Trends in Anticoagulant Utilization and Clinical Outcomes for Cancer-Associated Thrombosis: A Multicenter Cohort Study in Thailand's Upper-Middle-Income Country Setting.

INTRODUCTION

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common complication for patients with cancer. 1 These individuals face a higher risk of developing VTE compared with noncancer patients. 2 , 3 The management of VTE in patients with cancer necessitates the use of anticoagulants. 4 , 5 However, the potential bleeding events associated with the anticoagulant use can significantly affect the survival of these patients. 5 Consequently, the availability of effective and safe treatment options for cancer-associated thrombosis (CAT) is crucial for improving patient outcomes.

CONTEXT

Key Objective

To evaluate trends in anticoagulant regimens and their clinical outcomes for cancer-associated thrombosis (CAT) within an upper-middle–income country (UMIC) setting.

Knowledge Generated

Low-molecular-weight heparin (LMWH) remains the mainstay of anticoagulants used in line with international guidelines, whereas direct oral anticoagulants (DOACs) are less common. Warfarin, despite its higher risk of bleeding, was prescribed in 10% of cases. The study emphasizes that DOACs demonstrate effectiveness and safety profiles compared with LMWH, suggesting a potential shift in future CAT management practices in similar contexts.

Relevance

This study fills a crucial knowledge gap regarding CAT management within the UMIC, particularly in settings comparable with Thailand. It provides valuable insights for clinicians and policymakers to optimize CAT management, improve patient outcomes, and address the under-representation of Asian populations in clinical trials.

Current clinical guidelines endorse the use of low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) as preferred treatments for CAT. 4 , 5 This recommendation is supported by recent phase III randomized controlled trials (RCTs) demonstrating comparable efficacy and safety profiles of LMWH and DOACs in CAT patients. 6 - 9 Real-world studies have also confirmed the comparable effectiveness and safety of DOACs and LMWHs in patients with CAT. 10 - 13

It is important to recognize that most trials and real-world studies on CAT treatments, specifically DOACs and LMWH, have primarily been conducted in high-income countries (HICs). 10 - 13 This contrasts with upper-middle–income countries (UMICs) like Thailand, which face unique challenges that may hinder the adoption of these recommended treatments. 14 In Thailand, factors such as poor health literacy and poverty can serve as barriers to the effective use of injectable treatments like LMWH. 15 As a result, vitamin K antagonists (VKAs), such as warfarin, remain an alternative option for CAT in Thailand because of their affordability and oral administration. 4

In addition, there exist disparities in clinical and patient-related factors among patients with cancer in UMICs compared with HICs. 16 Notably, patients in Asian UMICs tend to have poor baseline nutritional status, low body weight, and an increased risk of bleeding when exposed to anticoagulants. 17 , 18 These differences, combined with differences in health care systems, can lead to divergent treatment outcomes between UMICs and HICs. 16 This multicenter cohort study in Thailand aims to assess trends in anticoagulant regimens and their clinical outcomes within an UMIC context. The findings could yield valuable insights into the risk-benefit profiles of various anticoagulants, offering guidance for policymakers for improving CAT management and enhancing patient care and outcomes in comparable health care settings.

METHODS

This retrospective cohort study was conducted across three tertiary care centers in Thailand, using comprehensive electronic health records. The study adhered to the principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the Center for Ethics in Human Research at Khon Kaen University, Khon Kaen, Thailand (Date: March 7, 2022, No. HE651139 ); the Ethics Committee of Buddhachinaraj Hospital, Phitsanulok, Thailand (Date: April 27, 2022, No. 027/65); and the Human Research Ethics Committee of the Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand (Date: December 28, 2022, No. REC.65-184-19-9). The study also complied with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. 9

Study Population

Patients diagnosed with VTE and cancer, who were hospitalized between January 1, 2017, and December 31, 2021, were included in this study. Inclusion criteria were as follows: (1) age at least 18 years; (2) diagnosis of either solid or hematologic malignancies; (3) having active cancer status, defined as receiving radiotherapy or systemic therapy, attending more than two oncology outpatient visits within a year, or being in advanced disease stages; and (4) having a confirmed diagnosis of VTE with anticoagulation treatment initiated and continued for a minimum of 2 weeks. VTE diagnoses, including DVT or PE, were on the basis of discharge summaries and verified through radiographic examinations, as determined by the attending physician.

Exclusion criteria included the following: (1) previous anticoagulant prescriptions before the index date, (2) previous VTE diagnosis before the index date, (3) pre-existing atrial fibrillation or valvular disorders before or during the index event admission, and (4) absence of follow-up visits postindex admission. Cancer diagnoses were established on the basis of International Classification of Diseases-10 Clinical Modification (ICD-10-CM) codes, which are detailed in Appendix Table A 1 .

Exposure and Covariates

The patients were classified into three treatment groups including LMWH, DOACs, and warfarin on the basis of their initial anticoagulant regimen. However, participants in the DOACs and warfarin groups may receive LMWH or unfractionated heparin during the first 2 weeks of their treatment. The DOACs used in this study were dabigatran, rivaroxaban, apixaban, and edoxaban. Decisions regarding drug dosage adjustments and temporary discontinuation of anticoagulation were at the discretion of the treating physicians. It is also important to note that, during the study’s conduct, only LMWH and warfarin were fully reimbursed in Thailand’s universal health coverage scheme. DOACs were not included in the national essential list of drugs and therefore were not eligible for reimbursement.

The study’s covariates consisted of patient demographics, clinical features, comorbidities, and concurrent medications. They were evaluated during the 6-month baseline period before and including the index date. The index date was defined as the first day of initiating anticoagulant therapy during the admission when the diagnosis was established. Patients were then followed from this index date for 1 year or until the occurrence of an outcome event, death, or the end of the study on December 31, 2022, whichever came first. To attribute outcomes to specific anticoagulant therapies and minimize crossover effects, patients were censored if they discontinued or switched therapies. Discontinuation was defined as having no new prescription after a 30-day grace period. However, switches within the same anticoagulant class were allowed and considered in the analysis.

Outcomes

The primary effectiveness outcome was the recurrence of VTE, whereas the primary safety outcome was major bleeding. Recurrent VTE was defined as the occurrence of DVT or PE within 12 months after the initiation of treatment. It is primarily identified by diagnoses confirmed by imaging studies revealing new thrombus formation. These diagnoses were categorized using the ICD-10-CM codes from discharge summaries, as detailed in Appendix Table A 2 .

Major bleeding was identified by inpatient admissions with a primary diagnosis of bleeding at critical sites, such as intracranial, intra-abdominal, retroperitoneal, intraocular, and spinal hemorrhages. The definition of major bleeding adhered to the 2020 American College of Cardiology Expert Consensus guidelines. 19 Two secondary outcomes were also analyzed including all-cause mortality and net clinical benefit. The net clinical benefit was defined as a composite end point of recurrent VTE and major bleeding, following the approach reported in pivotal RCTs. 6 - 9

Statistical Analysis

Categorical variables are presented as frequency percentages, whereas continuous variables are reported as means with standard deviations (SDs) for normal distributions and medians with IQRs for non-normal distributions. The inverse probability of treatment weighting (IPTW) method is used to balance potential confounding variables among treatment groups by using propensity scores (PSs). 20 PS was calculated using a multinomial logistic regression model that considered three treatment groups, with the LMWH group as the reference. Factors such as patient demographics, VTE type, the Charlson Comorbidity Index (CCI), concomitant medication use, presence of cancer metastases, and cancer-related treatment were considered in determining the likelihood of a patient receiving specific treatment. Covariate balance was assessed before and after IPTW weighting using standardized mean differences (SMDs).

The prescription trends of anticoagulants were estimated. Crude event rates were presented as Kaplan-Meier cumulative incidence functions. We used IPTW-adjusted Cox proportional hazard models to compare clinical outcomes between the treatment groups, with the LMWH group as the reference. To address covariate imbalances within the IPTW cohort, we used multivariable IPTW-adjusted Cox proportional hazard models. These models incorporated covariates such as age, sex, CCI, type of VTE, cancer type, metastatic cancer, active anticancer treatments, and concomitant treatment. Treatment associations were presented as hazard ratios (HRs) with 95% CIs. The prescription trends of anticoagulants were also estimated. To calculate subdistribution HRs, the Fine-Gray model was used, considering mortality as a competing risk. 21 The proportional hazards assumption of the Cox model was tested using Schoenfeld residuals and complementary log-log plots. All tests were two-sided, and a P < .05 was considered significant.

RESULTS

Patients

Among 4,395 patients with cancer diagnosed with VTE between January 2017 and December 2021, 1,611 met the eligibility criteria and were included in the analysis (Fig 1 ). Of these 1,611 patients, 988 patients (61.3%) were female. The mean age at the time of the index event was 58.8 (SD, 13.1) years, and the mean BMI was 22.3 (SD, 2.9) kg/m 2 . The VTE types were distributed as follows: 928 (57.6%) cases of DVT, 493 (30.6%) cases of PE, and 190 (11.8%) cases with a combination of DVT and PE. Primary cancer types included gynecological (428 patients [26.6%]), hepatobiliary (237 patients [14.7%]), and lung cancer (212 patients [13.2%]). More than half (962 patients [59.7%]) had metastatic disease. Hemoglobin levels were <10 g/dL in 682 patients (42.3%) and <8 g/dL in 192 patients (11.9%). Approximately 529 patients (32.8%) had a platelet count >350 × 10 3 /μL (Table 1 ).

Patient comorbidities were similar across the treatment groups, with a few notable differences. The warfarin group had a higher incidence of myocardial infarction (six patients [3.7%]), compared with the DOAC (one patient [1.6%]) and LMWH (11 patients [0.8%]). The DOAC group had a higher prevalence of congestive heart failure (six patients [9.4%]), compared with the warfarin (six patients [3.7%]) and LMWH (44 patients [3.2%]). Patients initiating DOAC were also more likely to have a CCI score of 3-4 (25 patients [39.1%]) than those on warfarin (48 patients [29.6%]) and LMWH (350 patients [25.3%]; Table 1 ). Baseline characteristics of the treatment groups, before the application of IPTW, are presented in Appendix Table A 3 . After the IPTW adjustment, there was a marked improvement in the comparability of covariates across treatment groups, as evidenced by significantly reduced SMDs. A more detailed account of the enhanced balance in baseline characteristics after IPTW application is provided in Appendix Table A 4 .

Anticoagulant Regimens

Most patients (1,358 [86.0%]) received LMWH with a median duration of 101 days (IQR, 32-145 days), whereas 427 (30.8%) of them continued LMWH for over 180 days. Warfarin was administered to 162 patients (10.0%), with a median duration of 92 days (IQR, 32-145 days; Table 2 ). DOACs were administered to 64 patients (4.0%), with a median duration of 102 days (IQR, 33-198 days). Of the DOACs, rivaroxaban was the most frequently used agent (44 patients [68.7%]), followed by apixaban (11 patients [17.2%]), edoxaban (five patients [7.8%]), and dabigatran (four patients [6.3%]). During the study period, the prescription rate for LMWH remained constant. However, there was a significant decrease in the prescription of VKAs, while the use of DOACs exhibited an increasing trend (Fig 2 ).

Detailed information on the frequency and pattern of switches in anticoagulant regimens is provided in Table 2 . Of the 162 patients who were initially prescribed warfarin, 24 (14.8%) switched to LMWH and three (4.7%) switched to DOACs. Among the 1,385 patients who were initially on LMWH, 79 (5.7%) changed to warfarin and 19 (1.4%) changed to DOACs. Of the 64 patients who started with DOACs, three (4.7%) switched to LMWH and two (3.1%) switched to warfarin.

Outcomes

Event numbers and treatment effects in both unadjusted and IPTW analyses are summarized in Table 3 . For the primary effectiveness outcome of VTE events, occurrences were noted in 158 (11.4%) cases with LMWH, six (9.4%) with DOACs, and 25 (15.4%) with warfarin. The IPTW analysis showed no significant difference in VTE rates between the DOAC group (weighted HR, 0.77 [95% CI, 0.22 to 2.70]; P = .679) and the warfarin group (weighted HR, 1.46 [95% CI, 0.75 to 2.84]; P = .271) compared with the LMWH group (Fig 3 A).

The primary safety outcome, major bleeding was reported in 52 (3.8%) cases for the LMWH, three (4.7%) for the DOACs, and 11 (6.8%) for the warfarin. Patients receiving warfarin had a significantly higher rate of major bleeding compared with those on LMWH (weighted HR, 2.74 [95% CI, 1.12 to 6.72]; P = .028). However, there were no significant differences in major bleeding events between DOAC and LMWH groups (HR, 0.62 [95% CI, 0.15 to 2.55]; P = .506; Fig 3 B).

In terms of secondary outcomes, the net clinical benefit, which is a composite end point of recurrent VTE and major bleeding, was observed in 200 (14.4%) cases in the LMWH group, eight (12.5%) in the DOAC group, and 34 (21.0%) in the warfarin group. The net clinical benefit rates did not significantly differ for DOACs compared with LMWH, with a weighted HR of 0.58 (95% CI, 0.22 to 1.54; P = .276). Similarly, for warfarin, the weighted HR was 1.73 (95% CI, 0.94 to 3.19; P = .075; Fig 4 A). There were no statistically significant differences observed among the three groups for all-cause mortality. The weighted HR for DOACs was 0.70 (95% CI, 0.29 to 1.70; P = .432), and for warfarin, it was 1.22 (95% CI, 0.54 to 2.78; P = .637; Fig 4 B). The IPTW results were consistent with the unadjusted analyses for all clinical outcomes.

DISCUSSION

This multicenter cohort study was done to evaluate anticoagulant trends and clinical outcomes in the management of CAT in Thailand. The study found that LMWH was the preferred anticoagulant for 86% of CAT patients, whereas only 4% were treated with DOACs. Our comparative analysis revealed that warfarin carries a significantly higher risk of bleeding compared with LMWH. Although DOACs are used less frequently, they have demonstrated comparable effectiveness and safety to LMWH. These findings are crucial for improving anticoagulant practice in Thailand and other UMIC settings, with the goal of optimizing patient care and outcomes.

The efficacy and safety of anticoagulants for CAT management are predominantly supported by phase III clinical trials. 6 - 9 However, it should be noted that the RCTs had strict inclusion criteria and a low representation of Asian patients, ranging from only 0.7% to 21.0% of trial participants. 6 - 9 , 14 Because of the lower incidence of CAT in Asian versus Western populations, especially those with advanced-stage diseases 22 , 23 and generally lower BMI, 24 the patients in these trials may not be representative of the Asian demographic in UMICs. Moreover, many RCTs exclude patients with advanced-stage cancer, severe comorbidities, or impaired organ function, which further limits their applicability. 6 - 9 This highlights the importance of real-world evidence from Asian UMIC populations to bridge this gap and provide a valuable complement to RCT data.

Our study found that LMWH and DOACs had similar rates of adverse clinical events in our population. Our findings are consistent with landmark trials such as SELECT-D, 9 Hokusai-VTE, 8 and Caravaggio, 6 along with previous observational studies 10 , 13 , 25 and a recent pragmatic RCT. 26 Despite the limited proportion of DOAC users in our cohort, we can conclude that DOACs are a viable alternative to LMWH on the basis of our results. For recurrent VTE outcomes, we observed similar rates between DOACs and LMWH, which is consistent with previous real-world studies, 25 , 27 However, this differs from the SELECT-D study, 9 which reported lower VTE recurrence with rivaroxaban compared with dalteparin.

The present study supports previous observational studies that have shown comparable bleeding rates between DOACs and LMWH, 10 , 12 , 13 thus strengthening the real-world safety of DOACs in Thailand and similar health care settings. Most real-world studies, 13 , 27 including this one, predominantly involve patients treated with rivaroxaban as it is the most used DOACs. Because of the limited number of patients who received apixaban, edoxaban, and dabigatran, it was not possible to conduct a meaningful comparison among the different DOACs. Therefore, larger-scale studies are necessary to provide a more comprehensive comparison of the effectiveness and safety of individual DOACs for Asian patients with CAT.

Although clinical trials have established that LMWH is superior to warfarin in preventing recurrent VTE, 28 real-world studies remain crucial for a comprehensive comparison of safety and effectiveness in clinical practice. Our study found comparable rates of recurrent VTE between warfarin and LMWH users, but warfarin users had a notably higher incidence of major bleeding (HR, 2.74; P = .028) in contrast to a US study that reported a nonsignificant bleeding risk with warfarin compared with LMWH. 13 This disparity may be attributed to genetic variances in response to warfarin among Asian patients, 29 particularly concerning VKORC genes, 30 and may lead to an elevated international normalized ratio (INR) level and potentially limit the application of warfarin therapy for CAT in this population. 31 , 32

Although VKAs have known limitations and variable effectiveness, they are still used, especially for patients who have limited access to DOACs or those with restricted functional status or family support. 4 In this context, regular monitoring of INR levels is critical to ensure patient safety when prescribing warfarin. Furthermore, the availability of low-cost, generic DOACs presents an opportunity for policymakers to reconsider their inclusion in reimbursement schemes, expanding treatment options for CAT patients in Thailand and similar UMIC settings.

Our study has some important limitations. First, the reliance on ICD-10-CM diagnosis codes to identify VTE cases may not definitely confirm disease presence, despite careful adherence to eligibility criteria. Identifying recurrent VTE events within health care databases is inherently challenging, and despite our best efforts, potential misclassification of outcomes might have diluted the true effects observed. Second, given the retrospective and nonrandomized nature of our study, we used an IPTW analysis to adjust for significant covariates. However, statistical adjustment cannot completely eliminate the potential for residual and unmeasured confounding effects. Third, because of the retrospective nature of the study design, we were unable to exclude the possibility of medication nonadherence with VTE treatment. Furthermore, our findings may not be representative of practices across all health care settings within UMICs. Despite these limitations, our study provides valuable real-world insights into CAT management in a UMIC context, offering guidance for clinicians in similar settings to enhance decision making and ultimately improve patient care and outcomes.

In conclusion, our study suggests that LMWH remains the primary anticoagulant regimen for CAT management, consistent with international guidelines. Although DOACs are used less frequently, we found that they demonstrate effectiveness and safety comparable with LMWH. Approximately 10% of CAT patients were administered warfarin, despite its recognized limitations. These patients experienced a notably higher risk of major bleeding compared with those on other treatments. DOACs have the potential to significantly affect CAT management in Thailand and other UMICs because of their similar efficacy and safety to LMWH. This suggests a shift in therapeutic strategies for these regions.

APPENDIX

SUPPORT

Supported by the Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand (grant number: 64-2(1)/2564). The funding source had no role in the study design, collection, analysis, and interpretation of data.

AUTHOR CONTRIBUTIONS

Conception and design: Kirati Kengkla, Warunsuda Sripakdee, Pirun Saelue, Aumkhae Sookprasert, Suphat Subongkot

Financial support: Kirati Kengkla, Suphat Subongkot

Administrative support: Aumkhae Sookprasert, Suphat Subongkot

Provision of study materials or patients: Pirun Saelue

Collection and assembly of data: Kirati Kengkla, Pirun Saelue, Kwanruethai Sengnoo, Suphat Subongkot

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center .

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians ( Open Payments ).

No potential conflicts of interest were reported.

REFERENCES

1. Khorana AA: Venous thromboembolism and prognosis in cancer. Thromb Res 125:490-493, 2010

2. Connolly GC, Francis CW: Cancer-associated thrombosis. Hematology Am Soc Hematol Educ Program 2013:684-691, 2013

3. Donnellan E, Khorana AA: Cancer and venous thromboembolic disease: A review. Oncologist 22:199-207, 2017

4. Key NS, Khorana AA, Kuderer NM, et al. : Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 38:496-520, 2020

5. Lyman GH, Carrier M, Ay C, et al. : American Society of Hematology 2021 guidelines for management of venous thromboembolism: Prevention and treatment in patients with cancer. Blood Adv 5:927-974, 2021

6. Agnelli G, Becattini C, Meyer G, et al. : Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 382:1599-1607, 2020

7. McBane Ii R, Loprinzi CL, Ashrani A, et al. : Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE trial. Thromb Haemost 117:1952-1961, 2017

8. Raskob GE, van Es N, Verhamme P, et al. : Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 378:615-624, 2018

9. Young AM, Marshall A, Thirlwall J, et al. : Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 36:2017-2023, 2018

10. Douros A, Filliter C, Azoulay L, et al. : Effectiveness and safety of direct oral anticoagulants in patients with cancer associated venous thromboembolism. Thromb Res 202:128-133, 2021

11. Fovel LM, Seabury RW, Miller CD, et al. : Safety and efficacy of direct oral anticoagulant therapy in patients with cancer. J Pharm Pract 34:710-714, 2021

12. Cohen AT, Keshishian A, Lee T, et al. : Effectiveness and safety of apixaban, LMWH, and warfarin among high-risk subgroups of VTE patients with active cancer. Curr Med Res Opin 37:1467-1482, 2021

13. Chen DY, Tseng CN, Hsieh MJ, et al. : Comparison between non-vitamin K antagonist oral anticoagulants and low-molecular-weight heparin in Asian individuals with cancer-associated venous thromboembolism. JAMA Netw Open 4:e2036304, 2021

14. Lee LH, Danchaivijitr P, Uaprasert N, et al. : Safe and effective treatment of venous thromboembolism associated with cancer: Focus on direct oral anticoagulants in Asian patients. Exp Hematol Oncol 11:79, 2022

15. Coughlin SS, Datta B, Vernon M, et al. : Health literacy among cancer survivors: Results from the 2016 behavioral risk factor surveillance system survey. Medicine (Baltimore) 101:e29010, 2022

16. Hanna TP, Kangolle AC: Cancer control in developing countries: Using health data and health services research to measure and improve access, quality and efficiency. BMC Int Health Hum Rights 10:24, 2010

17. Guo YT, Zhang Y, Shi XM, et al. : Assessing bleeding risk in 4824 Asian patients with atrial fibrillation: The Beijing PLA Hospital Atrial Fibrillation Project. Sci Rep 6:31755, 2016

18. Shinohara M, Wada R, Yano K, et al. : Relationship between the nutritional status and safety and efficacy outcomes in atrial fibrillation patients aged 80 years and over receiving oral anticoagulants. J Cardiol 77:147-153, 2021

19. Tomaselli GF, Mahaffey KW, Cuker A, et al. : 2020 ACC Expert Consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 76:594-622, 2020

20. Garrido MM, Kelley AS, Paris J, et al. : Methods for constructing and assessing propensity scores. Health Serv Res 49:1701-1720, 2014

21. Coviello V, Boggess M: Cumulative incidence estimation in the presence of competing risks. Stata J 4:103-112, 2004

22. Wang KL, Yap ES, Goto S, et al. : The diagnosis and treatment of venous thromboembolism in Asian patients. Thromb J 16:4, 2018

23. Angchaisuksiri P: Cancer-associated thrombosis in Asia. Thromb J 14:26, 2016. (suppl 1)

24. Lee S, Lee DH, Lee JH, et al. : Association of body mass index with survival in Asian patients with colorectal cancer. Cancer Res Treat 54:860-872, 2022

25. Bang SM, Kang JH, Hong MH, et al. : Treatment patterns and clinical outcomes in Korean cancer patients with venous thromboembolism: A retrospective cohort study. Clin Appl Thromb Hemost 27:1076029620979575, 2021

26. Schrag D, Uno H, Rosovsky R, et al. : Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer: A randomized clinical trial. JAMA 329:1924-1933, 2023

27. Ahmat A, Wan Puteh SE, Yusak S: Efficacy of rivaroxaban use in solid tumour malignancy: Experience from a tertiary care cancer centre. Asian Pac J Cancer Prev 22:3601-3606, 2021

28. Lee AY, Levine MN, Baker RI, et al. : Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146-153, 2003

29. Gaikwad T, Ghosh K, Shetty S: VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res 134:537-544, 2014

30. Yuen E, Gueorguieva I, Wise S, et al. : Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin. J Pharmacokinet Pharmacodyn 37:3-24, 2010

31. Sangviroon A, Panomvana D, Tassaneeyakul W, et al. : Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. Drug Metab Pharmacokinet 25:531-538, 2010

32. Kuanprasert S, Dettrairat S, Palacajornsuk P, et al. : Prevalence of CYP2C9 and VKORC1 mutation in patients with valvular heart disease in northern Thailand. J Med Assoc Thai 92:1597-1601, 2009