Comparison of Effectiveness and Safety Among 3 Direct Oral Anticoagulants in Patients With Venous Thromboembolism　― A Single-Center Retrospective Study ―

Abstract

Background: Direct oral anticoagulants (DOACs), including edoxaban, rivaroxaban, and apixaban, are administered for the treatment of venous thromboembolism (VTE) in Japan. However, only a few reports have compared the effectiveness and safety of these DOACs.

Methods and Results: We retrospectively enrolled 702 patients who received DOACs for VTE treatment between September 2014 and March 2020. We investigated patient demographics, VTE recurrence, major bleeding, and mortality until March 2021, and compared them among the 3 DOACs. Most patients (~70%; n=496) were prescribed edoxaban, followed by apixaban (n=107) and rivaroxaban (n=99). Age, body mass index, renal function, and the proportion of cancer patients did not differ significantly among the DOACs. Edoxaban was administered relatively more in women with low body weight and anemia. The rate of pulmonary embolism was significantly lower among patients receiving edoxaban than apixaban or rivaroxaban (24.4% vs. 41.1% and 53.5%, respectively). VTE reoccurred in 2 patients administered apixaban and 1 patient administered edoxaban. The cumulative incidence of major bleeding at 1 year was 11.7%, 18.5%, and 9.0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. There were no significant differences in the cumulative incidence of major bleeding and all-cause death, estimated by Kaplan-Meier analysis, among the DOACs (log-rank P=0.316 and 0.722, respectively).

Conclusions: The safety of the 3 DOACs did not differ significantly in clinical settings, despite differences in patient demographics.

Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major healthcare problem associated with significant morbidity and mortality. The global incidence rate of VTE is 115–269 per 100,000,¹ with annual incidence rates ranging from 39 to 115 per 100,000 population for PE and from 53 to 162 per 100,000 population for DVT.^1–3 Although the incidence of VTE in Japan remains lower than in Western countries, the annual incidence rate of PE is gradually increasing.^4,5

For decades, the standard treatment for VTE has been heparin administration, followed by the intake of a vitamin K antagonist.⁶ Recently, direct oral anticoagulants (DOACs) have been developed and approved for the treatment of VTE. Clinical trials evaluating the effectiveness and safety of DOACs for VTE therapy have demonstrated that DOACs are non-inferior to standard heparin/vitamin K antagonist regimens.^7–10 The introduction of DOACs has simplified VTE treatment, presenting a lower risk of bleeding regardless of the etiology or extent of VTE and making extended secondary prevention more reliable.¹¹ In Japan, 3 DOACs, namely edoxaban, rivaroxaban, and apixaban, are currently available for the treatment of VTE; however, these DOACs differ in their administration protocols. Edoxaban requires the initial use of parenteral anticoagulants, whereas apixaban and rivaroxaban are approved for initial double doses of 1 week and 3 weeks, respectively, with the latter 2 allowing a single drug regimen until the maintenance phase. In addition, there are some differences in pharmacokinetics among the DOACs,¹² which may affect the clinical course of VTE patients. However, few studies have evaluated differences in safety and efficacy in a direct comparison of DOACs for the treatment of VTE, although several reports investigating safety and efficacy in patients with non-valvular atrial fibrillation have been published.^13–15 Moreover, several studies comparing the effectiveness and safety of different DOACs have been conducted in Western countries,^16,17 and showed some differences in the VTE incidence and approved maintenance dose of DOAC between Japan and Western countries.^18,19 Therefore, in the present study, we investigated and compared mortality, recurrent VTE, and major bleeding in VTE patients treated with edoxaban, rivaroxaban, or apixaban at Nagasaki University Hospital.

Methods

Study Population

Patient data from medical records were reviewed retrospectively. We recruited 793 consecutive patients who had either started VTE treatment with parenteral anticoagulants followed by warfarin and DOACs (edoxaban [Lixiana^®; Daiichi-Sankyo, Tokyo, Japan], rivaroxaban [Xarelto^®; Bayer, Leverkusen, Germany], or apixaban [Eliquis^®; Bristol Myers Squibb/Pfizer, New York, NY, USA]) or were switched from other oral anticoagulants to DOACs for VTE treatment between September 2014 and March 2020 at Nagasaki University Hospital to the study. Considering the aim of this study, 91 patients treated with warfarin alone were excluded. Finally, 702 patients (496, 107, and 99 patients treated with edoxaban, apixaban, and rivaroxaban, respectively) were enrolled in the study (Figure 1).

Figure 1.

Study flow chart. This study recruited 793 patients with venous thromboembolism (VTE) who were treated with oral anticoagulants; 91 patients who treated with warfarin alone were excluded, leaving 702 patients who were treated with a direct oral anticoagulant (DOAC), namely edoxaban (n=496), apixaban (n=107), and 99 rivaroxaban (n=99). Changes in thrombus volume were evaluated in 340, 86, and 78 patients treated with edoxaban, apixaban, and rivaroxaban, respectively.

This study complied with the Declaration of Helsinki regarding investigations in humans, and was approved by the Ethics Committee of Nagasaki University Hospital (No. 1909914). The requirement for written informed consent was waived by the Ethics Committee of Nagasaki University Hospital due to the retrospective nature of the study.

Clinical Outcomes

The primary outcomes were recurrent VTE, major bleeding, and all-cause mortality. Recurrent VTE was defined as deterioration of VTE on imaging tests during drug administration and the presence of symptoms. Major bleeding was defined using the International Society of Thrombosis and Hemostasis criteria as follows: fatal bleeding, symptomatic bleeding in a critical area or organ, a reduction in the hemoglobin concentration by at least 2 g/dL, or transfusion of at least 2 units of blood.²⁰ These events were investigated during the administration of DOACs and 1 week after stopping DOACs. The occurrence of death was examined from the initiation of drug administration until March 31, 2021.

The presence of VTE was confirmed by ultrasound of the lower extremities and contrast-enhanced computed tomography (CE-CT). VTE was classified as DVT alone or PE with and without DVT, and the site of DVT was classified as proximal (popliteal vein and/or above), distal (below the popliteal vein), or other.

Changes in the extent of thrombosis were examined in patients who underwent at least 2 imaging tests (ultrasound of the lower extremities or CE-CT; before and after the administration of DOACs) as a secondary outcome. The classification of these changes was based on the judgment of radiologists, sonographers, and cardiologists as follows: normalized (no thrombus in the legs and lungs); improved (improvements in both the legs and lungs or improvement in either the legs or lungs without deterioration at the other site); unchanged (unchanged results for both legs and lungs); and deteriorated (any deterioration in either legs or lungs).²¹

Active cancer was defined as a diagnosis of or treatment for cancer within the 6 months prior to DOAC therapy, or recurrent or metastatic cancer.

Hematological data during the diagnosis of VTE were evaluated.

Statistical Analysis

Continuous variables were tested for normal distribution using the Shapiro-Wilk test. All continuous variables were non-parametric and data are expressed as the median and interquartile range (IQR). The significance of differences between groups was tested using the Kruskal-Wallis test (followed by multiple comparisons using the Steel-Dwass test, as appropriate) for non-parametric data. Categorical variables are presented as absolute numbers and percentage and were compared using the Pearson Chi-squared test when appropriate; otherwise, Fisher’s exact test was used. Kaplan-Meier analysis was used to estimate the cumulative incidence of events, and log-rank tests were used to compare groups. Patient deaths and those who developed recurrent VTE, major bleeding, and stopped or changed DOAC were censored. The significance level was set at 2-tailed P<0.05. All statistical analyses were performed using JMP version 16.0.0 (SAS Institute, Cary, NC, USA).

Results

Patient Demographics

Patient demographics are presented in Table 1. In this study, the median age and body weight were 68 years and 56.9 kg, respectively; 58.2% the patient cohort were women and 46.0% had active cancer. At baseline, the median creatinine clearance was 71.9 mL/min, and the median D-dimer level was 7.7 µg/mL. The median duration of DOAC administration was 101 days (IQR 29–292 days).

Table 1. Baseline Characteristics of All Patients and for Patients Treated With Each DOAC Separately

	All (n=702)	DOAC therapy
		Edoxaban (n=496)	Apixaban (n=107)	Rivaroxaban (n=99)	P value
Age (years)	68 [59–77]	68 [60–77]	69 [59–78]	66 [55–76]	0.154
Age ≥75 years	225 (32.1)	158 (31.9)	39 (36.4)	28 (28.3)	0.448
Female sex	409 (58.2)	306 (61.7)	52 (48.6)	51 (51.5)	0.015
Weight (kg)	56.9 [48.4–66.5]	55.8 [47.2–65.8]	58 [51–68.8]	58.9 [53.6–67]	0.008
Body mass index	22.8 [20–25.5]	22.4 [19.7–25.4]	23.4 [20.3–25.7]	23.4 [21.0–25.7]	0.054
History of VTE	33 (4.7)	21 (4.2)	7 (6.5)	5 (5.1)	0.583
Surgery within 1 month	205 (29.2)	151 (30.4)	29 (27.1)	25 (25.3)	0.511
Active cancer	323 (46.0)	234 (47.2)	50 (46.7)	39 (39.4)	0.361
Administration duration (days)	101 [29–292]	99 [29–301]	99 [28–213]	115 [32–375]	0.484
Laboratory data at diagnosis
Creatinine clearance (mL/min)	71.9 [53.2–95.4]	69.6 [52.0–97.4]	73.9 [53.3–90.9]	77.2 [58–96.3]	0.184
Red blood cells (×104/μL)	369 [319–421]	362 [313–411]	381 [318–442]	401 [345–435]	<0.001
Hemoglobin (g/dL)	11.1 [9.7–12.7]	10.9 [9.5–12.4]	11.5 [9.9–13.4]	11.6 [10.3–13.2]	0.002
White blood cells (/μL)	6,900 [5,300–6,900]	6,900 [5,150–9,600]	7,300 [5,400–9,900]	6,850 [5,500–9,800]	0.623
Platelets (×103/μL)	222 [153–297]	228 [155–299]	202 [141–273]	234 [165–318]	0.119
C-reactive protein (mg/dL)	1.7 [0.37–5.6]	1.9 [0.34–5.5]	1.7 [0.39–6.4]	1.3 [0.47–5.8]	0.990
D-dimer (μg/mL)	7.7 [3.4–17.8]	7.1 [3.0–17.6]	9.9 [4.6–20.3]	10.7 [4.2–17.0]	0.819
Site of VTE
Pulmonary embolism	218 (31.1)	121 (24.4)	44 (41.1)	53 (53.5)	<0.001
Deep vein thrombosis	658 (93.7)	468 (94.4)	101 (94.4)	89 (89.9)	0.237
Deep vein thrombosis alone	484 (68.9)	375 (75.6)	63 (58.9)	46 (46.5)	<0.001
Proximal	159 (32.8)	109 (29.1)	34 (54.0)	16 (34.8)	0.003
Distal	273 (56.4)	225 (60.0)	22 (34.9)	26 (56.5)
Others	52 (10.7)	41 (10.9)	7 (11.1)	4 (8.7)

Unless indicated otherwise, data are presented as the median [interquartile range] or as n (%). DOAC, direct oral anticoagulant; VTE, venous thromboembolism.

The most prescribed DOAC was edoxaban (n=496; 70.7%), followed by apixaban (n=107; 15.2%) and rivaroxaban (n=99; 14.1%; Table 1). The most prescribed daily maintenance dose of each DOAC was 30 mg for edoxaban, 10 mg for apixaban, and 15 mg for rivaroxaban (Supplementary Table). The edoxaban group had a significantly higher proportion of female patients and lower body weight than the other DOAC groups. The factors related to the risk of recurrent VTE, such as a history of VTE, surgery within 1 month, and active cancer, did not differ significantly among the 3 DOACs. Laboratory data at diagnosis, except for red blood cell count and hemoglobin concentration, did not differ significantly among the 3 DOAC groups. Considering the site of VTE, the proportion of patients with PE and DVT alone was significantly lower and higher, respectively, in the edoxaban group than in the apixaban and rivaroxaban groups. Proximal DVT was more common in the apixaban group than in the other groups (Table 1).

The primary cancer lesions were predominantly in the uterus and adnexa (27.4%), followed by the gastrointestinal tract (19.5%), lung (10.8%), blood (10.8%), and liver, bile duct, and pancreas (10.5%; Table 2). Patients with cancers of the oral cavity, pharynx, and larynx were administered rivaroxaban more frequently than the other 2 DOACs (Table 2).

Table 2. Site of Active Cancer in All Patients and in Patients Treated With Each DOAC Separately

	All (n=323)	DOAC therapy
		Edoxaban (n=234)	Apixaban (n=50)	Rivaroxaban (n=39)	P value
Uterus, adnexa	88 (27.4)	67 (28.6)	13 (26.0)	8 (20.5)	0.560
Gastrointestinal tract	63 (19.5)	44 (18.8)	10 (20.0)	9 (23.1)	0.820
Lung	35 (10.8)	25 (10.7)	5 (10.0)	5 (12.8)	0.905
Blood	35 (10.8)	24 (10.3)	7 (14.0)	4 (10.3)	0.736
Liver, bile duct, pancreas	34 (10.5)	26 (11.1)	5 (10.0)	3 (7.7)	0.806
Urinary, prostate	22 (6.8)	15 (6.4)	5 (10.0)	2 (5.1)	0.556
Oral cavity, pharynx, larynx	19 (5.9)	14 (6.0)	0 (0.0)	5 (12.8)	0.027
Brain	12 (3.7)	8 (3.4)	4 (8.0)	0 (0.0)	0.169
Breast	9 (2.8)	6 (2.6)	1 (2.0)	2 (5.1)	0.552
Others	6 (1.9)	5 (2.1)	0 (0.0)	1 (2.6)	0.656

Unless indicated otherwise, data are presented as n (%). DOAC, direct oral anticoagulant.

Primary Outcomes: VTE Recurrence, Major Bleeding, and All-Cause Mortality

Recurrent VTE occurred in 3 patients, 2 treated with apixaban and the other treated with edoxaban. All patients developed PE, including a case of massive PE. Kaplan-Meier analysis showed that the cumulative incidence of recurrent VTE was significantly different among the 3 groups (log-rank, P=0.042; Figure 2A).

Figure 2.

Cumulative incidence of (A) recurrent venous thromboembolism, (B) major bleeding, and (C) all-cause mortality in patients treated with edoxaban, apixaban, and rivaroxaban. The panels below each graph show the number of at-risk patients. DOACs, direct oral anticoagulants.

Major bleeding occurred in 8.6%, 9.3%, and 5.0% (cumulative incidence at 1 year; 11.7%, 18.5%, and 9.0%) of patients on edoxaban, apixaban, and rivaroxaban, respectively (Table 3). Gastrointestinal bleeding was the most common (n=25), followed by genital bleeding (n=11) and urinary tract bleeding (n=5). Major bleeding at each site did not differ among the 3 DOACs, except for the liver and gall bladder in the apixaban group (Table 3). Patients with active cancer had a significantly higher incidence of major bleeding than those without, and experienced, in particular, significant gastrointestinal and genital bleeding (Table 4). The cumulative incidence of major bleeding did not differ among the DOAC groups (log-rank, P=0.316; Figure 2B).

Table 3. Site of Major Bleeding in All Patients and in Patients Treated With Each DOAC Separately

	All (n=702)	DOAC therapy
		Edoxaban (n=496)	Apixaban (n=107)	Rivaroxaban (n=99)	P value
All major bleeding	58 (8.3)	43 (8.6)	10 (9.3)	5 (5.0)	0.445
Specific site
Gastrointestinal tract bleeding	25 (3.6)	20 (4.0)	3 (2.8)	2 (2.0)	0.729
Genital bleeding	11 (1.6)	7 (1.4)	2 (1.9)	2 (2.0)	0.699
Urinary tract bleeding	5 (0.7)	3 (0.6)	2 (1.9)	0 (0.0)	0.306
Cerebral bleeding	4 (0.6)	3 (0.6)	0 (0.0)	1 (1.0)	0.536
Respiratory bleeding	3 (0.4)	3 (0.6)	0 (0.0)	0 (0.0)	1.000
Liver/gall bladder bleeding	2 (0.3)	0 (0.0)	2 (1.9)	0 (0.0)	0.043
Postoperative bleeding triggered by DOACs	3 (0.4)	3 (0.6)	0 (0.0)	0 (0.0)	1.000
Others	5 (0.7)	4 (0.8)	1 (0.9)	0 (0.0)	0.655

Unless indicated otherwise, data are presented as (%). DOAC, direct oral anticoagulant.

Table 4. Site of Major Bleeding in Patients With and Without Active Cancer

	All (n=702)	With active cancer (n=323)	Without active cancer (n=379)	P value
All major bleeding	58 (8.3)	42 (13.0)	16 (4.2)	<0.001
Specific site
Gastrointestinal tract bleeding	25 (3.6)	18 (5.6)	7 (1.8)	0.008
Genital bleeding	11 (1.6)	10 (3.1)	1 (0.3)	0.003
Urinary tract bleeding	5 (0.7)	4 (1.2)	1 (0.3)	0.126
Intracranial bleeding	4 (0.6)	2 (0.6)	2 (0.5)	0.873
Respiratory bleeding	3 (0.4)	2 (0.6)	1 (0.3)	0.472
Liver/gall bladder bleeding	2 (0.3)	1 (0.3)	1 (0.3)	0.910
Postoperative bleeding triggered by DOACs	3 (0.4)	2 (0.6)	1 (0.3)	0.472
Others	5 (0.7)	3 (0.9)	2 (0.5)	0.529

Unless indicated otherwise, data are presented as n (%). DOACs, direct oral anticoagulants.

The mortality rate was 20.1% in the entire population during the study period, and there was no significant difference in mortality among the 3 DOACs (Table 5). Cancer-related death was the most common, whereas VTE recurrence and major bleeding rarely contributed to death (Table 5). No significant difference in the cumulative incidence of all-cause mortality was found among the 3 DOAC groups (log-rank, P=0.722; Figure 2C).

Table 5. Cause of Death Among All Patients and for Patients Treated With Each DOAC Separately

	All (n=702)	DOAC therapy
		Edoxaban (n=496)	Apixaban (n=107)	Rivaroxaban (n=99)	P value
All deaths	141 (20.1)	101 (20.4)	23 (21.5)	17 (17.2)	0.712
Specific causes of death
Recurrent VTE	0/141 (0.0)	0/101 (0.0)	0/23 (0.0)	0/17 (0.0)	–
Bleeding	5/141 (3.5)	3/101 (3.0)	1/23 (4.3)	1/17 (5.9)	0.439
Cancer-related death	116/141 (82.3)	83/101 (82.2)	18/23 (78.3)	15/17 (88.2)	0.778
Cardiovascular death	4/141 (2.8)	3/101 (3.0)	1/23 (4.3)	0/17 (0.0)	0.741
Other	12/141 (8.5)	9/101 (8.9)	2/23 (8.7)	1/17 (5.9)	1.000
Unknown	4/141 (2.8)	3/101 (3.0)	1/23 (4.3)	0/17 (0.0)	0.741

Unless indicated otherwise, data show n/N, with percentages in parentheses. DOAC, direct oral anticoagulant; VTE, venous thromboembolism.

Secondary Outcome: Changes in the Extent of Thrombosis

The median interval between the initiation of DOACs and follow-up imaging test was 61 days (IQR 14–123 days) in the edoxaban group, 33 days (IQR 8–102 days) in the apixaban group and 47 days (IQR 16–99 days) in the rivaroxaban group (P=0.140). The proportion of patients with normalization or improvement in thrombus volume was 85.9%, 82.6%, and 85.9% in the edoxaban, apixaban, and rivaroxaban groups, respectively, with no significant difference in the changes among the 3 DOAC groups (P=0.272; Figure 3).

Figure 3.

Changes in thrombosis in patients treated with edoxaban, apixaban, and rivaroxaban. Changes in thrombosis were defined as follows: normalized, no thrombus in the legs and lungs; improved, improvements in both the legs and lungs or improvement in either the legs or lungs without deterioration at the other site; unchanged, no changes in both legs and lungs; and deteriorated, any deterioration in either legs or lungs.

Discussion

The main findings of the present study are as follows. First, of the VTE patients treated with DOACs at Nagasaki University Hospital, approximately 70% were prescribed edoxaban, followed by apixaban and rivaroxaban. Edoxaban was prescribed more often in female and lower-weight patients for DVT alone than the other 2 DOACs. Second, the cumulative incidence of all-cause mortality and major bleeding did not differ among the DOAC groups. In contrast, there was a significant difference in the cumulative incidence of recurrent VTE, despite its very low incidence, and major bleeding occurred more frequently in the gastrointestinal and genital sites in patients with active cancer. Finally, in all DOAC groups, the thrombus normalized or improved in >80% of patients who underwent follow-up imaging tests.

Edoxaban was first approved for VTE treatment in Japan in September 2014, followed by rivaroxaban and apixaban in September 2015 and December 2015, respectively. After the approval and distribution of edoxaban, the proportion of patients receiving DOACs as an anticoagulant therapy for VTE increased markedly, whereas the proportion of patients receiving warfarin decreased from 94% in 2012 to 15% in 2017.²² Of the 3 DOACs evaluated in this study, edoxaban was the most prescribed. This is most likely due to differences in approval dates. In addition, edoxaban has dose reduction criteria based on weight, renal function, and concomitant medications, which may make it easier for physicians, especially those unfamiliar with VTE treatment, to determine the appropriate dosage. This, in turn, may result in the use of edoxaban in female patients with a low body weight. Given the higher proportion of patients with DVT alone or anemia, edoxaban was selected for patients with a lower severity of VTE and a higher risk of bleeding in the present study. In contrast, the rivaroxaban and apixaban treatment groups had a higher proportion of PE. These 2 drugs allow for an initial double dose and a single-drug regimen for the treatment of VTE, facilitating the treatment of relatively high-risk VTE. The rivaroxaban treatment group had the lowest incidence of death, major bleeding, and recurrent VTE among the 3 DOACs. Furthermore, patients taking rivaroxaban were the youngest, heaviest and had the highest creatinine clearance and fewest complications regarding active cancer among those taking the 3 DOACs, although the differences did not reach statistical significance. These results suggest that rivaroxaban may have been administered to patients with a low bleeding risk. As mentioned above, the choice of DOAC is at the discretion of the physician, which could have affected the main outcome of the present study.

Landmark studies of each DOAC compared to vitamin K antagonists showed that symptomatic VTE reoccurred in 3.2%, 2.3%, and 2.1% of VTE patients treated with edoxaban,⁷ apixaban,⁸ and rivaroxaban,^9,10 respectively. In the present study, the cumulative incidence of VTE recurrence at 1 year was 0.4%, 2.2%, and 0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. The incidence of recurrent VTE was lower in our patients than in the landmark studies. For Japanese VTE patients, the rate of incidence was reported to be 0.8% in 2 post-marketing surveillance studies of edoxaban²³ and apixaban²⁴ during the on-treatment period, and 3.1% within 12 months in a multicenter prospective observational cohort study of rivaroxaban.²⁵ It is difficult to compare the incidence of VTE recurrence between our study and previously published data because of differences in the study population size, the VTE details of the patients, and the follow-up periods. The incidence of VTE has been reported to be lower in Japanese than Caucasian populations;²⁶ therefore, racial differences may partly affect VTE recurrence under anticoagulant therapy.

Because of the low incidence of VTE recurrence, we investigated changes in the extent of thrombus formation caused by each DOAC as an indicator of effectiveness. We found that >80% of patients achieved normalization or improvement in thrombosis under the 3 DOACs, with no significant differences in the proportions among the 3 groups. In the J-EINSTEIN DVT and PE study, the thrombosis improved or normalized in 84.0% and 95.8% of rivaroxaban recipients at Day 22 and the end of the intended treatment period, respectively.²⁷ The AMPLIFY-J study showed that apixaban improved thrombosis burden in >70% of DVT patients and >90% of PE patients at 24 weeks after treatment.²⁸ We also previously reported that 89.6% and 94.1% of non-cancer and cancer patients treated with edoxaban, respectively, showed normalization or improvement in thrombosis.²¹ The results of the present study are consistent with those of the previous Japanese studies.

The cumulative incidence of major bleeding in the present study was not significantly different among the 3 DOACs. The incidence of major bleeding was higher in our patients than in those treated with DOACs in previous Japanese studies (11.7% vs. 2.6% for edoxaban,²³ 18.5% vs. 3.4% for apixaban,²⁴ and 9.0% vs. 2.9% for rivaroxaban²⁵). This may be due to the higher proportion of active cancer patients in the present study (46.0%) than in previous studies conducted in Japan (19.0–26.9%),^23–25 given that patients with active cancer had a significantly higher incidence of major bleeding than those without active cancer in this study. Patients with cancer-associated VTE have been reported to have a higher risk of recurrence and bleeding than those without active cancer.^29,30 Indeed, risk scores predicting major bleeding in VTE patients during anticoagulation therapy, such as the RIETE score³¹ and VTE-BLEED score,³² include active cancer as a component. Furthermore, the most frequent site of major bleeding in the present study was the gastrointestinal tract, which is similar to data from the RIETE³³ and COMMAND-VTE³⁴ registries. Randomized clinical trial data with head-to-head comparisons between DOACs and low-molecular-weight (LMW) heparins showed that DOACs have an overall similar effectiveness. However, a higher risk of bleeding was also observed in some of these studies.³⁵ A systematic review and meta-analysis showed that gastrointestinal bleeding occurred in 20 (1.5%) patients in the dalteparin (an LMW heparin)-treated group, compared with 39 (3.0%) patients in the DOAC-treated groups (risk ratio 0.53; 95% confidence interval 0.31–0.92; P=0.020).³⁶ In the Hokusai VTE Cancer trial, the rate of major bleeding was significantly higher with edoxaban than with dalteparin, which was due primarily to the higher rate of upper gastrointestinal tract bleeding in patients with gastrointestinal cancer treated with edoxaban.^37,38 The major bleeding was considered to be derived from tumor bleeding, bleeding from operative wounds, and gastric mucosal injury caused by anticancer drugs.³⁸ Taking all this into consideration, a relatively higher proportion of patients in this study had gastrointestinal tract cancer, resulting in a higher incidence of major bleeding, especially in the gastrointestinal tract.

Most causes of death were cancer related, and no differences in mortality were found among the 3 DOACs in the present study. In randomized multicenter trials in patients with cancer-associated thrombosis, all-cause mortality occurred in 39.5%, 23.6%, and 23.4% of patients treated with edoxaban,³⁷ rivaroxaban,³⁹ and apixaban,⁴⁰ respectively. In contrast, in a Japanese multicenter prospective observational study that included active cancer patients (19.0%), 9.3% of patients died.²⁵ The relatively high mortality rate (20.1%) in the present study was presumably due to the administration of DOAC to patients with advanced-stage cancer, although the stage of cancer was not recorded.

A few reports have compared the effectiveness and safety of DOACs for VTE treatment. A systematic review and network meta-analysis demonstrated that apixaban treatment was associated with the maximum safety profile among the DOACs, with a significantly reduced risk of major or clinically relevant non-major bleeding compared with rivaroxaban and edoxaban, although there were no significant differences between DOACs with regard to the risk of VTE and VTE-related death.⁴¹ Across the 9 network meta-analyses evaluating the safety and effectiveness of DOACs in acute and extended treatment of VTE, the indirect evidence consistently points to a significant reduction in the risk of major bleeding and clinically relevant bleeding with apixaban compared with the other DOACs.⁴² In contrast, Li et al indirectly compared the treatment effects among 4 DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) and found no significant difference in the risk of recurrent VTE and major bleeding.⁴³ This apparent discrepancy may be due to differences in the number of studies included in the indirect analysis. Retrospective cohort studies and indirect comparisons can provide some insights into the choice of DOACs for the treatment of VTE; however, they are still few. Therefore, our results may be meaningful in this regard. However, head-to-head trials to compare the effectiveness and safety of DOACs are warranted.

Study Limitations

This study has several limitations. First, it was a retrospective single-center observational study conducted through the evaluation of pre-existing patient medical records. Therefore, data on the risk of recurrent VTE, such as that pertaining to thrombogenicity, post-thrombotic syndrome in DVT patients, and right ventricular dysfunction in PE patients, were not completely available. Second, there were differences in the number and demographics of patients among the 3 DOAC groups due to physician discretion regarding drug administration or differences in drug approval dates. Third, there was no definite follow-up protocol for imaging and blood tests; therefore, the follow-up period and assessment method varied among patients, which may had led to an underestimation of recurrent VTE and bleeding. Finally, unlike large randomized multicenter studies^7–10 that enrolled patients with symptomatic VTE, we recruited patients with VTE diagnosed by imaging tests regardless of symptoms. This may have affected the results of this study; however, our results were derived from clinical practice.

Conclusions

In the present study, we demonstrated no significant difference in the safety of the 3 DOACs in the treatment of VTE. There were a few cases of VTE recurrence with the DOACs. The results may be due to the appropriate selection of DOACs for treatment by physicians, in accordance with patient demographics and the extent of VTE. Further studies, including direct comparisons, are required to clarify the differences in effectiveness and safety among DOACs.

Sources of Funding

This study did not receive any specific funding.

Disclosures

S.I. has received lecture fees from Daiichi-Sankyo Co., Ltd. K.M. has received lecture fees from Daiichi-Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and Pfizer Japan Inc., and donations/scholarship funds from Daiichi-Sankyo Co., Ltd. K.M. is a member of Circulation Reports’ Editorial Team.

IRB Information

The research protocol was approved by the Nagasaki University Hospital Ethics Committee (Approval no. 1909914).

Data Availability

The data, analytic methods, and study materials will not be made available to other researchers for reproducing the results or replicating the procedure.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circrep.CR-22-0095

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