Resolving the Gap in Evidence on the Role of Warfarin in Venous Thromboembolism Management in Japan

In venous thromboembolism (VTE) practice, the center of treatment is anticoagulant therapy,¹ in which, warfarin sodium has been the gold standard in oral anticoagulation for more than 50 years.^2,3 Since the emergence of direct oral anticoagulants (DOACs) 14 years ago in Japan, they have established their leadership role because of several advantages over warfarin. Owing to predictable bioavailability and pharmacokinetics, DOACs can be given at fixed doses without routine laboratory monitoring, and, compared with warfarin, there is little interaction when DOACs are administered at the same time as other medications. In term of clinical evidence, large-scale phase III randomized trials have shown that DOACs have the same efficacy, but a significant reduction in bleeding risk, as conventional anticoagulation therapy (heparin followed by warfarin). In the J-EINSTEIN DVT/PE⁴ and AMPLIFY-J trials,⁵ which comprised Japanese patients, rivaroxaban and apixaban revealed consistent efficacy and safety profiles with global clinical trials. For edoxaban, subanalysis of the Hokusai VTE trial showed results in East Asian patients consistent with overall study results.⁶ From analysis of JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases–Diagnosis Procedure Combination) data, after the release of DOACs for VTE management, the proportion of patients receiving DOACs increased dramatically in 2017, while the proportion of patients receiving warfarin decreased from 94% in 2012 to 15% in 2017.⁷

Article p 359

Although use of warfarin has decreased over time, it remains an important treatment option even in the era of DOACs for reasons such as contraindication for DOACs and treatment of special conditions.⁸ There is a lack of evidence to support the use of DOACs in patients with an estimated creatinine clearance (CrCl) <30 mL/min, as these patients were excluded from clinical trials comparing DOACs to warfarin for VTE treatment.^4–6 Because warfarin’s clearance does not rely on the renal route, it is the preferred oral anticoagulant option for patients with an estimated CrCl <30 mL/min. In a randomized, open-label study of high-risk patients with antiphospholipid syndrome, rivaroxaban was associated with an increased rate of thromboembolic and major bleeding events compared with warfarin.⁹ At present, DOACs are not an alternative to warfarin for patients with antiphospholipid syndrome.¹⁰

Although warfarin has been used in VTE management for a long time, a large-scale prospective study of warfarin therapy for VTE has not been conducted in Japan, and the clinical evidence for warfarin supporting consensus panel recommendations is not strong. Furthermore, the recommended prothrombin time-international normalized ratio (PT-INR) is 1.5–2.5 in the Japanese VTE guidelines without evidence,¹ whereas a PT-INR of 2.0–3.0 is recommended in Western guidelines based on sufficient research results.¹⁰ In a randomized and double-blind study of 738 patients with unprovoked VTE, it was shown that conventional-intensity warfarin therapy with a target INR of 2.0–3.0 was more effective than low-intensity warfarin therapy with a target INR of 1.5–1.9 for the long-term prevention of recurrent VTE.¹¹ In addition, the low intensity warfarin regimen did not reduce the risk of clinically important bleeding.

Therefore, a clinical study of VTE treatment with warfarin is needed to resolve some evidence gaps in Japan.

In this issue of the Journal, Nakamura et al report on a multicenter, prospective, observational cohort study, the AKAFUJI Study, that was conducted to investigate the efficacy and safety of warfarin for the treatment of Japanese patients with VTE in a real-world setting and to provide evidence to support the PT-INR recommended in the Japanese VTE guidelines.¹² The primary effectiveness outcome was the recurrence of symptomatic VTE during the treatment period. The principal safety outcome was major bleeding during the treatment period. From May 2014 to March 2017, study patients were enrolled at 57 institutions, and the full analysis set comprised data from 352 patients. The patients treated with warfarin were divided into the 3 groups: mean INR <1.5, 1.5–2.5, and >2.5 during warfarin therapy. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, but the incidence of recurrent VTE was not significantly different among groups. The main findings of the AKAFUJI study were that warfarin therapy is effective without increasing the incidence of bleeding complications, regardless of PT-INR of 1.5–2.5, and that warfarin therapy with a PT-INR of 1.5–2.5 might be appropriate for the treatment of VTE in Japanese patients.

Warfarin is recommended for VTE patients who have certain clinical conditions, and its role is still a work in progress. The AKAFUJI study could have provided valuable information on the remaining challenges of warfarin in the area of VTE practice in Japan.

Disclosures

The author has no conflicts of interest to disclose.

IRB Information

None.

References

• 1.   Japanese Circulation Society Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2017) (in Japanese). https://www.j-circ.or.jp/cms/wp-content/uploads/2017/09/JCS2017_ito_h.pdf (accessed July 17, 2023).
• 2.   Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Lärfars G, Nicol P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a firstepisode of venous thromboembolism. N Engl J Med 1995; 332: 1661–1665.
• 3.   Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901–907.
• 4.   Yamada N, Hirayama A, Maeda H, Sakagami S, Shikata H, Prins MH, et al. Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism: The J-EINSTEIN DVT and PE program. Thromb J 2016; 13: 2, doi:10.1186/s12959-015-0035-3.
• 5.   Nakamura M, Nishikawa M, Komuro I, Kitajima I, Uetsuka Y, Yamagami T, et al. Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J study). Circ J 2015; 79: 1230–1236.
• 6.   Nakamura M, Wang YQ, Wang C, Oh D, Yin WH, Kimura T, et al. Efficacy and safety of edoxaban for treatment of venous thromboembolism: A subanalysis of East Asian patients in the Hokusai-VTE trial. J Thromb Haemost 2015; 13: 1606–1614.
• 7.   Yamashita Y, Morimoto T, Yoshikawa Y, Yaku H, Sumita Y, Nakai M, et al. Temporal trends in the practice pattern for venous thromboembolism in Japan: Insight from JROAD-DPC. J Am Heart Assoc 2020; 9: e014582, doi:10.1161/JAHA.119.014582.
• 8.   Witt DM, Clark NP, Kaatz S, Schnurr T, Ansell JE. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016; 41: 187–205.
• 9.   Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatt A, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132: 1365–1371.
• 10.   Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41: 543–603.
• 11.   Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 631–639.
• 12.   Nakamura M, Tamaru S, Hirooka S, Hirayama A, Tsuji A, Hirata M, et al. Efficacy and safety of warfarin for the treatment of venous thromboembolism: A multicenter prospective observational cohort study in Japan (AKAFUJI Study). Circ J 2024; 88: 359–368.