The diagnosis and treatment of venous thromboembolism in Asian patients

Although Asian populations are subject to the same major acquired risk factors for VTE as Western populations, studies conducted in Asia have consistently reported lower rates of VTE in Asian populations than in Caucasians (Table 1) [3, 13, 15‐20]. These data are comparable to those obtained from Asian patients in Western countries [21, 22]. There are several possibilities that may explain the lower rate of VTE in Asian populations relative to Western populations. Firstly, the estimates may be lower than the true numbers because of the limited availability of epidemiological data in Asia and the asymptomatic nature of VTE. Secondly, historically, the difference in incidence rates reflects underdiagnosis in Asian patients as a result of low awareness toward thrombotic disease and/or manifestations, low clinical suspicion due to the perceived low incidence rate, and limited access to healthcare resources [23‐25]. In addition, low autopsy rates—mainly because of cultural and religious practices—may partially account for the perceived low incidence rate of VTE in Asia [25]. Autopsies reveal high rates of asymptomatic thrombosis [2], and autopsy studies indicate that the incidence of PE in Asian countries is comparable with that in Western countries [2, 26, 27]. Finally, the low rates of VTE in Asian populations may be attributed to the low prevalence of risk factors, such as obesity and mutations, in prothrombin or factor V Leiden genes [28‐31]. Accordingly, these data suggest that the rate of VTE in Asia may be underestimated, particularly because the thrombi tend not to advance to symptomatic thrombosis in Asian patients [32].

Heritable risk factors arise from genetic abnormalities in the components of the coagulation pathway that lead to hereditary thrombophilia, including mutations in factor V and prothrombin; and deficiencies of protein S, protein C, and antithrombin [28]. While factor V Leiden and prothrombin G20210A polymorphisms are exclusive to Caucasians, the prevalence of protein S, protein C, and antithrombin deficiencies in Asian populations are higher than those found in Caucasians (Table 2) [30, 33‐38].

Although the major inherited risk factors for VTE are different between Asian and Western populations, the major acquired risk factors in Asians are similar to those of the Western populations [39]. Risk factors, such as surgery, trauma, prolonged bed rest, immobility, and pregnancy, are transient and reversible, while risk factors, such as malignancy and paralysis due to nerve damages, are irreversible. The most common acquired risk factor for VTE in Asians is malignancy; 16% to 40% of VTE cases are cancer-associated [40‐42]. Other common acquired risk factors for VTE in Asians include surgery, immobility, obesity, advanced age, and the use of oral contraceptives [39, 43].

VTE is a serious complication after high-risk surgeries even when preventive measures are taken. The rates for symptomatic DVT and PE with low-molecular-weight heparin (LMWH) after orthopedic surgery are 0.8% and 0.35%, respectively [10]. Since Asian patients have a perceived lower risk for symptomatic VTE following surgery than in Western populations, regular prophylaxis in Asian patients at high risk for VTE is not always administered [44]. However, in studies involving Asian patients undergoing major surgery, the incidence of postoperative DVT was noted to be similar to that reported in Western populations [39, 45‐50]. The Assessment of the Incidence of Deep Vein Thrombosis in Asia (AIDA) study, which was conducted in 19 centers across Asia (China, Indonesia, Korea, Malaysia, the Philippines, Taiwan, and Thailand) in patients undergoing total hip or knee arthroplasty or hip fracture surgery and did not receive thromboprophylaxis, assessed the rate of DVT of the lower limbs using bilateral venography; DVT was diagnosed in 41% of patients (121/295) [51]. A meta-analysis of 22 studies done in Asian patients undergoing orthopedic procedures showed that Asian patients have similar overall DVT rates detected by venography, but a lower rate of symptomatic and proximal DVT than Western populations [52]. The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting ENDORSE) study was a multinational cross-sectional survey designed to assess the prevalence of VTE in accordance with the 2004 American College of Chest Physicians (ACCP) guidelines in the acute hospital care setting. In Asian countries (India, Thailand, Pakistan, and Bangladesh), the proportion of surgical patients at risk for VTE ranged from 44% to 62%, which was similar to the proportion reported for all countries studied (overall: 64%; range: 44%–80%) [9]. These findings suggest that surgical patients at risk for VTE in Asian countries should receive appropriate VTE prophylaxis.

In general, the clinical assessment and diagnostic testing for VTE are the same in Asian populations as they are in non-Asian populations. DVT usually originates in the deep veins of the calf and can extend into the popliteal and femoral veins [53]. DVT at the calf is generally asymptomatic, but it may produce symptoms once it extends proximally and obstructs venous outflow [53, 54]. Symptomatic DVT is suspected primarily on the basis of unilateral leg pain, swelling, and/or redness [55]. Once extended proximally, venous thrombi may give rise to fatal PE [54]. Common symptoms of PE include palpitation, dyspnea, chest pain, cough, and/or syncope [56, 57].

Careful clinical examinations of signs, symptoms, and risk factors associated with suspected VTE, and distinguishing it from other medical conditions, are important for accurate diagnosis of the disease. Clinical assessment, plasma D-dimer measurement, and imaging tests are recommended and validated for the diagnosis of DVT and PE. The most commonly proposed systematic diagnostic management techniques for VTE are illustrated in Fig. 1.

Selection of patients who are at low or high risk of VTE is crucial when considering prevention options for VTE. The development of VTE in patients is affected by the aforementioned risk factors, such as age, previous history of VTE, cancer, and surgery. Although orthopedic surgeries, such as total hip or knee arthroplasty and hip fracture surgery, are classified as high risk for VTE in Asia, VTE risk stratification is not routine and there is a strong need for a hospital VTE management protocol for VTE risk assessment [77].

The Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are the most extensively used prediction scores for the risk stratification in patients diagnosed with PE in order to guide therapeutic decision making [78, 79]. PE patients with a sPESI score of 0 have a 30-day all-cause mortality rate of 1%, whereas PE patients with a sPESI score of 1 or more have a 30-day all-cause mortality rate of 9% to 11% [79]. PE patients with a sPESI score of 0 are considered to be low risk and may be considered for outpatient treatment [57]. However, patients estimated to be high risk may benefit from inpatient management and/or higher levels of care (ie, intensive care setting). The Hestia criteria are also widely used for selecting patients with PE, including those with right ventricular (RV) dysfunction, for outpatient treatment [80, 81].

The bleeding risk assessment tools may be useful for distinguishing which patients are at low or high risk of bleeding and for identifying patients who might benefit from extended anticoagulation [82‐86]. A risk score based on VTE patients included in the RIETE registry identified VTE patients at low, intermediate, or high risk of major bleeding during the first 3 months of therapy. This score was based on 6 variables documented at entry—recent major bleeding, anemia, cancer, abnormal creatinine levels, age > 75 years, and PE diagnosis at baseline [84]. Similarly, the VTE-BLEED score was based on 6 variables—active cancer, male with uncontrolled arterial hypertension, anemia, history of bleeding, age ≥ 60 years, and renal dysfunction—and accurately predicted major bleeding events in VTE patients on anticoagulation [86, 87]. The predictive value of these bleeding risk scores is uncertain in Asian populations and needs to be validated with careful examination of independent risk factors in Asians.

The effectiveness of postoperative thromboprophylaxis in Western countries is well recognized [10, 11]. Recent studies conducted in Asia reported that postoperative thromboprophylaxis reduces VTE risk without significantly increasing the risk of bleeding [88]. For the prevention of VTE in patients undergoing high-risk surgeries, thromboprophylaxis with anticoagulants and/or mechanical prophylaxis are typically recommended based on patients’ risk of bleeding [11, 14]. The Asian Venous Thrombosis Forum—composed of experts from China, Hong Kong, Malaysia, the Philippines, Singapore, Taiwan, Thailand, India, Indonesia, Korea, Australia, and Europe—recommends using mechanical prophylaxis for patients with increased risk of bleeding, and mechanical prophylaxis in combination with pharmacological prophylaxis for patients with high risk of VTE [77]. Korean Society of Thrombosis and Hemostasis guidelines also recommend using mechanical prophylaxis for patients with increased risk of bleeding and pharmacological prophylaxis, including LMWH, fondaparinux, dabigatran, apixaban, rivaroxaban, low-dose unfractionated heparin, vitamin K antagonist (VKA; ie, warfarin), or aspirin, for patients undergoing major orthopedic surgery of the lower limbs, such as total hip or knee arthroplasty [89]. According to the latest update, the Asia-Pacific Thrombosis Advisory Board suggests routine use of postoperative thromboprophylaxis for VTE after major orthopedic surgery. They further suggest that the use of non-vitamin K antagonist oral anticoagulants (NOACs) may simplify patient management in Asia primarily due to no regular coagulation monitoring requirement because of their predictable pharmacokinetic (PK) and pharmacodynamic (PD) properties, and demonstrating no interactions with nonsteroidal anti-inflammatory drugs [88]. The Asian Venous Thrombosis Forum recommends LMWH (ie, enoxaparin), fondaparinux, NOACs, VKA, or aspirin with intermittent pneumatic compression for thromboprophylaxis in patients undergoing total hip or knee arthroplasty or hip fracture surgery [77]. Enoxaparin and fondaparinux are the standard therapy for the prevention of VTE in Japanese patients undergoing abdominal surgery or orthopedic surgery of the lower limbs [14]. However, results of a small sized randomized controlled trial conducted in Japan suggested that dabigatran reduces incidence of VTE in patients undergoing total knee arthroplasty with a safety profile comparable to placebo [90]. Furthermore, results from small sized phase 3 trials (STARS [Studying Thrombosis After Replacement Surgery]) indicated that edoxaban is superior to enoxaparin in preventing VTE in Japanese patients undergoing total hip and knee arthroplasty, and has similar safety and efficacy as enoxaparin in hip fracture surgery [91‐93]. The results of these clinical trials led to the approval of edoxaban for venous thromboprophylaxis in patients undergoing major orthopedic surgery in Japan [94]. In a postmarketing surveillance study done to monitor the adverse drug reactions of edoxaban during the first 6 months after its commercial launch in Japan, edoxaban’s safety data were consistent with its known safety profile [95].

The goal of the VTE treatment is to prevent thrombus extension and recurrence through pharmacological or mechanical interventions [96]. Japanese and Taiwanese guidelines were issued by the Japanese Circulation Society (JCS) in 2011 and by the Taiwan Society of Cardiology in 2016 [14, 72]. The ACCP VTE treatment guidelines and European Society of Cardiology PE guidelines are also widely used in Asia [57, 97]. According to the latest update, treatment with NOACs is suggested over VKA therapy. The suggested duration of treatment for symptomatic DVT (distal or proximal) or PE is at least 3 months, and patients should be evaluated for the risk-benefit ratio to determine the need for extended therapy (no scheduled stop date) (Fig. 2) [96]. However, the JCS guidelines recommend using intravenous unfractionated heparin (UFH) overlapped with, and followed by, VKA for a minimum of 3 months, and the recommended target international normalized ratio (INR) range is 1.5 – 2.5. This target INR range is lower than the range recommended in Western countries (ie, 2.0–3.0) perhaps because of increased bleeding tendency in Japanese patients [14, 43]. Although use of LMWH was adopted in the US and Europe to overcome the limitations of UFH for the treatment of VTE, LMWH has yet to be approved for this indication in Japan due to limited clinical evidence from Japanese patients [98]. The Taiwanese guidelines recommend using either intravenous UFH or LMWH overlapped with, and followed by, VKA with a maintenance target INR of 2.0 to 3.0 [72].

NOACs have been approved for the treatment of VTE in many countries in Asia; however, only a few countries provide reimbursements to patients. Dabigatran has been approved in Korea, Singapore, the Philippines, China, Thailand, and Taiwan; rivaroxaban and apixaban have been approved in Korea, Singapore, Japan, China, Thailand, and Taiwan; and edoxaban has been approved in Japan, South Korea, Hong Kong, Thailand, and Taiwan at the time of this review [94, 99, 100].