacokinetics, fewer drug-drug interactions, and no food-drug interactions.
Several NOACs (dabigatran, rivaroxaban, and apixaban) are approved and in use worldwide for VTE prophylaxis after major orthopaedic surgery. These NOACs were not inferior to or more effective than conventional therapy in patients undergoing major orthopaedic surgery in phase 3 trials and had comparable or reduced bleeding risks.40 In Japan, the only NOAC with approved benefits for “prophylaxis of VTE in patients undergoing lower limb orthopaedic surgery (TKA, THA, HFS)” is edoxaban, a direct, oral factor Xa inhibitor (approved on April 22, 2011), which has been marketed in Japan since 2011.28 Evaluation of the comparative efficacy and safety of edoxaban compared with enoxaparin was reported in the following three phase 3 clinical studies: STARS E-3, an international joint research study in Japan and Taiwan conducted in post-TKA patients,41 a study in post-HFS Japanese patients,42 and STARS J-V, conducted in post-THA Japanese patients.43 In these studies, the efficacy of edoxaban, measured as the incidence of thromboembolic events, was neither inferior41–43 or superior41,43 to enoxaparin with equivalent safety, as measured by the incidence of bleeding events (Table 3).
In Japan, 30 mg once daily is the recommended adult dose of edoxaban for the prevention of VTE in patients undergoing lower limb orthopaedic surgery.28 It is recommended that patients with a high risk of bleeding, hepatic function disorder, or renal impairment be closely monitored. A reduced dose of 15 mg once daily should be considered in patients with moderate renal impairment, a creatinine clearance of 30 to <50 mL/min. Postmarketing surveillance on edoxaban usage in a real-world setting was conducted in adherence with the Good Postmarketing Study Practice, a Japanese regulation, from February 1, 2012, by the manufacturer and marketer of edoxaban, Daiichi Sankyo Co., Ltd.44 The aim of this surveillance was to evaluate the safety of edoxaban in clinical use for primary prevention of VTE in patients undergoing lower limb orthopaedic surgery. Because edoxaban is a recently approved drug, the findings of this large-scale surveillance will help us understand its safety and efficacy in the real world. Patients who underwent lower limb orthopaedic surgery and received once daily edoxaban were enrolled. Information including patient characteristics, risk factors for VTE, medication, physiotherapy, adverse reactions, hemorrhagic adverse reactions were collected in the real-world clinical setting.
Hemorrhagic adverse reactions were classified as follows: major bleeding, clinically relevant nonmajor bleeding (CRNM), and minor bleeding based on criteria used in a previous phase 3 clinical trial for a factor X inhibitor.45 At the end of the enrollment period on January 31, 2013, a total of 2419 patients were registered and 2353 patients (excluding ineligible patients) were included in the safety analysis (Figure 3).44 Of 2353 patients, 396 (16.8%) were male, 1754 patients (74.5%) were 65 yr of age or older, and 1087 patients (46.2%) were 75 yr of age or older. A total of 152 patients (6.5%) had a low body weight (less than 40 kg), and 30 patients (1.3%) and 199 patients (8.5%) had decreased renal function with a creatinine clearance of less than 30 mL/min and 30 to <50 mL/min, respectively.44 Edoxaban was administered at a dose of 30 mg in 49.4% and at 15 mg in 50.6%, and the average administration period was 10.2 days. A dose of 15 mg was administered for renal impairment, advanced age, and low body weight. The doses were changed in 12 patients (0.5%); the drug was discontinued in 43 patients (1.8%), and edoxaban was readministered in two patients (0.1%). Reasons for the completion and discontinuation of administration included completion of scheduled administration period (2225 patients [94.6%]), the onset of adverse events (112 patients [4.8%]), and other reasons (32 patients [1.4%]).44 The onset of symptomatic VTE was observed in 0.4% of patients; however, all resolved (Table 4), resulting in an incidence of symptomatic VTE no greater than that observed in the phase 3 clinical testing.44 A total of 210 (8.9%) adverse reactions were reported; of these, 15 (0.6%) were serious adverse reactions. The onset of bleeding occurred in 104 patients (4.4%) (Table 4); these rates were consistent with the phase 3 clinical studies conducted prior to the approval of edoxaban.41–43 There was no report of lethal bleeding, including intracranial bleeding, and all reported adverse bleeding reactions were resolved or alleviated. The presence of hepatic disease and the number of days from the last day of surgery to initial administration of the drug were identified as potentially significant risk factors for adverse bleeding reactions. The adverse bleeding reactions occurred in 88 (4.0%) patients with hepatic disease, 14 (10.9%) patients without hepatic disease (P=0.0010, multivariable logistic regression), and 62 (5.7%) patients who started edoxaban administration within 1 day, 28 (3.5%) patients at 2 days, seven (2.2%) patients at 3 days, and seven (4.4%) patients at 4 or more days from the end of surgery (P=0.025, multivariable logistic regression). In Japan as of December 2015, four deaths due to drug-related cerebral hemorrhage and one death due to drug-related hemorrhagic shock were reported after edoxaban.46 These postmarketing data demonstrate that, in Japan, the efficacy and safety of edoxaban for VTE prophylaxis in actual clinical practice were comparable or better when compared with the results of the pivotal phase 3 studies. These results support the safety and efficacy of edoxaban for VTE prophylaxis after lower limb surgery in Japanese patients.
Rivaroxaban and apixaban are approved for VTE prophylaxis after elective TKA and THA in Europe and in the US. The efficacy and safety of these NOACs relative to enoxaparin were demonstrated in clinical studies,40 and in postmarketing surveillance47 for VTE prophylaxis after TKA and THA.
Although new anticoagulants are available for VTE prophylaxis after major orthopaedic surgery, risk of adverse reactions is unavoidable. Therefore, it is very important to understand the factors associated with the high risk of VTE and adverse reactions so as to achieve more effective and safer prophylaxis. Biomarkers might be helpful in predicting future VTE risk or bleeding risk. D-dimer is considered to be a potential predictor of VTE, and many previous researchers have suggested that high D-dimer levels are associated with high VTE incidence after surgery.48 However, the issue of creating clear guidance for utilizing D-dimer to predict future VTE risk has yet to be addressed. Moreover, because poor correlations have been found between NOAC concentrations and general clinical indices such as prothrombin time and activated prothrombin time,49 biomarkers for predicting future bleeding risk should be explored. To ensure more effective and safer prophylaxis, appropriate timing for restarting anticoagulants after surgery, influence of concomitant medications, mechanical prophylaxis, and transfusion (including autologous transfusion) also should be investigated.
In this review, the pertinent phase 3 clinical studies and the status of treatment using NOACs in orthopaedic surgery are summarized. In cases with a high risk of VTE in postoperative THA, TKA, and HFS, a thromboprophylactic procedure is recommended. The recent introduction of NOACs may result in simpler anticoagulant therapy. However, there is still a certain level of bleeding risk. Therefore, prophylaxis should be determined based upon each individual case with careful consideration given to the risk-benefit. Since the incidence rates of VTE and bleeding events observed in real-world observational studies did not exceed those in clinical trials, NOACs may be an optimal choice for VTE prophylaxis if the dose is appropriately selected according to dosing guidance.
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