# Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?
    
    
    RESEARCH ARTICLE
    Long-Term Anticoagulant Therapy of
    Patients with Venous Thromboembolism.
    What Are the Practices?
    Isabelle Mahé1*, Raluca Sterpu2, Laurent Bertoletti3, Luciano López-Jiménez4,
    Meritxell Mellado Joan5, Javier Trujillo-Santos6, Aitor Ballaz7, Luis Manuel Hernández
    Blasco8, Pablo Javier Marchena9, Manuel Monreal10, RIETE investigators¶
    1 Department of Internal Medicine, Hôpital Louis Mourier, Colombes (APHP), University Paris 7, EA REMES
    7334, Université Paris Diderot, Sorbonne Paris Cité, France, 2 Department of Internal Medicine, Hôpital
    Louis Mourier, Colombes, (APHP), University Paris 7, Paris, France, 3 Department of Vascular and
    Therapeutic Medicine, CHU Saint-Etienne, Hôpital Nord, Saint-Etienne, France, 4 Department of Internal
    Medicine, Hospital Provincial Reina Sofía, Córdoba, Spain, 5 Department of Angiology and Vascular
    Surgery, Hospital del Mar, Barcelona, Spain, 6 Department of Internal Medicine, Complejo Hospitalario
    Universitario de Cartagena, Murcia, Spain, 7 Department of Pneumonology, Hospital de Galdakao, Vizcaya,
    Spain, 8 Department of Pneumonology, Hospital General Universitario de Alicante, Alicante, Spain,
    9 Department of Internal Medicine, Parc Sanitari Sant Joan de Deu-Hospital General, Barcelona, Spain,
    10 Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
    OPEN ACCESS
    Citation: Mahé I, Sterpu R, Bertoletti L, LópezJiménez L, Mellado Joan M, Trujillo-Santos J, et al.
    (2015) Long-Term Anticoagulant Therapy of Patients
    with Venous Thromboembolism. What Are the
    Practices? PLoS ONE 10(6): e0128741. doi:10.1371/
    journal.pone.0128741
    Academic Editor: Russell R. Lonser, Ohio State
    University, UNITED STATES
    Received: March 5, 2015
    Accepted: May 1, 2015
    Published: June 15, 2015
    Copyright: © 2015 Mahé et al. This is an open
    access article distributed under the terms of the
    Creative Commons Attribution License, which permits
    unrestricted use, distribution, and reproduction in any
    medium, provided the original author and source are
    credited.
    Data Availability Statement: All relevant data are
    within the paper.
    Funding: This Registry is supported by unrestricted
    educational grants from Sanofi Spain and Bayer
    Pharma AG. The funding source had no role in the
    design, protocol development, or conduct of the
    study; data collection, management, or analysis;
    interpretation, preparation, review, or approval of the
    manuscript; or the decision to submit the manuscript
    for publication.
    ¶ A full list of RIETE investigators is provided in the Acknowledgments.
    * isabelle.mahe@lmr.aphp.fr
    Abstract
    Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists
    (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy
    with low-molecular weight heparin (LMWH) for those with cancer. We used data from
    RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without
    cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378
    patients with cancer, 66% received long term LMWH as monotherapy. In patients without
    cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26–3.23), age >70 years (OR 1.15,
    95% CI 1.06–1.24), immobility (OR 2.06, 95% CI 1.93–2.19), renal insufficiency (OR 2.42,
    95% CI 2.15–2.71) and anemia (OR 1.75, 95% CI 1.65–1.87) predicted poor adherence to
    guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64–2.06), immobility (OR 1.51,
    95% CI 1.30–1.76) and metastases (OR 3.22, 95% CI 2.87–3.61) predicted long-term
    LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that
    a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.
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    Competing Interests: The RIETE Registry was
    supported with an unrestricted educational grant from
    Sanofi Spain and Bayer Pharma AG. Bayer Pharma
    AG’s support was limited to the part of RIETE outside
    Spain, which accounts for a 20.05% of the total
    patients included in the RIETE Registry. The authors
    have nothing to disclose. The authors have declared
    that no competing interests exist.
    Introduction
    For many years, the American College of Chest Physicians (ACCP) recommend that patients
    with acute venous thromboembolism (VTE) to be treated initially with parenteral anticoagulation (low-molecular-weight heparin [LMWH], fondaparinux or unfractionated heparin
    [UFH]) (Grade 1B) [1]. Then, for patients without cancer they suggest early initiation (eg,
    same day as parenteral therapy is started) of vitamin K antagonists (VKA) over LMWH (Grade
    2C). In patients with active cancer, concordant clinical trials lead to a specific recommendation
    in favour of LMWH over VKA therapy since 2004 (Grade 2B) [1]. However, the implementation of recommendations on practices is the only relevant feature but little is known about patterns of management of VTE in real life, particularly after hospital discharge. Such information
    could possibly contribute to identify remediable gaps in patient care.
    The RIETE (Registro Informatizado de Enfermedad TromboEmbólica) Registry is an ongoing, multicenter, international (Spain, Italy, France, Israel, Greece, Switzerland, Czech Republic
    and Macedonia), observational registry of consecutive patients with symptomatic, objectively
    confirmed, acute VTE. It started in Spain in 2001, and 6 years later the database was translated
    into English with the aim to expand the Registry to other countries, ultimately allowing physicians worldwide to use the database to select the most appropriate therapy for their patients.
    Data from this registry have been used to evaluate outcomes after acute VTE, such as the frequency of recurrent VTE, bleeding and mortality, and risk factors for these outcomes [2–5]. In
    the current analysis, we evaluated anticoagulant practices for VTE treatment over more than
    10 years, and tried to identify determinants and patient-related factors for VTE management,
    according to international guidelines.
    Patients and Methods
    Consecutive patients with symptomatic, acute deep vein thrombosis (DVT) or pulmonary embolism (PE), confirmed by objective tests (compression ultrasonography or contrast venography for DVT; helical CT-scan or ventilation-perfusion lung scintigraphy for PE), were enrolled
    in RIETE. Patients were excluded if they were currently participating in a therapeutic clinical
    trial with a blinded therapy. All patients (or their relatives) provided written or oral consent for
    participation in the registry, in accordance with local ethics committee requirements.
    We certify that RIETE counts with IRB's approval, always in accordance with the internal
    requirements of each of the centers participating. This analysis was approved by the Institutional Review Board (IRB) of Hospital Universitari Germans Trias i Pujol (Badalona, Spain)
    and the NorthShore University HealthSystem (Evanston, Illinois, USA). As to the need for
    written consent, RIETE started in 2001 and then oral consent was enough. For France we got
    the approval of the INSERM Ethical committee for oral consent solely, as it is only an epidemiological study. However, as more and more centers have been joining us, most of them have
    obtained approval only if consent was written. We have the copies of these approvals.
    Physicians participating in the RIETE registry ensured that eligible patients were consecutively enrolled. Data were recorded on to a computer-based case report form at each participating hospital and submitted to a centralized coordinating center through a secure website. The
    study coordinating center assigned patients with a unique identification number to maintain
    patient confidentiality and was responsible for all data management. Data quality was regularly
    monitored electronically, including checks to detect inconsistencies or errors, which were resolved by contacting the local coordinators. Data quality was also monitored by periodic visits
    to participating hospitals by contract research organizations that compared medical records
    with the submitted data.
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    Baseline variables
    The following parameters were recorded when the qualifying episode of VTE was diagnosed:
    patient's gender, age, and body weight and height; presence of coexisting conditions; concomitant therapies; additional risk factors for VTE including active cancer (defined as newly diagnosed cancer or cancer that is being treated [i.e. surgery, chemotherapy, radiotherapy,
    hormonal, support therapy, or combined treatments]) and prior VTE; laboratory data, and use
    of anticoagulant therapy (drug, dose, date of start and date of discontinuation for each drug).
    Treatment and Follow-up
    Patients were managed according to the clinical practice of each participating hospital (i.e.,
    there was no standardization of treatment). Patients were followed-up for up to 3 months in
    the outpatient clinic. During each visit, any signs or symptoms suggesting PE recurrences or
    bleeding complications were noted. Each episode of clinically suspected recurrent VTE was investigated by repeat CUS ultrasonography, lung scanning, helical-CT scan or pulmonary angiography as appropriate. Most outcomes were classified as reported by the clinical centers.
    However, if staff at the coordinating center were uncertain how to classify a reported outcome,
    that event was reviewed by a central adjudicating committee (less than 10% of events).
    Indicators for VTE treatment description
    The ACCP Consensus Guidelines on Antithrombotic Therapy1 was used as a benchmark for quality of VTE care. Since 2004 and consistently in 2008 and 2012, initial treatment using heparin or
    LMWH with a VKA bridging at day 1 has been recommended for non-cancer-related VTE. In the
    same recommendations and in line with publication of major clinical trials, 3–6 months LMWH
    therapy has become the recommended strategy for treating patients with cancer-related VTE.
    Therefore, we used the following indicators for VTE treatment description: long-term therapy was the treatment followed by the patient 7 days after the thromboembolic treatment. Patients were classified in two different strategies: long-term LMWH therapy and long-term
    VKA. For patients receiving long-term VKA, we separated patients starting VKA within the
    first week of therapy; and those receiving VKA after the first week of therapy. We reported separately patients receiving fondaparinux as initial VTE therapy.
    Statistical analysis
    Every test of two proportions was a Student's t test for independent samples with a binary variable
    as the response (0/1). Every test of two means was a Student’s t test (if variances were homogeneous) or a Welch’s test (if variances were heterogeneous). Logistic regression models were used
    to examine the individual relationship between each variable and the choice of treatment in the
    two populations. We compared baseline characteristics of patients who were treated with: a) VKA
    starting within the first week; b) VKA starting beyond the first week and c) long-term LMWH
    therapy using chi-square tests for categorical variables (or Fisher exact test where appropriate)
    and ANOVA test for continuous variables. Two multivariate analyses were performed: one to
    identify predictors of starting VKA within the first week versus VKA starting beyond the first
    week or long-term LMWH in non-cancer patients; and a second analysis to identify predictors of
    VKA versus LMWH therapy in patients with cancer. We chose as covariates all variables with a
    p value <0.02 on univariate analysis and those considered by expert opinion. Logistic regression
    analyses were performed using a forward stepwise method with a p<0.10 and p>0.05 as inclusion
    and exclusion criteria using a score test for likelihood ratio criteria. All analyses were performed
    using a commercial software package (SPSS 20 for Mac, SPSS Inc., and Chicago, IL, USA).
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    Table 1. Patients without cancer: Clinical characteristics according to long-term anticoagulant therapy.
    VKA start <7 days
    VKA start >7 days
    LMWH alone
    N
    22,986
    6,041
    6,253
    Gender (males)
    11,313 (49%)
    2,893 (48%)
    Patients
    Clinical characteristics
    Mean age (years±SD)
    64±18
    ‡
    2,526 (40%)‡
    68±20‡
    63±18
    ‡
    Age >75 years
    8,332 (36%)
    2,015 (33%)
    3,131 (50%)‡
    Body weight (kg±SD)
    76±15
    76±15
    71±15‡
    Chronic heart failure
    1,473 (6.4%)
    392 (6.5%)
    580 (9.3%)‡
    Underlying conditions
    Chronic lung disease
    2,530 (11%)
    683 (11%)
    683 (11%)
    CrCl level 30–60 ml/min
    7,111 (31%)
    1,867 (31%)
    2,477 (40%)‡
    CrCl levels <30 mL/min
    1,098 (4.8%)
    273 (4.5%)
    2,105 (12%)‡
    Recent major bleeding
    183 (0.8%)
    ‡
    268 (4.3%)‡
    141 (2.3%)
    ‡
    Anemia
    5,248 (23%)
    1,834 (30%)
    2,618 (42%)‡
    Chronic liver disease
    104 (0.5%)
    33 (0.5%)
    53 (0.8%)‡
    Inﬂammatory bowel disease
    78 (0.3%)
    34 (0.6%)*
    48 (0.8%)‡
    Postoperative
    2,250 (9.8%)
    741 (12%)‡
    Risk factors for VTE
    720 (12%)‡
    Immobility 4 days
    4,913 (21%)
    1,454 (24%)
    2,502 (40%)‡
    Estrogen use
    1,378 (6.0%)
    315 (5.2%)*
    177 (2.8%)‡
    ‡
    315 (5.0%)‡
    Pregnancy/puerperium
    143 (0.6%)
    ‡
    129 (2.1%)
    ‡
    None of the above
    14,314 (62%)
    3,463 (57%)
    2,708 (43%)‡
    Prior VTE
    3,875 (17%)
    968 (16%)
    827 (13%)‡
    Pulmonary embolism
    11,804 (51%)
    3,212 (53%)*
    2,536 (41%)‡
    Proximal DVT alone
    9,255 (40%)
    2,350 (39%)
    3,094 (49%)‡
    Initial VTE presentation
    ‡
    Bilateral DVT alone
    183 (1.6%)
    80 (2.8%)
    120 (3.2%)‡
    Upper-extremity DVT
    533 (4.8%)
    155 (5.5%)
    245 (6.6%)‡
    Abbreviations: VKA, vitamin K antagonists; LMWH, low-molecular-weight heparin; SD, standard deviation; CrCl, creatinine clearance; VTE, venous
    thromboembolism; DVT, deep vein thrombosis. Differences between patients starting VKA within the ﬁrst week and the other groups
    * p <0.05
    ‡
    p <0.001.
    doi:10.1371/journal.pone.0128741.t001
    Results
    Up to October 2013, 48,481 patients were recruited in RIETE. Only patients receiving VKA
    starting within the first 90 days after initial therapy with UFH or LMWH, or those treated with
    long-term therapy LMWH after an initial therapy with UFH or LMWH, were considered for
    the analysis. The following patients were not considered: 4,787 treated with rivaroxaban or
    combinations, 698 with thrombolytics, 608 undergoing an inferior vena cava filter, 26 receiving
    no anticoagulants and 927 experiencing an adverse event within the first 5 days. Thus, 41,625
    patients were considered for the current study. Major demographic features are summarized in
    Table 1 for non-cancer patients and in Table 2 for those with cancer, according to choice of
    long-term therapy (VKA or LMWH). Long-term therapy is presented according to the country
    in non-cancer patients (Table 3) and in those with cancer (Table 4).
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    Table 2. Cancer patients: Clinical characteristics according to long-term anticoagulant therapy.
    VKA start <7 days
    VKA start >7 days
    LMWH alone
    1,516
    619
    4,210
    Patients
    N
    Clinical characteristics
    Gender (males)
    840 (55%)
    350 (57%)
    2,243 (53%)
    Mean age (years±SD)
    70±12
    67±13‡
    66±13‡
    Age >75 years
    632 (42%)
    199 (32%)
    1176 (28%)
    Body weight (kg±SD)
    74±13
    73±13
    71±14‡
    Chronic heart failure
    87 (5.7%)
    31 (5.0%)
    152 (3.6%)‡
    Chronic lung disease
    199 (13%)
    70 (11%)
    377 (9.0%)‡
    CrCl level 30–60 ml/min
    575 (38%)
    226 (37%)
    1,454 (35%)
    CrCl levels <30 mL/min
    87 (5.7%)
    30 (4.8%)
    253 (6.0%)
    Recent major bleeding
    15 (1.0%)
    18 (2.9%)†
    Underlying conditions
    ‡
    95 (2.3%)†
    Anemia
    757 (50%)
    361 (58%)
    2,926 (70%)‡
    Metastases
    455 (30%)
    200 (32%)
    2,550 (61%)‡
    Pulmonary embolism
    791 (52%)
    331 (54%)
    2,060 (49%)*
    Proximal DVT alone
    627 (41%)
    246 (40%)
    1,952 (46%)‡
    Bilateral DVT alone
    27 (3.7%)
    19 (6.6%)*
    143 (6.7%)†
    Upper-extremity DVT
    46 (6.3%)
    32 (11%)*
    395 (18%)‡
    Cancer characteristics
    Initial VTE presentation
    Abbreviations: VKA, vitamin K antagonists; LMWH, low-molecular-weight heparin; SD, standard deviation; CrCl, creatinine clearance; VTE, venous
    thromboembolism; DVT, deep vein thrombosis. Differences between patients staring VKA within the ﬁrst week and the other groups
    * p <0.05
    †
    p <0.01
    ‡
    p <0.001.
    doi:10.1371/journal.pone.0128741.t002
    Patients without cancer
    Among 35,280 patients without cancer, 22,986 (65%) started VKA within the first week, 6,041
    (17%) beyond the first week, and 6,253 (18%) did not switch to VKA and received long-term
    LMWH therapy (Table 1). Overall, 65 patients received fondaparinux as initial VTE therapy:
    48 (0.2%) started VKA within the first week, 11 (0.2%) beyond the first week and 6 (0.1% received long-term LMWH therapy. Compared to patients starting VKA within the first week,
    those starting VKA after the first week more likely to have recent bleeding, anemia, inflammatory bowel disease, recent surgery or immobilization, and more likely presented as PE initially
    Table 3. Patients without cancer: country and long-term anticoagulant therapy.
    VKA start <7 days
    VKA start >7 days
    LMWH alone
    N
    22,986
    6041
    6253
    Spain
    18,912 (64%)
    5236 (18%)
    5205 (18%)
    France
    1195 (74%)
    198 (12%)
    227 (14%)
    Israel
    424 (60%)
    83 (12%)
    199 (28%)
    Italy
    1622 (70%)
    304 (13%)
    396 (17%)
    Other countries
    833 (65%)
    220 (17%)
    226 (18%)
    Patients
    Countries
    doi:10.1371/journal.pone.0128741.t003
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    Table 4. Patients with cancer: country and long-term anticoagulant therapy.
    VKA start <7 days
    VKA start >7 days
    LMWH alone
    N
    1516
    619
    4210
    Spain
    1211 (25%)
    515 (11%)
    3173 (65%)
    France
    63 (21%)
    21 (7.0%)
    215 (72%)
    Israel
    29 (8.5%)
    9 (2.6%)
    304 (89%)
    Italy
    121 (24%)
    46 (9.1%)
    338 (67%)
    Other countries
    92 (31%)
    28 (9.3%)
    180 (60%)
    Patients
    Countries
    doi:10.1371/journal.pone.0128741.t004
    (instead of DVT alone). Compared to those under VKA, patients receiving long-term therapy
    with LMWH were more likely to be female and significantly older, weighed less and more likely
    had chronic heart failure, renal insufficiency, recent bleeding, anemia, liver disease, chronic inflammatory disease, mental disorders (dementia, depression, schizophrenia or bipolar disorder), recent surgery, immobility or pregnancy. By contrast, they less likely had prior VTE or
    initial VTE presentation as PE.
    Patients with cancer
    Among 6,345 patients with cancer, 1,516 (24%) started VKA within the first week, 619 (9.8%)
    beyond the first week, and 4,210 (66%) received long-term LMWH therapy (Table 2). Overall,
    10 patients received fondaparinux as initial VTE therapy: 5 (50%) started VKA within the first
    week and 5 (50% received long-term LMWH therapy. Compared with patients starting VKA
    within the first week, those starting VKA after the first week were younger and more likely had
    recent surgery. Compared to those under VKA, patients receiving long-term therapy with
    LMWH were younger, less likely had chronic heart failure, lung disease or renal insufficiency,
    and more likely had anemia, immobility or metastases. They less likely had prior VTE or initial
    VTE presentation as PE.
    Dynamic evolution of anticoagulant prescription
    In non-cancer patients, the number of patients receiving VKA on day 6, 10 and 90 was: 19,783,
    24,670 and 26,640, respectively (Fig 1). In patients with cancer, the number of LMWH prescriptions decreased steadily over time, reflecting the poorer prognosis of patients with cancer.
    The amount of patients receiving VKA on day 6, 10 and 90 was: 2,246, 1,634 and 1,828 respectively (Fig 2). The evolution over time of the different anticoagulant strategies (VKA starting
    within the first week, VKA starting beyond the first week, long-term LMWH therapy) since the
    beginning of the RIETE registry is displayed in Fig 3. There was an overall stability of anticoagulant strategies in patients without cancer over time. In patients with cancer, there was a dramatic increase on long-term LMWH treatment from 2004 on, concomitantly with a decrease
    of VKA prescriptions.
    Factors associated with poor guidelines adherence
    In patients without cancer, female gender, recent bleeding, anemia, recent surgery or immobilization, renal insufficiency, chronic liver disease, inflammatory bowel disease, mental disturbances and initial presentation as DVT independently predicted not starting VKA within the
    first week (Table 5). Inversely, prior VTE independently predicted a VKA initiation within the
    first week.
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    In cancer patients, age >70 years, chronic heart or lung disease and initial presentation as
    PE independently predicted poor adherence to the ACCP recommendations (Table 3). The
    presence of metastases, anemia and recent immobility independently predicted the use of longterm LMWH therapy.
    Discussion
    The objective of our study was to identify associations of anticoagulant use in the setting of venous thromboembolism in usual care. To achieve this objective, we obtained clinical practicebased data from the RIETE registry, the largest database on the management of symptomatic
    VTE. Our analyses provide useful information on clinical features of patients, management of
    VTE. Our data reveal that only 65% of patients without cancer started VKA within the first
    week, and only 66% of those with cancer received LMWH as monotherapy. Among patients
    without cancer, 17% started VKA therapy after the first week and 18% received long-term
    LMWH for at least the first 3 months.
    Major factors to the anticoagulant decision were slightly different according to the presence
    or absence of cancer. In patients without cancer, the choice for treatment was driven by factors
    Fig 1. Prescription of long-term therapy within the first 90 days in non-cancer patients.
    doi:10.1371/journal.pone.0128741.g001
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    Fig 2. Prescription of long-term therapy within the first 90 days in patients with cancer.
    doi:10.1371/journal.pone.0128741.g002
    (recent bleeding, anemia, renal insufficiency, chronic liver disease, inflammatory bowel disease,
    mental disturbances) that have been associated with an increased risk for bleeding [6,7]. In patients with cancer, the choice for anticoagulation strategy was mostly influenced by the presence of metastases, anemia or immobility [8]. Of note, age and renal insufficiency influenced
    differently according to the presence or absence of cancer: In patients without cancer, renal insufficiency not only did not discourage clinicians from prescribing long-term LMWH, but
    strongly drove the decision toward long-term LMWH therapy, while age over 70 had no impact. In patients with cancer, renal insufficiency had no impact but age over 70 years discouraged clinicians from prescribing the recommended LMWH therapy. A number of studies have
    reported a higher incidence of major bleeding events in VTE patients receiving anticoagulant
    therapy in real life than in randomized clinical trials, most likely due to the strict exclusion criteria for patients recruited in these trials [9–12]. Thus, it should not be unexpected to find that
    the adherence to guidelines in real life was poor, as in other studies [13,14].
    Interestingly, there was an evolution over time of anticoagulant strategies in patients with
    cancer: the publication of the CANTHANOX, CLOT and LITE studies [15–17] were associated
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    Fig 3. Evolution over years of prescriptions of the three modalities of long-term anticoagulant therapy in cancer and non-cancer patients.
    doi:10.1371/journal.pone.0128741.g003
    Table 5. Variables at baseline independently correlated to poor adherence to guidelines (VKA start <7 days for patients without cancer, and
    LMWH alone for patients with cancer).
    Patients without cancer
    OR (95% CI)
    Patient characteristics
    p
    Patients with cancer
    OR (95% CI)
    p
    Gender (males)
    0.89 (0.84–0.95)
    <0.001
    -
    -
    Age >70 years
    -
    -
    1.39 (1.24–1.56)
    <0.001
    Chronic heart disease
    -
    -
    1.50 (1.15–1.95)
    0.003
    Chronic lung disease
    -
    -
    1.36 (1.14–1.63)
    0.001
    Recent major bleeding
    2.72 (2.28–3.24)
    <0.001
    -
    -
    Anemia
    1.72 (1.62–1.83)
    <0.001
    0.55 (0.49–0.62)
    <0.001
    Postoperative
    1.20 (1.09–1.32)
    <0.001
    -
    -
    Immobility 4 days
    1.98 (1.86–2.10)
    <0.001
    0.67 (0.58–0.78)
    <0.001
    Prior VTE
    0.87 (0.80–0.94)
    0.001
    -
    -
    Pulmonary embolism (vs. DVT)
    0.59 (0.56–0.63)
    <0.001
    1.15 (1.03–1.28)
    0.015
    CrCl levels >60 mL/min
    1 (ref.)
    CrCl levels 30–60 mL/min
    1.40 (1.30–1.52)
    CrCl levels <30 mL/min
    Chronic liver disease
    -
    -
    <0.001
    -
    -
    2.31 (2.06–2.59)
    <0.001
    -
    -
    1.82 (1.30–2.55)
    0.001
    -
    -
    Inﬂammatory bowel disease
    2.06 (1.44–2.94)
    <0.001
    -
    -
    Mental disturbances
    2.82 (2.48–3.21)
    <0.001
    -
    -
    Abbreviations: OR, odds ratio; CI, conﬁdence intervals; CrCl, creatinine clearance; VTE, venous thromboembolism; DVT, deep vein thrombosis.
    doi:10.1371/journal.pone.0128741.t005
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    in an increase of long-term LMWH prescriptions, as suggested in a previous study [18]. In
    non-cancer patients, no change has been observed over 10 years. Repeated recommendations
    with a high level of evidence did not result in any implementation in practice. Similar observations were made for thromboprophylaxis in medical in-patients [19,20].
    Current guidelines on antithrombotic therapy provide a critical review of the literature related
    to the management of patients with VTE and lay the scientific groundwork for the standard of
    care, based largely on data from randomized controlled clinical trials [1]. However, a number of
    VTE patients are often excluded from randomized clinical trials. Thus, there is scarce evidence on
    what would be the best therapeutic approach for these patients. The RIETE Registry was designed
    to gather and analyze data on treatment patterns and outcomes in patients with acute VTE. In
    contrast to randomized controlled trials, there is no imposed experimental intervention: management is determined solely by physicians. Thus, it provides data on patients with VTE in a realworld situation with an unselected patient population. Data from RIETE are hypothesis-generating and provide feedback from real-world clinical situations. Strengths of the current analysis include that a large number of consecutive unselected patients were enrolled, and that fatal PE is by
    far the most important outcome during the treatment of acute PE. In our approach, we studied
    patients and treatment related factors contributing to anticoagulant decision. But other factors
    may play a role such as cost, reimbursement or need for periodical biological monitoring. Choice
    of treatment in patients with and without cancer is also sensitive to the individual patient’s tolerance for daily injections and perceived risk for bleeding (by the patient and the physician). Unfortunately, our registry could not assess these parameters. Of note, no country effect was observed.
    Conclusion
    In conclusion, our results indicate that there are differences in practice from the guidelines, as
    starting VKA therapy to treat VTE in patients without cancer, and as using LMWH as monotherapy in those with cancer. These differences are likely due to comorbid conditions in patients with and without cancer and some concern about the risk of bleeding, particularly in
    patients who deserve quick VKA initiation. The impact of direct oral anticoagulants (which
    seems to have a better safety profile) may modify these unappropriated prescriptions.
    Acknowledgments
    Coordinator of the RIETE Registry:
    Dr. Manuel Monreal (Spain)
    RIETE Steering Committee Members:
    Dr. Hervé Decousus (France)
    Dr. Paolo Prandoni (Italy)
    Dr. Benjamin Brenner (Israel)
    RIETE National Coordinators:
    Dr. Raquel Barba (Spain)
    Dr. Pierpaolo Di Micco (Italy)
    Dr. Laurent Bertoletti (France)
    Dr. Sebastian Schellong (Germany)
    Dr. Manolis Papadakis (Greece)
    Dr. Inna Tzoran (Israel)
    Dr. Abilio Reis (Portugal)
    Dr. Marijan Bosevski (R.Macedonia)
    Dr. Henri Bounameaux (Switzerland)
    Dr. Radovan Malý (Czech Republic)
    RIETE Registry Coordinating Center:
    S & H Medical Science Service
    doi:10.1371/journal.pone.0128741.t006
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    Treatment of Thromboembolic Events in Real Life
    Members of the RIETE Group
    SPAIN: Ameneiro E, Arcelus JI, Ballaz A, Barba R, Barrón M, Barrón-Andrés B, Bascuñana
    J, Blanco-Molina A, Bueso T, Casado I, Conget F, del Molino F, del Toro J, Falgá C, FernándezCapitán C, Font L, Fuentes MI, Gallego P, García-Bragado F, García-Lorenzo MD, Gómez V,
    González J, González-Bachs E, Guil M, Gutiérrez J, Hernández L, Hernández-Huerta S, Jaras
    MJ, Jiménez D, Lecumberri R, Lobo JL, López-Jiménez L, López-Montes L, López-Reyes R,
    López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Madridano O, Marchena PJ, Martín M,
    Mellado M, Monreal M, Mora JM, Nauffal D, Nieto JA, Núñez MJ, Ogea JL, Paul H, Pedrajas
    JM, Peris ML, Porras JA, Riera-Mestre A, Rivas A, Rodríguez-Dávila MA, Román P, Rosa V,
    Ruiz-Giménez N, Ruiz J, Sahuquillo JC, Samperiz A, Sánchez R, Sánchez Muñoz-Torrero JF,
    Soler S, Suriñach JM, Tiberio G, Tilván RM, Tolosa C, Trujillo-Santos J, Uresandi F, Valdés M,
    Valero B, Valle R, Vela J, Vidal G, Vilella V, Villalta J, BELGIUM: Verhamme P, Peerlinck K,
    CANADA: Wells P, CZECH REPUBLIC: Malý R, Hirmerova J, Kaletova M, FRANCE: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Hij A, Mahe I, Merah A, GERMANY: Schellong S,
    GREECE: Babalis D, Papadakis M, Tzinieris I, ISRAEL: Braester A, Brenner B, Tzoran I, Zeltser
    D, ITALY: Amitrano M, Apollonio A, Barillari G, Ciammaichella M, Dalla Valle F, Di Micco P,
    Duce R, Guida A, Maida R, Pasca S, Piovella C, Prandoni P, Rota L, Tiraferri E, Tonello D,
    Tufano A, Visonà A, Zalunardo B, PORTUGAL: Brinquinho M, Miranda D, Sousa MS, REPUBLIC OF MACEDONIA: Bosevski M, Kovacevic D, SWITZERLAND: Alatri A, Bounameaux H, Calanca L, Mazzolai L.
    We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted
    educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG’s support was limited to the part of RIETE outside Spain, which accounts for a 20,05% of the total patients included in the RIETE Registry. We also thank the
    RIETE Registry Coordinating Center, S & H Medical Science Service, for their quality control
    data, logistic and administrative support.
    Author Contributions
    Conceived and designed the experiments: IM RS MM. Performed the experiments: IM RS LB
    LLJ MMJ JTS AB LMHB PJM MM. Analyzed the data: IM RS MM JTS PM. Contributed reagents/materials/analysis tools: IM RS LB LLJ MMJ JTS AB LMHB PJM MM. Wrote the paper:
    IM RS LB LLJ MMJ JTS AB LMHB PJM MM. Study concept and design: IM RS MM. Acquisition of data: LB MMJ AB LMHB MM. Analysis and interpretation of data: IM LB JTS PJM
    MM. Drafting of the manuscript: IM RS MM. Critical revision of the manuscript for important
    intellectual content: LB JTS. Final approval of the article: IM RS LB LLJ MMJ JTS AB LMHB
    PJM MM. Had full access to all the data in the study and take responsibility for the integrity of
    the data: IM MM.
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