Abstract
Aims: Direct oral anticoagulants (DOACs) are used to treat venous thromboembolism (VTE). However, their impact on thrombus regression and the clinical outcomes after 2-week post-therapy computed tomography (CT) monitoring remains unexplored. This study aimed to elucidate the characteristics of patients with VTE treated with individual DOACs, assess the incidence of clinical events, and evaluate their impact on pulmonary artery thrombus regression.
Methods: This prospective, multicenter study in Japan included 175 patients with VTE treated with rivaroxaban, apixaban, and edoxaban. We employed 2-week post-therapy CT monitoring to compare thrombus regression rates, patient backgrounds, and clinical outcomes.
Results: Rivaroxaban users had higher body weight, hemoglobin levels, pulmonary embolism prevalence, and larger thrombus volume, but a lower prevalence of active cancer than apixaban and edoxaban users. The median thrombus regression rate after approximately 2 weeks of treatment was 89.9%, with no significant differences between the DOACs. During the 13.5-month follow-up, the recurrence or aggravation of symptomatic VTE did not differ significantly among the groups; however, the apixaban group exhibited a slightly higher major bleeding rate. Among the 95 patients receiving rivaroxaban intensive therapy, 34 (35.8%) experienced early termination due to sufficient thrombus resolution within 2 weeks compared to the standard duration group. This did not increase VTE recurrence, aggravation, or mortality.
Conclusions: Substantial thrombus regression and a low incidence of VTE and bleeding support the effectiveness of DOACs. Terminating intensive therapy in one-third of the rivaroxaban group after 2-week CT monitoring did not increase the occurrence of VTE events, thereby suggesting suitability for patients at a high risk of bleeding.
See editorial vol. 32: 673-675
Clinical Trial Registration Number: SAKURA PE/DVT REGISTRY
(UMIN Clinical Trials Registry: UMIN000047671, Registration Date: May 6, 2022)
Abbreviations: BMI, body mass index; CrCl, creatinine clearance; CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; PA, pulmonary artery; PE, pulmonary embolism; VTE, venous thromboembolism
Introduction
Pulmonary embolism (PE) and deep vein thrombosis (DVT) are collectively referred to as venous thromboembolism (VTE), because they are a series of diseases. VTE is a common acute cardiovascular disease1, 2) and a major medical problem worldwide3). Approximately 12% of patients with PE and 6% of those with DVT die within one month of diagnosis4). In Japan, the incidence of PE is rapidly increasing owing to the aging of the population, improved diagnostic rates, increased number of patients with cancer, and improved diagnostic accuracy in clinical practice5). Against this background, prompt and appropriate treatment of VTE is an urgent clinical issue. Recently, evidence for the use of direct oral anticoagulants (DOACs) in patients with VTE has been established, and they are becoming more widely used clinically. DOACs are not only simpler than conventional therapy with heparin and warfarin, but they are also reported to have equal or superior efficacy and safety compared to conventional therapy with heparin and warfarin6-9). However, there are limited reports from Japan comparing the patient characteristics, thrombus regression effect, and clinical event rates between DOACs, including rivaroxaban, apixaban, and edoxaban, in VTE practice. Additionally, physicians are concerned about bleeding risks associated with rivaroxaban intensive therapy, as the prescribed dosage is 30 mg/day for 3 weeks. However, there may be a certain number of patients whose thrombi resolve early and do not require 3-week intensive therapy.
Aim
This study primarily aimed to elucidate the characteristics of patients with VTE treated with individual DOACs, assess the incidence of clinical events, and evaluate their impact on pulmonary artery (PA) thrombus regression. The secondary aim was to explore whether monitoring PA thrombus regression through the performance of early computed tomography (CT) scans conducted 2 weeks after initiating rivaroxaban intensive therapy could identify patients with significant PA thrombus regression. Subsequently, this information could be utilized to safely and effectively shorten the duration of rivaroxaban intensive therapy in these patients. This study originated from a registry-based multicenter observational study, the SAKURA PE/DVT REGISTRY (UMIN Clinical Trials Registry: UMIN000047671, Registration Date: May 6, 2022), designed to explore the real-world landscape of VTE treatment in Japan.
Methods
Study Population
The SAKURA PE/DVT REGISTRY is a multicenter, prospective, observational cohort study established for follow-up tests and clinical events of patients diagnosed with acute symptomatic or asymptomatic PE, DVT, or both for at least 1 year after enrollment from July 2021 to December 2023. The enrollment period was from July 2021 to December 2022. The participating centers consisted of two cardiovascular centers (Nihon University Itabashi Hospital and Nihon University Hospital) and seven affiliated or regional hospitals.
Eligible patients were enrolled if they had been diagnosed with acute symptomatic/asymptomatic PE, DVT, or both and had received anticoagulation with DOAC for the treatment and prevention of VTE. The primary exclusion criteria were contraindications to DOAC, chronic thromboembolic pulmonary hypertension (CTEPH) excluding CTEPH plus acute PE or DVT, and active bleeding. Patients treated only with warfarin or unfractionated heparin, those who had used heparin for more than 7 days, and those who had to discontinue or change DOACs due to drug-related disorders within 2 weeks were excluded from the study. Additionally, patients who had difficulty obtaining consent, refused to participate in the study, or were otherwise deemed inappropriate for inclusion in the study by the principal investigator were excluded.
All patients provided their written informed consent and were enrolled in the study within three weeks of initiating anticoagulation therapy. Patients were followed up for a minimum of 1 year and to the end of the follow-up period whenever possible, regardless of whether anticoagulation therapy was continued, discontinued, or terminated at the patient’s request or physician’s discretion. The severity of PE was defined according to Japanese guidelines2) as follows: acute PE with cardiac arrest or collapse, massive acute PE with sustained hypotension, and hemodynamics with right ventricular overload. DVT was classified according to the location of the thrombus: proximal if the thrombus was centrally located, including the popliteal vein, and distal if the thrombus was peripheral to the popliteal vein. All patient entry and follow-up data were obtained from other centers by physicians or research coordinators in charge of the facility.
The SAKURA PE/DVT REGISTRY study was conducted in accordance with the principles of the Declaration of Helsinki and all legal and regulatory requirements applicable to Japan. The Institutional Review Board of Nihon University Itabashi Hospital reviewed and approved the protocol and related documents (RK-210511-2). Ethical approval was obtained from all participating institutions. Informed consent was obtained from all the participants.
Treatment and Prevention of VTE
The choice of doses and duration of treatment with DOACs was at the discretion of the treating physicians. Each DOAC for the treatment and prevention of VTE was generally administered as follows: rivaroxaban, 15 mg twice daily for 3 weeks after the diagnosis of DVT or PE, and 15 mg once daily thereafter. However, early termination of rivaroxaban intensive therapy was possible at the physician’s discretion depending on the results of CT scans approximately 2 weeks after initiating the treatment. Apixaban: 10 mg twice daily for 1 week after the diagnosis of DVT or PE and 5 mg twice daily thereafter. Edoxaban: 60 mg once daily; however, patients with a body weight of ≤ 60 kg or with creatinine clearance (CrCl) ＜15 mL per minute or with P-glycoprotein inhibitor in the concomitant medication were given 30 mg once daily. Conversely, the initial dose of each DOAC was sometimes administered at the physician’s discretion. Rivaroxaban was administered at 20, 15, or 10 mg/day, apixaban at 10 or 5 mg/day, and edoxaban at 30 mg/day despite fulfilling the criteria for a 60 mg dose or 15 mg/day despite fulfilling the criteria for a 30 mg dose.
Early CT Scan Monitoring and Thrombus Regression Assessment
In all patients, an early contrast-enhanced CT scan was conducted to examine the thrombus regression rate in the intrapulmonary arteries during the recovery period, specifically from 10–14 days after initiating treatment. The amount of thrombus in the pulmonary arteries was quantified by manually tracing the thrombus in all pulmonary arteries using a Ziostation 2 workstation (version 2.9.8; Ziosoft Inc., Tokyo, Japan) on contrast-enhanced CT images obtained at diagnosis and during recovery. This method was used in a previous study10) and was confirmed by two cardiologists and one radiologist. The thrombus was analyzed before and after anticoagulant therapy and the thrombus regression rate was measured. The thrombus regression rate was calculated as follows: (thrombus volume in the acute phase, thrombus volume in the recovery phase) / thrombus volume in the acute phase×100 (Fig.1). DVT was evaluated using contrast-enhanced CT or ultrasound of the lower extremities, defined as normalized (no thrombus in the legs), improved (improvements in both legs or improvement in either leg without deterioration at the other site), unchanged (unchanged results for both legs), or deteriorated (any deterioration in either leg)11).
Patients were followed-up on an outpatient basis at 1 and 3 months after onset and then every 1–3 months for at least 1 year. Three months after onset, D-dimer required a blood test. The continuation or discontinuation of DOAC was at the physician’s discretion. Data from other centers were entered by the physician in charge of the facility. Patients who were transferred or visited other hospitals during the follow-up period were contacted, and information was obtained from the patient, relatives, or facility which the patient had visited.
Endpoints
The primary endpoint was the thrombus regression rate in the intrapulmonary artery on early contrast-enhanced CT scan. The secondary endpoints were clinical events that occurred during the follow-up period. Clinical events included recurrence or aggravation of symptomatic VTE, PE, DVT, bleeding, vascular events (acute coronary syndrome or ischemic stroke), death from any cause, death related to cancer, and composite clinical events. Bleeding was divided into major and minor bleeding, with major bleeding defined using the International Society of Thrombosis and Hemostasis criteria as follows: fatal bleeding, symptomatic bleeding in a critical area or organ, reduction in the hemoglobin concentration by at least 2 g/dL, or transfusion of at least 2 units of blood12). Composite clinical events were defined as the recurrence or aggravation of symptomatic VTE, major bleeding, and all-cause death. For the incidence of bleeding, only events that occurred during DOAC use were included. Active cancer was defined as a diagnosis of or treatment for cancer within 6 months before DOAC therapy or recurrent or metastatic cancer.
Statistical Analysis
Continuous variables are presented as the mean±standard deviation or median with the 25th and 75th percentiles, and categorical variables are reported as the number and percentage of patients. The significance of group differences was compared using Student’s t-test for continuous variables, the chi-square test or Fisher’s exact test for categorical variables, and the Kruskal–Wallis test for non-parametric data (followed by multiple comparisons using the Steel–Dwass test, as appropriate). The Kaplan–Meier method was used to estimate the cumulative event rates, and the log-rank test was used for group comparisons. Incidence rates for each treatment group were expressed as percentages per patient-year. Univariate and multivariate Cox proportional hazard regression analyses were performed to evaluate the factors that affected clinical events. All statistical analyses were performed using the JMP Pro 11 software program (SAS Institute, Cary, NC, USA). Statistical significance was set at P＜0.05.
Results
Baseline Patient Characteristics
A total of 198 patients were enrolled at nine sites between July 2021 and December 2022. A flowchart showing the derivation of the final population from the patients enrolled in the study is shown in Fig.2. Eleven patients were treated with warfarin, two patients with unfractionated heparin only, five patients with unfractionated heparin for more than 7 days before DOAC, and five patients changed or stopped DOAC due to drug-related disorders within 2 weeks. These patients were excluded from the analysis and 175 patients with VTE were included in the baseline and follow-up analyses.
The baseline characteristics of the patients with VTE treated with DOACs are summarized in Table 1. The most commonly prescribed DOAC in patients with VTE were rivaroxaban (n=111; 63.4%), apixaban (n=41; 23.4%), and edoxaban (n=23; 13.1%).
Table 1.Baseline characteristics of stratified patients with VTE by DOACs
| Variables |
Total
n = 175
|
Rivaroxaban
n = 111 (63.4%)
|
Apixaban
n = 41 (23.4%)
|
Edoxaban
n = 23 (13.1%)
|
P-value
|
| Age (years) |
65±16 |
63±17 |
66±14 |
67±14 |
0.45 |
| ≥ 75 years |
55 (31.4%) |
30 (27.0%) |
15 (36.6%) |
10 (43.5%) |
0.22 |
| Female sex |
91 (52.0%) |
52 (46.9%) |
26 (63.4%) |
13 (56.5%) |
0.17 |
| Body weight (kg) |
60.8±14.6 |
63.2±15.6 |
57.8±12.1 |
54.7±13.5 |
0.014 |
| ＜60 kg |
84 (48.0%) |
44 (39.6%) |
25 (61.0%) |
15 (65.2%) |
0.014 |
| Body mass index (kg/m2)
|
23.2±4.5 |
23.8±5.0 |
22.2±3.5 |
21.7±3.7 |
0.036 |
| Laboratory examination |
| CrCl (mL/min) |
80.8±36.3 |
81.2±36.5 |
82.2±39.1 |
76.4±29.2 |
0.81 |
| ＜50 mL/min |
35 (20.0%) |
20 (18.0%) |
10 (24.4%) |
5 (21.7%) |
0.67 |
| D-dimer (μg/mL) |
12.6 (5.6–24.5) |
13.5 (5.9–22.8) |
11.8 (5.2–25.7) |
13.3 (5.1–38.1) |
0.65 |
| Hemoglobin (g/dL) |
12.5±2.4 |
13.0±2.2 |
11.7±2.4 |
11.8±2.8 |
0.004 |
| NT-proBNP (pg/mL) |
233 (89–1082) |
410 (93–1342) |
221 (81–503) |
130 (50–217) |
0.019 |
| Medical history |
| Hypertension |
82 (46.9%) |
51 (46.0%) |
20 (48.8%) |
11 (47.8%) |
0.95 |
| Diabetes mellitus |
23 (13.1%) |
12 (10.8%) |
4 (9.8%) |
7 (30.4%) |
0.031 |
| Heart failure and coronary artery disease |
26 (14.9%) |
17 (15.3%) |
4 (9.8%) |
5 (21.7%) |
0.42 |
| Atrial fibrillation |
11 (6.3%) |
6 (5.4%) |
5 (12.2%) |
0 (0.0%) |
0.13 |
| Chronic lung disease |
28 (16.0%) |
18 (16.2%) |
8 (19.5%) |
2 (8.7%) |
0.52 |
| Stroke |
15 (8.6%) |
11 (9.9%) |
1 (2.4%) |
3 (13.0%) |
0.25 |
| Risk factor |
| Previous VTE |
11 (6.3%) |
7 (6.3%) |
3 (7.3%) |
1 (4.4%) |
0.90 |
| Active cancer |
45 (25.7%) |
18 (16.2%) |
16 (39.0%) |
11 (47.8%) |
＜0.001 |
| Recent surgery |
17 (9.7%) |
12 (10.8%) |
3 (7.3%) |
2 (8.7%) |
0.80 |
| Recent trauma |
18 (10.3%) |
12 (10.8%) |
4 (9.8%) |
2 (8.7%) |
0.95 |
| Inactivity |
54 (30.9%) |
37 (33.3%) |
11 (26.8%) |
6 (26.1%) |
0.65 |
| Thrombophilia |
19 (10.9%) |
16 (14.4%) |
3 (7.3%) |
0 (0.0%) |
0.09 |
| Unprovoked |
40 (22.9%) |
25 (22.5%) |
9 (22.0%) |
6 (26.1%) |
0.92 |
| Concomitant medications |
| Antiplatelets |
21 (12.0%) |
13 (11.7%) |
3 (7.3%) |
5 (21.7%) |
0.23 |
| Estrogen preparation |
10 (5.7%) |
10 (9.0%) |
0 (0.0%) |
0 (0.0%) |
0.047 |
| Anticancer agents |
22 (12.6%) |
8 (7.2%) |
7 (17.1%) |
7 (30.4%) |
0.006 |
| NSAIDs |
28 (16.0%) |
13 (11.7%) |
11 (26.8%) |
4 (17.4%) |
0.08 |
| Prior treatment |
| Inferior vena cava filter |
6 (3.4%) |
4 (3.6%) |
1 (2.4%) |
1 (4.4%) |
0.91 |
| Thrombolytic therapy |
4 (2.3%) |
2 (1.8%) |
1 (2.4%) |
1 (4.4%) |
0.76 |
| Catheterization |
3 (1.7%) |
3 (2.7%) |
0 (0.0%) |
0 (0.0%) |
0.41 |
| PE with/without DVT |
153 (87.4%) |
106 (95.5%) |
33 (80.5%) |
14 (60.9%) |
＜0.001 |
| DVT |
122 (69.7%) |
79 (71.2%) |
24 (58.5%) |
19 (82.6%) |
0.11 |
| proximal |
77 (44.0%) |
51 (46.0%) |
14 (34.2%) |
12 (52.2%) |
0.30 |
| distal |
43 (24.6%) |
28 (25.2%) |
8 (19.5%) |
7 (30.4%) |
0.60 |
| Asymptomatic VTE |
56 (32.0%) |
30 (27.0%) |
14 (34.2%) |
12 (52.2%) |
0.06 |
| DOAC treatment |
| Intensive therapy |
122 (69.7%) |
95 (85.6%) |
27 (65.9%) |
- |
0.011 |
| Duration (days) |
204 (92–450) |
207 (91–493) |
204 (105–426) |
116 (80–442) |
0.44 |
| CT follow-up duration (days) |
13 (11–14) |
13 (11–14) |
13 (10–14) |
14 (12–15) |
0.10 |
Data are shown as n (%), median (interquartile range), or mean±standard deviation unless otherwise stated. CrCl, creatinine clearance; CT, computed tomography; DOAC, direct oral anticoagulant; DVT, deep venous thrombosis; NSAIDs, nonsteroidal anti-inflammatory drugs; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PE, pulmonary embolism; VTE, venous thromboembolism.
The factors of age and female sex did not differ among the three DOAC groups; however, the rivaroxaban group was the heaviest of the three DOAC groups (63.2±15.6 vs. 57.8±12.1 vs. 54.7±13.5 kg; P=0.014). CrCl and D-dimer did not differ among the three DOAC groups; however, hemoglobin (13.0±2.2 vs. 11.7±2.4 vs. 11.8±2.8 g/dL; P=0.004) and N-terminal pro-brain natriuretic peptide (410 [93–1342] vs. 221 [81–503] vs. 130 [50–217] pg/mL; P=0.019) levels were the highest in the rivaroxaban group among the three DOAC groups. The prevalence of diabetes (10.8% vs. 9.8% vs. 30.4%; P=0.031) and active cancer (16.2% vs. 39.0% vs. 47.8%; P＜0.001) were most common in the edoxaban group among the three DOAC groups. At the site of VTE, PE was most common in the rivaroxaban group (95.5% vs. 80.5% vs. 60.9%; P＜0.001); however, proximal DVT (46.0% vs. 34.2% vs. 56.5%; P=0.29) and distal DVT (25.2% vs. 19.5% vs. 24.6%; P=0.20) did not differ among the three DOAC groups. Asymptomatic VTE tended to be most common in the edoxaban group among the three DOAC groups (27.0% vs. 34.2% vs. 52.2%; P=0.06). More patients received intensive therapy in the rivaroxaban group than in the apixaban group (85.6% vs. 65.9%, P=0.011).
Thrombus Regression Rate by DOAC
The median CT scan interval from acute to recovery was 13 days (interquartile range, 11–14 days), with no significant difference observed between the three DOAC groups (13 [11–14] vs. 13 [10–14] vs. 14 [12–15] pg/mL; P=0.10) (Table 1). Of the 153 patients with PE, thrombus measurement could not be evaluated in nine patients due to poor image quality. A CT analysis of PA thrombi was possible in 144 and 142 patients in the acute and recovery phases, respectively. Two patients did not undergo a CT scan during the recovery period because of an exacerbation of the underlying disease and due to an allergy to contrast agents.
A significant difference was found in the amount of thrombus in the PA in the acute phase between the rivaroxaban, apixaban, and edoxaban groups (6.7 [2.1–15.4] vs. 2.1 [0.7–5.1] vs. 1.7 [0.4–14.0] mm3; P＜0.001). The acute-phase intrapulmonary arterial thrombus volume in the rivaroxaban group was higher than that in the apixaban group (6.7 [2.1–15.4] vs. 2.1 [0.7–5.1] mm3; P=0.002) and tended to be higher than that in the edoxaban group (6.7 [2.1–15.4] vs. 1.7 [0.4–14.0] mm3; P=0.08) (Fig.3). Conversely, there was no difference in the thrombus regression rate among the three DOAC groups (88.6 [76.0–99.5]% vs. 94.2 [73.9–100.0]% vs. 94.4 [70.0–100.0]%; P=0.38) (Fig.3). The median thrombus regression rate after approximately 2 weeks of treatment was 89.9%.
Relationship between Clinical Events and DOAC
Patients with VTE were followed up until December 2023, with a median follow-up period of 13.5 months (interquartile range, 11.7–17.9 months) for those with VTE. The clinical events in patients with VTE treated with DOAC are summarized in Table 2.
Table 2.Clinical outcomes of stratified patients with VTE by DOACs
|
Total
n=175
|
Rivaroxaban
n=111 (63.4%)
|
Apixaban
n=41 (23.4%)
|
Edoxaban
n=23 (13.1%)
|
P-value
|
| n (%)
|
per-patient year (95% CI) |
n (%)
|
per-patient year (95% CI) |
n (%)
|
per-patient year (95% CI) |
n (%)
|
per-patient year (95% CI) |
| Recurrence or aggravation of symptomatic VTE |
11 (6.3%) |
1.5 (0.8–2.7) |
4 (3.6%) |
0.8 (0.2–2.1) |
4 (9.8%) |
2.7 (0.7–6.9) |
3 (13.0%) |
3.8 (0.8–11.2) |
0.09 |
| Recurrence or aggravation of symptomatic PE |
7 (4.0%) |
0.9 (0.4–2.0) |
3 (2.7%) |
0.6 (0.1–1.8) |
2 (4.9%) |
1.3 (0.2–4.6) |
2 (8.7%) |
2.4 (0.3–8.7) |
0.32 |
| Recurrence or aggravation of symptomatic DVT |
4 (2.3%) |
0.5 (0.1–1.4) |
1 (0.9%) |
0.2 (0.0–1.1) |
2 (4.9%) |
1.3 (0.2–4.8) |
1 (4.3%) |
1.2 (0.0–6.8) |
0.23 |
| Major bleeding |
14 (8.0%) |
3.1 (1.7–5.1) |
7 (6.3%) |
2.2 (0.9–4.5) |
6 (14.6%) |
6.2 (2.3–13.5) |
1 (4.3%) |
2.4 (0.1–13.4) |
0.048 |
| Minor bleeding |
8 (4.6%) |
1.7 (0.7–3.3) |
6 (5.4%) |
1.9 (0.7–4.1) |
1 (2.4%) |
0.9 (0.0–5.2) |
1 (4.3%) |
2.2 (0.1–12.5) |
0.67 |
| Acute coronary syndrome |
0 (0.0%) |
- |
0 (0.0%) |
- |
0 (0.0%) |
- |
0 (0.0%) |
- |
- |
| Ischemic stroke |
4 (2.3%) |
0.5 (0.1–1.4) |
2 (1.8%) |
0.4 (0.0–1.4) |
1 (2.4%) |
0.6 (0.0–3.5) |
1 (4.3%) |
1.2 (0.0–6.5) |
0.72 |
| Death from any cause |
18 (10.3%) |
2.2 (1.2–3.7) |
9 (8.1%) |
2.1 (0.9–3.9) |
6 (14.6%) |
3.6 (1.2–8.3) |
3 (13.0%) |
1.6 (0.0–8.7) |
0.28 |
| Death related to cancer |
14 (8.0%) |
1.9 (1.0–3.1) |
6 (5.4%) |
1.2 (0.4–2.6) |
5 (12.2%) |
3.2 (1.0–7.4) |
3 (13.0%) |
3.6 (0.7–10.5) |
0.16 |
| Composite clinical events |
38 (21.7%) |
5.6 (3.9–7.6) |
17 (15.3%) |
3.6 (2.1–5.7) |
15 (36.6%) |
11.3 (6.3–18.7) |
6 (26.1%) |
7.9 (2.9–17.3) |
0.007 |
Data are shown as n (%) or % per patient-year unless otherwise stated. CI, confidence interval; DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Composite clinical events included recurrence or aggravation of symptomatic VTE, major bleeding, and all-cause death.
Recurrence or aggravation of symptomatic VTE occurred in 11 patients, with four, four, and three patients (0.8, 2.7, and 3.8 events per patient-year) in the rivaroxaban, apixaban, and edoxaban groups, respectively, with no significant difference among the three DOAC groups (Log-rank P=0.09). However, when compared to the rivaroxaban and edoxaban groups, there was a significant difference (Log-rank P=0.04) (Fig.4). Major bleeding occurred in 14 patients, with seven, six, and one patient (2.2, 6.2, and 2.4 events per patient-year, respectively) in the rivaroxaban, apixaban, and edoxaban groups, respectively, with a significant difference among the three DOAC groups (Log-rank P=0.048), which was driven by significant differences between the rivaroxaban and apixaban groups (Log-rank P=0.019) (Fig.4). Of the six patients in the apixaban group who experienced major bleeding, three had major bleeding within seven days. However, only one of them was receiving apixaban intensive therapy. The other two patients had active cancer, and their treatment was initiated at an underdose at the physician’s discretion. Death from any cause occurred in 18 patients, with nine, six, and three patients (2.1, 3.6, and 1.6 events per patient-year) in the rivaroxaban, apixaban, and edoxaban groups, respectively, with no significant difference among the three DOAC groups (Log-rank P=0.28). Additionally, cancer-related deaths accounted for 14 patients (77.8%) of all-cause deaths. A total of 17, 15, and 6 patients in the rivaroxaban, apixaban, and edoxaban groups, respectively (event rates of 3.6, 11.3, and 7.9 per patient-year), experienced composite clinical events, including either recurrence or a aggravation of symptomatic VTE, major bleeding, and all-cause mortality (Log-rank P=0.007) (Table 2). Other clinical events occurred in low numbers, and there were no differences in the incidence rates among the three DOAC groups.
We performed a univariate Cox proportional hazard regression analysis on 22 bleeding events (major and minor bleeding) and 38 composite clinical events (Table 3). Anemia (hemoglobin less than 11 g/dL) was significantly associated with higher risks of bleeding events (hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.31–6.95; P=0.009) and composite clinical events (HR, 3.95; 95% CI, 2.05–7.61; P＜0.001). A history of major bleeding increased the risk of bleeding events (HR, 3.95; 95% CI, 1.46–10.72; P=0.007), whereas active cancer was linked to a higher risk of composite clinical events (HR, 5.10; 95% CI, 2.67–9.74; P＜0.001). The apixaban group also had a significantly higher risk of composite clinical events than the rivaroxaban group (HR, 2.91; 95% CI, 1.45–5.84; P=0.003). Multivariate Cox proportional hazard regression analyses were adjusted using model 1 (DOACs [apixaban and edoxaban] with rivaroxaban as the reference, age, and active cancer) and model 2 (DOACs [apixaban and edoxaban] with rivaroxaban as the reference, age, and anemia) (Table 4). The apixaban group was associated with a higher risk of composite clinical events than the rivaroxaban group, but this difference became nonsignificant after adjustment in model 1 (HR, 1.89; 95% CI, 0.92–3.90; P=0.08) and model 2 (HR, 2.00; 95% CI, 0.96–4.16; P=0.07). No significant differences in bleeding risk were observed between the apixaban and rivaroxaban groups, or between the edoxaban and rivaroxaban groups.
Table 3.Predictors of the clinical events for VTE patients in a univariate Cox proportional hazard regression analysis
| Variables |
Bleeding events Univariate analysis |
Composite clinical events Univariate analysis |
| HR (95% CI) |
P-value
|
HR (95% CI) |
P-value
|
| Age ≥ 75 years |
1.97 (0.88–4.42) |
0.10 |
1.96 (1.03–3.72) |
0.040 |
| Female sex |
1.69 (0.73–3.91) |
0.22 |
0.88 (0.46–1.67) |
0.70 |
| Body weight ＜60 kg |
1.93 (0.84–4.41) |
0.12 |
1.53 (0.80–2.92) |
0.19 |
| CrCl ＜50 mL/minute |
1.91 (0.79–4.63) |
0.15 |
1.48 (0.70–3.12) |
0.31 |
| Hemoglobin ＜11 g/dL |
3.01 (1.31–6.95) |
0.009 |
3.95 (2.05–7.61) |
＜0.001 |
| Hypertension |
0.59 (0.25–1.39) |
0.23 |
1.03 (0.55–1.95) |
0.92 |
| History of major bleeding |
3.95 (1.46–10.72) |
0.007 |
2.38 (0.93–6.13) |
0.07 |
| Active cancer |
1.40 (0.58–3.38) |
0.46 |
5.10 (2.67–9.74) |
＜0.001 |
| sPESI score ≥ 1 |
1.64 (0.60–4.49) |
0.33 |
2.46 (0.94–6.45) |
0.07 |
| DOAC |
| Rivaroxabn |
Ref |
- |
Ref |
- |
| Apixaban |
1.65 (0.69–3.96) |
0.26 |
2.91 (1.45–5.84) |
0.003 |
| Edoxaban |
0.70 (0.16–3.11) |
0.64 |
2.06 (0.81–5.25) |
0.13 |
CI, confidence interval; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; HR, hazard ratio; sPESI, simplified pulmonary embolism severity index; VTE, venous thromboembolism.
Composite clinical events included recurrence or aggravation of symptomatic VTE, major bleeding, and all-cause death. The three DOACs were analyzed using rivaroxaban as a reference.
Table 4.A multivariate Cox proportional hazard regression analysis of bleeding and composite clinical events in the apixaban or edoxaban groups compared to rivaroxaban
|
Model 1 |
Model 2 |
| HR (95% CI) |
P-value
|
HR (95% CI) |
P-value
|
| Bleeding events |
| Apixaban |
1.45 (0.59–3.55) |
0.42 |
1.11 (0.44–2.81) |
0.83 |
| Edoxaban |
0.50 (0.10–2.41) |
0.39 |
0.47 (0.10–2.13) |
0.32 |
| Composite clinical events |
| Apixaban |
1.89 (0.92–3.90) |
0.08 |
2.00 (0.96–4.16) |
0.07 |
| Edoxaban |
0.88 (0.32–2.43) |
0.80 |
1.53 (0.59–3.97) |
0.38 |
CI, confidence interval; Composite clinical events include recurrence or aggravation of symptomatic VTE, major bleeding, and all-cause death; DOAC, direct oral anticoagulant; HR, hazard ratio. Model 1: DOACs [apixaban and edoxaban], with rivaroxaban as the reference, age, and active cancer. Model 2: DOACs [apixaban or edoxaban] with rivaroxaban as the reference, age, and anemia.
Ninety-five patients received intensive rivaroxaban therapy (initial dose, 15 mg twice daily). After confirming a thrombus regression rate of 94.0 [83.8–100.0]%) at an early follow-up enhanced CT scan (13 days (interquartile range, 11–14 days) after initiating intensive therapy), 34 (35.8%) patients completed intensive therapy early (within 1–16 days: 13 days (interquartile range, 11–15 days)) and then switched to maintenance therapy (initial dose 15 mg once daily) (short-duration group). Due to an insufficient thrombus regression rate of 81.8 [70.0–96.0]% (P=0.007 vs. short-duration group) at an early follow-up CT scan (13 days (interquartile range, 11–15 days) after initiation of intensive therapy, P=0.94 vs. short-duration group), the remaining 61 (64.2%) patients continued intensive therapy for 3 weeks (17–24 days, 21 days (interquartile range, 21–21 days)) before being switched to maintenance therapy (standard-duration group). Patient backgrounds and clinical events were compared between the short- and standard-duration groups (Table 5). There were no differences in age, female sex, CrCl, D-dimer, prevalence of active cancer or DVT, or severity of PE between the two groups; however, the short-duration group had a lower body weight and body mass index (BMI) than the standard duration group. There was a trend towards a higher percentage of patients achieving a thrombus regression rate ＞90% and complete resolution of thrombus in the short-duration group (33.3% vs. 18.2%; P=0.12). Regarding the incidence of clinical events at completion of rivaroxaban intensive therapy, there was no significant difference in the incidence of recurrence or aggravation of symptomatic VTE and death from any cause between the two groups (Table 6). However, both major and minor bleeding events tended to occur more frequently in the short-duration intensive therapy group than in the standard-duration group (5.9% [4/34] vs. 0%; P=0.13) (Table 6). Among the four patients who experienced bleeding, two with major bleeding during intensive therapy stopped taking DOACs the next day, while the other two with minor bleeding continued DOAC therapy. The physician decided to switch these two patients to the maintenance dose 15 days after confirming a ＞90% thrombus regression rate during the 14-day follow-up CT scans. Additionally, there were no differences in the subsequent annual incidence of recurrence or aggravation of symptomatic VTE (2.9% [1/34] vs. 3.3% [2/61]; P=1.00), major bleeding (0% vs. 4.9% [3/61]; P=0.55), or death from any cause (8.8% [3/34] vs. 1.6% [1/61]; P=0.13) between the two groups (Table 6).
Table 5.Patient baseline characteristics, clinical outcomes and a CT analysis stratified by duration of rivaroxaban intensive therapy
| Variables |
Total |
Rivaroxaban intensive therapy |
P-value
|
|
Short-duration
(1–16 days)
|
Standard-duration
(17–24 days)
|
|
n= 95
|
n= 34
|
n= 61
|
|
| Age (years) |
62±17 |
63±19 |
62±16 |
0.70 |
| Female sex |
46 (48.4%) |
18 (52.9%) |
28 (45.9%) |
0.53 |
| Body weight (kg) |
64.0±15.8 |
59.2±15.3 |
66.7±16.0 |
0.029 |
| Body mass index (kg/m2)
|
24.3±5.0 |
22.3±4.8 |
25.3±5.0 |
0.006 |
| CrCl (mL/min) |
84.0±37.9 |
80.3±32.9 |
86.1±40.3 |
0.47 |
| D-dimer (μg/mL) |
12.6 (5.9–22.5) |
11.8 (5.7–19.1) |
12.6 (5.9–23.0) |
0.58 |
| Active cancer |
11 (11.6%) |
5 (14.7%) |
6 (9.8%) |
0.52 |
| With DVT |
68 (71.6%) |
24 (70.6%) |
44 (72.1%) |
1.00 |
| Asymptomatic VTE |
22 (23.2%) |
6 (17.7%) |
16 (26.2%) |
0.45 |
| Severer than sub-massive |
45 (47.4%) |
17 (50.0%) |
28 (45.9%) |
0.83 |
| DOAC treatment |
| Intensive therapy duration (days) |
21 (14–21) |
13 (11–15) |
21 (21–21) |
＜0.001 |
| Total treatment duration (days) |
210 (94–505) |
196 (93–625) |
338 (108–470) |
0.87 |
| CT follow-up duration (days) |
13 (11–14) |
13 (11–14) |
13 (11–15) |
0.94 |
|
n= 86
|
n= 31
|
n= 55
|
|
| Thrombus volume in the acute phase (mL) |
7.2 (2.8–15.4) |
7.0 (1.6–13.7) |
7.7 (3.5–16.6) |
0.23 |
|
n= 85
|
n= 30
|
n= 55
|
|
| Thrombus-regression rate (%) |
89.1 (75.3–99.3) |
94.0 (83.8–100.0) |
81.8 (70.0–96.0) |
0.007 |
| Thrombus-regression rate ＞90% |
41 (48.2%) |
18 (60.0%) |
23 (41.8%) |
0.08 |
| Thrombus-regression rate= 100% |
20 (23.5%) |
10 (33.3%) |
10 (18.2%) |
0.12 |
Data are shown as n (%), median (interquartile range), or mean±standard deviation unless otherwise stated. CrCl, creatinine clearance; CT, computed tomography; DOAC, direct oral anticoagulant; DVT, deep venous thrombosis; VTE, venous thromboembolism
Table 6.Clinical outcomes that occurred while receiving rivaroxaban, stratified by the duration of intensive therapy
|
Period of intensive therapy (30 mg/day)
Rivaroxaban intensive therapy
|
P-value
|
Period of maintenance therapy (15 mg/day)
Rivaroxaban intensive therapy
|
P-value
|
|
Short-duration group
n=34
|
Standard-duration group
n=61
|
Short-duration group
n=34
|
Standard-duration group
n=61
|
| Recurrence or aggravation of symptomatic VTE |
0 (0.0%) |
0 (0.0%) |
- |
1 (2.9%) |
2 (3.3%) |
1.00 |
| Major bleeding |
2 (5.9%) |
0 (0.0%) |
0.13 |
0 (0.0%) |
3 (4.9%) |
0.55 |
| Minor bleeding |
2 (5.9%) |
0 (0.0%) |
0.13 |
3 (8.8%) |
2 (3.3%) |
0.35 |
| Death from any cause |
0 (0.0%) |
0 (0.0%) |
- |
3 (8.8%) |
1 (1.6%) |
0.13 |
| Death related to cancer |
0 (0.0%) |
0 (0.0%) |
- |
2 (5.9%) |
0 (0.0%) |
0.13 |
Data are shown as n (%) unless otherwise stated. VTE, venous thromboembolism
Discussion
This study has the following three major findings: 1) Patients taking rivaroxaban had a higher body weight and hemoglobin levels and a lower prevalence of active cancer complications than other DOAC users. Despite these differences, the cumulative incidence of recurrence or aggravation of symptomatic VTE was similar among the three DOAC groups, with apixaban showing a slightly higher incidence of bleeding events. 2) Rivaroxaban intensive therapy resulted in a similar thrombus regression rate at early follow-up contrast CT scans compared to other DOACs, despite the greater thrombus volume in rivaroxaban users. 3) Early follow-up contrast CT scans led to a de-escalation from rivaroxaban intensive therapy to maintenance therapy in one-third of the patients. However, these patients had a similar low incidence of recurrence or aggravation of symptomatic VTE, with a higher incidence of bleeding events than those who received standard-duration intensive therapy.
Patient Characteristics and Clinical Outcomes Based on the Three DOACs
In this registry, we observed differences in the patient characteristics among the three DOAC groups, primarily influenced by physician discretion when considering those at a high risk of bleeding and the role of DOACs in treating VTE, including PE with or without DVT or DVT only. Due to the prolonged duration of rivaroxaban intensive therapy, physicians chose to administer rivaroxaban to patients with PE and a larger thrombus volume who had a relatively low risk of bleeding, as indicated by their body weight and hemoglobin levels. The short-duration regimen of apixaban intensive therapy resulted in apixaban being primarily administered to patients with PE and a smaller thrombus volume, who had a high risk of bleeding, as indicated by their low body weight and hemoglobin levels, as well as a relatively high prevalence of active cancers. In contrast, edoxaban, not having an intensive therapy regimen, was administered to 39% of patients with DVT only or for those with a minimal thrombus volume in PE, low body weight and hemoglobin levels, and a high prevalence of active cancer. The patient characteristics for each DOAC in this registry were similar to those in a previous study comparing the patient characteristics and events for each DOAC in retrospective VTE practice in Japan13, 14), thus indicating a trend in selecting DOAC at the discretion of physicians in VTE practice in Japan. Despite the largest thrombus volume in the rivaroxaban group, the thrombus regression rate was comparably high among the three DOAC groups (88.6 [76.0–99.5] vs. 94.2 [73.9–100.0] vs. 94.4 [70.0–100.0]%; P=0.38). The cumulative annual incidence of recurrence or aggravation of symptomatic VTE was also comparably low (0.8%, 2.7%, and 3.8% in the rivaroxaban, apixaban, and edoxaban groups, respectively; Log-rank P=0.09). The incidence of recurrence or an aggravation of symptomatic VTE in the J’xactly Study15), STANDARD-VTE16), and ETNA-VTE-Japan17), which are large studies of rivaroxaban, apixaban, and edoxaban in Japanese VTE treatment, was 2.6%, 0.8%, and 1.8%, respectively. Our data reinforces the acceptable effectiveness of all DOACs in Japan. The cumulative incidences of major bleeding in this registry were 2.2%, 6.2%, and 2.4% in the rivaroxaban, apixaban, and edoxaban groups, respectively, showing a particularly higher event incidence in the apixaban group in this registry than in the three largest studies (the cumulative rates of major bleeding in the J’xactly Study, STANDARD-VTE, and ETNA-VTE-Japan were 2.9%, 3.4%, and 2.6%, respectively). These results may be related to the higher proportion of patients with active cancer, particularly in the apixaban and edoxaban groups (16.2%, 39.0%, and 47.8% in the rivaroxaban, apixaban, and edoxaban groups, respectively, vs. 19.0%, 21.3%, and 26.9% in the J’xactly Study, STANDARD-VTE, and ETNA-VTE-Japan groups, respectively). Cancer is a risk factor for both recurrent VTE and fatal bleeding18, 19). A sub-analysis of the COMMAND VTE Registry, which is a large study of VTE in Japan19), also showed that patients with VTE and active cancer have a poorer prognosis, with higher rates of VTE recurrence, major bleeding, and all-cause death than those without active cancer20). Apixaban and edoxaban were frequently prescribed to patients with active cancer in this registry because of the dose reduction criteria for edoxaban and the safety profile of apixaban reported by the Caravaggio trial21). The Caravaggio trial reported that apixaban did not increase major bleeding, including gastrointestinal bleeding, in the treatment of VTE associated with active cancer compared to dalteparin. In our registry, apixaban intensive therapy might carry a potentially increased risk of bleeding, as shown in Fig.4, which shows that major bleeding events in the apixaban group occurred within the first few weeks. However, as only one of the six patients who experienced major bleeding received intensive apixaban therapy, this suggests that it may not be the primary cause. However, there are reports that edoxaban in the Hokusai VTE Cancer Study22) and rivaroxaban in the SELECT-D23) caused more major bleeding than dalteparin in the treatment of cancer-related VTE; therefore, it is important to continue monitoring the use of DOACs for cancer-related VTE and to collect data in Japan. Additionally, several guidelines have indicated that patients with VTE and active cancer should be indefinitely anticoagulated because active cancer is a strong risk factor for VTE recurrence2, 24-26). In Japan, edoxaban treatment was reported to be better at 12 months than at 3 months for the composite outcome of symptomatic recurrent VTE or VTE-related death in patients with cancer with isolated distal DVT27). Therefore, the indications for anticoagulation should be carefully evaluated because the risk of bleeding is considerably higher with increased cancer activity28).
Insights from Early Follow-up CT Monitoring on Thrombus Regression and The Clinical Outcomes
Although the proportion of patients with active cancer in the rivaroxaban group in this registry was similar to that in the J’xactly Study (16.2% vs. 19.0%)15), the rates of recurrence or aggravation of symptomatic VTE (0.8% vs. 2.6%), major bleeding (2.2% vs. 2.9%), and death from any cause (2.1% vs. 5.5%) were lower in the rivaroxaban group than in the J’xactly Study group. Additionally, more patients received rivaroxaban intensive therapy (85.6% vs. 65.6%) and intensive therapy of short duration (1–16 days) (35.8% vs. 23.6%) in this registry than in the J’xactly Study29, 30). The results of this registry study revealed the impact of early follow-up CT monitoring on clinical outcomes. In this registry, 23.5% of patients treated with rivaroxaban intensive therapy had their thrombi completely resolved after 2 weeks of treatment. This rapid resolution aligns with sub-analyses of the EINSTEIN-PE trial31) and J-EINSTEIN-PE trial32), where a complete resolution of thrombus was observed in 44% and 30.8% of patients, respectively, after 3 weeks of rivaroxaban treatment. Notably, early follow-up CT monitoring enabled early cessation of intensive therapy in 35.8% of the patients. Among them, only two patients who had major bleeding discontinued rivaroxaban intensive therapy immediately, and two patients who had minor bleeding confirmed sufficient thrombus resolution with early CT scans and ended intensive therapy early. These results suggest that, in most patients, the doctor was likely to have decided to stop the treatment early, based on the fact that sufficient thrombus regression was observed in the 2-week follow-up CT. Patients in the short-duration rivaroxaban group, as characterized by a lower body weight and BMI, showed comparable thrombus volumes in the acute phase but demonstrated higher thrombus regression rates, particularly those trending towards complete resolution by approximately 2 weeks. Although the short-duration group showed a trend towards a higher bleeding incidence during intensive therapy, no instances of recurrence or aggravation of symptomatic VTE were found, in contrast to the standard-duration group. Previous studies have suggested that early termination of rivaroxaban therapy may increase the risk of VTE recurrence30). However, the results of this registry indicate that early cessation of rivaroxaban therapy, guided by early follow-up CT monitoring, is feasible without increasing the risk of VTE recurrence, especially in those at high bleeding risk. This finding suggests the possibility of safely shortening rivaroxaban intensive therapy in specific patients, thereby indicating a potential improvement in acute PE treatment strategies.
Limitations
This study is associated with some limitations. First, the sample size was relatively small and the number of clinical events was limited. There were relatively large differences among the three DOAC user groups due to physician discretion, which could not be controlled. Therefore, the multivariate analysis of this registry was limited. Second, this registry only included Japanese patients. Genetic predispositions to venous thrombosis differ between the Japanese and Western populations. For instance, protein S deficiency is more frequently associated with venous thrombosis in Japan33), whereas type V Leiden in Western countries34). Therefore, it remains unclear whether our findings are directly applicable to western populations. Finally, an imaging analysis of DVT was not performed in this registry. The reasons for this are that DVT areas are difficult to evaluate for analysis with CT because they are prone to contrast irregularities, and contrast of the lower extremities is frequently omitted in incidentally discovered PE and CT scans performed urgently in the emergency department.
Conclusions
This study found that rivaroxaban users had a higher body weight and hemoglobin levels, a higher prevalence of PE with a larger thrombus volume, and a lower prevalence of active cancer than apixaban and edoxaban users. Physicians appeared to choose DOAC based on the bleeding risk inferred from these factors and the need for acute intensive therapy in acute PE. The subsequent annual incidence of a recurrence or aggravation of symptomatic VTE did not differ significantly among the three DOAC groups. Major bleeding was slightly higher in the apixaban group than in the rivaroxaban and edoxaban groups, likely because of the higher bleeding risk in this cohort. These results support the effectiveness and safety of DOACs based on physician discretion in real-world practice, which is consistent with previous studies.
Among the patients receiving rivaroxaban intensive therapy, 35.8% of patients with lower body weight had their intensive therapy terminated early after CT showed adequate thrombus resolution approximately 2 weeks after starting treatment. Importantly, in these patients, the early termination of intensive therapy did not increase the risk of recurrence, aggravation of symptomatic VTE, or death from any cause. These findings suggest that rivaroxaban intensive therapy with an early termination could be a viable approach for future VTE treatment in patients at a high risk of bleeding.
Grant Support
This study did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
We gratefully acknowledge the contributions of members of the participating institutions to the SAKURA-PE/DVT REGISTRY: Nihon University Itabashi Hospital, Tokyo; Nihon University Hospital, Tokyo; Itabashi Medical Association Hospital, Tokyo; Kawaguchi Municipal Medical Center, Saitama; Yokohama Chuo Hospital, Kanagawa; TMG Asaka Medical Center, Saitama; Tokyo Rinkai Hospital, Tokyo; Kasukabe Municipal Hospital, Saitama; and Sekishindo Hospital, Saitama.
Conflicts of Interest
S.M., D.F., N.M., Y.S., K.T., N.M., K.O., E.T., K.O., H.H., K.N., K.A., M.I., H.U., K.T., M.O., and T.N. had no relationships relevant to the content of this study. Y.O. received research funding from Bayer Healthcare and Biosense Webster, Inc., and received a scholarship grant from Boston Scientific Japan, who received speaker honoraria from Daiichi-Sankyo, Bayer Healthcare, Bristol-Meyers Squibb, AstraZeneca K.K., Ono Pharmaceutical, and Medtronic Japan, and affiliated with endowed courses from Boston Scientific Japan, Japan Lifeline, Fukuda Denshi, Abbott Medical Japan, BIOTRONIK Japan, and Medtronic Japan.
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