Citation: Clin Transl Sci (2021) 14, 335–342; doi:10.1111/cts.12876 ARTICLE Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised? Giuseppe Camporese1,*, Paolo Simioni2, Pierpaolo Di Micco3, Carmen Fernández-Capitán4, Agustina Rivas5, Carme Font6, Joan Carles Sahuquillo7, Paula Villares8, Paolo Prandoni9, Manuel Monreal10 and the RIETE Investigators† Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12–42.4) and a signifi- cant higher mortality rate (HR 31.1; 95% CI 4.63–262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54–133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ✔ We know the efficacy and safety of edoxaban in long- ✔ Edoxaban seems to be effective and safe, but the crite- term treatment of venous thromboembolism from rand- ria for dose reduction have scarce influence on outcome. omized trials only. Real-life data are lacking. HOW MIGHT THIS CHANGE CLINICAL PHARMA­ WHAT QUESTION DID THIS STUDY ADDRESS? COLOGY OR TRANSLATIONAL SCIENCE? ✔ Are the recommended doses of edoxaban safe and ✔ Further studies are needed to more precisely identify effective? those patients in whom the dose should be reduced. Current guidelines of antithrombotic therapy,1,2 based on was based applied strict exclusion criteria, aimed to ex- the evidence from randomized trials,3–7 recommend the clude patients with a presumed high risk of bleeding. The use of direct oral anticoagulants (DOACs) as initial and International Regulatory Authorities encourage the phar- long-term therapy in patients with venous thromboembo- maceutical companies to develop postauthorization safety lism (VTE). However, the pivotal trials where their indication studies that should start shortly after the approval of the † A full list of RIETE investigators is given in the Acknowledgments. Registration: ClinicalTrials.gov identifier: NCT02832245 1 Department of Cardiac, Thoracic, and Vascular Sciences, Unit of Angiology, University Hospital of Padua, Padua, Italy; 2Department of Internal Medicine, General Medicine Unit, Thrombotic and Haemorrhagic Disorders Unit, University Hospital of Padua, Padua, Italy; 3Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy; 4Department of Internal Medicine, Hospital Universitario La Paz, Madrid, Spain; 5Department of Pneumonology, Hospital Universitario Araba, Álava, Spain; 6Department of Medical Oncology, Hospital Clínic, Barcelona, Spain; 7Department of Internal Medicine, Hospital Municipal de Badalona, Barcelona, Spain; 8Department of Internal Medicine, Hospital de Madrid Norte Sanchinarro, Madrid, Spain; 9Department of Cardiovascular Sciences, Vascular Medicine Unit, University of Padua, Padua, Italy; 10Department of Internal Medicine, Hospital Germans Trias i Pujol, Universidad Autónoma de Barcelona, Barcelona, Spain. *Correspondence: Giuseppe Camporese (giuseppe.camporese@aopd.veneto.it) Received: February 21, 2020; accepted: August 8, 2020. doi:10.1111/cts.12876 Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 336 new drugs. Edoxaban is among the last DOACs approved angiography for suspected pulmonary embolism (PE)). All by the US Food and Drug Administration (FDA) and the patients were managed according to the clinical practice European Medicines Agency (EMA). Unlike other DOACs of each participating hospital and were not subject to any (dabigatran, rivaroxaban, or apixaban),8–11 edoxaban cur- predetermined intervention. rently can provide data only from the pivotal randomized trial. Two postauthorization safety studies have been com- Variables missioned by the EMA, but conclusive data are not yet The following parameters were recorded in RIETE: clini- available.12,13 cal status, including coexisting conditions such as chronic In the current study, we used the data from the Registro heart or lung disease, recent bleeding, anemia, or renal Informatizado Enfermedad TromboEmbólica (RIETE), a pro- insufficiency; risk factors for VTE; the treatment received spective multinational registry of patients with objectively upon VTE diagnosis (drug, doses, regimen, and duration), confirmed VTE (ClinicalTrials.gov identifier: NCT02832245), and the outcomes during follow-up. Immobilized patients to assess the efficacy and safety of edoxaban for long-term were defined as nonsurgical patients who had been im- therapy of VTE in real-life clinical practice.14,15 According to mobilized (i.e., total bed rest with or without bathroom the product label, the recommended dose of edoxaban for privileges) for ≥ 4 days in the 2-month period prior to VTE long-term therapy is 60 mg daily, but this dose should be diagnosis. Surgical patients were defined as those who had reduced to 30 mg daily in patients with creatinine clearance undergone an operation in the 2 months prior to VTE. Active (CrCl) levels 15–50 mL/minute, body weight ≤ 60 kg, or con- cancer was defined as newly diagnosed cancer or when comitant use of P-glycoprotein inhibitors, because they are receiving antineoplastic therapy of any type (i.e., surgery, perceived as being at increased risk for bleeding. Thus, we chemotherapy, radiotherapy, hormonal, support, or com- compared the rate of the composite of VTE recurrences or bined therapies). Unprovoked VTE was considered in the major bleeding during the course of edoxaban therapy in pa- absence of active cancer, recent immobility, surgery, estro- tients receiving recommended vs. non-recommended doses gen use, pregnancy, or postpartum. Recent major bleeding of edoxaban. was considered in patients having suffered major bleeding < 30 days prior to VTE. Anemia was defined as hemoglobin METHODS levels < 13 g/dL for men and < 12 g/dL for women. CrCl lev- Study design els at baseline were measured using the Cockcroft–Gault Edoxaban was first marketed in Europe for VTE therapy on formula. April 2015, and the first patient receiving edoxaban in RIETE was recruited in October 2015. Thus, we used prospec- Follow-up tively collected data from consecutive patients enrolled in All patients were managed according to the clinical practice the RIETE registry from October 2015 to November 2019. of each participating hospital and were not subject to any Only patients receiving edoxaban after at least 5 days of ini- predetermined intervention. All patients were followed up tial therapy with a parenteral anticoagulant (unfractionated for at least 3 months. During follow-up, special attention heparin, low-molecular-weight heparin, or fondaparinux) was paid to any signs or symptoms suggesting recurrent were considered. The major outcome was the composite of DVT, PE, or major bleeding. Each episode of clinically sus- symptomatic VTE recurrences or major bleeding occurring pected recurrent DVT or PE was documented by repeat during the course of edoxaban therapy. objective imaging. Bleeding complications were classified According to the product label, the recommended dose of as “major” if they were overt and required a transfusion of edoxaban is 60 mg once daily following initial therapy with two units of blood or more, or were retroperitoneal, spi- heparin, low-molecular-weight heparin, or fondaparinux for nal, intraocular, hemopericardium, or intracranial, or when at least 5 days. However, this dose should be reduced to they were fatal.5,15 Fatal bleeding was defined as any death 30 mg once daily in patients who meet any of the following occurring < 10 days after a major bleeding episode, in the criteria: moderate renal impairment (CrCl levels 15–50 mL/ absence of any alternative cause of death.15 Fatal PE, in the minute), body weight ≤ 60 kg, or concomitant use of potent absence of autopsy, was defined as any death occurring P-glycoprotein inhibitors. Thus, we compared the rates of < 10 days after PE diagnosis, in the absence of any alterna- the composite outcome in patients receiving edoxaban at tive cause of death. recommended doses vs. those receiving non-recommended doses in the two clinical scenarios (in patients meeting cri- Statistical analyses teria for dose reduction and in those not meeting criteria). Categorical variables were compared using the χ 2 test (two-sided) and Fisher’s exact test (two-sided). Continuous Patients variables were compared using Student t-test. The in- The rationale and methodology of RIETE has been previ- cidence rates of VTE recurrences or major bleeding ously reported elsewhere.15 In brief, RIETE started in Spain appearing during the course of therapy with edoxaban in 2001 and in subsequent years has expanded the sites were calculated as cumulative incidence (events/100 pa- in several countries. For this study, we only included pa- tient-years) and compared using the hazard ratios (HRs) tients with acute symptomatic VTE confirmed by objective and 95% confidence intervals (CIs). Then, a multivariable tests (compression ultrasonography for suspected deep analysis was performed to identify independent predictors vein thrombosis (DVT); ventilation-perfusion lung scan, for the composite of VTE recurrences or major bleeding. helical computed tomography (CT) scan, or conventional Because we anticipated different mortality risks between Clinical and Translational Science Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 337 subgroups, risks of the composite event were assessed developed VTE recurrences, no patient had major bleed- using competing risk models, with mortality (not due to ing. Most patients in both subgroups (81% vs. 70%) were recurrent VTE or major bleeding, respectively) as the com- initially treated with low-molecular-weight heparin, with a peting risk. Covariates entering in the model were selected median duration from VTE diagnosis to start of edoxaban by a significance level of P < 0.10 on univariable analysis, therapy of 7 days (Table 2). Median duration of edoxaban or by a well-known association reported in the literature. therapy was similar in patients receiving recommended or Statistical analyses were conducted using the Statistical non-recommended doses. Package for Social Sciences (SPSS) program (version 25.0 During the course of therapy, two patients developed for Windows; SPSS, Chicago, IL). recurrent DVT, five had major bleeding (gastrointestinal 2, vaginal 1, hemoptysis 1, and hematoma 1), and five patients Institutional review board approval died (because of bleeding 2, heart failure 1, multi-organ All patients provided oral or written informed consent failure 1, and unknown 1). No patient developed PE re- to their participation in the registry, according to the re- currences. Patients receiving non-recommended doses of quirements of the institutional review boards within each edoxaban (30 mg daily) had a significantly higher rate of enrolling center. the composite outcome (HR 8.37; 95% CI 1.12–42.4) and a higher mortality rate (HR 31.1; 95% CI 4.63–262) than those RESULTS receiving 60 mg daily (Table 3). Since October 2015 to November 2019, 22,015 patients Patients meeting criteria for dose reduction with VTE were recruited in RIETE, of whom 562 (2.6%) re- Among 146 patients in this subgroup, 54 (37%) received ceived edoxaban for long-term therapy (Figure 1). Of these, non-recommended doses (60 mg instead of 30 mg daily) 146 (26%) met criteria for dose reduction: because of body of edoxaban. Patients receiving non-recommended doses weight ≤ 60 kg in 43 patients, CrCl levels ≤ 50 mL/minute in were younger (71 ± 17 vs. 79 ± 17 years; P < 0.05) and had 73 patients, and both conditions in 30 patients. No data are higher CrCl levels at baseline (57 ± 29 vs. 47 ± 27 mL/minute) available for concomitant intake of P-glycoprotein inhibitors than those receiving 30 mg daily (Table 1). One patient had because it was an item not included in the registry. developed major bleeding before starting edoxaban, and no patient had VTE recurrences. Median time elapsed from VTE Patients not meeting criteria for dose reduction diagnosis to the start of edoxaban was similar in both sub- Among 416 patients not meeting criteria for dose reduction, groups (7 days). Median duration of therapy was also similar. 23 (5.5%) received non-recommended doses of edoxaban During the course of edoxaban therapy, one patient bled (30 mg daily). Patients receiving non-recommended doses (in the gastrointestinal tract) and four patients died (infection were significantly older (74 ± 14 vs. 62 ± 15 years; P < 0.001), 1, myocardial infarction 1, multi-organ failure 1, and unknown weighed less (73 ± 12 vs. 82 ± 13 kg; P < 0.01), and had reason 1). No patient had VTE recurrences. Interestingly, lower CrCl levels at baseline (79 ± 24 vs. 99 ± 34 mL/min- none of the 73 patients weighing < 60 kg and none of the ute; P < 0.001) than those receiving recommended doses 54 patients meeting criteria for dose reduction but receiv- (Table 1). They also were nonsignificantly more likely to ing 60 mg daily developed major bleeding. The only major have active cancer. During initial therapy with parenteral an- bleed appeared in a patient receiving 30 mg daily. However, ticoagulants (before starting edoxaban), three patients had patients receiving 60 mg daily had a nonsignificantly higher Figure 1 Proportion of patients receiving low-molecular-weight heparin (LMWH), vitamin K antagonists (VKAs), or direct oral anticoagulants for long-term therapy over time. www.cts-journal.com Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 338 Table 1 Clinical characteristics of the patients according to criteria for dose reduction and use of recommended doses of edoxaban Weight > 60 kg and CrCl levels > 50 mL/minute Weight ≤ 60 kg or CrCl levels ≤ 50 mL/minute Non-recommended Recommended doses Non-recommended Recommended doses Patients, N 23 393 54 92 Clinical characteristics, Male sex 9 (39%) 217 (55%) 14 (26%) 17 (18%) Mean age, years ± SD 74 ± 14* 62 ± 15 71 ± 17* 79 ± 17 Mean body weight, kg ± SD 73 ± 12* 82 ± 13 65 ± 12 63 ± 12 Body weight ≤ 60 kg 0 0 26 (48%) 47 (51%) Risk factors for VTE, Active cancer 6 (26%) 49 (12%) 9 (17%) 8 (8.7%) Recent surgery 2 (8.7%) 44 (11%) 3 (5.6%) 5 (5.4%) Recent immobility ≥ 4 days 5 (22%) 65 (17%) 11 (20%) 30 (33%) Estrogen use 1 (4.3%) 22 (5.6%) 6 (11%) 3 (3.3%) Pregnancy/puerperium 0 3 (0.76%) 1 (1.9%) 1 (1.1%) None of the above 12 (52%) 235 (60%) 29 (54%) 47 (51%) Prior VTE 1 (4.3%) 58 (15%) 7 (13%) 20 (22%) Underlying diseases Chronic lung disease 2 (8.7%) 33 (8.4%) 7 (13%) 9 (9.8%) Chronic heart failure 2 (8.7%) 15 (3.8%) 6 (11%) 6 (6.5%) Recent major bleeding 0 7 (1.8%) 1 (1.9%) 1 (1.1%) Laboratory tests Anemia 7 (30%) 86 (22%) 22 (41%) 42 (46%) CrCl levels, mL/minute ± SD 79 ± 24* 99 ± 34 57 ± 29* 47 ± 27 CrCl levels > 95 mL/minute 7 (30%) 201 (51%) 9 (17%) 9 (9.8%) CrCl levels ≤ 50 mL/minute 0 0 32 (59%)* 71 (77%) CrCl levels < 15 mL/minute 0 0 1 (1.9%) 0 Initial VTE presentation Pulmonary embolism 10 (43%) 169 (43%) 27 (50%) 37 (40%) DVT 13 (57%) 206 (52%) 26 (48%) 54 (59%) Superficial vein thrombosis 0 18 (4.6%) 1 (1.9%) 1 (1.1%) Events during initial therapy VTE recurrences 2 (0.51%) 1 (4.3%) 0 0 Major bleeding 0 0 1 (1.1%) 0 P values refer to comparisons between patients with non-recommended vs. those on recommended doses of edoxaban. CrCl, creatinine clearance; DVT, deep vein thrombosis; VTE, venous thromboembolism. *P < 0.001; P = 0.01; P = 0.002; P = 0.005; P = 0.048; P = 0.025. mortality rate (HR 5.04; 95% CI 0.54–133) than those receiv- therapy, 2 patients (0.36%) developed recurrent DVT and 6 ing 30 mg daily (Table 3). (1.07%) suffered major bleeding, 2 of which were fatal. No On competing risk multivariable analysis, after adjusting patient had recurrent PE. These results compare favorably for patient’s age, sex, body weight, cancer, transient risk with those obtained in the pivotal trial that served to ap- factors for VTE, chronic heart or lung disease, anemia, CrCl prove the indication of edoxaban for secondary prevention levels at baseline, initial VTE presentation, and the daily dose of VTE.5 In the HOKUSAI trial, 3,385 patients received edox- of edoxaban, only patients with active cancer (HR 7.40; aban 60 mg daily for 3–12 months, and 733 received 30 mg 95% CI 1.83–30.0), chronic heart failure (HR 10.9; 95% CI daily. Our patients were older (71 vs. 56 years), more likely to 1.80–66.3), or initially presenting with PE (HR 8.97; 95% CI have active cancer (13% vs. 9.2%), or CrCl levels 30–50 mL/ 1.05–76.7) were at an increased risk for the composite event minute (14% vs. 6.5%) than those in HOKUSAI. Moreover, (Table 4). The HR for the composite event of patients with 4.6% of patients in our cohort (none in HOKUSAI) had CrCl CrCl levels ≤ 50 mL/minute was 0.36 (95% CI 0.03–3.49), levels < 30 mL/minute. During the course of therapy, their and the HR for body weight ≤ 60 kg was impossible to calcu- rate of VTE recurrences (3.2%) was 10-fold higher than late because no patient weighing ≤ 60 kg in our cohort bled. in our cohort, and their rate of major bleeding was similar (1.4%). Therefore, our findings validate the effectiveness and DISCUSSION safety of edoxaban in a cohort of real-life patients with VTE (with no exclusion criteria), as those recruited in HOKUSAI. This is the first real-life study on patients receiving edoxaban According to the product label, the recommended dose for long-term therapy of VTE. After a median of 106 days of of edoxaban for long-term therapy of VTE is 60 mg daily, Clinical and Translational Science Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 339 Table 2 Treatment details and clinical outcomes during edoxaban therapy Weight > 60 kg and CrCl levels >50 mL/minute Weight ≤ 60 kg or CrCl levels ≤ 50 mL/minute Non-recommended Recommended doses Non- recommended Recommended doses Patients, N 23 393 54 92 Initial therapy (before edoxaban) Median days (IQR) 8 (6–37) 7 (5–14) 7 (5–13) 7 (5–11) Over 10 days 10 (43%) 132 (34%) 16 (30%) 26 (28%) LMWH 16 (70%) 319 (81%) 44 (81%) 73 (79%) Unfractionated heparin 2 (8.7%) 7 (1.8%) 2 (3.7%) 1 (1.1%) Thrombolytics 0 3 (0.76%) 2 (3.7%) 1 (1.1%) Fondaparinux 4 (17%) 55 (14%) 5 (9.3%) 12 (13%) Inferior vena cava filter 0 7 (1.8%) 0 0 Edoxaban therapy 60 mg once daily - 393 (100%) 54 (100%) - 30 mg once daily 23 (100%) - - 92 (100%) Mean days (± SD) 136 ± 91 165 ± 149 145 ± 107 142 ± 130 Median days (IQR) 107 (69–196) 111 (87–190) 101 (84–187) 96 (84–178) Over 90 days 13 (57%) 262 (67%) 31 (57%) 53 (58%) CrCl, creatinine clearance; IQR, interquartile range; LMWH, low-molecular-weight heparin. Table 3 Clinical outcomes during edoxaban therapy according to the existence of criteria for dose reduction and the use of recommended vs. non-recommended doses Hazard ratio Non-recommended doses Recommended doses (95% CI) Events per 100 Events per 100 N patient-years N patient-years Weight > 60 kg and CrCl levels > 50 mL/minute Patients, N 23 393 PE recurrences 0 - 0 - - DVT recurrences 1 11.8 (0.59–58.1) 1 0.56 (0.03–2.77) 20.9 (0.54–817) Major bleeding 1 11.6 (0.58–57.5) 4 2.25 (0.71–5.43) 5.18 (0.21–41.2) Gastrointestinal 1 11.6 (0.58–57.5) 1 0.56 (0.03–2.77) 20.7 (0.53–809) Hematoma 0 - 1 0.56 (0.03–2.77) - Vaginal 0 - 1 0.56 (0.03–2.77) - Hemoptysis 0 - 1 0.56 (0.03–2.77) - Composite outcome 2 23.5 (3.95–77.8) 5 2.81 (1.03–6.23) 8.37 (1.12–42.4)* Death 3 35.0 (8.89–95.2) 2 1.12 (0.19–3.71) 31.1 (4.63–262)* Fatal bleeding 1 11.6 (0.58–57.5) 1 0.56 (0.03–2.77) 20.7 (0.53–809) Heart failure 1 11.6 (0.58–57.5) 1 0.56 (0.03–2.77) 20.7 (0.53–809) Unknown reason 1 11.6 (0.58–57.5) 0 - - Patients, N Weight ≤ 60 kg or CrCl levels ≤ 50 mL/minute 54 92 PE recurrences 0 - 0 - - DVT recurrences 0 - 0 - - Major bleeding 0 - 1 2.79 (0.14–13.7) - Gastrointestinal 0 - 1 2.79 (0.14–13.7) - Composite outcome 0 - 1 2.79 (0.14–13.7) - Death 3 14.0 (3.57–38.2) 1 2.79 (0.14–13.7) 5.04 (0.54–133) Infection 1 4.68 (0.23–23.1) 0 - - Myocardial infarction 1 4.68 (0.23–23.1) 0 - - Unknown 1 4.68 (0.23–23.1) 0 - - Multi-organ failure 0 - 1 2.79 (0.14–13.7) - P values refer to comparisons between patients with non-recommended vs. those on recommended doses of edoxaban. CI, confidence interval; CrCl, creatinine clearance; DVT, deep vein thrombosis; PE, pulmonary embolism. *P = 0.04; P = 0.001. www.cts-journal.com Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 340 Table 4 Univariable and multivariable analysis for the composite outcome (recurrent VTE or major bleeding) Univariable analysis Multivariable analysis (competing risk analysis) Clinical characteristics Male sex 2.14 (0.52–8.65) 1.79 (0.44–7.17) Age > 70 years 0.71 (0.17–2.98) 0.36 (0.03–3.3) Body weight ≤ 60 kg - - Risk factors for VTE Unprovoked VTE Ref. Ref Active cancer 7.11 (1.68–30.2)* 7.40 (1.83–30.0)* Transient risk factors 0.41 (0.05–3.25) 0.54 (0.10–2.76) Underlying diseases Chronic lung disease 1.85 (0.23–14.4) 1.52 (0.38–5.95) Chronic heart failure 7.21 (1.47–35.4)* 10.9 (1.8–66.3)* Recent major bleeding - - Laboratory tests Anemia 2.89 (0.70–11.8) 1.02 (0.16–6.41) CrCl levels ≤ 50 mL/minute 0.69 (0.08–5.74) 0.36 (0.03–3.49) Initial VTE presentation Pulmonary embolism 8.47 (1.07–66.8)* 8.97 (1.05–76.7)* Edoxaban doses, 30 mg daily 2.54 (0.60–10.7) 4.88 (0.93–25.4) P values refer to comparisons between patients with non-recommended vs. those on recommended doses of edoxaban. Results expressed as hazard ratio (95% confidence intervals). CrCl, creatinine clearance; Ref., reference; VTE, venous thromboembolism. *P = 0.005; P = 0.007; P = 0.009; P = 0.015; P = 0.043; P = 0.045. but this dose should be reduced to 30 mg daily in patients bled. The only major bleeding appeared in a patient receiv- with CrCl levels 15–50 mL/minute, body weight ≤ 60 kg, or ing 30 mg daily. Thus, our findings suggest that edoxaban concomitant use of P-glycoprotein inhibitors. This recom- seems to be safe in patients with renal insufficiency or low mendation is mainly based on studies performed in patients body weight. Similarly, no dose reduction was prescribed receiving the drug for VTE treatment.16–18 However, none of in the presence of the same clinical conditions, in all the the 73 patients weighing ≤ 60 kg and only 1 of 103 patients randomized clinical trials for VTE treatment with rivarox- with CrCl levels 15–50 mL/minute in our cohort developed aban (EINSTEIN-DVT and EINSTEIN-PE) or with apixaban major bleeding. On the other hand, patients with active can- (AMPLIFY), unlike in nonvalvular atrial fibrillation studies in cer (4 of 72) or chronic heart failure (2 of 29) had a much which a dose reduction was scheduled. Certainly, patients higher influence on the risk for the composite outcome. receiving 60 mg daily had a 5-fold higher mortality rate, but Thus, our findings suggest that the recommendation for none of the reported causes of death (heart failure, myo- dose reduction based on prior studies performed in patients cardial infarction, and multi-organ failure) seems to be a with atrial fibrillation may not be optimal in patients with VTE. potential consequence of anticoagulant therapy. Some additional variables (such as cancer or heart failure) This study has a number of potential limitations. First, may have a higher influence on the risk for bleeding. RIETE is an observational registry, and our data are hypoth- Twenty-three of 416 patients (5.5%) not meeting criteria esis-generating. There might be a useful basis for future for dose reduction in our cohort received edoxaban 30 mg controlled clinical trials comparing different therapeutic daily (instead of 60 mg). These patients were older, weighed strategies, but we should be extremely cautious in suggest- less, had lower CrCl levels, and were (nonsignificantly) more ing changes in treatment strategies based on uncontrolled likely to have active cancer than those receiving 60 mg daily. registry data. On the contrary, our data should caution clini- We hypothesize that these may have been the reasons why cians against empirically dose reducing based on off-label their attending doctors prescribed 30 mg instead of the recommendations. Second, given the small sample size, recommended dose of 60 mg daily. During the course of there is a risk of overestimation and underestimation, also edoxaban therapy, patients receiving 30 mg daily had an type I and II errors. In addition, given the median follow-up 8-fold higher rate of the composite event than those receiv- time was only 4 months, any error occurring in the analy- ing 60 mg. The 20-fold higher rate of VTE recurrences could sis might be multiplied when using event rate as “per 100 be, in part, explained by the use of lower doses of edox- person-years,” especially among the reduced-dose group. aban, but the 5-fold higher rate of major bleeding could not. However, our study includes subgroups of patients (the very No patient meeting criteria for dose reduction developed elderly, those with disseminated cancer, or with severe renal VTE recurrences. Interestingly also, none of the 54 patients failure) that almost never appear in randomized clinical trials. meeting criteria for dose reduction but receiving 60 mg daily Third, a variety of practitioners entered data into the registry, Clinical and Translational Science Edoxaban criteria for long-term therapy of venous thromboembolism Camporese et al. 341 which may lend itself to potential inaccuracies in the data González-Martínez J, Grau E, Guirado L, Gutiérrez J, Hernández-Blasco being reported. Fourth, in the registry, information about L, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou I, Lacruz B, the concomitant use of P-glycoprotein inhibitors was not Lalueza A, Lecumberri R, Lima J, Lobo JL, López-Brull H, López-Jiménez collected (because few patients with VTE use ciclosporin, L, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, dronedarone, erythromycin, or ketoconazole); then, we have Lorente MA, Lorenzo A, Loring M, Madridano O, Maestre A, Marchena no information about potential interactions and/or side ef- PJ, Martín del Pozo M, Martín-Martos F, Martínez-Baquerizo C, Mella C, fects related to this concomitant administration. Fifth, given Mellado M, Mercado MI, Moisés J, Monreal M, Morales MV, Muñoz-Blanco the observational nature of the study, the finding of an in- A, Muñoz-Guglielmetti D, Muñoz-Rivas N, Nart E, Nieto JA, Núñez MJ, creased risk for major bleeding in patients receiving a lower Olivares MC, Ortega-Recio MD, Osorio J, Otalora S, Otero R, Paredes D, than recommended dose is likely to be a result of confound- Parra P, Parra V, Pedrajas JM, Pellejero G, Peris ML, Pesántez D, Porras ing by indication. Unfortunately, this does not appear to be JA, Portillo J, Ramos E, Reig L, Riera-Mestre A, Rivas A, Rodríguez-Cobo adjustable given the small number of the study outcomes, A, Rodríguez-Matute C, Rogado J, Rosa V, Rubio CM, Ruiz-Artacho P, which limits the maximum number of independent variables Ruiz-Giménez N, Ruiz-Ruiz J, Ruiz-Sada P, Sahuquillo JC, Salgueiro G, entering into a multivariable Cox proportional hazards re- Sampériz A, Sánchez-Muñoz-Torrero JF, Sancho T, Sigüenza P, Sirisi M, gression model. The main strength of our observation is that Soler S, Suárez S. Suriñach JM, Tiberio G, Torres MI, Tolosa C, Trujillo- the population sample we used describes the effects of an- Santos J, Uresandi F, Usandizaga E, Valle R, Vela JR, Vidal G, Vilar C, Villares ticoagulant therapy in “real-world” clinical care, as opposed P, Zamora C, Argentina: Gutiérrez P, Vázquez FJ, Belgium: Vanassche to in a protocol-driven randomized trial, and enhances the T, Vandenbriele C, Verhamme P, Czech Republic: Hirmerova J, Malý R, generalizability of our findings. The broad range of patients Ecuador: Salgado E, France: Benzidia I, Bertoletti L, Bura-Riviere A, Crichi from multiple medical centers, countries, and treatment set- B, Debourdeau P, Espitia O, Farge-Bancel D, Helfer H, Mahé I, Moustafa tings enrolled in the RIETE registry decreased the likelihood F, Poenou G, Germany: Schellong S, Israel: Braester A, Brenner B, Tzoran of the inclusion of a skewed population in this study. I, Italy: Amitrano M, Bilora F, Bortoluzzi C, Brandolin B, Ciammaichella M, Colaizzo D, Dentali F, Di Micco P, Giammarino E, Grandone E, Mangiacapra CONCLUSION S, Mastroiacovo D, Maida R, Mumoli N, Pace F, Pesavento R, Pomero F, Prandoni P, Quintavalla R, Rocci A, Siniscalchi C, Tufano A, Visonà A, Vo In summary, our data validate the effectiveness and safety of Hong N, Zalunardo B, Latvia: Maķe K, Meilanden K, Skride A, Portugal: edoxaban for long-term therapy of VTE in real life. However, Ferreira M, Fonseca S, Martins F, Meireles J, Republic Of Macedonia: the criteria (body weight and renal function) used to recom- Bosevski M, Zdraveska M, Switzerland: Bounameaux H, Mazzolai L, USA: mend a dose reduction seem to have scarce influence on Caprini JA, Tafur AJ, Weinberg I, Wilkins H, Vietnam: Bui HM. outcome. Further studies are needed, using larger samples of patients receiving edoxaban, to more precisely identify Funding. No funding was received for this work. those patients in whom the dose should be reduced. Conflict of Interest. The authors declared no competing interests Acknowledgments. The authors express our gratitude to Sanofi for this work. Spain for supporting this Registry with an unrestricted educational grant. We also thank the RIETE Registry Coordinating Center, S&H Medical Author Contributions. G.C., M.M., and P.D.M. wrote the manu- Science Service, for their quality control data, logistic and administrative script. G.C., M.M., and P.D.M. designed the research. C.F.C., C.F., A.R., support and Prof. Salvador Ortiz, Universidad Autónoma Madrid and Silvia J.C.S., and P.V. performed the research G.C., M.M., and P.D.M. analyzed Galindo, both Statistical Advisors in S&H Medical Science Service, for the the data. P.S. and P.P. contributed new analytical tools. statistical analysis of the data presented in this paper. Coordinator of the RIETE Registry: Manuel Monreal. 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