TYPE Original Research PUBLISHED 25 November 2022 DOI 10.3389/fmed.2022.991376 Predictors of use of direct oral OPEN ACCESS anticoagulants in patients with EDITED BY Alejandro Lazo-Langner, Western University, Canada venous thromboembolism: REVIEWED BY Andreina Carbone, Findings from the Registro University of Campania Luigi Vanvitelli, Italy Gianluca Di Micco, Informatizado Enfermedad Ospedale Buon Consiglio Fatebenefratelli, Italy Tromboembólica registry *CORRESPONDENCE Alicia Lorenzo alicia.loher@gmail.com Alicia Lorenzo1*, Patricia Beroiz2,3 , Salvador Ortiz4 , †A full list of RIETE investigators is Jorge del Toro5 , Lucia Mazzolai6 , Alessandra Bura-Riviere7 , given in Appendix Adriana Visonà8 , Peter Verhamme9 , Pierpaolo Di Micco10 , SPECIALTY SECTION This article was submitted to Giuseppe Camporese11 , Teresa Sancho Bueso1 , Hematology, Manuel Monreal12,13 and the RIETE Investigators† a section of the journal Frontiers in Medicine 1 Department of Internal Medicine, Hospital Universitario La Paz, Madrid, Spain, 2 Department of Geriatrics, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain, 3 Department of Medicine, RECEIVED 11July 2022 Universidad Autónoma de Barcelona, Barcelona, Spain, 4 Department of Applied Economics, ACCEPTED 05 October 2022 Universidad Autónoma Madrid, S&H Medical Science Service Advisor, Madrid, Spain, 5 Department PUBLISHED 25 November 2022 of Internal Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 6 Department CITATION of Angiology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 7 Department Lorenzo A, Beroiz P, Ortiz S, del Toro J, of Vascular Medicine, Hôpital de Rangueil, Toulouse, France, 8 Department of Vascular Medicine, Mazzolai L, Bura-Riviere A, Visonà A, Ospedale Castelfranco Veneto, Castelfranco Veneto, Italy, 9 Vascular Medicine and Haemostasis, Verhamme P, Di Micco P, University of Leuven, Leuven, Belgium, 10 Department of Internal Medicine and Emergency Room, Camporese G, Sancho Bueso T, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy, 11 Angiology Unit, Department of Cardiac, Monreal M and the RIETE Investigators Thoracic and Vascular Sciences, Padua University Hospital, Padua, Italy, 12 Department of Internal (2022) Predictors of use of direct oral Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain, 13 Chair for the Study anticoagulants in patients with venous of Thromboembolic Disease, Faculty of Health Sciences, UCAM—Universidad Católica San Antonio thromboembolism: Findings from de Murcia, Murcia, Spain the Registro Informatizado Enfermedad Tromboembólica registry. Front. Med. 9:991376. doi: 10.3389/fmed.2022.991376 Background: Current guidelines recommend the use of direct oral COPYRIGHT © 2022 Lorenzo, Beroiz, Ortiz, del anticoagulants (DOACs) for patients with venous thromboembolism (VTE). Toro, Mazzolai, Bura-Riviere, Visonà, However little is known about the use of DOACs in daily practice. Verhamme, Di Micco, Camporese, Sancho Bueso, Monreal and the RIETE Methods: We used the RIETE registry to identify predictors of use of DOACs Investigators. This is an open-access article distributed under the terms of for initial and/or long-term therapy of VTE based on patient-related factors, the Creative Commons Attribution institution-related factors or over time. License (CC BY). The use, distribution or reproduction in other forums is Results: Among 41,678 patients from March 2013 to September 2021, 12,286 permitted, provided the original author(s) and the copyright owner(s) (29%) used DOACs: for initial therapy 6,456; for long-term therapy 12,046. are credited and that the original On multivariable analysis, independent predictors were: age < 65 years (odds publication in this journal is cited, in accordance with accepted academic ratio [OR]: 1.30; 95% CI: 1.23–1.38), body weight <50 kg (OR: 0.54; 95% CI: practice. No use, distribution or 0.45–0.65) or >120 kg (OR: 0.64; 95% CI: 0.53–0.77), initial VTE presentation reproduction is permitted which does as pulmonary embolism (OR: 1.18; 95% CI: 1.13–1.25), recent bleeding (OR: not comply with these terms. 0.53; 95% CI: 0.45–0.63), renal insufficiency (OR: 0.44; 95% CI: 0.38–0.51), liver cirrhosis (OR: 0.32; 95% CI: 0.20–0.52), thrombocytopenia (OR: 0.40; 95% CI: 0.34–0.49), atrial fibrillation (OR: 1.58; 95% CI: 1.42–1.75) and prior Frontiers in Medicine 01 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 VTE (OR: 1.14; 95% CI: 1.06–1.22). The DOACs were more likely used in other European countries (OR: 8.97; 95% CI: 8.49–9.49), America (OR: 6.35; 95% CI: 5.67–7.11) or in other countries of the world (OR: 2.99; 95% CI: 2.70–3.31) than in Spain, and progressively increased from 2013–2015 to 2016–2018 (OR: 2.78; 95% CI: 2.62–2.95) and 2019–2021 (OR: 6.36; 95% CI: 5.95–6.80). Conclusion: In this large multinational VTE registry, variations were observed in the use of DOACs according to patient or country factors, and over time. The safety, costs, and influence of the DOACs on VTE-related outcomes in daily practice warrant further investigation. KEYWORDS venous thromboembolism, direct oral anticoagulants, anticoagulant therapy, predictors, RIETE, different countries Introduction mortality, and risk factors for these outcomes (13). In the current study, we aimed to determine the potential variations Current guidelines of anticoagulant therapy recommend the in the use of DOACs in patients with confirmed VTE, based on use of direct oral anticoagulants (DOACs) for initial and long- patient-related factors, institution-related factors, and over time. term therapy of patients with venous thromboembolism (VTE) (1, 2). The risk reduction of recurrent VTE with DOACs is similar to the risk reduction with low-molecular-weight heparin Patients and methods (LMWH) and vitamin K antagonists (VKAs), while the risk of bleeding is less with DOACs than with standard therapy Inclusion criteria (3). However, the use of DOACs has not completely replaced the use of standard therapy. There are patient-related factors, Consecutive patients with acute deep vein thrombosis and also institutional or logistical reasons that may limit the (DVT) or pulmonary embolism (PE) confirmed by objective use of DOACs in daily practice. Patient-related factors include tests (compression ultrasonography for suspected DVT; older age, extreme body weights (where there may be doubts helical CT-scan, ventilation-perfusion lung scintigraphy or about the optimal dose) or concomitant diseases (where there conventional angiography for suspected PE) were enrolled may be concern about the risk of bleeding) (4–12). In addition, in RIETE. Patients were excluded if they were currently resource availability may also drive the choice of therapies. participating in a therapeutic clinical trial with a blinded A better knowledge of the reasons why physicians prescribe therapy. All patients (or their legal power of attorney) provided the use of DOACs for the initial and/or long-term therapy of written or oral consent for participation in the registry, in VTE could lead to design randomized trials for subgroups of accordance with local ethics committee requirements. patients where its use is lower than expected (to reassure on the efficacy and safety of DOACs) or higher than expected (to avoid undesirable outcomes). Study design The RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry is an international, ongoing Data were collected from March 2013 (corresponding to registry of consecutive patients with symptomatic, objectively the time when the prescription of DOACs was allowed) to confirmed, acute VTE (ClinicalTrials.gov identifier: July 2021. The primary goal of this study was to determine NCT02832245). Since its inception in 2001, data from this the potential variations in the use of DOACs in patients with registry have been used to evaluate outcomes after acute symptomatic, objectively confirmed VTE, based on patient- VTE, such as the frequency of recurrent VTE, bleeding and related factors, or institution-related factors. As such, the main outcome was the proportion of patients using DOACs vs. those Abbreviations: DOACs, direct oral anticoagulants; VTE, venous using other anticoagulant drugs. Secondary outcomes were the thromboembolism; OR, odds ratio; CI, confidence intervals; LMWH, low- proportion of patients using each DOAC (vs. the other DOACs), molecular-weight heparin; VKAs, vitamin K antagonists; PE, pulmonary embolism; DVT, deep vein thrombosis; CT-scan, computed tomography and the proportion of patients using lower-than recommended scan; CrCl, creatinine clearance. doses of DOACs. Recommended dosing was defined as dosing Frontiers in Medicine 02 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 consistent with FDA-labeled dosing for treatment of VTE as author had full access to all the data in the study and had final of September 2021. responsibility for the decision to submit for publication. Patient-related factors explored in this study included demographics (sex, age, body weight), initial VTE presentation (PE with or without concomitant DVT vs. isolated DVT), Results concomitant diseases that could contraindicate the use of DOACs [including recent (<30 days before) major bleeding, Among 41,678 patients with VTE recruited from January biopsy-proven liver cirrhosis, creatinine clearance (CrCl) levels 2013 to September 2021 in RIETE, 12,286 (29%) used DOACs: <30 mL/min and platelet count <100,000/µLat baseline], and 6,456 for initial therapy and 12,046 for long-term therapy. concomitant disorders that could lead to prolong the duration Among the 41,678 patients, 20,896 (50%) were men; mean of anticoagulant therapy (prior VTE and atrial fibrillation). age was 65 ± 17 years; 23,458 (56%) initially presented We also evaluated the proportion of fragile patients that used with PE; 970 (2.3%) had recent major bleeding; CrCl levels DOACs (fragile patients defined as those aged ≥75 years, <30 mL/min 2,097 (5.0%); liver cirrhosis 209 (0.5%); platelet with CrCl levels ≤50 mL/min or body weight ≤50 kg) (14). count < 100,000/µL 1,055 (2.5%); atrial fibrillation 2,361 Institutional factors assessed in the current study included the (5.7%) and prior VTE 5,818 (14%). In total, 16,767 patients country of enrolment. Further, we explored the trends in the use (40%) were fragile. of DOACs over the study years. Most patients (65%) were attended in Spanish centers, 25% in other European countries, 3.7% in America and 6.0% in the rest of the world (Table 1). For initial therapy, 5,141 patients Treatment (12%) used rivaroxaban and 1,315 (3.2%) apixaban. For long- term therapy, 6,631 patients (16%) used rivaroxaban, apixaban Patients were managed according to the clinical practice of 3,548 (8.5%), edoxaban 1,473 (3.5%), and dabigatran 394 each participating hospital (i.e., there was no standardization of (0.9%). The proportion of patients using DOACs progressively treatment). The decision on the type and duration of therapy increased over time (Figure 1). was left to the attending physicians. Patients were followed-up for at least 3 months in the outpatient clinic or physician’s office. Predictors of use of direct oral anticoagulants vs. other drugs Statistical analysis Overall, 12,286 patients (29%) used DOACs for initial Categorical variables were compared using the chi-square and/or for the long-term therapy of VTE. The proportion of test (two-sided) and Fisher’s Exact Test (two-sided). Continuous patients using DOACs was highest among those aged <65 years variables were compared using Student t test. To identify (33%), with atrial fibrillation (33%) or prior VTE (34%), and predictors of prescription of drugs we used logistic regression lowest in patients with CrCl levels < 30 mL/min (15%), liver analyses. All the analyses were adjusted for sex, age (65 years; cirrhosis (11%) or thrombocytopenia (16%) (Table 2) The use 65–79; >79 years), body weight (<50 kg; 50–120; >120 kg), of DOACs was lowest in Spain (17%) and highest in other initial VTE presentation (symptomatic PE; isolated DVT), European countries (59%) or America (50%), and progressively recent major bleeding, liver cirrhosis, CrCl levels at baseline increased over time: from 17% in 2013–2015 to 47% in 2019– <30 mL/min, platelet count <100,000/µL, atrial fibrillation, 2021. Among 12,286 patients using DOACs, 2,154 (18%) used prior VTE, the country where the VTE was diagnosed (Spain; lower-than recommended doses. The subgroups of patients that other European countries; America; rest of the world) and years were more likely to use lower-than recommended doses of of VTE diagnosis (2013–2015; 2016–2018; 2019–2021). Odds DOACs were: patients aged >79 years (30%), with CrCl levels ratios (OR) and corresponding 95% confidence intervals (CI) <30 mL/min (44%) or with atrial fibrillation (30%). Only 4,105 were calculated, and a p value < 0.05 was considered to be of the 17,767 fragile patients with VTE (24%) used DOACs: 25% statistically significant. Statistical analyses were conducted with at lower than recommended doses. SPSS for Windows Release 25.0 (SPSS, Inc.). On multivariable analysis, independent predictors for the use of DOACs (vs. other anticoagulants) were: age <65 years (OR: 1.30; 95% CI: 1.23–1.38) body weight <50 kg (OR: 0.54; Role of the funding source 95% CI: 0.45–0.65) or > 120 kg (OR: 0.64; 95% CI: 0.53– 0.77) initial VTE presentation as PE (OR: 1.18; 95% CI: 1.13– The sponsors of the RIETE registry (Sanofi, Leo Pharma and 1.25) recent bleeding (OR: 0.53; 95% CI: 0.45–0.63) CrCl levels Rovi) had no role in study design, data collection, data analysis, <30 mL/min (OR: 0.44; 95% CI: 0.38–0.51) liver cirrhosis (OR: data interpretation or writing of the report. The corresponding 0.32; 95% CI: 0.20–0.52) platelet count <100,000/µL (OR: 0.40; Frontiers in Medicine 03 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 TABLE 1 Prescription of DOACs over time in different countries. Total 2013–2014 2015–2016 2017–2018 2019–2021 All patients 41,678 10,526 10,798 10,653 9,701 Rivaroxaban initially 5,141 (12.3%) 1,041 (9.9%) 1,481 (13.7%) 1,288 (12.1%) 1,331 (13.7%) Apixaban initially 1,315 (3.2%)‡ 5 (0.1%)‡ 226 (2.1%)‡ 402 (3.8%)‡ 682 (7.0%)‡ Rivaroxaban long-term 6,631 (15.9%) 1,367 (13.0%) 1,929 (17.9%) 1,658 (15.6%) 1,677 (17.3%) Apixaban long-term 3,548 (8.5%)‡ 74 (0.7%)‡ 727 (6.7%)‡ 1,025 (9.6%)‡ 1,722 (17.7%) Edoxaban long-term 1,473 (3.5%)‡ 9 (0.1%)‡ 54 (0.5%)‡ 451 (4.2%)‡ 959 (9.9%)‡ Dabigatran long-term 394 (0.9%)‡ 21 (0.2%)‡ 111 (1.0%)‡ 140 (1.3%)‡ 122 (1.3%)‡ Spain 27,245 6,542 7,066 7,122 6,515 Rivaroxaban initially 991 (3.6%) 198 (3.0%) 228 (3.2%) 256 (3.6%) 309 (4.7%) Apixaban initially 341 (1.2%)‡ 1 (0.02%)‡ 43 (0.6%)‡ 76 (1.1%)‡ 221 (3.4%)‡ Rivaroxaban long-term 1,879 (6.9%) 326 (5.0%) 460 (6.5%) 498 (7.0%) 595 (9.1%) Apixaban long-term 1,659 (6.1%)‡ 53 (0.8%)‡ 305 (4.3%)‡ 437 (6.1%)∗ 864 (13.3%)‡ Edoxaban long-term 873 (3.2%)‡ 8 (0.1%)‡ 32 (0.4%)‡ 184 (2.6%)‡ 649 (10.0%) Europe, other 10,414 2,647 2,873 2,419 2,475 Rivaroxaban initially 3,308 (31.8%) 624 (23.6%) 1,068 (37.2%) 794 (32.8%) 822 (33.2%) Apixaban initially 730 (7.0%)‡ 2 (0.1%)‡ 156 (5.4%)‡ 264 (10.9%)‡ 308 (12.4%)‡ Rivaroxaban long-term 3,795 (36.4%) 793 (30.0%) 1,232 (42.9%) 901 (37.2%) 869 (35.1%) Apixaban long-term 1,488 (14.3%)‡ 10 (0.4%)‡ 351 (12.2%)‡ 484 (20.0%)‡ 643 (26.0%)‡ Edoxaban long-term 586 (5.6%)‡ 0 21 (0.7%)‡ 266 (11.0%)‡ 299 (12.1%)‡ America 1,530 446 294 543 247 Rivaroxaban initially 454 (29.7%) 165 (37.0%) 118 (40.1%) 85 (15.6%) 86 (34.8%) Apixaban initially 116 (7.6%)‡ 1 (0.2%)‡ 9 (3.1%)‡ 33 (6.1%)‡ 73 (29.5%) Rivaroxaban long-term 549 (35.9%) 190 (42.6%) 153 (52.0%) 112 (20.6%) 94 (38.1%) Apixaban long-term 169 (11.0%)‡ 3 (0.7%)‡ 17 (5.8%)‡ 60 (11.1%)‡ 89 (36.0%) Edoxaban long-term 2 (0.1%)‡ 0 1 (0.3%)‡ 1 (0.2%)‡ 0 Rest of the world 2,489 891 565 569 464 Rivaroxaban initially 388 (15.6%) 54 (6.1%) 67 (11.9%) 153 (26.9%) 114 (24.6%) Apixaban initially 128 (5.1%)‡ 1 (0.1%)‡ 18 (3.2%)‡ 29 (5.1%)‡ 80 (17.2%)∗ Rivaroxaban long-term 408 (16.4%) 58 (6.5%) 84 (14.9%) 147 (25.8%) 119 (25.6%) Apixaban long-term 232 (9.3%)‡ 8 (0.9%)‡ 54 (9.6%)∗ 44 (7.7%)‡ 126 (27.2%) Edoxaban long-term 12 (0.5%)‡ 1 (0.1%)‡ 0 0 11 (2.4%)‡ Differences between patients receiving rivaroxaban vs. other drugs: *p < 0.05; † p < 0.01; ‡ p < 0.001. Bold words are the main subjects to study. Years of prescription, number of patients Italic words apply for the total number of patients in each period of study and in the different parts of the world. 95% CI: 0.34–0.49) atrial fibrillation (OR: 1.58; 95% CI: 1.42– <65 years (OR: 1.51; 95% CI: 1.39–1.63) weighing > 120 kg 1.75) and prior VTE (OR: 1.14; 95% CI: 1.06–1.22) (Table 3) (OR: 1.61; 95% CI: 1.21–2.15) or with prior VTE (OR: 1.23; 95% The use of DOACs was more likely in other European countries CI: 1.12–1.36) (Table 4). Apixaban was the preferred DOAC (OR: 8.97; 95% CI: 8.49–9.49) America (OR: 6.35; 95% CI: 5.67– among patients >79 years (OR: 1.59; 95% CI: 1.43–1.76) in those 7.11) or in the rest of the world (OR: 2.99; 95% CI: 2.70–3.31) initially presenting with PE (OR: 1.17; 95% CI: 1.08–1.27) with than in Spain, and progressively increased from 2013–2015 to recent bleeding (OR: 1.80; 95% CI: 1.37–2.35) renal insufficiency 2016–2018 (OR: 2.78; 95% CI: 2.62–2.95) and 2019–2021 (OR: (OR: 1.89; 95% CI: 1.51–2.38) atrial fibrillation (OR: 1.62; 95% 6.36; 95% CI: 5.95–6.80). CI: 1.39–1.88) or in fragile patients (OR: 1.79; 95% CI: 1.65– 1.94) Edoxaban was much more likely used in Spain than in other countries. Predictors of use of one direct oral Independent predictors for the use of rivaroxaban (vs. other anticoagulant vs. the rest of direct oral DOACs) were: male gender (OR: 1.20; 95% CI: 1.10–1.30), age anticoagulants <65 years (OR: 1.47; 95% CI: 1.34–1.61) initial presentation as PE (OR: 1.16; 95% CI: 1.07–1.26) and VTE diagnosis in Among patients using DOACs, rivaroxaban was more likely non-Spanish European countries (OR: 2.17; 95% CI: 1.99–2.36) used in men (OR: 1.26; 95% CI: 1.18–1.36) in patients aged America (OR: 2.80; 95% CI: 2.32–3.37) or in other countries Frontiers in Medicine 04 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 30,00 25,00 20,00 15,00 10,00 5,00 0,00 2013 2014 2015 2016 2017 2018 2019 2020 2021 Rivaroxaban Apixaban Edoxaban FIGURE 1 Cumulative rates of patients receiving DOACs for initial and/or long-term therapy of VTE over time. (OR: 2.67; 95% CI: 2.24–3.18) Rivaroxaban was less prescribed 16) but it seems it is not a reason from prescription in some for >79 years (OR: 0.70; 95% CI: 0.62–0.78) recent bleeding countries as Spain. Also, its use was much lower in Spain (where (OR: 0.58; 95% CI: 0.43–0.79) and atrial fibrillation (OR: 0.72; the DOACs are not reimbursed) and progressively increased 95% CI: 0.61–0.85) (Table 4) Independent predictors for the over time. However, there were surprising findings in some use of apixaban were: male gender (OR: 0.88; 95% CI: 0.81– subgroups of patients. For example, while the use of DOACs was 0.95) >79 years (OR: 1.46; 95% CI: 1.30–1.64) recent major lower than expected in the subgroups of patients where they had bleeding (OR: 1.77; 95% CI: 1.33–2.36) atrial fibrillation (OR: demonstrated to be superior to standard therapy, they were not 1.22; 95% CI: 1.04–1.44) Apixaban was less used in age <65 infrequently used in patients with contraindications to their use. years (OR: 0.72; 95% CI: 0.65–0.79) and VTE diagnosis in non- Subgroup analyses from randomized trials revealed that Spanish European countries (OR: 0.67; 95% CI: 0.61–0.73) or in the DOACs had advantages over standard anticoagulation in America (OR: 0.82; 95% CI: 0.68–0.98) Independent predictors fragile patients with VTE. In the EINSTEIN trials, the risk for the use of edoxaban were: body weight >120 kg (OR: 0.53; for major bleeding in fragile patients using rivaroxaban was 95% CI: 0.29–0.97) initial VTE presentation as PE (OR: 0.64; significantly lower than in those on standard therapy (17– 95% CI: 0.57–0.72) liver cirrhosis (OR: 3.86; 95% CI: 1.21–12.3) 19). This difference was not found in non-fragile patients. prior VTE (OR: 0.80; 95% CI: 0.67–0.95) and being diagnosed in In the HOKUSAI trial, fragile patients using edoxaban had Spain. Interestingly, the use of rivaroxaban (comparatively with a significantly higher efficacy than those on VKAs (19). the other two DOACs) progressively decreased over time. The superiority of the DOACs over standard therapy in fragile patients with VTE was subsequently confirmed in real- life conditions (20, 21). However, only 24% of the 17,767 Discussion fragile patients in our cohort used DOACs. We hypothesize that a higher use of DOACs in fragile patients with VTE Our findings, obtained from a large cohort of patients with (40% of the whole series) might have been associated with acute VTE in up to 30 countries over the world, reveal large improved outcomes. variations in the use of DOACs according to patient factors, On the other hand, the use of DOACs is contraindicated institutional factors and also over time. As it could have been in patients with severe liver or renal insufficiency, in pregnant expected, the DOACs were more likely used in young patients, or breast-feeding women, and in patients perceived to be at those with normal body weight and with no exclusion criteria high risk for bleeding (4). Because most of these patients to be enrolled in the pivotal trials where their indication was with were excluded from the clinical trials, data regarding based (i.e., recent bleeding, renal insufficiency, liver cirrhosis or their effectiveness and safety are only available through thrombocytopenia) Studies about patients preferences usually non-randomized studies of which statistical type I/type II report more satisfied patients with DOAC than VKA drugs (15, errors could play a role (6, 22). Despite this knowledge Frontiers in Medicine 05 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 TABLE 2 Univariable and multivariable analyses for predictors of use of DOACs vs. other drugs. Total Patients Patients with Any DOACs (vs. other drugs) patient with DOACs at low DOACs doses Univariable OR Multivariable OR (95% CI) (95% CI) Patients, N 41,678 12,286 (29%) 2,154 (18%) Male gender 20,896 6,323 (30%) 1,011 (16%) 1.08 (1.03–1.12)* 1.01 (0.96–1.06) Age 65–79 years 14,110 3,957 (28%) 627 (16%) Ref. Ref. Age < 65 years 17,944 6,009 (33%) 825 (14%) 1.29 (1.23–1.36)‡ 1.30 (1.23–1.38)‡ Age > 79 years 9,624 2,320 (24%) 702 (30%) 0.81 (0.77–0.86)‡ 0.96 (0.89–1.03) Body weight 50–120 kg 39,960 11,882 (30%) 2,073 (17%) Ref. Ref. Body weight < 50 kg 977 190 (19%) 54 (28%) 0.57 (0.49–0.67)‡ 0.54 (0.45–0.65)‡ Body weight > 120 kg 740 213 (29%) 27 (13%) 0.96 (0.81–1.12) 0.64 (0.53–0.77)‡ Initial VTE presentation Isolated DVT 18,220 5,020 (27%) 904 (18%) Ref. Ref. Pulmonary embolism 23,458 7,266 (31%) 1,250 (17%) 1.18 (1.13–1.23)† 1.18 (1.13–1.25)‡ Concomitant disorders Recent major bleeding 970 224 (23%) 57 (25%) 0.71 (0.61–0.83)† 0.53 (0.45–0.63)‡ CrCl levels < 30 mL/min 2,097 310 (15%) 137 (44%) 0.40 (0.35–0.45)† 0.44 (0.38–0.51)‡ Liver cirrhosis 209 23 (11%) 6 (26%) 0.29 (0.19–0.45)† 0.32 (0.20–0.52)‡ Platelet count < 100,000/µL 1,055 168 (16%) 46 (27%) 0.45 (0.38–0.53)† 0.40 (0.34–0.49)‡ Atrial fibrillation 2,361 783 (33%) 237 (30%) 1.20 (1.10–1.31)† 1.58 (1.42–1.75)‡ Prior VTE 5,818 1,994 (34%) 357 (18%) 1.30 (1.22–1.37)† 1.14 (1.06–1.22)‡ Fragile patients 16,767 4,105 (24%) 1,034 (25%) 0.66 (0.63–0.69)† – Countries Spain 27,245 4,645 (17%) 859 (18%) Ref. Ref. Rest of Europe 10,414 6,152 (59%) 956 (16%) 7.02 (6.68–7.38)‡ 8.97 (8.49–9.49)‡ America 1,530 768 (50%) 130 (17%) 4.90 (4.41–5.45)‡ 6.35 (5.67–7.11)‡ Rest of the world 2,489 721 (29%) 209 (29%) 1.98 (1.81–2.18)‡ 2.99 (2.70–3.31)‡ Years 2013–2015 16,114 2,784 (17%) 502 (18%) Ref. Ref. 2016–2018 15,863 4,954 (31%) 968 (20%) 2.17 (2.06–2.29)‡ 2.78 (2.62–2.95)‡ 2019–2021 9,701 4,548 (47%) 684 (15%) 4.23 (3.99–4.47)‡ 6.36 (5.95–6.80)‡ *p < 0.05; † p < 0.01; ‡ p < 0.001. DOACs, direct oral anticoagulants; CI, confidence intervals; VTE, venous thromboembolism; DVT, deep vein thrombosis; CrCl, creatinine clearance; Ref., reference. Bold words are the main subjects to study. Years of prescription, number of patients Italic words apply for the total number of patients in each period of study and in the different parts of the world. gap, 23% of patients with recent major bleeding, 15% with associated with decreased efficacy and no benefit in safety (26– CrCl levels <30 mL/min, 11% with cirrhosis, and 16% with 29). Apixaban was seen to be the most frequent DOAC with thrombocytopenia in our cohort used DOACs. There are few dose modification. It could be argued that attending physician data about resuming anticoagulation after major bleeding with has used the same adjustment for dose that has to be made DOAC. In the study from Little (23), reassumption of DOAC in atrial fibrillation, as it’s supposed in the study from, about in extracranial non-gastrointestinal bleeding was accompanied changing pattern of type of anticoagulant use and in off-label by reduction in thrombosis. We haven’t studied DOAC in use a cohort from Switzerland (30). Also low doses are used in pregnancy in RIETE as opposite to GARFIELD study (24). atrial fibrillation (31, 32). Data of DOAC used in patient with recently bleeding are an Finally, because patients at extremes of body weight were interesting finding since the lack of a monitoring assays say and underrepresented in DOAC clinical trials and randomized reversal agents (25) have been important safety concerns for trials for these patient subgroups are currently unavailable, clinicians. A substantial proportion of these patients (25, 44, 26, the International Society of Thrombosis and Hemostasis and 27%, respectively) received lower than recommended doses. Scientific and Standardization Committee recently suggested This is also of concern, since under-dosing of DOACs has been that rivaroxaban and apixaban can be adequate for VTE therapy Frontiers in Medicine 06 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 TABLE 3 Multivariable analyses for predictors of use of every DOAC (vs. the rest of DOACs). Rivaroxaban Apixaban Edoxaban Patients, N 6,886 3,601 1,473 Clinical characteristics Male gender 1.20 0.88 0.89 (0.79–1.00) (1.10–1.30)‡ (0.81–0.95)† Age 65–79 years Ref. Ref. Ref. Age < 65 years 1.47 0.72 0.88 (0.77–1.01) (1.34–1.61)‡ (0.65–0.79)‡ Age > 79 years 0.70 1.46 0.99 (0.84–1.17) (0.62–0.78)‡ (1.30–1.64)‡ Body weight 50–100 kg Ref. Ref. Ref. Body weight < 50 kg 1.04 (0.75–1.43) 1.06 (0.77–1.47) 0.91 (0.56–1.50) Body weight > 120 kg 1.21 (0.88–1.67) 1.04 (0.75–1.44) 0.53 (0.29–0.97)∗ Initial VTE presentation Isolated DVT Ref. Ref. Ref. Pulmonary embolism 1.16 1.08 (0.99–1.17) 0.64 (1.07–1.26)‡ (0.57–0.72)‡ Concomitant disorders Recent major bleeding 0.58 1.77 0.88 (0.54–1.43) (0.43–0.79)‡ (1.33–2.36)‡ CrCl levels < 30 mL/min 0.88 (0.67–1.14) 1.10 (0.85–1.41) 1.17 (0.82–1.67) Liver cirrhosis 1.23 (0.48–3.19) 0.24 (0.05–1.05) 3.86 (1.21–12.3)∗ Platelet count < 100,000/µL 0.93 (0.66–1.30) 1.18 (0.84–1.65) 0.84 (0.48–1.48) Atrial fibrillation 0.72 1.22 0.81 (0.63–1.05) (0.61–0.85)‡ (1.04–1.44)∗ Prior VTE 1.03 (0.92–1.14) 1.10 (0.99–1.23) 0.80 (0.67–0.95)∗ Countries Spain Ref. Ref. Ref. Rest of Europe 2.17 0.67 0.56 (1.99–2.36)‡ (0.61–0.73)‡ (0.50–0.63)‡ America 2.80 0.82 0.02 (2.32–3.37)‡ (0.68–0.98)∗ (0.00–0.06)‡ Rest of the world 2.67 0.97 (0.82–1.16) 0.07 (2.24–3.18)‡ (0.04–0.12)‡ Years 2013–2015 Ref. Ref. Ref. 2016–2018 0.20 3.54 15.9 (0.17–0.22)‡ (3.09–4.05)‡ (9.89–25.5)‡ 2019–2021 0.10 4.74 36.6 (0.09–0.12)‡ (4.14–5.43)‡ (22.9–58.6)‡ Results are expressed as odds ratio and 95% confidence intervals (in brackets). *p < 0.05; † p < 0.01; ‡ p < 0.001. VTE, venous thromboembolism; DVT, deep vein thrombosis; CrCl, creatinine clearance; Ref., reference. Bold words are the main subjects to study. Years of prescription, number of patients Italic words apply for the total number of patients in each period of study and in the different parts of the world. regardless of body weight, and suggested not using dabigatran, major bleeding or atrial fibrillation. On the other hand, edoxaban or betrixaban in patients weighing >120 kg (12). In rivaroxaban was preferred in the young, and edoxaban our cohort, 12 patients weighing >120 kg used edoxaban (5.6% in those with liver cirrhosis. However, in the absence of the obese patients using DOACs). of clinical trials comparing the DOACs each other, there Among patients receiving DOACs in our cohort, there is no evidence to support that one specific DOAC is was some preference for apixaban over rivaroxaban or superior to any other in terms of efficacy or safety in any edoxaban in the elderly (33) and in patients with recent clinical scenario. Frontiers in Medicine 07 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 TABLE 4 Univariable analyses for predictors of use of each DOAC vs. the rest of DOACs. Rivaroxaban Apixaban Edoxaban N OR (95% CI) N OR (95% CI) N OR (95% CI) Patients, N 6,886 3,601 1,473 Clinical characteristics Male gender 3,721 1.26 (1.18–1.36)† 1,709 0.80 (0.74–0.86)† 723 0.90 (0.80–1.00) Age 65–79 years 2,109 Ref. 1,223 Ref. 502 Ref. Age < 65 years 3,799 1.51 (1.39–1.63)‡ 1,415 0.69 (0.63–0.75)‡ 660 0.85 (0.75–0.96)† Age > 79 years 978 0.64 (0.58–0.71)‡ 963 1.59 (1.43–1.76)‡ 311 1.07 (0.92–1.24) Body weight 50–120 kg 6,646 Ref. 3,478 Ref. 1,439 Ref. Body weight < 50 kg 96 0.80 (0.60–1.07) 69 1.38 (1.02–1.86)∗ 22 0.95 (0.61–1.49) Body weight > 120 kg 143 1.61 (1.21–2.15)† 54 0.82 (0.60–1.12) 12 0.43 (0.24–0.78)† Initial VTE presentation Isolated DVT 2,845 Ref. 1,373 Ref. 672 Ref. Pulmonary embolism 4,041 0.96 (0.89–1.03) 2,228 1.17 (1.08–1.27)† 801 0.80 (0.72–0.89)† Concomitant disorders Recent major bleeding 103 0.66 (0.51–0.86)† 95 1.80 (1.37–2.35)† 20 0.72 (0.45–1.14) CrCl levels < 30 mL/min 122 0.50 (0.40–0.63)† 135 1.89 (1.51–2.38)† 47 1.32 (0.96–1.81) Liver cirrhosis 15 1.47 (0.62–3.47) 2 0.23 (0.05–0.98)∗ 5 2.04 (0.76–5.51) Platelet count < 100,000/µL 92 0.95 (0.70–1.29) 56 1.21 (0.87–1.67) 15 0.72 (0.42–1.22) Atrial fibrillation 337 0.57 (0.49–0.66)† 308 1.62 (1.39–1.88)† 83 0.86 (0.68–1.09) Prior VTE 1,202 1.23 (1.12–1.36)† 569 0.96 (0.86–1.06) 179 0.69 (0.58–0.81)† Fragile patients 1,896 0.55 (0.51–0.59)† 1,541 1.79 (1.65–1.94)† 538 1.17 (1.04–1.31)† Countries Spain 1,919 Ref. 1,669 Ref. 873 Ref. Rest of Europe 3,935 2.52 (2.33–2.73)‡ 1,509 0.58 (0.53–0.63)‡ 586 0.45 (0.41–0.51)‡ America 569 4.06 (3.42–4.82)‡ 181 0.55 (0.46–0.66)‡ 2 0.01 (0.00–0.05)‡ Rest of the world 463 2.55 (2.17–3.00)‡ 242 0.90 (0.76–1.06) 12 0.07 (0.04–0.13)‡ Years 2013–2015 2,409 Ref. 305 Ref. 18 Ref. 2016–2018 2,724 0.19 (0.17–0.21)‡ 1,550 3.70 (3.24–4.23)‡ 496 17.1 (10.7–27.4)‡ 2019–2021 1,753 0.10 (0.09–0.11)‡ 1,746 5.06 (4.43–5.79)‡ 959 41.1 (25.7–65.6)‡ *p < 0.05; † p < 0.01; ‡ p < 0.001. VTE, venous thromboembolism; DVT, deep vein thrombosis; CrCl, creatinine clearance; Ref., reference. Bold words are the main subjects to study. Years of prescription, number of patients Italic words apply for the total number of patients in each period of study and in the different parts of the world. The main strength of this study is the large size of the Third, some countries had fewer participating centers or RIETE registry, which enabled us to explore the variations enrolled only a few patients. As such, although findings from across multiple settings, including across patient-related factors, this multicenter, multinational study demonstrate regional across geographic regions as well over time. As such, the variations in diagnostic practices, accurate comparisons for data related to temporal, institutional, and particularly patient- point estimates are not feasible for some countries. Finally, level variations per clinical subgroups provide real-world future research needs to consider the impact of patient evidence about contemporary practice and could be helpful preferences in DOAC therapy decisions. for practice management, policy making, and designing future This is the first of a series of studies to explore the use of research studies. However, a number of limitations of this DOACs in patients with VTE and their potential consequences. study must be acknowledged. First, we did not evaluate The focus of the current study was on the assessment and the role of patient income and sociodemographic variables description of potential variations in the choice of drugs for as they relate to patient’s willingness to pay for DOACs. VTE therapy. Future studies are required to explore the reasons Second, factors related to DOACs therapy choice may change behind the variations, the accuracy of each approach, and to over time as prescribers and patients gain more familiarity assess the impact of these variations on VTE-related and non- and experience with the newer DOACs, and additional VTE-related outcomes in adjusted analyses. research will be needed to identify predictors of treatment In conclusion, in a large multicenter, multinational registry and changes in DOAC treatment patterns in the future. of patients with VTE, we observed noticeable variations in the Frontiers in Medicine 08 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 choice of DOACs according to the underlying patient factors Conflict of interest and institutional factors. The authors declare that the research was conducted in the absence of any commercial or financial Data availability statement relationships that could be construed as a potential conflict of interest. The original contributions presented in this study are included in the article further inquiries can be directed to the corresponding author. Publisher’s note All claims expressed in this article are solely those of the Author contributions authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the PB, SO, JT, TS, LM, and AB-R: review of draft. All authors reviewers. Any product that may be evaluated in this article, or contributed to the article, approved the submitted version, and claim that may be made by its manufacturer, is not guaranteed contributed to the patients’ enrollment. or endorsed by the publisher. References 1. Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, et al. 12. Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, American Society of Hematology 2020 guidelines for management of venous Moll S. Use of direct oral anticoagulants in patients with obesity for treatment thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. and prevention of venous thromboembolism: updated communication from the Blood Adv. (2020) 4:4693–738. doi: 10.1182/bloodadvances.2020001830 ISTH SSC subcommittee on control of anticoagulation. J Thromb Haemost. (2021) 19:1874–82. doi: 10.1111/jth.15358 2. Stevens SM, Woller SC, Baumann-Kreuziger L, Bounameaux H, Doerschug K, Geersing G, et al. Antithrombotic therapy for VTE disease: second update of 13. Bikdeli B, Jiménez D, Hawkins M, Ortíz S, Prandoni P, Brenner B, et al. the CHEST guideline and expert panel report. Chest. (2021) 160:e545–608. doi: Rationale, design and methodology of the computerized registry of patients with 10.1016/j.chest.2021.07.055 venous thromboembolism (RIETE). Thromb Haemost. (2018) 118:214–24. doi: 10.1160/TH17-07-0511 3. Van Es N, Coppens M, Schulman S, Middeldorp S, Büller H. Direct oral anticoagulants compared with vitamin K antagonists for acute venous 14. Einstein-Pe Investigators, Büller HR, Prins MH, Lensin AW, Decousus H, thromboembolism: evidence from phase 3 trials. Blood. (2014) 124:1968–75. doi: Jacobson BF, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N 10.1182/blood-2014-04-571232 Engl J Med. (2010) 363:2499–510. 4. Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance 15. Afzal SK, Hasan SS, Babar ZU. A systematic review of patient-reported for the practical management of the direct oral anticoagulants (DOACs) in VTE outcomes associated with the use of direct-acting oral anticoagulants. Br J Clin treatment. J Thromb Thrombolys. (2016) 41:206–32. doi: 10.1007/s11239-015- Pharmacol. (2019) 85:2652–67. doi: 10.1111/bcp.13985 1310-7 16. Keita I, Aubin-Auger I, Lalanne C, Aubdert JR, Chassany O, Durancisky M, 5. Toorop MMA, Lijfering WM, Scheres LJJ. The relationship between DOAC et al. Assessment of quality of life, satisfaction with anticoagulation therapy, and levels and clinical outcomes: the measures tell the tale. J Thromb Haemost. (2020) adherence to treatment in patients receiving long-course vitamin K antagonists or 18:3163–8. doi: 10.1111/jth.15104 direct oral anticoagulants for venous thromboembolism. Patient Prefer Adherence. (2017) 11:1625–34. doi: 10.2147/PPA.S131157 6. Weber J, Olyaei A, Shatzel J. The efficacy and safety of direct oral anticoagulants in patients with kidney disease. Eur J Haematol. (2019) 102:312–8. 17. Einstein Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, doi: 10.1111/ejh.13208 Decousus H, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. (2012) 366:1287–97. doi: 10.1056/NEJMoa1113572 7. Cheung CYS, Parikh J, Farrell A, Lefebvre M, Summa-Sorgini C, Battistella M. Direct oral anticoagulant use in chronic kidney disease and dialysis patients 18. Prins MH, Lensing A, Bauersachs R, van Bellen B, Bounameaux H, with venous thromboembolism: a systematic review of thrombosis and bleeding Brighton TA, et al. Oral rivaroxaban versus standard therapy for the treatment of outcomes. Ann Pharmacother. (2021) 55:711–22. doi: 10.1177/106002802096 symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT 7635 an PE randomized studies. Thromb J. (2013) 11:21–31. doi: 10.1186/1477-9560-11- 21 8. Ting C, Rhoten M, Dempsey J, Nichols H, Fanikos J, Ruff CT. Evaluation of direct oral anticoagulant prescribing in patients with moderate to severe 19. Hokusai-Vte Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, renal impairment. Clin Appl Thromb Hemost. (2021) 27:1076029620987900. doi: Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic 0.177/1076029620987900 venous thromboembolism. N Engl J Med. (2013) 369:1406–15. doi: 10.1056/ NEJMoa1306638 9. Elhosseiny S, Al Moussawi H, Chalhoub JM, Lafferty J, Deeb L. Direct oral anticoagulants in cirrhotic patients: current evidence and clinical observations. 20. López-Núñez JJ, Pérez-Andrés R, Di Micco P, Schellong S, Gómez Cuervo Can J Gastroenterol Hepatol. (2019) 2019:4383269. doi: 10.1155/2019/438 C, Sahuquillo JC. Direct oral anticoagulants or standard anticoagulant therapy 3269 in fragile patients with venous thromboembolism. TH Open. (2019) 3:e67–76. doi: 10.1055/s-0039-1683970 10. Speed V, Green B, Roberts LN, Woolcombe S, Bartoli-Abdou J, Barsam S, et al. Fixed dose rivaroxaban can be used in extremes of body weight: a population 21. Trujillo-Santos J, Beroiz P, Alonso A, Morejón E, López-Reyes R, Casado pharmacokinetic analysis. J Thromb Haemost. (2020) 18:2296–307. doi: 10.1111/ I, et al. Rivaroxaban or apixaban in fragile patients with acute venous jth.14948 thrombo-embolism. Thromb Res. (2020) 193:160–5. doi: 10.1016/j.thromres.2020. 06.035 11. Katel A, Aryal M, Neupane A, Gosain R, Pathak R, Bhandari Y, et al. Efficacy and safety of direct oral anticoagulants in venous thromboembolism compared 22. Derebail VK, Rheault MN, Kerlin BA. Role of direct oral anticoagulants in to traditional anticoagulants in morbidly obese patients: a systematic review and patients with kidney disease. Kidney Int. (2020) 97:664–75. doi: 10.1016/j.kint.2019. meta-analysis. Cureus. (2021) 13:e14572. doi: 10.7759/cureus.14572 11.027 Frontiers in Medicine 09 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 23. Little DHW, Sutradhar R, Cerasuolo JO, Perez R, Douketis J, Holbrook A, 29. Deitelzweig S, Keshishian A, Li X, Kang A, Dhamane AD, et al. Rates of rebleeding, thrombosis and mortality associated with resumption Luo X, et al. Comparisons between oral anticoagulants among older of anticoagulant therapy after anticoagulant-related bleeding. CMAJ. (2021) nonvalvular atrial fibrillation patients. J Am Geriatr Soc. (2019) 67: 193:E304–9. doi: 10.1503/cmaj.201433 1662–71. doi: 10.1111/jgs.15956 24. Jerjes-Sánchez C, Rodriguez D, Farjat AE, Kayani G, MacCallum P, Lopes RD, 30. Eschler C, Antelo A, Funk GC, Exadaktylos AK, Lindner G. High fluctuation et al. Pregnancy-associated venous thromboembolism: insights from GARFIELD- between anticoagulants, frequent off-label dosing, and no difference concerning VTE. TH Open. (2021) 5:e24–34. doi: 10.1055/s-0040-1722611 outcomes: results of a real-life cohort study. Am J Med. (2021) 134:e165–70. doi: 10.1016/j.amjmed.2020.09.018 25. Shih AW, Crowther MA. Reversal of direct oral anticoagulants: a practical 31. Navarro-Almenzara B, Cerezo-Manchado JJ, Caro-Martinez C, García- approach. Hematology Am Soc Hematol Educ Program. (2016) 2016:2012–9. doi: Candela C, Flores Blanco PJ, Elvira Ruiz G, et al. Real-life behaviour of direct 10.1182/asheducation-2016.1.612 oral anticoagulants in a Spanish cohort with non-valvular atrial fibrillation: refase 26. Trujillo-Santos J, Di Micco P, Dentali F, Douketis J, Díaz-Peromingo JA, registry. Curr Med Res Opin. (2019) 35:2035–41. doi: 10.1080/03007995.2019. Núñez MJ, et al. Real-life treatment of venous thromboembolism with direct 1647735 oral anticoagulants: the influence of recommended dosing and regimens. Thromb 32. Ruiz Orti M, Muñiz J, Raña Míguez P, Roldán I, Marín F, Esteve- Haemost. (2017) 117:382–9. doi: 10.1160/TH16-07-0494 Pastor A, et al. Inappropriate doses of direct oral anticoagulants in real- 27. Dentali F, Fantoni C. Is it reasonable to use a lower DOAC dose in some world clinical practice: prevalence and associated factors. A subanalysis of the patients with VTE? No. Intern Emerg Med. (2017) 12:565–7. doi: 10.1007/s11739- FANTASIIA registry. Europace. (2018) 20:1577–83. doi: 10.1093/europace/eux 017-1695-8 316 28. Chopard R, Serzian G, Humbert S, Falvo N, Morel-Aleton M, Bonnet B, et al. 33. Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous Non-recommended dosing of direct oral anticoagulants in the treatment of acute thromboembolism in the elderly: efficacy and safety of non-VKA oral pulmonary embolism is related to an increased rate of adverse events. J Thromb anticoagulants. Thromb Jour. (2014) 12:21. doi: 10.1186/1477-9560- Thrombolysis. (2018) 46:283–91. doi: 10.1007/s11239-018-1690-6 12-21 Frontiers in Medicine 10 frontiersin.org Lorenzo et al. 10.3389/fmed.2022.991376 Appendix Members of the RIETE Group SPAIN: Adarraga MD, Agudo P, Aibar J, Aibar MA, Amado C, Arcelus JI, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón- Andrés B, Bascuñana J, Blanco-Molina A, Beddar Chaib F, Botella E, Camón AM, Castro J, Chasco L, Criado J, de Ancos C, de Miguel J, del Toro J, Demelo-Rodríguez P, Díaz-Brasero AM, Díaz-Pedroche MC, Díaz-Peromingo JA, Díaz-Simón R, Domínguez IM, Dubois- Silva A, Escribano JC, Espósito F, Farfán-Sedano AI, Fernández-Capitán C, Fernández-Reyes JL, Fidalgo MA, Font C, Francisco I, Gabara C, Galeano-Valle F, García MA, García-Bragado F, García de Herreros M, García de la Garza R, García-Díaz C, García-Mullor MM, Gil-Díaz A, Gómez-Cuervo C, Gómez-Mosquera AM, González-Martínez J, Grau E, Guirado L, Gutiérrez J, Hernández-Blasco L, Jara-Palomares L, Jaras MJ, Jiménez D, Jiménez R, Jiménez-Alfaro C, Jou I, Joya MD, Lainez-Justo S, Latorre-Díez A, Lalueza A, Lecumberri R, Lobo JL, López-Brull H, López-De la Fuente M, López-Jiménez L, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorenzo A, Lumbierres M, Madridano O, Maestre A, Marchena PJ, Marcos M, Martín-Martos F, Martínez-Urbistondo D, Mella C, Mellado M, Mercado MI, Monreal M, Muñoz-Blanco A, Muñoz-Gamito G, Morales MV, Nieto JA, Núñez-Fernández MJ, Olid-Velilla M, Otalora S, Otero R, Parra P, Parra V, Pedrajas JM, Pellejero G, Peris ML, Porras JA, Portillo J, Rivera A, Roca M, Rosa V, Ruiz-Artacho P, Ruiz-Giménez N, Ruiz-Ruiz J, Ruiz-Sada P, Salgueiro G, Sánchez-Muñoz-Torrero JF, Sancho T, Sigüenza P, Soler S, Suriñach JM, Torres MI, Trujillo-Santos J, Uresandi F, Usandizaga E, Valle R, Varona JF, Vela L, Vela JR, Villalobos A, Villares P, Zamora C, AUSTRIA: Ay C, Nopp S, Pabinger I, BELGIUM: Engelen MM, Vanassche T, Verhamme P, COLOMBIA: Esguerra G, Montenegro AC, Roa J, CZECH REPUBLIC: Hirmerova J, Malý R, FRANCE: Accassat S, Bertoletti L, Bura-Riviere A, Catella J, Chopard R, Couturaud F, Espitia O, El Harake S, Helfer H, Le Mao R, Mahé I, Moustafa F, Poenou G, Sarlon-Bartoli G, Suchon P, GERMANY: Schellong S, ISRAEL: Braester A, Brenner B, Kenet G, Tzoran I, ITALY: Basaglia M, Bilora F, Bortoluzzi C, Brandolin B, Ciammaichella M, Colaizzo D, De Angelis A, Di Micco P, Grandone E, Imbalzano E, Mastroiacovo D, Merla S, Pesavento R, Prandoni P, Siniscalchi C, Tufano A, Visonà A, Vo Hong N, Zalunardo B, LATVIA: Kalejs RV, Rusa E, Skride A, PORTUGAL: Fonseca S, Manuel M, Meireles J, REPUBLIC OF MACEDONIA: Bosevski M, Krstevski G, SWITZERLAND: Bounameaux H, Mazzolai L, USA: Caprini JA, Weinberg I, VIETNAM: Bui HM. Coordinator of the RIETE Registry: Manuel Monreal. RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner, and Dominique Farge-Bancel. RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), Hanh My Bui (Vietnam). RIETE Registry Coordinating Center: S&H Medical Science Service. Acknowledgments We express our gratitude to Sanofi Spain, LEO PHARMA and ROVI for supporting this Registry with an unrestricted educational grant. We also thank the RIETE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support and Prof. Salvador Ortiz, Universidad Autónoma Madrid and Silvia Galindo, both Statistical Advisors in S&H Medical Science Service for the statistical analysis of the data presented in this paper. Frontiers in Medicine 11 frontiersin.org