Patterns and Persistence of Anticoagulant Use in the Treatment of Venous Thromboembolism: Insights from South Korea

Dynamic Patterns and Persistence of Anticoagulation Therapy in Patients with Venous Thromboembolism in South Korea: A Nationwide Cohort Study

When used in fixed doses for the treatment of venous thromboembolism (VTE) in patients with or without cancer, direct oral anticoagulants (DOACs) have improved risk–benefit profiles compared with vitamin K antagonists (VKAs), and have better convenience than parenteral anticoagulants such as low-molecular-weight heparins (LMWHs).[1] [2] The DOACs, which include rivaroxaban, edoxaban, dabigatran, and apixaban, have been approved for the treatment of VTE in various countries since 2011, and current guidelines prefer DOACs over VKAs for the treatment of VTE in patients without cancer, and recommend DOACs as acceptable alternatives to LMWHs in patients with cancer-associated VTE.

Postmarketing studies indicate that DOACs have overtaken VKAs for many indications and have facilitated the uptake of anticoagulant therapy, but these studies have been performed mostly in non-Asian countries and in populations with atrial fibrillation.[3] [4] Studies reporting on patterns and persistence of anticoagulant use in Asia and in indications other than atrial fibrillation (such as treatment of cancer-associated VTE) are few, and the available data may not necessary be generalizable because of differences in populations, health care systems, and prescription medication coverage. Accordingly, there is a need for more data in Asia and in other indications to understand country-specific trends, and barriers to and facilitators of anticoagulant therapy. This is important given some differences noted between Asians and non-Asians, for example, in relation to bleeding related to antithrombotic therapy.[5] [6]

In the current issue of the journal, Yoon et al examine trends in the use of DOACs, VKAs, and parenteral anticoagulants in 48,504 and 7,255 patients with a new diagnosis of VTE without and with cancer, respectively, from 2013 to 2019, to provide important information on the pattern of anticoagulant uptake and treatment persistence in the treatment of VTE in South Korea.[7] Using data from a large national administrative database (Korean Health Insurance Review and Assessment Service), their study reports three relevant findings. First, consistent with studies in other populations, DOACs have become the most prescribed anticoagulants for the treatment of VTE in South Korea. Indeed, the use of DOACs (particularly, rivaroxaban) has increased from 22% in 2013, when reimbursement for this indication first became available, to 81% in the first semester of 2019 and has overtaken warfarin and parenteral anticoagulant prescriptions for this indication by 2014 (see [Fig. 1]). Second, treatment nonpersistence and discontinuation at 3 and 6 months were common regardless of anticoagulant type and cancer status. Interestingly, there was a sharper decline in DOAC continuation (compared with other anticoagulants) at 6 months, coinciding with the end of the period of reimbursement, thereby highlighting the impact of drug affordability on treatment persistence. It would be interesting to see how the expanded and streamlined reimbursement beyond 6 months in 2019 affected longer term DOAC continuation and persistence in future studies. The issues of treatment discontinuation and nonpersistence were even more problematic in cancer-associated VTE despite guidelines recommending indefinite anticoagulation because of the high risk of VTE recurrence in this setting and the associated prognostic implications.[8-10] About 60% of patients with cancer-associated VTE discontinued anticoagulants, and another 30% experienced treatment switch or interruption or died by 6 months. These high rates of treatment discontinuation and nonpersistence are consistent with data from the Global Anticoagulant Registry in the FIELD–Venous Thromboembolic Events (GARFIELD-VTE), which showed that 53% of patients with cancer-associated VTE discontinued anticoagulation after 6 months.[11] Third, there was unexpectedly high proportion of patients receiving parenteral anticoagulation in the treatment of noncancer VTE. About 16% of patients with VTE outside the setting of active cancer were treated with parenteral anticoagulants. It is likely that these patients were selected by physicians for parenteral anticoagulant because of a perceived higher risk of recurrence or bleeding or other contraindications as evidenced by the older age, higher incidence of pulmonary embolism, higher bleeding risk as measured by the HAS-BLED score, and the observations that these patients had the highest rates of treatment discontinuation, nonpersistence, and mortality.

Fig. 1 Milestones in the approval and reimbursements of DOACs and the relative uptake of anticoagulants for the treatment of VTE in South Korea. AF, atrial fibrillation; DOACs, direct oral anticoagulants; PAC, parenteral anticoagulants; VKA, vitamin K antagonist; VTE, venous thromboembolism.

The main strengths of this study are the comprehensive analysis of trends in anticoagulant use, as well as treatment discontinuation and persistence; the large sample size made possible by leveraging the use of a nationwide health insurance database; and the focus on an understudied population and indication. As expected with studies based on administrative database, the study has several limitations, some of which were discussed by the investigators and include potential exposure mis-classification and mis-ascertainment of diagnoses when using prescription data and International Classification of Diseases codes; issues with and the lack of reporting of missing data; the inability to confirm whether patients were truly taking the anticoagulant prescribed; and the lack of granularity regarding the causes for treatment discontinuation, interruption, and switch. In addition, without information about provoking factors, it is challenging to interpret the data on treatment discontinuation for patients without cancer because those with provoked VTE are expected to complete treatment by 3 months and for patients with unprovoked VTE, only those at highest risk without bleeding contraindications are expected to continue treatment indefinitely. Likewise, information was not provided about the remission status of patients with cancer-associated VTE.

Nonetheless, the findings provide novel and important information on the patterns of anticoagulation uptake and treatment persistence in the treatment of VTE in South Korea. The finding of an increasing uptake of DOACs relative to other anticoagulants in VTE in patients with or without cancer is consistent with data from the United States,[12] France,[13] Denmark,[14] and Japan,[15] indicating that DOACs are being used in more than 80% of the treatment-naïve patients with VTE by the late 2010s. The high uptake of DOACs in South Korea is not unexpected because it is a high-income country[16] in which approximately 60% of the health coverage spending was covered by publicly mandated schemes in 2019 and where the average per capita public spending on health care is growing at a speed higher than most countries.[17] Common factors such as regulatory approval and guideline recommendations are expected to facilitate the adoption of DOACs but country-specific factors such as reimbursement also have important impact on the uptake of DOACs. Preferential uptake among the DOACs may be influenced by regional biases related to participation in pivotal trials, the effectiveness of dissemination and promotional campaigns, and the time to first approval and reimbursement. Interestingly, the findings by Yoon et al highlight the close relation between timing of approval, prescription reimbursement, and the increased uptake of DOACs, particularly rivaroxaban in South Korea ([Fig. 1]). It would be interesting to have more data in other Asian countries stratified by gross national income and reimbursement status for comparison and confirmation.

More importantly, the data from Yoon et al highlight a major missed opportunity. Despite recommendations of guidelines, there are major gaps in treatment continuation and persistence resulting in the under-treatment of high-risk patients, which could contribute to preventable morbidity and mortality. It is sobering to observe the dramatic decline in treatment persistence in patients with cancer-associated VTE, in whom guidelines recommend indefinite anticoagulation. Although the study did not examine the causes and impact of treatment discontinuation, the sharp decline in DOAC continuation after the eligible 6 months of reimbursement suggests an important contribution from drug affordability and lack of reimbursement. Drug affordability is one of the many barriers to treatment initiation and persistence and is expected to be worse in low- to middle-income countries, where there is an important burden of VTE.[16] [18] Consequently, there is a pressing need for more research to understand general and country-specific barriers to anticoagulant therapy, and to develop innovative and effective interventions to maximize the appropriate and cost-effective use of anticoagulants, and their long-term adherence.

Publication History

Received: 14 July 2023

Accepted: 17 July 2023

Accepted Manuscript online:
18 July 2023

Article published online:
17 August 2023

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