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DOI: 10.1055/a-2497-4089
Treatment of Venous Thromboembolism with Edoxaban over 18 Months: Results from ETNA-VTE Europe
Funding Daiichi Sankyo Europe GmbH, Munich, Germany.
- Abstract
- Introduction
- Methods
- Comparison of ETNA-VTE with PREFER-VTE and HOKUSAI-VTE
- Results
- Discussion
- Limitations
- Conclusion
- References
Abstract
Background
The benefits and risks of extending anticoagulant treatment beyond the first 3 to 6 months in patients with venous thromboembolism (VTE) in clinical practice are not well understood.
Methods
ETNA-VTE Europe is a prospective, noninterventional, post-authorization study in unselected patients with VTE treated with edoxaban in eight European countries for up to 18 months. Recurrent VTE, major bleeding, and all-cause death were the primary study outcomes.
Results
The median age of the 2,644 patients was 65 years; 46.6% were female, and 22.8% had a history of VTE. The median treatment duration was 50.6 weeks (interquartile range: 23.4–77.7). VTE recurrence occurred in 100 patients (3.8% at an annual rate of 2.7%/year); 37 patients (1.4%) were on edoxaban at the time of the event, with a corresponding annualized rate of 1.6%/year. Major bleeding was experienced by 37 patients (1.4%) during edoxaban treatment, corresponding to an annualized rate of 1.5%/year. Overall, 95 patients died (3.6%; annualized rate 2.6%/year), with the majority for reasons other than VTE- and cardiovascular (CV)-related causes. Out of 15 deaths (1.9%; annualized rate 2.1%/year) that occurred during edoxaban treatment, 1 was related to VTE and 11 related to CV (annualized rate 0.0%/year and 0.5%/year).
Conclusions
ETNA-VTE Europe provides evidence for the real-world effectiveness of edoxaban treatment (up to 18 months) based on a low rate of VTE recurrence, all-cause death, and major bleeding, and is aligned with the results of the randomized clinical trial reassuring the use of edoxaban in the treatment of VTE in routine clinical practice.
Introduction
Venous thromboembolism (VTE) is one of the most common acute cardiovascular disorders, along with acute coronary syndromes and stroke.[1] Annual incidence rates are estimated at 39 to 115 per 100,000 people for pulmonary embolism (PE) and 53 to 162 per 100,000 people for deep venous thrombosis (DVT).[2] [3] The management of VTE substantially changed after the introduction of direct oral anticoagulants (DOACs), which were shown to be at least as effective but safer than vitamin K antagonists (VKAs).[4]
The initial 3 to 6 months after a VTE event is usually considered to be a period of high risk for VTE recurrence,[5] [6] and it is generally covered by anticoagulant treatment that is often discontinued thereafter. The discontinuation of anticoagulant treatment is associated with an increased risk of VTE recurrence. The risk of bleeding on anticoagulant treatment remains relatively stable. Consequently, assessment of the benefits and risks of anticoagulant treatment extended beyond 6 months remains rather complex.[5]
“Edoxaban Treatment in routiNe clinical prActice in patients with Venous ThromboEmbolism in Europe” (ETNA-VTE Europe) is a noninterventional study of unselected patients with an acute VTE that occurred in 2 weeks prior to the study inclusion and who were treated with edoxaban for up to 18 months.[7] [8] [9] In the present analysis, we sought to assess the annualized rates of (1) recurrent VTE, (2) bleeding events, and (3) VTE-relevant clinical events. The results were assessed in relation to the actual duration of edoxaban treatment received. In addition, we compared the results with the results of data obtained in the Prevention of Thrombolic Events–European Registry in Venous Thromboembolism (PREFER-VTE) disease registry and the edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism (HOKUSAI-VTE) clinical study.
Methods
ETNA-VTE Europe is a prospective, noninterventional, post-authorization safety study conducted in hospitals and outpatient clinics in eight European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Switzerland, and the United Kingdom). The study design,[8] characteristics of the patient population,[9] and benefits and risks of edoxaban after the first 3 months of treatment[7] have been previously described. Approval was obtained from the responsible Ethics Committees or Institutional Review Boards, and compliance with the Declaration of Helsinki was ensured throughout the study. Additionally, the study design was discussed and approved by the European Medicines Agency (EMA). Patients provided written informed consent prior to their inclusion in the study.
Patient Population
Consecutive patients with symptomatic or incidental first episode or recurrent proximal or distal DVT and/or PE that had occurred ≤2 weeks prior to enrollment and for whom a decision to administer edoxaban was made at the discretion of the treating physician were included in the study. The dose of edoxaban (30 or 60 mg) administered and the duration of treatment were left to the discretion of the treating physician. Any concomitant treatment was allowed, and changes to medications were unrestricted. Exclusion criteria were a lack of written informed consent and participation in a simultaneous interventional study.
Data Collection
Data were collected from medical records and telephone calls between the patients and their respective treating physicians. Since heparin lead-in is required prior to edoxaban treatment as per Summary of Product Characteristics (SmPC) guidelines, the baseline was defined as the first day of heparin/fondaparinux administration after the index acute VTE event. The first data entry was completed within 2 weeks after the VTE event. Patient data were collected and documented throughout 18 months of the study during each visit at months 1, 3, 6, 12, and 18. At the last patient out of each country, the last known patient status was documented for each patient enrolled in the respective country. Also, the final assessment data, including recurrence of symptomatic VTE (defined as any PE-only, DVT-only, and PE with DVT that occurred after the index event), bleeding, and death (all-cause, VTE-related, or CV-related), were documented at any follow-up data collection point or at premature study termination.
Major bleeding was defined as fatal or symptomatic bleeding in a critical area/organ or causing a ≥2 g/dL fall in hemoglobin and/or ≥6.0% fall in hematocrit; clinically relevant nonmajor bleeding (CRNMB) was defined as requiring medical attention but not fulfilling major bleeding criteria; minor bleeding was defined as any other bleeding that did not fulfil the criteria for major bleeding/CRNMB.[8] [9] Key outcome variables, such as recurrent VTE, bleeding events (major bleeding and CRNMB), and deaths, were adjudicated by an independent committee.[8]
Statistics
Patient Disposition
All patients with signed informed consent with trustworthy data comprised all documented patient sets (APS). The baseline analysis set (BAS) comprised APS after excluding patients based on the exclusion criteria. Finally, the full analysis set (FAS) included all BAS patients except those without any follow-up data (including the last assessment). All analyses presented in this paper were conducted using data from FAS.
For categorical variables, the number of patients and corresponding percentages are presented, and medians and interquartile ranges (IQRs) are shown. Imputation was performed for specific incomplete data related to the exposure and outcome events. Imputation followed a worst-case approach, i.e., for events, the earliest possible occurrence was assumed and for exposure, the longest possible intake (to not underestimate the rate of events that occurred on edoxaban). For all other data, no imputation was performed, and data was analyzed and presented as if they were recorded in the database.
Outcome rates were calculated as the number of patients with the specific event divided by the number of patients in the analysis group. Annualized outcome rates (on edoxaban) were calculated as the number of patients with at least one event (on edoxaban) within 18 months divided by the sum of all individual patient time (on edoxaban) until the first event or censoring within 18 months multiplied by 100 (years). Outcomes were also analyzed during the whole observational period, considering on-treatment events as those that occurred during edoxaban treatment or up to 3 days after its discontinuation. The statistical analyses were performed using SAS version 9.4 and were descriptive and exploratory in nature.
Comparison of ETNA-VTE with PREFER-VTE and HOKUSAI-VTE
In this study, we compared the results from the ETNA-VTE study with PREFER-VTE and HOKUSAI-VTE clinical studies. PREFER-VTE was a prospective, observational, multicenter registry conducted in seven European countries to assess the characteristics and management of patients with VTE with a follow-up of 12 months from baseline. HOKUSAI-VTE was a multinational, multicenter, randomized, double-blinded, double-dummy, parallel-group, phase-three study on VTE patients with 1-year follow-up.
As both PREFER-VTE and HOKUSAI-VTE had an observation period of 1 year, for the comparison with ETNA-VTE, the corresponding summary statistics, frequencies, and rates, respectively, were taken after 12 months. The 95% CIs were also provided. These results were compared with the results from the PREFER-VTE and HOKUSAI-VTE registries. These comparisons were purely descriptive/explorative, and there was no joint model that compared the different treatments directly. Furthermore, although every effort was made to align the endpoint definitions of the ETNA-VTE as much as possible to the endpoint definitions of the PREFER-VTE and HOKUSAI-VTE, the compared endpoints were highly harmonized but not necessarily identical.
Results
A total of 2,809 patients (APS) were enrolled in ETNA-VTE Europe, of which 165 (5.9%) were excluded for the reasons shown in [Fig. 1], resulting in 2,644 patients in the FAS.
Patient and Treatment Characteristics
Patients had a median age of 65.0 years, and 46.6% were female ([Table 1]). Hypertension was the most frequent comorbid condition (43.5%), followed by dyslipidemia (20.2%), chronic venous insufficiency (11.4%), diabetes (11.3%), and chronic obstructive pulmonary disease (COPD; 6.7%). Overall, 22.8% patients had a history of VTE. Prolonged immobilization (15.5%) and history of major surgery or trauma (13.8%) were the most frequent risk factors for VTE.
Abbreviations: COPD, chronic obstructive pulmonary disease; DVT, deep venous thrombosis; FU, follow-up; PE, pulmonary embolism; VTE, venous thromboembolism.
Note: aPercentage calculation can sum to >100% because subjects can fall in more than one category.
Among all 2,644 patients, 58.2% (n = 1540) of the patients had a DVT (only) as the index event, with the remaining suffering a PE only (n = 584; 22.1%) or PE with DVT (n = 520 [19.7%]; [Table 1]). Patient characteristics were generally similar in patients across groups with minor differences in age, weight, BMI, and history of hypertension. Chronic venous insufficiency (14.2% vs. 9.8% vs. 5.5%) and a history of DVT only (20.1% vs. 11.9% vs. 9.5%) were more common in patients with a DVT only, COPD (11.0% vs. 5.6% vs. 5.4%) was common in PE only, whereas prior PE with DVT (6.9% vs. 3.5% and 3.1% respectively) was more prevalent in patients with PE with DVT.
Out of the total patients (n = 2,644), 1,985 patients did not discontinue edoxaban treatment permanently at 6 months, and 612 patients discontinued treatment permanently ([Supplementary Table S1], available in the online version). Patients with permanent discontinuation were younger (58.6 ± 17.6 years vs. 64.0 ± 15.2 years), had less comorbidity burden, and had less frequent formal history of VTE (86.6% vs. 73.9%). However, it has a higher prevalence of VTE-specific causes (like prolonged immobilization, more than 5 days in bed, or a history of major surgery or trauma). The major reason for the permanent discontinuation of edoxaban was that the treatment was no longer necessary in most patients, followed by the occurrence of adverse drug reaction (ADR) or a clinical event ([Supplementary Table S2], available in the online version).
Regarding the dose of edoxaban at the initiation of treatment, 87.7% of the patients received the 60-mg dose, and 12.3% received the 30-mg dose of edoxaban. The median treatment duration was 50.6 weeks (IQR: 23.4–77.7) ([Table 2]). Treatment was ongoing at month 3 in 89.4% of the patients, 70.2% at month 6, and 48.5% at month 12. A total of 27.2% of patients remained on treatment at the end of the study period (18 months). Treatment was significantly longer in patients with PE with DVT than in patients with DVT only.
Abbreviations: DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
The results from ETNA-VTE patients (FAS; n = 2,644) were compared with PREFER-VTE patients treated with VKA (n = 917) and non-vitamin K antagonist oral anticoagulant (NOAC) (n = 501). The gender distribution and medical history in the ETNA-VTE population were largely comparable to the PREFER-VTE population ([Supplementary Table S3], available in the online version). The rate of chronic venous insufficiency was higher in the PREFER-VTE VKA population compared with ETNA-VTE (17.7% vs. 11.4%). More subjects in ETNA-VTE were documented with DVT only (58.2%) than in PREFER-VTE VKA (50.0%).
Additionally, we compared results from ETNA-VTE edoxaban patients (FAS; n = 2,644) with HOKUSAI-VTE edoxaban (n = 2,391), and warfarin patients (n = 2,398), only from Europe indicated to treat recurrent VTE.
Compared with the HOKUSAI-VTE population treated with edoxaban, patients in ETNA-VTE were older (median age of 65.0 vs. 58.0 years), were less often males (53.4% vs. 60.5%), and had higher rates of chronic venous insufficiency (11.4% vs. 2.3%) ([Supplementary Table S4], available in the online version). Nominally, more subjects underwent prolonged immobilization in ETNA-VTE (15.5%) than in HOKUSAI-VTE (5.9%). In contrast, there were more subjects with a history of major surgery or trauma in HOKUSAI-VTE than there were in ETNA-VTE (17.1% vs. 13.8%, respectively). More ETNA-VTE subjects had a history of VTE than in HOKUSAI-VTE edoxaban, with higher rates seen for DVT only in particular (16.2% vs. 7.6%).
VTE Recurrence
The cumulative incidence of recurrent VTEs is displayed in the upper panel of [Fig. 2]. Out of 100 patients with recurrent VTE events, 37 occurred while being on edoxaban treatment. Recurrence was higher in patients with PE with or without DVT than in patients with DVT only ([Fig. 2], lower panel). Overall, 100 patients (3.8%) suffered from recurrent VTE events ([Table 3]), corresponding to an annualized rate of 2.7%/year. Of these, 37 (1.4%) had a recurrent VTE during edoxaban treatment (annualized rate: 1.6%/year). When comparing the VTE recurrence every 6 months in patients who continued with anticoagulant treatment for 18 months, there is an increase in the VTE recurrence (annualized rate baseline to 6 months: 0.4%/year; 6 to 12 months: 1.2%/year; 12 to 18 months: 2.8%/year), which is driven by DVT only ([Supplementary Table S5], available in the online version). Comparing VTE recurrence from month 6 to month 18 in patients who had permanently discontinued edoxaban within the first 6 months compared with events on edoxaban in patients who had not permanently discontinued edoxaban within the first 6 months showed higher annual rates in patients who had permanent discontinuation (2.6%/year vs. 1.4%/year at a hazard ratio of 1.9 [95% CI 0.96, 3.79]; [Supplementary Table S6], available in the online version).
Abbreviations: CI, confidence interval; CV, cardiovascular; DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Note: aAdjudicated events.
Assessing the rates of VTE recurrence in patients on edoxaban based on an initial dose of 30/60 mg from baseline to 18 months showed a higher incidence of recurrent VTE (2.1% vs. 1.3%; annualized rate 1.5%/year vs. 0.9%/year) in patients receiving 30 mg than patients with 60 mg ([Supplementary Table S7], available in the online version). Also, during the first 6 months, the VTE recurrence rate was slightly higher (annualized rate: 1.1%/year vs. 0.5%/year) in patients with 30 mg compared with 60 mg ([Supplementary Table S8], available in the online version).
The rate of recurrent symptomatic VTE within the first 12 months of the study was lower in ETNA-VTE overall compared with the PREFER-VTE VKA overall and PREFER-VTE NOAC (2.4% vs. 3.3% vs. 3.4%; [Supplementary Table S9], available in the online version). Similarly, on edoxaban treatment, the rates of recurrent VTE were lower in ETNA-VTE than in PREFER-VTE during VKA treatment and NOAC treatment (1.0% vs. 2.3% vs. 2.8%).
In the HOKUSAI-VTE study, the overall rate of recurrent VTE in patients treated with edoxaban and warfarin within the first 12 months was comparable with the rate documented in ETNA-VTE overall (2.8% vs. 3.3% vs. 2.4%, respectively) ([Supplementary Table S10], available in the online version). No differences were observed during the edoxaban treatment (1.3% in HOKUSAI-VTE-edoxaban vs. 1.8% in HOKUSAI-VTE-warfarin vs. 1.0% in ETNA-VTE-edoxaban).
Bleeding Events
During the 18-month study period, 305 patients (11.5%) suffered from bleeding events (any) while on edoxaban treatment (annualized rate 13.5%/year) ([Table 4]). Among them, 37 patients (1.4%) had major bleeding at an annualized rate of 1.5%/year. Assessing the severity of bleeding events, 9.0% were classified as major, 19.5% as CRNMB, and 71.4% as minor. The majority of events (71.5%) were spontaneous, while 28.5% had a potentially transient, identifiable cause.
Abbreviations: CI, confidence interval; CRNMB, clinically relevant non-major bleeding; CV, cardiovascular; DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Note: aAdjudicated events.
In 18 months of follow-up of FAS overall, the annualized rate of any bleeding events and at least one major bleeding event was 10.3%/year and 1.2%/year, respectively. Bleeding events tended to be more common in the first 3 months ([Fig. 3], upper panel) and tended to occur more often in patients who had PE with DVT. When comparing the bleeding events every 6 months in patients who continued with anticoagulant treatment for 18 months, there is a decrease over time (annualized rate of any bleeding: baseline to 6 months: 6.8%/year; 6 to 12 months: 2.2%/year; 12 to 18 months: 2.7%/year; [Supplementary Table S5], available in the online version).
Assessing the bleeding rates in patients on edoxaban based on a dose of 30/60 mg from baseline to 18 months showed a higher incidence of any bleeding events (13.0% vs. 11.3%; annualized rate 9.3%/year vs. 7.8%/year) and major bleeding events (3.0% vs. 1.2%; annualized rate 2.2%/year vs. 0.8%/year) in patients receiving 30 mg than patients with 60 mg ([Supplementary Table S7], available in the online version). Also, during the first 6 months, the any bleeding rate was higher (annualized rate:10.1%/year vs. 8.2%/year) in patients with 30 mg compared with 60 mg ([Supplementary Table S8], available in the online version).
In the PREFER-VTE study, major bleeding events within the first 12 months were reported in seven patients (0.8%) receiving VKA and in two patients (0.4%) receiving NOAC, which is lower compared with the rate reported in ETNA-VTE (1.3%) ([Supplementary Table S11], available in the online version). The rates of CRNMB were comparable (2.3% in ETNA-VTE vs. 2.6% in PREFER-VTE VKA and 2.0% PREFER-VTE NOAC).
Within the first 12 months of edoxaban treatment, the rates of hemorrhagic stroke (0.1% in ETNA-VTE) and major bleeding (1.3% in ETNA-VTE) were not substantially different compared with HOKUSAI-VTE edoxaban subjects (0.1 and 1.2%, respectively) ([Supplementary Table S12], available in the online version). There was a reduced rate of CRNMB observed in ETNA-VTE subjects (2.3%) compared with the rates documented in HOKUSAI-VTE subjects on edoxaban (6.3%) and warfarin (7.0%).
Death
The cumulative incidence of all-cause deaths was low in the overall FAS population ([Fig. 4]). A total of 95 deaths (3.6%) were reported, corresponding to an annualized rate of 2.6%/year. A total of 50 deaths (1.9%) occurred during edoxaban treatment (annualized rate 2.1%/year), and 45 (1.7%) occurred after edoxaban discontinuation ([Table 5]). Overall, 71 deaths were unrelated to CV or VTE causes. On edoxaban treatment, only one VTE-related death was reported during the first month of the study (annualized rate 0.0%/year), and 11 (0.4%) CV-related death was reported (annualized rate 0.5%/year).
Abbreviations: CI, confidence interval; CV, cardiovascular; DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Note: aAdjudicated events.
Overall, the 12-month rate of all-cause death was higher in the ETNA-VTE population than in the PREFER-VTE patient groups (2.8% in ETNA-VTE vs. 1.5% in PREFER-VTE VKA and 1.6% PREFER-VTE NOAC), which was also observed during the edoxaban treatment (1.6% vs. 1.0% and 0.6%, respectively) ([Supplementary Table S13], available in the online version).
Compared with the HOKUSAI-VTE population, the rate of all-cause death within the first 12 months in ETNA-VTE patients on edoxaban was higher (1.6% in ETNA-VTE vs. 0.7% HOKUSAI-VTE on edoxaban and 0.5% in HOKUSAI-VTE on warfarin; [Supplementary Table S14], available in the online version).
Discussion
In a large, real-world dataset collected from consecutive patients with an acute VTE who were treated with edoxaban, it was shown that: (1) recurrent VTE persisted beyond the initial 6 months, with less occurrence among patient on edoxaban treatment compared with the overall population (annualized rate 1.6%/year vs. 2.7%/year); (2) the rate of major bleeding on edoxaban was low (annualized rate of 1.5%/year), and (3) the risk of death appeared to be low (annualized rate 2.1%/year) in patients who received edoxaban treatment (up to 18 months) with low annual rate of CV (0.5%/year) or VTE-related death (and 0.0%/year). However, edoxaban treatment based on 30/60 mg dose from baseline to 18 months showed a higher incidence of any bleeding events (annualized rate 9.3%/year vs. 7.8%/year) and major bleeding events (annualized rate 2.2%/year vs. 0.8%/year) in patients receiving 30 mg compared with patients with 60 mg. Assessing the rates of VTE recurrence based on dose showed a higher incidence of recurrent VTE (annualized rate 1.5%/year vs. 0.9%/year) in patients receiving 30 mg than patients with 60 mg. Also, during the first 6 months, the VTE recurrence rate was slightly higher (annualized rate: 1.1%/year vs. 0.5%/year) in patients with 30 mg. This is likely due to patient characteristics and the fact that patients perceived to have a higher risk of bleeding had their anticoagulation dose reduced. Overall, the results indicated that edoxaban treatment for up to 18 months was associated with a low rate of VTE recurrence, major bleeding, and death. These results are aligned with those of the randomized clinical trial, reassuring the use of edoxaban in the treatment of VTE in routine clinical practice.
Patient Characteristics and Study Outcomes
Compared with the HOKUSAI-VTE clinical study (considering those patients from Europe), patients included in the ETNA-VTE Europe were older, more often female, and had more comorbid diseases. Furthermore, more patients in ETNA-VTE Europe had a low body weight (≤60 kg) and reduced creatinine clearance (CrCl ≤50 mL/min). Dose adjustment was already required in the HOKUSAI-VTE study for low body weight and those with low creatinine clearance. However, fewer subjects with these parameters were enrolled in the study than in ETNA-VTE. Less well-preserved renal function in ETNA-VTE may indicate a specific selection of subjects in the randomized controlled clinical study (HOKUSAI-VTE), as reflected by stringent inclusion and exclusion criteria.
Previous studies have shown that the risk of VTE recurrence is higher in patients ≥70 years than in younger subjects.[10] Furthermore, age has been found to increase the risk of bleeding related to anticoagulant treatment. Recent studies indicated that the increase in risk of VTE recurrence and bleeding events in patients ≥70 years is less pronounced with DOACs than with VKA.[11] [12] [13] Reduced CrCl is also a risk factor for bleeding and seems to affect VKA more than DOACs.[11] It is reassuring to note that edoxaban treatment in ETNA-VTE Europe was effective and demonstrated a good safety profile in a real-world population, which included a high proportion of older patients (50.4% of patients ≥65 years) and patients with reduced renal function (37.2%).
Effectiveness of Extended Use of Edoxaban
The proportion of patients with recurrent VTE steadily increased from baseline until the end of the 18-month follow-up, with no particular risk increase during the first 3 months. About two-thirds of recurrent VTE events occurred when subjects had discontinued edoxaban treatment. The overall rate of recurrent VTE was nominally lower in ETNA-VTE than in the PREFER-VTE observational study at a comparable 12-month time window (2.4% vs. 3.3% on VKA and 3.4% on other NOACs) and also lower than in the HOKUSAI-VTE study (2.4% vs. 2.8% on edoxaban and 3.3% on warfarin). The proportion of patients who died (all-cause) steadily increased from baseline until the end of the 18-month follow-up, with no particular risk increase during the first 3 months. One patient died due to VTE. Although all-cause death was higher in ETNA-VTE on edoxaban than in the HOKUSAI-VTE population, the difference might be explained by the fact that the subjects of ETNA-VTE were older, were less often male, and had a higher prevalence of venous insufficiency than subjects in the HOKUSAI-VTE clinical study.
Safety of Extended Use of Edoxaban
The proportion of subjects with at least one major bleeding event on edoxaban in ETNA-VTE at 12 months was nominally higher than in either subgroup from PREFER-VTE (1.3% vs. 0.8% on VKA and 0.4% on NOAC). On the other hand, the major bleeding rate in ETNA-VTE (1.3%) was comparable with the results of HOKUSAI-VTE (1.2% for edoxaban and 1.3% for warfarin; all rates are on treatment). A meta-analysis showed no apparent difference in preventing major bleeding events between secondary thromboprophylaxis (warfarin or aspirin) and placebo (OR 1.84, 95% CI 0.87 to 3.85; low-quality evidence) and also between rivaroxaban and aspirin (OR 3.06, 95% CI 0.37 to 25.51; p = 0.30; moderate-quality evidence).[14] There was, however, a reduced rate of CRNMB observed in ETNA-VTE (2.3%) compared with the rates documented in HOKUSAI-VTE on edoxaban (6.3%). A potential reason for this difference may be a common underreporting of clinically less severe events in observational studies.
Clinical Implications
International guidelines state that anticoagulation after a VTE event should be continued for not less than 3 months[5] [15] or, more explicitly, for 3 to 6 months.[6] Some physicians believe that treatment should be given for a minimum of 6 months,[16] especially as VTE recurrence risk is not resolved within the first 6 months of anticoagulation.[17]
This analysis has provided reasonable evidence of the effectiveness of extended edoxaban treatment (up to 18 months) in preventing recurrent VTE. A low rate of recurrent VTE, low death rate, as well as bleeding, indicate a favorable benefit–risk profile of edoxaban treatment in clinical practice. Furthermore, the prolonged use of edoxaban led to improved survival, but three-quarters of deaths in this study population were not related to either CV or VTE events.
Patient safety is paramount and needs to be considered when deciding on treatment, particularly for the long term. We have shown that extended edoxaban treatment (up to 18 months) is effective in patients with recurrent VTEs.
Limitations
First, no control group was included in this study. Second, patients were only enrolled in this study if they were treated with edoxaban at the prescribing physician's discretion after the initial baseline event, and the impact of this selection is unknown. Lastly, this is an observational study on large-scale patients from eight countries. Therefore, inherent limitations to observational registries, such as minor incompleteness or inaccuracies in patient data is unavoidable, although measures such as the careful design of care report form, data monitoring, and verification were performed to minimize such instances. However, the study has a high level of completeness of patient data and treatment adherence up to 18 months, making it a valuable source of evidence for the real-world use of edoxaban.
Conclusion
Based on data collected in routine clinical practice, ETNA-VTE Europe provides robust evidence for the extended (up to 18 months) use of edoxaban in patients with an initial or recurrent acute VTE (distal or proximal DVT and/or PE) where the risk/benefit ratio of this extension could be positive. These results reassure the use of edoxaban in the treatment of VTE in routine clinical practice as it included a population at a substantially higher risk compared with those of the randomized clinical trial, such as HOKUSAI-VTE.
What is known about this topic?
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The risk of VTE recurrence extends beyond the initial 3 to 6 months post-event, but oral anticoagulants (OACs) are often discontinued around that time.
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The availability of effective and safe anticoagulation is crucial when making decisions regarding the extension of OAC treatment beyond 3 to 6 months.
What does this paper add?
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Data from the prospective ETNA-VTE registry showed that edoxaban therapy (up to 18 months) resulted in low annualized on-treatment rates of recurrent VTE (1.6%/year).
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The annualized rate of major bleeding and all-cause death occurring on edoxaban was low (1.5%/year and 2.1%/year, respectively) with low CV- and VTE-related death (0.5%/year and 0.0%/year, respectively).
Conflict of Interest
The members of the Steering Committee received honoraria for their advice in the planning of the Registry. They also received honoraria and travel reimbursements from Daiichi Sankyo Europe GmbH for their participation in Steering Committee Meetings. G.A. received honoraria for lectures from Bristol-Myers-Squibb and Pfizer. A.T.C., D.J., and B.B. have received research support and/or honoraria for lectures from several pharmaceutical companies including Daiichi Sankyo, the sponsor of the registry. U.H. received honoraria for lectures from Bayer, Daiichi-Sankyo, Leo Pharma, Pfizer, Bristol-Meyers, Aspen, Sanofi-Aventis, Amgen. Advisory board membership for Bayer, Daiichi-Sankyo, Leo Pharma, Sanofi-Aventis, and Amgen. P.H. received honoraria from Daiichi Sankyo Europe GmbH for lectures and advisory board membership. S.G. received honoraria and fees for lectures advisory board and/or drug safety committee work from Actelion, Altavent, Bayer, Daiichi-Sankyo, Gossamer-Bio, Janssen, MSD, and United Therapeutics. C.A. received honoraria for lectures from Sanofi, Pfizer/BMS, Daiichi-Sankyo, and Bayer. Advisory board membership for Pfizer/BMS, Daiichi-Sankyo, Boehringer Ingelheim, and Bayer. M.C. has received research support or fees for lecturing or consulting from Alexion, Anthos, Bayer, CSL Behring, Daiichi Sankyo, F. Hoffman-La Roche, Novo Nordisk, Octapharma, Pfizer, Sobi, Spark Therapeutics, and Viatris. Non-financial conflicts of interest: Chair of the working group Thrombosis & Haemostasis of the Dutch Society of Vascular Medicine (NVIVG), part of the Dutch Internist's Society (NIV). M.S. has received speaker fees from Abbott, Aspen, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, and Sanofi; travel grants from Bard, Bayer, Bristol-Myers Squibb, Medtronic, and Terumo; research grants from Cook, Daiichi Sankyo, and Terumo; and consulting fees from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi. P.L. received honoraria for lectures from AbbVie, Amgen, Gilead, GSK, Novo Nordisk, and ViiV. Advisory board membership for AbbVie, Actelion, Amgen, Astellas, Bayer, Biogen, Boehringer Ingelheim, Celgène, Daiichi Sankyo, Eli Lilly, EOS, GSK, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, Shire, and Vertex. L.P. received honoraria from Daiichi Sankyo Europe GmbH, SOTIO Biotech, and Beckman-Coulter companies for statistical analysis and consultations. P.L., E.-M.F., M.C.M., and J.S. are employees of Daiichi Sankyo Europe GmbH. P.B. received research funding and consultancy honoraria from Daiichi Sankyo Europe GmbH.
Acknowledgment
We are indebted to Dr. Paul-Egbert Reimitz for his work on this project and it is with great sadness that we share news of his passing. We know he would have been delighted to see the results of his work being published. Editorial support was provided by Anjaly Vijayan from the Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany and funded by Daiichi Sankyo Europe GmbH, Munich, Germany.
Ethical Approval Statement
Approval from the responsible Ethics Committees and Institutional Review Boards was obtained prior to protocol implementation. Informed consent was obtained from all patients prior to enrolment, and compliance with the Declaration of Helsinki was ensured throughout the study.
Data Availability Statement
Available from the corresponding author upon reasonable request with the level of detail required.
Authors' Contribution
All authors have contributed to the design of the registry and/or the preparation of the manuscript. E.M.F. was responsible for the analysis of data. G.A. and P.B. drafted the first version of the manuscript and the remaining authors made substantial revisions to the manuscript. All authors have approved the version to be published. Apart from the selection of the countries, all design aspects were decided by the scientific Steering Committee and executed by independent Contract Research Organizations.
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References
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- 4 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
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Konstantinides SV,
Meyer G,
Becattini C.
et al;
ESC Scientific Document Group.
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed
in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41
(04) 543-603
MissingFormLabel
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- 9 Cohen AT, Hoffmann U, Hainaut P. et al; ETNA-VTE-Europe investigators. ETNA VTE Europe: a contemporary snapshot of patients treated with edoxaban in clinical practice across eight European countries. Eur J Intern Med 2020; 82: 48-55
- 10 Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014; 12: 21
- 11 van Hout B, Hawe E, Cohen AT. Impact of patient characteristics on treatment outcomes in symptomatic venous thromboembolism: results of HOKUSAI-VTE randomized trial analysis. TH Open 2020; 4 (03) e245-e254
- 12 Schulman S, Kakkar AK, Goldhaber SZ. et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
- 13 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
- 14 Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. Cochrane Database Syst Rev 2017; 12 (12) CD011088
- 15 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149 (02) 315-352
- 16 Antonucci E, Migliaccio L, Abbattista M. et al; START POST VTE Investigators. Treatment decision-making of secondary prevention after venous thromboembolism: data from the real-life START2-POST-VTE register. Clin Appl Thromb Hemost 2020; 26: 1076029620945792
- 17 Fernandes CJ, Calderaro D, Piloto B, Hoette S, Jardim CVP, Souza R. Extended anticoagulation after venous thromboembolism: should it be done?. Ther Adv Respir Dis 2019; 13: 1753466619878556
Address for correspondence
Publication History
Received: 14 May 2024
Accepted: 02 December 2024
Article published online:
16 January 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
- 2 Keller K, Hobohm L, Ebner M. et al. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J 2020; 41 (04) 522-529
- 3 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
- 4 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
- 5
Konstantinides SV,
Meyer G,
Becattini C.
et al;
ESC Scientific Document Group.
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed
in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41
(04) 543-603
MissingFormLabel
- 6 Mazzolai L, Aboyans V, Ageno W. et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function. Eur Heart J 2018; 39 (47) 4208-4218
- 7 Agnelli G, Hoffmann U, Hainaut P. et al; ETNA-VTE-Europe investigators. ETNA-VTE Europe: benefits and risks of venous thromboembolism treatment using edoxaban in the first 3 months. Thromb Res 2020; 196: 297-304
- 8 Cohen AT, Ay C, Hainaut P. et al; ETNA-VTE-Europe investigators. Design and rationale of the non-interventional, edoxaban treatment in routiNe clinical prActice in patients with venous ThromboEmbolism in Europe (ETNA-VTE-Europe) study. Thromb J 2018; 16: 9
- 9 Cohen AT, Hoffmann U, Hainaut P. et al; ETNA-VTE-Europe investigators. ETNA VTE Europe: a contemporary snapshot of patients treated with edoxaban in clinical practice across eight European countries. Eur J Intern Med 2020; 82: 48-55
- 10 Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014; 12: 21
- 11 van Hout B, Hawe E, Cohen AT. Impact of patient characteristics on treatment outcomes in symptomatic venous thromboembolism: results of HOKUSAI-VTE randomized trial analysis. TH Open 2020; 4 (03) e245-e254
- 12 Schulman S, Kakkar AK, Goldhaber SZ. et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
- 13 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
- 14 Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. Cochrane Database Syst Rev 2017; 12 (12) CD011088
- 15 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149 (02) 315-352
- 16 Antonucci E, Migliaccio L, Abbattista M. et al; START POST VTE Investigators. Treatment decision-making of secondary prevention after venous thromboembolism: data from the real-life START2-POST-VTE register. Clin Appl Thromb Hemost 2020; 26: 1076029620945792
- 17 Fernandes CJ, Calderaro D, Piloto B, Hoette S, Jardim CVP, Souza R. Extended anticoagulation after venous thromboembolism: should it be done?. Ther Adv Respir Dis 2019; 13: 1753466619878556