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Intern Med. 2024 Jul 1; 63(13): 1845–1853.
Published online 2023 Nov 20. doi:10.2169/internalmedicine.2524-23
PMCID: PMC11272507
PMID: 37981306
Yuki Ueno,1 Satoshi Ikeda,1 Tetsufumi Motokawa,1 Tomohiro Honda,1 Masaya Kurobe,1 Ryohei Akashi,1 Tsuyoshi Yonekura,1 Tsuyoshi Yoshimuta,1 Masamichi Eguchi,1 Hiroaki Kawano,1 and Koji Maemura1
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Associated Data
- Supplementary Materials
Abstract
Objective
Edoxaban is an anticoagulant used for venous thromboembolism (VTE) treatment and requires pretreatment with parenteral anticoagulants. However, pretreatment is not always performed in the clinical setting. In this study, we investigated the safety and effectiveness of edoxaban treatment in patients with VTE with or without pretreatment.
Methods
We retrospectively enrolled 364 patients who received edoxaban for VTE treatment between September 2014 and March 2020 and investigated patient demographics, VTE recurrence, and major bleeding as clinical outcomes in patients with or without pretreatment. Furthermore, the factors contributing to pretreatment decisions were assessed.
Results
Patients without pretreatment (n=208) had more active cancer cases and fewer pulmonary embolism complications than those with pretreatment (n=156). Lower levels of hemoglobin and higher levels of white blood cell counts, C-reactive protein, and D-dimer at the diagnosis were found in patients who received pretreatment than in those without pretreatment. No symptomatic VTE recurrence was observed. After propensity score matching, the cumulative incidence of major bleeding was not significantly higher in patients with pretreatment than in those without it (log-rank test, p=0.136). The incidence of deteriorated VTE on imaging did not significantly differ between patients with and without pretreatment, even after propensity matching (log-rank test, p=0.414).
Conclusion
In a real-world clinical setting, where physicians determined the use of parenteral anticoagulant lead-in according to their experience, patient demographics, and VTE characteristics, no significant differences were found regarding safety and effectiveness in edoxaban-treated VTE patients with or without pretreatment with parenteral anticoagulants.
Keywords: pretreatment, recurrent venous thromboembolism, major bleeding, edoxaban
Introduction
Anticoagulation is the cornerstone of treatment for acute venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) (1,2). Conventional treatment in Europe consists of parenteral treatment, usually low-molecular-weight heparin (LMWH), for at least five days (3). A recent guideline update in Europe stated that LMWH or fondaparinux is preferable to unfractionated heparin for initial anticoagulation in PE, as these agents carry a lower risk of causing major bleeding or heparin-induced thrombocytopenia and do not require routine monitoring of anti-Xa levels (2).
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 (4-7). In Japan, the DOACs, edoxaban, rivaroxaban, and apixaban are currently available for the treatment of VTE. Edoxaban was first approved for the treatment of VTE in Japan in September 2014. It requires parenteral anticoagulation administration, unlike the other two DOACs, which allows for a single-drug regimen until the maintenance phase.
We previously reported that 37.5% of non-cancer patients and 55.7% of cancer patients with VTE received no parenteral anticoagulants before edoxaban administration (8). Toshima et al. demonstrated that a single-drug approach with edoxaban was a potential treatment option for non-acute cancer-associated thrombosis (9). However, few studies have directly compared the differences in patients' VTE treatment and outcomes in the context of edoxaban, with or without pretreatment.
Therefore, we investigated the frequency of parenteral anticoagulant lead-in therapy and the effect of pretreatment on clinical outcomes, such as VTE recurrence and bleeding. Furthermore, factors contributing to the choice of lead-in therapy were assessed in a clinical setting.
Materials and Methods
Study population
We retrospectively reviewed the medical records of 364 patients who were administered edoxaban (LixianaⓇ; Daiichi-Sankyo, Tokyo, Japan) for VTE treatment between September 2014 and March 2020 (Fig. 1). Patients with concomitant atrial fibrillation and those for whom the exact reason for edoxaban administration was unknown were excluded.
Figure 1.
Study flow chart. This study enrolled 364 patients with venous thromboembolism (VTE) who were treated with edoxaban with or without pretreatment with parenteral anticoagulants (n=156 and n=208, respectively). Changes in the extent of thrombus on imaging were evaluated in 104 and 148 patients with and without pretreatment, respectively. Deteriorated VTE on imaging was analyzed for VTE recurrence.
This study complied with the Declaration of Helsinki regarding human investigations, and the Ethics Committee of our hospital approved the protocol (No. 19090914). The requirement for written informed consent was waived by the Ethics Committee of our institution because of the retrospective nature of the study.
Clinical outcomes
The clinical outcomes in terms of safety and effectiveness were major bleeding and VTE recurrence, respectively. 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, reduction in hemoglobin level by at least 2 g/dL, or transfusion of at least 2 units of blood (10). These events were defined as occurring from the initiation of DOAC treatment until one week after DOAC cessation. The presence of VTE was confirmed by ultrasonography of the lower extremities and contrast-enhanced computed tomography (CE-CT). VTE was classified as DVT alone or PE with or without DVT, and the site of DVT was classified as proximal (popliteal vein and/or above), distal (below the popliteal vein), or other. The severity of PE was classified into arrest/collapse, massive, sub-massive, and non-massive according to the Guidelines for Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (11). Recurrent VTE was defined as deterioration of VTE on imaging tests during drug administration with the presence of symptoms.
We also assessed changes in the extent of thrombosis in patients who underwent at least 2 imaging tests: ultrasonography of the lower extremities or CE-CT before and after the administration of DOACs (n=252, Fig. 1). Any deteriorations in either the legs or lungs on the imaging tests, based on the judgment of radiologists, sonographers, and cardiologists, were defined as deteriorated VTEs (8,12). We compared the cumulative incidence of these clinical outcomes between patients with and without parenteral anticoagulant lead-in therapy (labeled “with pretreatment” or “without pretreatment,” respectively).
Active cancer was defined as the diagnosis or treatment of cancer within six months before DOAC therapy initiation or recurrent or metastatic cancer. Patients with surgery within the past month and bed rest ≥1 week prior to the onset of VTE and overweight with a body mass index (BMI) ≥25 were evaluated as having a VTE risk. Hematological data at the time of the VTE diagnosis were also evaluated. Creatinine clearance (Ccr) was estimated using the co*ckcroft (C-G) formula as follows: estimated Ccr=(140-age)×mass (kg)×(0.85 if a woman) / 72×[serum creatinine (mg/dL)].
Statistical analyses
Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviation for normally distributed variables and as medians [interquartile range (IQR)] for skewed variables, which were compared using the unpaired t-test and Mann-Whitney U-test, respectively. Categorical variables are presented as absolute numbers and percentages and were compared using the Pearson chi-square test when appropriate; otherwise, Fisher's exact test was used. A Kaplan-Meier analysis was used to estimate the cumulative incidence of events, and the log-rank test was used to compare the groups. Patients who developed recurrent VTE/deteriorated VTE, major bleeding, or stopped edoxaban were censored. A multivariable logistic regression model was used to examine the independent predictors of the choice of parenteral anticoagulant lead-in therapy at the initiation of VTE treatment, which included variables with p<0.1, in the univariate analysis. Adjustments were made for variables, including the sex, body weight, PE complications, proximal site of DVT, active cancer, platelet count, and levels of hemoglobin, Ccr, C-reactive protein (CRP), and D-dimer at the diagnosis.
To reduce selection bias, patients were propensity-matched for treatment assignment. Logistic regression was used to calculate propensity scores, and the variables for major bleeding were the age, sex, body weight, active cancer, VTE type (PE or proximal DVT), platelet count, hemoglobin level, and Ccr. The variables for deteriorated VTE were age, sex, BMI, active cancer, and VTE type (PE or proximal DVT). The matched cohort was generated using 1:1 nearest-neighbor matching with a caliper 0.2 for the standard deviation of the logit propensity score. After propensity score matching, the standardized mean difference for all variables was <0.1.
The significance level was set at p<0.05. All statistical analyses were performed using the IBM SPSS Statistics software program (version 23.0; SPSS, Chicago, IL, USA) or EZR (Easy R) (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) (13).
Results
Patient characteristics
Table 1 shows the baseline characteristics of patients with VTE treated with edoxaban, with or without pretreatment with parenteral anticoagulants (156 and 208 patients, respectively). The most commonly prescribed daily maintenance dose was 30 mg. Of the patients who received 30 mg, 16 (16.2%) and 24 (15.7%) with and without pretreatment, respectively, were underdosed based on body weight and Ccr (p=0.920). Patients without pretreatment were more likely to be women and had more cases of active cancer than those with pretreatment. Based on laboratory data at the time of the diagnosis, patients with pretreatment had significantly lower hemoglobin levels and platelet counts and significantly higher white blood cell (WBC) counts and CRP and D-dimer levels than those without pretreatment. Regarding the site of VTE, patients with pretreatment had a higher proportion of PE and, conversely, a lower proportion of DVT alone than those without pretreatment. Regarding the severity of PE, non-massive PE was most common in each group, while arrest/collapse and massive PE were not observed in patients without pretreatment. Bed rest for one or more weeks and surgery within one month prior to VTE were more common in patients with pretreatment than in those without pretreatment. In contrast, the proportions of overweight and concomitant antiplatelet use did not significantly differ between the groups. The parenteral anticoagulants administered prior to edoxaban were unfractionated heparin (n=136); unfractionated heparin and urokinase (n=17); unfractionated heparin, urokinase, and tissue plasminogen activator (n=1); and low-molecular-weight heparin (n=2). The patients who received thrombolytic therapy did not develop major bleeding. The median pretreatment duration was 7 days (IQR 3-12 days). Anticoagulant therapy was initiated during or after hospitalization in 156 (100%) and 166 (79.8%) patients with and without pretreatment, respectively.
Table 1.
Baseline Characteristics of Edoxaban-treated Venous Thromboembolism Patients with or without Pretreatment of Parenteral Anticoagulants.
| Without pretreatment (n=208) | With pretreatment (n=156) | p value | ||||
|---|---|---|---|---|---|---|
| Daily dose of edox aban | ||||||
| Maintenance dose, n (%) | 60 mg: 50 (24.0) | 60 mg: 53 (34.0) | ||||
| 30 mg: 153 (73.6) | 30 mg: 99 (63.5) | 0.101 | ||||
| 15 mg: 5 (2.4) | 15 mg: 4 (2.6) | |||||
| Administration duration, days | 97.0 (30.8 - 259.3) | 71.0 (14.0 - 290.3) | 0.084 | |||
| Age, y | 70.0 (61.0 - 77.3) | 67.0 (59.0 - 77.0) | 0.109 | |||
| Female, n (%) | 139 (66.8) | 87 (55.8) | 0.038 | |||
| Weight, kg | 55.2 (47.1 - 64.4) | 58.1 (49.3 - 66.4) | 0.119 | |||
| Body-mass index | 22.2 (19.7 - 25.6) | 22.8 (20.0 - 25.6) | 0.383 | |||
| Overweight, n (%) | 62 (29.8) | 49 (31.4) | 0.742 | |||
| Active cancer, n (%) | 103 (49.5) | 58 (37.2) | 0.020 | |||
| Antiplatelet use, n (%) | 14 (6.7) | 6 (3.8) | 0.232 | |||
| Bed rest, n (%) | 70 (33.7) | 99 (63.5) | <0.001 | |||
| Surgery, n (%) | 61 (29.3) | 64 (41.0) | 0.020 | |||
| Laboratory data at diagnosis | ||||||
| Ccr, mL/min | 68.8 (53.0 - 92.2) | 73.1 (50.1 - 105.3) | 0.400 | |||
| RBC, ×104/μL | 373.2±68.4 | 355.4±69.3 | 0.015 | |||
| Hemoglobin, g/dL | 11.3 (9.9 - 12.7) | 10.4 (9.1 - 12.0) | 0.001 | |||
| WBC, /μL | 6,500 (4,900 - 8,500) | 8,400 (5,975 - 11,225) | <0.001 | |||
| Platelets,×103/μL | 243.5 (183.8 - 312.0) | 199.5 (143.5 - 278.5) | 0.001 | |||
| CRP, mg/dL | 1.12 (0.23 - 3.94) | 2.99 (0.81 - 7.08) | <0.001 | |||
| D-dimer, μg/mL | 5.0 (2.2 - 11.5) | 12.4 (4.4 - 25.3) | <0.001 | |||
| Site of venous thromboembolism | ||||||
| PE, n (%) | 26 (12.5) | 63 (40.4) | <0.001 | |||
| arrest/collapse, n (%) | 0 (0.0) | 2 (3.2) | ||||
| massive, n (%) | 0 (0.0) | 4 (6.3) | 0.179 | |||
| sub-massive, n (%) | 1 (4.0) | 9 (14.3) | ||||
| non-massive, n (%) | 24 (96.0) | 48 (76.2) | ||||
| DVT alone, n (%) | 182 (87.5) | 93 (59.6) | <0.001 | |||
| proximal, n (%) | 26 (12.5) | 68 (43.6) | ||||
| distal, n (%) | 157 (75.5) | 66 (42.3) | <0.001 | |||
| others, n (%) | 25 (12.0) | 22 (14.1) |
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Values are shown as means±SD, medians (interquartile range), or number (%).
VTE: venous thromboembolism, Ccr: creatinine clearance, RBC: red blood cell, WBC: white blood cell, CRP: C-reactive protein, PE: pulmonary embolism, DVT: deep vein thrombosis
Decisions regarding administering anticoagulant therapy with or without pretreatment were most often made by cardiologists (61.5%), followed by stroke center physicians (7.1%), orthopedic surgeons (5.8%), emergency physicians (4.9%), gynecologists (4.4%), and gastroenterologists (3.8%). Cardiologists and non-cardiologists decided to perform the pretreatment in 99 patients (44.2%) and 57 patients (40.7%), respectively (p=0.456).
The primary cancer lesions were predominantly in the uterus and adnexa (29.2%), followed by the gastrointestinal tract (14.9%), lungs (13.7%), liver, bile duct, pancreas (11.2%), and blood (9.9%) (Table 2).
Table 2.
Cancer Site in All Patients and in Patients with or without Pretreatment with Parenteral Anticoagulants.
| All (n=161) | Without pretreatment (n=103) | With pretreatment (n=58) | p value | |||||
|---|---|---|---|---|---|---|---|---|
| Uterus, adnexa | 47 (29.2) | 33 (32.0) | 14 (24.1) | 0.290 | ||||
| Gastrointestinal tract | 24 (14.9) | 15 (14.6) | 9 (15.5) | 0.870 | ||||
| Lung | 22 (13.7) | 15 (14.6) | 7 (12.1) | 0.658 | ||||
| Liver, Bile duct, Pancreas | 18 (11.2) | 11 (10.7) | 7 (12.1) | 0.788 | ||||
| Blood | 16 (9.9) | 10 (9.7) | 6 (10.3) | 0.897 | ||||
| Urinary, Prostate | 9 (5.6) | 4 (3.9) | 5 (8.6) | 0.285 | ||||
| Oral cavity, Pharynx, Larynx | 9 (5.6) | 6 (5.8) | 3 (5.2) | 1.000 | ||||
| Brain | 7 (4.3) | 2 (1.9) | 5 (8.6) | 0.099 | ||||
| Breast | 6 (3.7) | 5 (4.9) | 1 (1.7) | 0.420 | ||||
| Others | 3 (1.9) | 2 (1.9) | 1 (1.7) | 1.000 |
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Values are shown as number (%)
Major bleeding
The cumulative incidence of major bleeding was 12.1% and 9.2% at 1 year in patients with and without pretreatment, respectively. A Kaplan-Meier analysis showed that the incidence did not significantly differ between the groups (log-rank p=0.568; Fig. 2A). Gastrointestinal bleeding was the most common cause of major bleeding (n=13), followed by genital bleeding (n=4); postoperative bleeding triggered by edoxaban (n=3); and urinary tract, cerebral, and respiratory bleeding (n=2 each). There was no significant difference in bleeding sites between patients with and without pretreatment (Table 3). The propensity score-matched cohort consisted of 97 patients in each group (Supplementary material 1). The cumulative incidence of major bleeding in the matched cohort was likely to be higher in the patients with pretreatment than in those without it, but there was no significant difference between the groups (log-rank p=0.136; Fig. 2B).
Figure 2.
A comparison of the cumulative incidence of major bleeding between patients with and without pretreatment of parenteral anticoagulants. Analyses of all patients (A) and propensity-matched cohorts (B). The lower panels below each graph illustrate the number of at-risk patients.
Table 3.
Site of Major Bleeding in Patients with or without Pretreatment with Parenteral Anticoagulants.
| Without pretreatment | With pretreatment | p value | ||||
|---|---|---|---|---|---|---|
| All | 15 (7.2) | 13 (8.3) | 0.691 | |||
| Gastrointestinal tract bleeding | 5 (2.4) | 8 (5.1) | 0.166 | |||
| Genital bleeding | 3 (1.4) | 1 (0.6) | 0.638 | |||
| Postoperative bleeding | 1 (0.5) | 2 (1.3) | 0.579 | |||
| Urinary tract bleeding | 2 (1.0) | 0 (0.0) | 0.509 | |||
| Cerebral bleeding | 1 (0.5) | 1 (0.6) | 1.000 | |||
| Respiratory bleeding | 1 (0.5) | 1 (0.6) | 1.000 | |||
| Others | 2 (1.0) | 0 (0.0) | 0.509 |
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Values are presented as n (%)
Recurrent/deteriorated VTE
Symptomatic VTE recurrence did not occur during the study period; therefore, the incidence of deteriorated VTE on imaging tests was compared between the groups (median duration between the initiation of edoxaban and the imaging test: 32 and 71 days in patients with and without pretreatment, respectively) (Table 4). The incidence rates at 1 month were 3.5% and 4.2% in patients with and without pretreatment, respectively. The cumulative incidence of deteriorated VTE did not differ markedly between the two groups (log-rank p=0.807; Fig. 3A). After propensity score matching, no significant difference in the incidence rates was observed (Supplementary material 2, Fig. 3B).
Table 4.
Baseline Characteristics of Edoxaban-treated Venous Thromboembolism Patients who Underwent Follow-up Imaging Tests with or without Pretreatment of Parenteral Anticoagulants.
| Without pretreatment (n=148) | With pretreatment (n=104) | p value | ||||
|---|---|---|---|---|---|---|
| Daily dose of edoxaban | ||||||
| Maintenance dose, n (%) | 60 mg: 38 (25.7) | 60 mg: 42 (40.4) | ||||
| 30 mg: 108 (73.0) | 30 mg: 60 (57.7) | 0.027 | ||||
| 15 mg: 2 (1.4) | 15 mg: 2 (1.9) | |||||
| Administration duration, days | 139.0 (76.0 - 354.5) | 105.5 (29.3 - 388.3) | 0.252 | |||
| Age, y | 68.0 (58.0 - 77.0) | 65.0 (54.8 - 76.3) | 0.099 | |||
| Female, n (%) | 97 (65.5) | 56 (53.8) | 0.068 | |||
| Weight, kg | 55.7 (47.1 - 65.3) | 57.9 (50.8 - 67.8) | 0.106 | |||
| Body-mass index | 22.2 (19.6 - 25.5) | 22.9 (20.6 - 25.7) | 0.184 | |||
| Overweight, n (%) | 41 (27.7) | 34 (32.7) | 0.394 | |||
| Active cancer, n (%) | 79 (53.4) | 33 (31.7) | 0.001 | |||
| Antiplatelet use, n (%) | 8 (5.4) | 4 (3.8) | 0.567 | |||
| Bed rest, n (%) | 47 (31.8) | 63 (60.6) | <0.001 | |||
| Surgery, n (%) | 41 (27.7) | 46 (44.2) | 0.007 | |||
| Laboratory data at diagnosis | ||||||
| Ccr, mL/min | 68.9 (53.0 - 93.4) | 76.0 (50.0 - 110.4) | 0.211 | |||
| RBC, ×104/μL | 378.3±72.0 | 360.5±73.1 | 0.056 | |||
| Hemoglobin, g/dL | 11.5 (10.1 - 12.9) | 10.3 (9.1 - 12.0) | 0.001 | |||
| WBC, /μL | 6,350 (4,675 - 8,425) | 8,450 (6,075 - 11,300) | <0.001 | |||
| Platelets,×103/μL | 243.5 (183.0 - 300.3) | 193.5 (140.8 - 280.0) | 0.004 | |||
| CRP, mg/dL | 0.98 (0.19 - 4.07) | 3.04 (0.91 - 8.00) | <0.001 | |||
| D-dimer, μg/mL | 4.1 (2.0 - 10.6) | 13.9 (4.3 - 29.0) | <0.001 | |||
| Site of venous thromboembolism | ||||||
| PE, n (%) | 22 (14.9) | 45 (43.3) | <0.001 | |||
| arrest/collapse, n (%) | 0 (0.0) | 1 (2.2) | ||||
| massive, n (%) | 0 (0.0) | 2 (4.4) | 0.479 | |||
| sub-massive, n (%) | 1 (4.5) | 5 (11.1) | ||||
| non-massive, n (%) | 21 (95.5) | 37 (82.2) | ||||
| DVT alone, n (%) | 126 (85.1) | 59 (56.7) | <0.001 | |||
| proximal, n (%) | 18 (12.2) | 49 (47.1) | ||||
| distal, n (%) | 111 (75.0) | 36 (34.6) | <0.001 | |||
| others, n (%) | 19 (12.8) | 19 (18.3) |
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Values are shown as means±SD, medians (interquartile range), or number (%).
Ccr: creatinine clearance, RBC: red blood cell, WBC: white blood cell, CRP: C-reactive protein, PE: pulmonary
embolism, DVT: deep vein thrombosis
Figure 3.
A comparison of the cumulative incidence of deteriorated venous thromboembolism on imaging tests between patients with and without pretreatment of parenteral anticoagulants. Analyses of all patients (A) and propensity-matched cohorts (B). The lower panels below each graph show the number of at-risk patients.
Discussion
Regarding the main findings of the current study, first, of the VTE patients treated with edoxaban at our hospital, approximately 60% did not undergo the parenteral anticoagulant lead-in. Compared to patients without pretreatment, patients with pretreatment had a higher proportion of PE and proximal DVT, more inflammatory reactions, higher D-dimer levels, a lower proportion of active cancer comorbidity, and lower hemoglobin levels. Second, the cumulative incidence of major bleeding after propensity score matching tended to be higher in patients with pretreatment than in those without, but the difference was not significant. Third, VTE deterioration on imaging tests showed no significant difference between patients with and without pretreatment, even after propensity score matching.
In previous reports on untreated and treated patients with anticoagulants, approximately 25% of untreated symptomatic distal leg vein thromboses extended to the proximal veins, mostly within 1 week of presentation (14,15). A post-hoc analysis of the Hokusai-VTE trial showed that the rate of VTE recurrence was highest (54%) during the first 30 days after the acute VTE (16). Therefore, early anticoagulant therapy is required at the onset of VTE. Evidence has shown that heparin administered immediately after the diagnosis of VTE is highly effective in preventing progression or recurrence (1). The summary of product characteristics for edoxaban currently recommends heparin lead-in treatment for at least five days (17). The recommendation for heparin lead-in is based on the HOKUSAI-VTE trial design and also used for vitamin K antagonist (VKA) oral anticoagulants (4). However, lead-in treatment prior to edoxaban administration has not always been performed in clinical settings (8).
In ETNA-VTE-Japan, a prospective observational study conducted as part of a post-marketing study, 38.1% of Japanese patients with VTE were pretreated with unfractionated heparin before edoxaban (18). The proportion was similar to that of our patients with VTE (42.9%). In contrast, in ETNA-VTE Europe, 84.7% of patients received heparin lead-in therapy, and patients with PE and DVT were more likely to receive it (91.3%) than those with DVT alone (80.0%) (19,20). In addition, 66.4% of patients received heparin lead-in treatment for at least 5 days (19,20). Regarding the differences in the proportion of lead-in heparin therapy, the ETNA-VTE Europe study demonstrated that there was a regional variation with far fewer patients receiving heparin in Ireland and the United Kingdom than in the Benelux states; therefore, the choice of lead-in therapy may be more strongly influenced by individual healthcare systems and hospital treatment pathways than by patient and VTE characteristics (20). In addition, the difference in the proportion of pretreatment between Japan and Europe may be due to differences in the availability of LMWH, administered by body weight, as a parenteral anticoagulant for VTE treatment. In Japan, unfractionated heparin (UFH), which requires dose adjustment based on activated partial thromboplastin time (APTT) or activated clotting time (ACT), is typically used for pretreatment. It may be bothersome for physicians to pretreat with UFH; therefore, physicians in Japan are more likely to choose no pretreatment than pretreatment.
Few studies have reported differences in clinical outcomes, such as major bleeding and VTE recurrence, between DOAC-treated patients with VTE with and without heparin lead-in therapy. A meta-analysis of patients with PE from RECOVER, RE-COVER II, EINSTEIN-PE, AMPLIFY, and Hokusai-VTE showed that the relative risk of recurrent VTE with DOAC treatment versus heparin/VKA was 0.76 [95% confidence interval (CI): 0.56-1.05; recurrence rates 2.7% vs. 3.5%] with heparin lead-in (edoxaban and dabigatran) and 1.05 (95% CI: 0.76-1.46; recurrence rates 2.1% vs. 2.0%) without heparin lead-in (apixaban and rivaroxaban) (21). This suggests a possible benefit of heparin lead-in before starting DOACs. However, the incidence of VTE recurrence in the control arm of the studies with and without heparin lead-in DOAC therapy was 3.5% and 2.0%, respectively, implying that PE patients at a higher risk of recurrence were enrolled in the heparin lead-in studies (21). Toshima et al. evaluated the thrombus disappearance rate on CE-CT at the first test within three months of the initiation of edoxaban without lead-in heparin therapy in Japanese patients with cancer. The disappearance rate was 62.5% (95% CI, 43.7-78.9), which met the study's primary endpoint, and the rate of thrombus recurrence and bleeding was 6.25%. They concluded that a single-drug approach with edoxaban is a potential treatment option for non-acute cancer-associated thrombosis, although this study was conducted in a single arm (9).
In the present study, we compared major bleeding and VTE deterioration in edoxaban-treated VTE patients with and without pretreatment; however, there were some significant differences in the baseline characteristics between the two groups, such as the site of VTE (PE or proximal DVT), comorbidity of active cancer, proportion of bed rest and surgery, and levels of CRP, D-dimer, and hemoglobin. These factors may affect the recurrence of VTE or major bleeding events. Regarding the site of VTE, PE is a serious, potentially fatal venous thromboembolic event. Patients with PE are at an increased risk of VTE recurrence and serious complications, such as chronic thromboembolic pulmonary hypertension (22). D-dimer is a fibrin degradation product present after a clot is degraded, which has been reported to provide support for the diagnosis of VTE (23). D-dimer levels are also elevated in a variety of conditions, including atrial fibrillation, coronary artery disease, acute aortic dissection, disseminated intravascular coagulation, and viral infection (24). This suggests that elevated D-dimer levels may reflect the severity of the systemic condition as well as thrombus formation. CRP is a marker of inflammation, and the inflammatory process is considered to be strongly involved in the pathophysiology of VTE (25). In addition, CRP on admission is associated with 30-day mortality and bleeding in VTE patients (26). Active cancer has been reported to be a high risk of recurrence of VTE and bleeding (27,28). The pathogenesis of cancer-associated coagulopathy is complex and involves various mechanisms, such as the activation of blood coagulation by tumor cells, the hemostatic adverse effects of oncological treatments, and the background characteristics of patients (29-31). Regarding the bleeding events in cancer patients, a recent study from Japan demonstrated that the cumulative five-year incidence of major bleeding was higher in active cancer patients than in patients with unprovoked and major/minor transient risk (32). Any major bleeding in cancer patients treated with edoxaban was considered to be derived from tumor bleeding, bleeding from operative wounds, and gastric mucosal injury related to anti-cancer drugs (33). Anemia is a risk factor for bleeding in VTE patients treated with anticoagulants and is included in various bleeding prediction scores, such as the RIETE score (34) and VTE-BLEED score (35). Despite these differences in patient background characteristics between the two groups, the incidences of VTE deterioration and major bleeding were not significantly different. The propensity score matching data also showed no significant difference between the two groups, despite a trend toward a higher incidence of bleeding in patients with pretreatment than in those without it. These findings suggest the effectiveness and safety of edoxaban treatment for VTE with and without parenteral anticoagulant lead-in therapy in a real-world clinical setting.
The actual reasoning behind a physician's decision to apply pretreatment to patients with VTE is unknown. The decision to administer pretreatment was made by cardiologists and non-cardiologists in a ratio of approximately 6:4, and there was no significant difference in the choice of pretreatment between cardiologists and non-cardiologists. We speculate that the severity of the patients' general condition at the onset of VTE, based on the differences in patient background between the two groups, may have influenced the physician's decision. In addition, the unavailability of an antagonist of edoxaban, andexanet alfa, during this study in Japan, and the easy dosing of edoxaban based on the body weight, renal function (Ccr), and concomitant P-glycoprotein inhibitors may have had some impact on the decision of the physician.
Study limitations
Several limitations associated with the present study warrant mention. First, it was a retrospective, single-center, observational study that evaluated the medical records of preexisting patients. Therefore, complete data on the risk of recurrent VTE, including thrombogenicity, are unavailable. Second, there was no definite follow-up protocol for imaging and blood tests; therefore, the follow-up period and assessment method varied among the patients, which may have led to an underestimation of recurrent VTE. Third, we did not investigate the dose or effect of heparin as assessed by APTT or ACT. Fourth, the incidence of major bleeding was higher in our patients than in those treated with DOACs in the ETNA-VTE Japan (18), Europe (19), and Hokusai-VTE studies (4). This may be due to the higher proportion of active cancer patients in this study (44.2%) than in previous studies (3.6%-26.9%) (4,18,19). In the present study, symptomatic VTE recurrence was not observed. The incidence rate was 0.8% in the ETNA-VTE Japan study (18) and 0.34% (at 3 months) in the ETNA-VTE Europe study (19), suggesting that recurrence during edoxaban administration may be lower in the clinical setting. Finally, in this study, we aimed only to provide real-world data on edoxaban administration in patients with VTE. Therefore, the results of this study do not support the administration of edoxaban without parenteral pretreatment.
Conclusion
In the present study, the difference in safety and effectiveness between edoxaban-treated VTE patients with and without prior parenteral anticoagulant therapy was not significant for patients with differing demographics, including VTE type, active cancer comorbidity, and severity of the condition of the patient. Further prospective studies are warranted to clarify the differences among heparin lead-in therapies.
Author's disclosure of potential Conflicts of Interest (COI).
Satoshi Ikeda: Lecture fees, Daiichi-Sankyo. Koji Maemura: Lecture fees, Daiichi-Sankyo; Donations/Scholarship funds, Daiichi-Sankyo.
Supplementary Material
Table S1.
Baseline characteristics of propensity score-matched groups for major bleeding
Click here to view.(97K, pdf)
Table S2.
Baseline characteristics of propensity score-matched groups for deteriorated venous thromboembolism
Click here to view.(96K, pdf)
Acknowledgement
We thank Dr. Shimpei Morimoto at the Clinical Research Center of Nagasaki University Hospital for their advice on the statistical analysis.
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