Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　― A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study) ―

Abstract

Background: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.

Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5–2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer.

Conclusions: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Conventional therapy for venous thromboembolism (VTE) includes a 5- to 10-day course of heparin followed by oral anticoagulation therapy with warfarin, a vitamin K antagonist, which has been widely used for 60 years. Although the efficacy of warfarin treatment has been proven,^1,2 it has several disadvantages, including the inconvenience of dietary restrictions and the requirement for routine coagulation monitoring. Since 2014, the mainstay of anticoagulation during VTE treatment in Japan has been direct oral anticoagulant (DOAC) therapy because it has several advantages over warfarin.^3–5 Nevertheless, warfarin is still used for reasons such as contraindications for DOAC.

However, a large-scale prospective study of warfarin therapy has not been conducted in Japan. Furthermore, the recommended prothrombin time-international normalized ratio (PT-INR) is 1.5–2.5 in the Japanese VTE guidelines without evidence,⁶ whereas a PT-INR of 2.0–3.0 is recommended in Western guidelines based on sufficient research results.^7,8 Therefore, we conducted a multicenter prospective observational cohort study (A Key prospective surveillAnce study oF venoUs thromboembolism for Japanese patIents [AKAFUJI] study) 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.

Methods

Study Design

The AKAFUJI study was a multicenter prospective observational cohort study designed to obtain real-world evidence of clinical outcomes in Japanese patients with acute symptomatic/asymptomatic VTE (deep vein thrombosis [DVT], pulmonary thromboembolism [PE], or both) treated with warfarin in real-world clinical practice and followed-up for 1 year after diagnosis; the target number of patients was 1,000.

Patients

Eligible patients were those diagnosed with acute symptomatic PE and acute symptomatic/asymptomatic DVT, including isolated distal DVT by imaging techniques, and for whom DOAC had not been prescribed within the study period. All patients provided written informed consent before registration.

Variables

The survey variables were as follows: data on patients’ background characteristics, including risk factors for VTE and clinical characteristics; medication status and drugs used concomitantly; non-pharmacological therapy for VTE; invasive treatment, including minor surgery other than therapy for VTE; clinical course; clinical laboratory test results; adverse events (AEs), including bleeding; and clinical events, including the recurrence of symptomatic VTE according to established imaging techniques. PT-INR was obtained at each visit. Bleeding AEs were classified by the attending physicians based on the criteria of the International Society on Thrombosis and Haemostasis with slight modifications. Data were collected from each patient’s case report form after 12 months of participation in the study.

Outcome Assessments

Data on the survey variables were used in the evaluation of the safety and efficacy of warfarin in clinical practice. The primary effectiveness outcome was the recurrence of symptomatic VTE during the treatment period. The principal safety outcome was major bleeding that occurred during the treatment period. Blinded adjudication of outcomes was conducted by an independent clinical events committee.

Statistical Analysis

All analyses were performed excluding missing data. For categorical variables, data are presented as frequencies and percentages. For continuous variables, data are presented as the mean±SD. To identify risk factors for recurrence and bleeding, a multivariate Cox proportional hazards model with a step-wise variable selection method (significance level 5%) was used. The variables used in the multivariate analysis for recurrence and bleeding were patient background characteristics.

Patients were divided into 2 groups according to whether they received warfarin. Categorical variables were compared between the groups using the Chi-squared test; continuous variables were compared using Student’s t-test. Patients were also divided into 3 groups according to transient risk factors and cancer. Categorical variables were compared among these groups using the Chi-squared test, whereas continuous variables were compared using a 1-way analysis of variance (ANOVA). Incidence rates of recurrence and bleeding were calculated as cumulative incidence and person-time (events/100 patient-years). The Kaplan-Meier method was used to investigate the characteristics of recurrence and bleeding in each group, and the curves were compared using the log-rank test.

Statistical analyses were performed using SAS version 9.4 (SAS Institute Japan, Tokyo, Japan), and statistical significance was set at P<0.05 (2-tailed). The target sample size was calculated by the width of the 95% confidence interval (CI). For acute symptomatic PE and acute proximal DVT, assuming 3.9% recurrence and 3.2% bleeding incidence rates,⁹ the width of the 95% CI was set within ±1.8%. The target sample size was 500, assuming that approximately 10% of cases would drop out, be censored, or missing. For acute isolated distal DVT, assuming 4.1% recurrence and 3.2% bleeding incidence rates, the width of the 95% CI was set within ±1.9%. The target sample size was 500, assuming that approximately 15% of cases would drop out, be censored, or missing. The total target sample size was 1,000, which was the sum of these 2 estimates.

Ethics Statement

The AKAFUJI Study was conducted in accordance with the principles of the Declaration of Helsinki, the Ethical Guidelines for Clinical Studies from the Japanese Ministry of Health, Labour and Welfare, and all applicable laws in Japan. The protocol of the present study was reviewed and approved by the Clinical Research Ethics Review Committee of Mie University Hospital (Reference no. 2729), along with the institutional review boards of all participating institutions. Data were reviewed by an independent data and safety monitoring committee. The AKAFUJI trial is registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000014132).

Results

Patient Characteristics at Baseline

From May 2014 to March 2017, 401 patients were enrolled at 57 institutions (Supplementary Table 1). All patients were enrolled within 4 weeks after the diagnosis of VTE and were followed up until the end of the follow-up period. Figure 1 shows a flow diagram of how the final population was derived from patients enrolled in the study. Patients were followed up until March 2018, and the median follow-up period was 336.0 days (interquartile range 1–392 days). Data from 49 of these 401 patients were excluded from analysis for the following reasons: DOAC prescribed (10 patients), doctor’s decision (6 patients), duplicate registration (3 patients), diseases not covered in this study (2 patients), death at registration (2 patients), no consent (7 patients), and inadequate procedure according to the ethics review board (20 patients). Therefore, the full analysis set comprised data from 352 patients.

Figure 1.

Study flowchart. Venous thromboembolism (VTE) included symptomatic acute pulmonary embolism (PE), acute proximal deep vein thrombosis (DVT), and acute distal DVT. DOAC, direct oral anticoagulant.

The baseline characteristics of the patients in this study (n=352) are summarized in Table 1. For continuous variables, the number of observations is also provided in Table 1. Across the entire study population, the mean age was 67.7±14.8 years, 57% of patients were female, mean body weight was 60.3±12.8 kg, and the mean creatinine level was 0.98±0.97 mg/dL. The percentage of patients with a diagnosis of symptomatic PE, proximal DVT, and isolated distal DVT was 39.2%, 34.1%, and 26.7%, respectively. Fourteen patients had thrombophilia and no recurrence of symptomatic VTE.

Table 1. Patient Characteristics (n=352)

Baseline clinical characteristics
Male sex (%)	153 (43.5)
Age (years) (n=352)	67.7±14.8
Height (cm) (n=344)	158.38±10.08
Weight (kg) (n=351)	60.28±12.79
BMI (kg/m2) (n=344)	24.02±4.00
BMI ≥30 kg/m2 (%)	28 (8.0)
Hemoglobin (g/mL) (n=350)	11.93±2.24
Platelets (×104/μL) (n=351)	224.9±89.0
Serum creatinine (mg/dL) (n=350)	0.979±0.966
eGFR (mL/min/1.73 m2) (n=350)	68.46±31.58
AST (IU/L) (n=349)	32.8±40.7
ALT (IU/L) (n=350)	28.0±34.6
PT-INR (n=342)	1.11±0.30
aPTT (s) (n=338)	35.7±17.2
Allergy	37 (10.5)
Smoking	40 (11.4)
VTE classification
Acute symptomatic PE	138 (39.2)
Acute proximal DVT	120 (34.1)
Acute isolated distal DVT	94 (26.7)
Severity classification of PE
Cardiac arrest collapse	7 (5.1)
Massive	16 (11.6)
Submassive	60 (43.5)
Non-massive	55 (39.9)
Symptomatic proximal DVT
Lower limbs (lower leg or thigh)	98 (81.7)
Lower leg	33 (27.5)
Thigh	98 (81.7)
Pelvis	48 (40.0)
Symptomatic isolated distal DVT	54 (45.0)
Image diagnosis (with duplicate diagnosis)
Computed tomography	243 (69.0)
Lower extremity venous ultrasound	240 (68.2)
Venography	7 (2.0)
Pulmonary artery angiography	4 (1.1)
Pulmonary blood flow scintigraphy	3 (0.9)
Others	2 (0.6)
Warfarin treatment	284 (80.7)
Risk factors for VTE
Thrombophilia	14 (4.0)
Protein S	6 (42.9)
Protein C	6 (42.9)
Antithrombin III	2 (14.3)
Lower limb paralysis	10 (2.8)
Pregnancy	11 (3.1)
Hypohydration	13 (3.7)
Bed rest	50 (14.2)
Injury and/or fracture	31 (8.8)
Lower limb immobilization	15 (4.3)
Recent surgery (within 3 months)	89 (25.3)
Active cancer	59 (16.8)
Chemotherapy	25 (7.1)
Infection	19 (5.4)
Active inflammatory diseases	24 (6.8)
HRT	19 (5.4)
History of VTE	39 (11.1)
COPD	15 (4.3)
Varicosis	27 (7.7)
Central venous catheter	14 (4.0)
CKD	39 (11.1)
Other diseases	37 (10.5)
History and combination disease
Cerebrovascular disease	33 (9.4)
Brain infarction	23 (69.7)
Cerebral hemorrhage	3 (9.1)
Subarachnoid hemorrhage	3 (9.1)
Cardiovascular disease	154 (43.8)
Ischemic heart disease	20 (13.0)
Hypertension	133 (86.4)
Arrhythmia	17 (11.0)
Heart failure	4 (2.6)
History of cancer	74 (21.0)
Metabolic disease	129 (36.6)
Dyslipidemia	82 (63.6)
Diabetes	54 (41.9)
Hyperuricemia	31 (24.0)
Others	2 (1.6)

Data given as the mean±SD or n (%). For continuous variables, the number of observations is also provided. ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; HRT, hormone replacement therapy; PE, pulmonary thromboembolism; PT-INR, prothrombin time-international normalized ratio; VTE, venous thromboembolism.

Efficacy and Safety of Warfarin Therapy

In the study cohort, 284 and 68 patients were treated with and without warfarin, respectively (Supplementary Table 1). The percentages of patients with symptomatic PE (with/without DVT), proximal DVT (without PE), and isolated distal DVT differed significantly between the 2 groups. The cumulative incidence of recurrent symptomatic VTE was higher in the group of patients without warfarin than among those with warfarin on-treatment (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018; Figure 2A). The cumulative incidence of bleeding complications was not significantly different between the 2 groups (4.0 vs. 1.8 per 100 person-years for warfarin on-treatment vs. without warfarin, respectively; P=0.434; Figure 2B). Multivariate analyses of patients who received warfarin treatment identified lower leg paralysis as a risk factor associated with recurrent VTE (Table 2A) and active inflammatory diseases and surgical procedure as risk factors associated with bleeding complications (Table 2B).

Figure 2.

Cumulative incidence of the primary (A) efficacy and (B) safety outcomes in the warfarin treatment and untreated groups. (A) Kaplan-Meier curves of the first occurrence of symptomatic recurrent venous thromboembolism, a composite of deep vein thrombosis and pulmonary embolism, in the overall study period. (B) Kaplan-Meier curves of major bleeding.

Table 2. (A) Differences in the Recurrence of Symptomatic VTE Among Background Factors According to the Cox Proportional Hazard Model (On-Treatment With Warfarin Administration), (B) Differences in Bleeding Complications Among Background Factors According to the Cox Proportional Hazard Model (On-Treatment With Warfarin Administration)

(A)	Univariate analysis				Multivariate analysis
	HR	95% CI		P value	HR	95% CI		P value
		Lower	Upper			Lower	Upper
Patient characteristics
Age	1.007	0.945	1.074	0.823
Male sex	0.259	0.029	2.320	0.227
Height	0.916	0.816	1.028	0.137
Weight	0.945	0.872	1.023	0.164
Smoking	1.059	0.118	9.481	0.959
In-hospital onset	0.924	0.103	8.322	0.944
Risk factors for VTE
Lower limb paralysis (yes)	11.443	1.242	105.407	0.031	11.443	1.242	105.407	0.031
Injury and/or fracture (yes)	2.432	0.271	21.802	0.427
Cerebrovascular disease (yes)	7.137	1.192	42.721	0.031
Cardiovascular disease (yes)	0.927	0.155	5.549	0.934
History of cancer (yes)	2.806	0.469	16.795	0.258
Active cancer (yes)	1.610	0.179	14.441	0.671
Metabolic disease (yes)	1.245	0.208	7.453	0.811
COPD (yes)	6.376	0.712	57.115	0.098
Varicosis (yes)	2.573	0.287	23.065	0.398
CKD (yes)	1.904	0.213	17.041	0.565
Baseline laboratory test
Hemoglobin	0.770	0.527	1.123	0.174
Platelets	1.002	0.992	1.011	0.709
Serum creatinine	0.961	0.377	2.451	0.933
AST	0.996	0.965	1.027	0.779
ALT	0.994	0.958	1.030	0.735
PT-INR	0.786	0.043	14.515	0.871
aPTT	1.009	0.970	1.049	0.670
SBP	0.973	0.951	0.996	0.021
DBP	0.973	0.922	1.028	0.329
Drug treatment
Unfractionated heparin (yes)	0.713	0.080	6.382	0.763
Intervention treatment (yes)	1.458	0.163	13.065	0.736
Treatment other than drugs (yes)	3.321	0.371	29.744	0.283
Combination drugs (yes)	1.143	0.191	6.839	0.884
Diagnosis
Symptomatic acute PE (yes)	0.274	0.031	2.454	0.247
Acute distal DVT (yes)	4.207	0.700	25.271	0.116
(B)	Univariate analysis				Multivariate analysis
	HR	95% CI		P value	HR	95% CI		P value
		Lower	Upper			Lower	Upper
Patient characteristics
Age	1.007	0.960	1.056	0.780
Male sex	1.328	0.357	4.946	0.672
Height	0.987	0.925	1.053	0.689
Weight	0.980	0.929	1.034	0.457
Allergy (yes)	1.097	0.137	8.777	0.931
Quit smoking (yes)	1.136	0.284	4.542	0.857
Onset in-hospital (yes)	2.828	0.758	10.558	0.122
Second recurrence (yes)	0.790	0.099	6.323	0.824
Risk factors of VTE
Injury and/or fracture (yes)	2.385	0.494	11.511	0.279
Burns (yes)	1.219	0.152	9.759	0.852
Lower limb immobilization (yes)	2.868	0.358	22.989	0.321
Recent surgery (within 3 months) (yes)	1.156	0.240	5.565	0.857
Cerebrovascular disease (yes)	3.125	0.649	15.049	0.155
Cardiovascular disease (yes)	1.126	0.302	4.196	0.859
Active cancer (yes)	0.528	0.066	4.225	0.547
History of cancer (yes)	0.812	0.101	6.512	0.845
Infection (yes)	2.881	0.360	23.048	0.319
Inflammation (yes)	3.811	0.791	18.347	0.095	5.206	1.010	26.836	0.049
HRT (yes)	2.368	0.296	18.968	0.417
History of VTE (yes)	0.722	0.090	5.777	0.759
Metabolic disease (yes)	0.899	0.225	3.594	0.880
COPD (yes)	2.960	0.370	23.682	0.306
Varicosis (yes)	1.278	0.160	10.224	0.817
CKD (yes)	2.173	0.451	10.462	0.333
Other diseases (yes)	1.114	0.139	8.916	0.919
Baseline laboratory test
Hemoglobin	0.902	0.667	1.221	0.505
Platelets	1.001	0.993	1.009	0.844
Serum creatinine	1.016	0.551	1.874	0.959
AST	1.004	0.996	1.012	0.329
ALT	0.996	0.971	1.023	0.779
PT-INR	0.364	0.011	12.408	0.575
aPTT	1.012	0.986	1.038	0.386
SBP	1.004	0.968	1.041	0.840
DBP	0.986	0.941	1.033	0.558
Drug treatment for VTE
Unfractionated heparin (yes)	0.346	0.086	1.382	0.133
Thrombolytics (yes)	0.594	0.074	4.748	0.623
Treatment for VTE other than drugs
Intervention treatment (yes)	0.705	0.088	5.634	0.741
Surgical procedure for VTE treatment (yes)	8.827	1.103	70.633	0.040	13.004	1.518	111.414	0.019
Elastic stockings (yes)	0.668	0.167	2.670	0.568
NSAIDs (yes)	0.894	0.112	7.151	0.916
Others (yes)	0.495	0.103	2.383	0.380
Diagnosis
Symptomatic acute PE (yes)	0.584	0.146	2.333	0.446
Acute distal DVT (yes)	0.743	0.093	5.939	0.779

CI, confidence interval; DBP, diastolic blood pressure; HR, hazard ratio; NSAIDs, non-steroidal anti-inflammatory drugs; SBP, systolic blood pressure. Other abbreviations as in Table 1. (A) There were no recurrences with the following factors: allergy, quit smoking, second recurrence, third or more recurrence, thrombophilia, pregnancy, delivery, hypohydration, bed rest, burns, lower limb immobilization, recent surgery (within 3 months), chemotherapy, infection, inflammation, hormone replacement therapy, oral contraceptives, anti-phospholipid antibody syndrome, inflammatory bowel disease, history of VTE, hyperhomocysteinemia, central venous catheter, catheterization treatment, vasculitis, polycythemia, fondaparinux, thrombolytics, warfarin, surgical procedure for VTE treatment, elastic stockings, intermittent pneumatic compression, anti-platelet therapy, non-steroidal anti-inflammatory drugs. (B) There were no bleeding complications with the following factors: third or more recurrence, pregnancy, delivery, hypohydration, bed rest, lower limb immobilization, chemotherapy, oral contraceptives, thrombophilia, anti-phospholipid antibody syndrome, hyperhomocysteinemia, central venous catheter, catheterization treatment, vasculitis, polycythemia, fondaparinux, warfarin, intermittent pneumatic compression, and anti-platelet drugs.

Clinical Outcomes Associated With PT-INR and Patient Characteristics

The mean PT-INR was calculated from the PT-INR obtained at each visit. The mean PT-INR during warfarin on-treatment was <1.5 in 180 patients, 1.5–2.5 in 97 patients, and >2.5 in 6 patients (Supplementary Table 2). Baseline characteristics did not differ significantly among the 3 groups, except for hereditary thrombophilia, active inflammatory diseases, and hormone replacement therapy. The incidence of bleeding complications was significantly higher in patients with a PT-INR >2.5 than in those with a PT-INR <1.5 or 1.5–2.5 (33.3% vs. 1.7% and 4.1%, respectively; P<0.001), whereas the incidence of recurrent VTE did not differ significantly among the 3 groups (Table 3).

Table 3. Recurrence Rates of Symptomatic VTE and Onset of Bleeding Events at 52 Weeks in Terms of the PT-INR

	PT-INR<1.5 (n=180)	1.5≤PT-INR≥2.5 (n=97)	2.5<PT-INR (n=6)	P value
Recurrence of symptomatic VTE
Yes	3 (1.7)	2 (2.1)	0 (0.0)	0.920
No	177 (98.3)	95 (97.9)	6 (100.0)
Major bleeding
Yes	3 (1.7)	4 (4.1)	2 (33.3)	<0.001
No	177 (98.3)	93 (95.9)	4 (66.7)
Major bleeding or clinically significant bleeding
Yes	3 (1.7)	4 (4.1)	3 (50.0)	<0.001
No	177 (98.3)	93 (95.9)	3 (50.0)
All bleeding
Yes	9 (5.0)	8 (8.2)	3 (50.0)	<0.001
No	171 (95.0)	89 (91.8)	3 (50.0)

Unless indicated otherwise, data are given as n (%). The rate of existence was calculated by the number of cases including censoring. Targeting events during the period included warfarin administration. The prothrombin time-international normalized ratio (PT-INR) is the average of measured values, excluding one case of warfarin administration without PT-INR measurement. Recurrence of symptomatic venous thromboembolism (VTE): if the onset of major bleeding is censored. Major bleeding: if the recurrence of symptomatic VTE is censored. Recurrence of symptomatic VTE: even if major bleeding was not censored.

Study patients were divided into 3 groups based on the following characteristics: VTE provoked by a transient risk factor; unprovoked VTE; and cancer-associated VTE. Patients with associated active cancer were classified into the cancer-associated VTE group. Patients with a transient risk factor for VTE excluding active cancer were classified into the VTE provoked by a transient risk factor group. Patients without active cancer and a transient risk factor for VTE were classified into the unprovoked VTE group. The VTE provoked by a transient risk factor, unprovoked VTE, and cancer-associated VTE groups comprised 89, 145, and 50 patients, respectively (Supplementary Table 3). The proportions of men and index VTE at presentation differed significantly among the 3 groups. The cumulative incidence of recurrent VTE (Figure 3A) and bleeding complications (Figure 3B) did not differ significantly among the 3 groups.

Figure 3.

Cumulative incidence of the efficacy and safety outcomes by risk factor. (A) Kaplan-Meier curves of the first occurrence of symptomatic recurrent venous thromboembolism (VTE), a composite of deep vein thrombosis and pulmonary embolism, in the overall study period. (B) Kaplan-Meier curves for major bleeding. Transient risk factors were surgery within 3 months, prolonged bed rest, central venous catheter, pregnancy or puerperium, trauma/fracture, burns, infections, and hormone replacement therapy.

Discussion

Warfarin therapy for VTE treatment in Japan has only been investigated in a small number of short-term Phase 3 clinical trials.^4,5 Since the approval of DOAC in Japan in 2014, most patients with VTE are currently treated with DOAC instead of warfarin. Therefore, prospective studies of VTE treatment with warfarin will be difficult in the future in Japan. The main findings of the present study were that warfarin therapy is effective without increasing the incidence of bleeding complications, regardless of patient characteristics, and a PT-INR of 1.5–2.5, as recommended by the Japanese VTE guidelines, is appropriate for patients with VTE.

In the present study, the incidence of recurrent symptomatic VTE in patients with a PT-INR of 1.5–2.5 was similar to that in patients with a PT-INR of 1.5–2.0 in a Western study that investigated appropriate warfarin therapy,¹⁰ but higher than that with a PT-INR of 2.0–3.0 in the same Western study. In contrast, the incidence of bleeding complications in patients with a PT-INR of >2.5 in the present study was higher than that in the Western study,¹⁰ whereas that bleeding complications in those with a PT-INR of 1.5–2.5 in the present study were comparable to those in the Western study.¹⁰ In addition, in a subanalysis of East Asian patients in the Hokusai-VTE trial, the incidence of bleeding complications in patients with a PT-INR of 2.0–3.0 following warfarin therapy was significantly greater among East Asian (including Japanese) patients than among Western patients.³ The superiority of warfarin therapy with a PT-INR of 1.5–2.5 over that with a PT-INR of <1.5 could not be proven in the present study. However, based on some other indications^9,11 and a slightly higher incidence of recurrent VTE in the present study, it is considered that warfarin therapy with a PT-INR of 1.5–2.5 is better than with a PT-INR of <1.5. Overall, warfarin therapy may be appropriate for the treatment of VTE in Japanese patients with a PT-INR of 1.5–2.5.

In previous retrospective studies in Japan, cancer patients with VTE had a higher recurrence and bleeding morbidity than other VTE patients, and cancer was a significant risk factor for recurrence and bleeding in VTE patients in multivariate analyses.^12–14 In contrast, the incidence of VTE recurrence and bleeding complications in patients with cancer in the present study were not higher than those in the other patient groups. Furthermore, cancer was not a risk factor for recurrence and bleeding in the present study. The reason for the discrepant results may be the prospective design of the present study. The annual all-cause mortality rate of patients in the previous retrospective study was relatively high,¹² whereas that in the present prospective study was low because patients with a poor prognosis are unlikely to be enrolled in prospective studies. Therefore, warfarin therapy with appropriate PT-INR control according to Japanese VTE guidelines is considered to be effective for patients with cancer who have a relatively good life expectancy.

The present study identified one independent predictor of VTE recurrence, namely lower leg paralysis, and 2 independent predictors of bleeding complications, namely active inflammatory diseases and surgical procedure. Except for surgical procedure,⁶ these factors have not been confirmed previously as predictors of VTE recurrence or bleeding. Despite several predictors of VTE recurrence and bleeding complications having been identified, no major predictor identified in previous studies was identified in the present study. Several prediction scores for VTE recurrence and bleeding complications have been developed, yet their applicability in clinical practice is limited, especially during anticoagulant therapy.^15,16

Study Limitations

This study has several limitations. First, this was a prospective observational study. The decisions regarding the intensity and duration of warfarin therapy were at the discretion of the treating physicians. Second, the study population was small, which especially affected the subgroup analyses. The target number of VTE patients could not be enrolled because DOAC therapy was available in Japan during the course of this study. Third, patients with isolated distal DVT were included in the study population, whereas previous VTE studies had excluded patients with isolated distal DVT. In this regard, the patients with isolated distal DVT enrolled in the present study were considered by an experienced physician to require treatment.

Conclusions

Warfarin therapy is effective for the treatment of Japanese patients with VTE without increasing the incidence of bleeding complications, regardless of patient characteristics. Moreover, the PT-INR (1.5–2.5) recommended by Japanese guidelines for patients with VTE is appropriate.

Acknowledgments

The authors appreciate the support and collaboration of the coinvestigators participating in the AKAFUJI Study. The authors thank Editage (www.editage.com) for English language editing. The authors also acknowledge the members of the AKAFUJI Study Group (see Appendix).

Sources of Funding

The AKAFUJI Study was funded by Daiichi Sankyo Co., Ltd., Tokyo, Japan. The sponsor had no role in the study design, conduct of the study, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosures

A.H. and H. Shimokawa are members of Circulation Journal’s Editorial Team. M.N. reports lecture fees from Daiichi Sankyo Co., Ltd. S.H. reports lecture fees from Daiichi Sankyo Co., Ltd. and Bayer Inc. M.M. reports lecture fees from Daiichi Sankyo Co., Ltd., Bayer Inc., and Bristol-Myers Squibb Company.

IRB Information

The AKAFUJI Study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (Reference no. 2729), along with the institutional review boards of all participating institutions.

Data Availability

The deidentified participant data will not be shared.

Appendix

Members of the AKAFUJI Study Group are listed below:

Principal Investigator

Hidamarinooka Nakamura Medical Clinic: Mashio Nakamura

Research Office

Department of Cardiology, Kuwana City Medical Center: Norikazu Yamada

Steering Committee

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital: Takeshi Yamamoto; Department of Cardiovascular Surgery, Fukushima Medical University Hospital, Fukushima (Japanese Red Cross Society Fukushima Hospital): Hirono Satokawa; Department of Cardiology, Musashino Red Cross Hospital: Toru Obayashi

Study Sites Recruiting at Least 1 Patient

Saiseikai Yamagata Saisei Hospital: Shigeki Hirooka; Nihon University School of Medicine: Atsushi Hirayama; National Cerebral and Cardiovascular Center: Akihiro Tsuji; Kitasato University Hospital: Mitsuhiro Hirata; National Hospital Organization Okayama Medical Center (Okayama Rosai Hospital): Mitsuru Munemasa; Wajokai Eniwa Hospital: Izumi Nakagawa; Kamiichi General Hospital: Masahiro Toshima; Tohoku University Graduate School of Medicine: Hiroaki Shimokawa, Hitoshi Goto; Fukushima Medical University Hospital (Japanese Red Cross Society Fukushima Hospital): Hirono Satokawa; Nagasaki University Graduate School of Biomedical Sciences: Koji Maemura; Saiseikai Kumamoto Hospital: Yusei Kawahara; Japanese Red Cross Musashino Hospital: Toshihiro Nozato; Yokohama City University Medical Center: Kazuo Kimura; Nagoya City University Graduate School of Medical Sciences (Seijukai Kawana Hospital): Kazuaki Wakami; Osaka Prefectural Hospital Organization Osaka International Cancer Institute: Mikio Mukai; Kyoto City Hospital: Eiji Yamamoto; Hamamatsu Red Cross Hospital: Kenichi Koyano; Mie University Graduate School of Medicine: Yoshito Ogihara; Yokohama Minami Kyosai Hospital: Makoto Mo; Kansai Medical University Medical Center: Hiroyoshi Komai; JR Sendai Hospital: Masataka Ichiki; Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital: Kiyoto Yamamoto; Kokura Memorial Hospital: Kenji Ando; Tomei Atsugi Hospital Social Medical Corporation Sanshikai: Atsuo Kojima; Dokkyo Medical University Nikko Medical Center: Takaaki Nakamoto; Hiratsuka Kyosai Hospital: Yuko Onishi; Kurume University School of Medicine: Yoshihiro Fukumoto; Munakata Suikokai General Hospital: Teiji Okazaki; Tokushima University Hospital: Masataka Sata; Hiroshima University Graduate School of Biomedical and Health Sciences: Yasuki Kihara; Kanazawa Medical University Hospital: Shigeru Sakamoto; Tokyo Medical University Hospital: Jun Yamashita; Nishinomiya Municipal Central Hospital: Tetsuya Kurimoto; Aichi Medical University: Hiroyuki Ishibashi; International University of Health and Welfare Hospital: Atsubumi Murakami; Nippon Medical School Hospital: Wataru Shimizu; Murase Hospital: Mashio Nakamura; Saiseikai Yokohamashi Nanbu Hospital: Tsutomu Endo; Tokyo Medical University Hachioji Medical Center: Shunya Shindo; National Hospital Organization Kyoto Medical Center: Masaharu Akao; Tokai University School of Medicine: Takuya Aoki; Hamamatsu University School of Medicine: Naoki Unno; Hamamatsu Medical Center: Naoto Yamamoto; Nara Medical University: Masanori Yoshikawa; Toho University: Kazuhiro Shimizu; National Hospital Organization Kumamoto Medical Center: Kazuteru Fujimoto; Saitama Medical University: Makoto Nagata; Tokai University Hachioji Hospital: Fumio Sakamaki; National Hospital Organization Nagasaki Medical Center: Kenji Kumagai; Kumamoto University Hospital: Kenichi Tsujita; Kyorin University Faculty of Medicine: Toru Sato, Yutaka Hosoi; Seirei Mikatahara General Hospital: Yasushi Wakabayashi; National Hospital Organization Osaka National Hospital: Motoo Date; Ehime University Hospital: Takumi Yasugi; Jichi Medical University Hospital: Masahisa Shimpo; Chiba University Hospital: Keiichi Ishida; Saitama Medical Center: Juno Deguchi

Event Adjudication Committee

Miharadai Hospital: Yoshiyuki Miyahara; Hitachi Memorial Hospital: Shigetsugu Ohgi; Kinki Health Administration Center, Mie Division: Masakatsu Nishikawa; Mie Prefectural General Medical Center: Hideo Wada

Clinical Research Support

Clinical Research Support Center, Mie University Hospital: Satoshi Tamaru

Biostatistician

Clinical Research Support Center, Mie University Hospital: Toru Ogura

Data Management

Clinical Research Support Center, Mie University Hospital: Yuki Nishimura, Chieko Fujimoto

Audit

NPO Mie Chiken Iryo Net: Yoko Uhira

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0158

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