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Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy

Published:October 03, 2014DOI:https://doi.org/10.1016/j.ejim.2014.09.010

      Highlights

      • Antiplatelets were stopped in 62% of VTE patients—mostly women and DVT patients.
      • VTE patients continuing antiplatelets had a higher rate of major adverse outcomes.
      • Combined antiplatelet/anticoagulant therapy did not raise bleeding risk in VTE.

      Abstract

      Introduction

      Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis.

      Methods

      Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course.

      Results

      1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p < 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p < 0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p < 0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in major bleeding rate.

      Conclusion

      Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.

      Keywords

      1. Introduction

      Venous thromboembolism (VTE) is a commonly diagnosed condition with significant morbidity and mortality [
      • Kearon C.
      • Akl E.A.
      • Comerota A.J.
      • Prandoni P.
      • Bounameaux H.
      • Goldhaber S.Z.
      • et al.
      Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. Current guidelines recommend patients with VTE to be initially treated with low-molecular-weight heparin (LMWH), fondaparinux or unfractionated heparin, followed by long-term anticoagulation, which is usually accomplished with vitamin K antagonists (VKA) [
      • Hansen M.L.
      • Sorensen R.
      • Clausen M.T.
      • Fog-Petersen M.L.
      • Raunso J.
      • Gadsboll N.
      • et al.
      Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.
      ,
      • Shireman T.I.
      • Howard P.A.
      • Kresowik T.F.
      • Ellerbeck E.F.
      Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients.
      ]. However, a number of patients with acute VTE are using antiplatelet therapy for prior myocardial infarction, stroke or other arterial events [
      • Andrade J.G.
      • Deyell M.W.
      • Khoo C.
      • Lee M.
      • Humphries K.
      • Cairns J.A.
      Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis.
      ,
      • Goldhaber S.Z.
      Pulmonary embolism.
      ,
      • Denas G.
      • Padayattil Jose S.
      • Gresele P.
      • Erba N.
      • Testa S.
      • De Micheli V.
      • et al.
      Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study.
      ]. This is important since concomitant use of anticoagulant and antiplatelet therapy may increase the risk for bleeding [
      • Shireman T.I.
      • Howard P.A.
      • Kresowik T.F.
      • Ellerbeck E.F.
      Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients.
      ,
      • Andrade J.G.
      • Deyell M.W.
      • Khoo C.
      • Lee M.
      • Humphries K.
      • Cairns J.A.
      Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis.
      ].
      The Registro Informatizado de Enfermedad ThromboEmbolica (RIETE) is an ongoing, multicentre, international (Spain, France, Italy, Israel, Switzerland, Greece, Czech Republic and Republic of Macedonia), prospective registry of consecutive patients presenting with symptomatic acute VTE. Data from this registry have been used to evaluate outcome after acute VTE, such as bleeding, recurrent VTE, mortality and risk factors for these outcomes. The current analysis was aimed to evaluate VTE patients who used antiplatelet therapy at baseline, and to compare their clinical outcomes with regard to the decision to discontinue or not antiplatelet agents.

      2. Patients and methods

      Consecutive patients with acute VTE confirmed by objective tests such as contrast venography or ultrasonography for suspected deep vein thrombosis (DVT); and pulmonary angiography, lung scintigraphy or helical computed tomography scan for pulmonary embolism (PE), were enrolled in RIETE. Patients were excluded if they were participating in a therapeutic clinical trial with blinded therapy. All patients provided written or oral consent for participation in the registry, in accordance with local ethic committee requirements.
      In the RIETE registry, participating physicians ensure that eligible patients were consecutively enrolled. Data were recorded in 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 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 submitted data.

      2.1 Study design

      This analysis was limited to patients who received antiplatelet therapy at baseline. Their clinical characteristics and outcomes were compared according to the doctor's decision of discontinuing or not antiplatelet drugs. The rates of subsequent ischemic events, major bleeding or death during the course of anticoagulation were considered the primary outcome of the study. Ischemic events were defined as myocardial infarction (chest pain, ECG changes, elevation of cardiac biomarkers), ischemic stroke (new neurological changes, brain CT with characteristic pathology), lower limb amputation and mesenteric ischemia (abdominal pain and changes on abdominal CT scan) as diagnosed by physicians in participating hospitals. Major bleeding was defined as an overt bleeding that required a transfusion of two or more units of blood, or was retroperitoneal, spinal, intracranial, or fatal. Fatal bleeding was defined as any death occurring within 10 days of a major bleeding episode, in the absence of an alternative cause of death. Fatal ischemia was defined as any death occurring with 10 days from the event, in absence of an alternative cause of death.

      2.2 Baseline variables

      The following parameters were recorded when the qualifying episode of VTE was diagnosed: patient's sex, age and body weight; presence of arterial disease and its risk factors such as smoking, diabetes, hypertension and hyperlipidemia; presence of coexisting conditions such as chronic heart or lung disease; recent (<30 days prior to VTE) major bleeding; presence of risk factors for VTE, including cancer, immobilization, surgery; and initial presentation of VTE.

      2.3 Treatment and follow-up

      Patients were managed according to the clinical practice of each participating hospital (i.e., treatment was not standardized). The type, dose and duration of anticoagulant therapy were recorded. Patients were followed for up to a year in the outpatient clinics. During each visit, any signs or symptoms suggesting ischemic event (chest pain, neurological deficit, limb or abdominal pain) or bleeding complications were registered. Each episode of clinically suspected ischemic event was investigated using appropriate methods (ECG, laboratory tests, angiography or appropriate CT scan).
      Most outcomes were classified as reported by the clinical centers. However, if the staff at the coordinating center was uncertain how to classify a reported outcome, the event in question was reviewed by the central adjudication committee (<10% of events).

      2.4 Statistical analysis

      Student's t test and X2 test (or Fisher's exact test where appropriate) were used to compare continuous and categorical variables (respectively) between patients being treated with antiplatelet drugs at VTE diagnosis that continued with these drugs versus those in whom this therapy was stopped. Incidence rates of ischemic events, major bleeding, recurrent VTE, as well as overall and specific causes of death were calculated and compared between the two groups of patients and expressed as the number of events per 100 patient-years on anticoagulant therapy. Odds ratios and corresponding 95% confidence intervals (CI) were calculated for clinical outcomes during the anticoagulant therapy. A p value <0.05 was considered to be statistically significant for all these comparisons.
      Because patients were not randomly assigned to continue antiplatelet therapy when VTE index events were diagnosed, we used propensity score matching to adjust for differences in baseline characteristics. Variables that were considered in the calculation of the propensity score included: gender, age, body weight, inpatient care, prior coronary artery disease, prior cerebral ischemia, prior peripheral artery disease, current smoking, diabetes, hypertension, chronic heart failure, chronic lung disease, creatinine clearance <30 mL/min, anemia, abnormal platelet count, recent major bleeding, postoperative state, immobility ≥4 days, cancer, and pulmonary embolism. We built a logistic regression model in which antiplatelet treatment at baseline was a dependent variable and the variables eventually related to either arterial ischemic events, major bleeding, recurrent VTE or overall death were independent variables. These models made it possible to calculate a propensity score, indicating the likelihood that any individual patient would have received antiplatelet treatment, given all other known covariates.
      We used the full matching method for the previously calculated propensity scores in order to make comparable patients in whom antiplatelet treatment was continued versus those in whom it was withdrawn. Full matching makes use of all individuals in the dataset by forming a series of matched sets in which each set has either one treated individual and multiple comparison individuals or one comparison individual and multiple treated individuals. Full matching has been shown to be particularly effective at reducing bias related to observed confounding variables [
      • Hansen B.B.
      Full matching in an observational study of coaching for the SAT.
      ]. After matching, we estimated covariate balance between patients continuing and withdrawing antiplatelets using absolute standardized differences [
      • D'Agostino Jr., R.B.
      Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group.
      ], which directly quantifies the bias in the means and proportions of covariates across the groups, expressed as a percentage of the pooled standard deviations. We employed matched univariate logistic regression analysis to estimate associations of antiplatelet use with various outcomes. Propensity score matching was performed using the optmatch, RItools and MatchIt packages for R program v 2.15.1 and IBM SPSS software for Mac version 20 were used for analysis of the rest of data.

      3. Results

      As of January 2014, 1178 patients in RIETE were receiving antiplatelet drugs at the time of VTE diagnosis. The mean follow-up was 213 days for patients who continued antiplatelet treatment and 242 days for those who discontinued this therapy. Antiplatelet therapy was discontinued in 729 (62%). Discontinuation of antiplatelet therapy was less frequently observed in males, patients initially presenting with PE, or having prior coronary heart disease, anemia, recent surgery or cancer (Table 1).
      Table 1Clinical characteristics and treatment strategies of patients who continued or stopped antiplatelet therapy.
      Antiplatelet drugs withdrawnAntiplatelet drugs continued
      Patients, no.729449
      Clinical characteristics
      Gender (males)346 (48%)
      p<0.001.
      260 (58%)
      Mean age (years ± SD)76 ± 1174 ± 11
      Body weight (kg ± SD)76 ± 1676 ± 16
      Inpatients229 (32%)129 (30%)
      Arterial disease
      Prior coronary artery disease129 (18%)
      p<0.001.
      171 (39%)
      Prior cerebral ischemia169 (24%)100 (23%)
      Prior peripheral artery disease87 (12%)62 (14%)
      Current smoking73 (10%)51 (12%)
      Diabetes213 (30%)141 (32%)
      Hypertension531 (75%)332 (76%)
      Underlying conditions
      Chronic heart failure180 (25%)100 (22%)
      Chronic lung disease179 (25%)
      p<0.01.
      79 (18%)
      Abnormal creatinine levels199 (28%)141 (32%)
      Creatinine clearance <30 mL/min73 (10%)60 (13%)
      Anemia265 (36%)
      p<0.001.
      211 (47%)
      Recent major bleeding23 (3.2%)13 (2.9%)
      Risk factors for VTE
      Postoperative52 (7.1%)
      p<0.001.
      62 (14%)
      Immobility ≥4 days232 (32%)128 (29%)
      Cancer76 (10%)
      p<0.01.
      70 (16%)
      None of the above398 (55%)224 (50%)
      Prior VTE144 (20%)79 (18%)
      VTE presentation at baseline
      Pulmonary embolism477 (65%)
      p<0.01.
      256 (57%)
      Initial therapy
      Low-molecular-weight heparin633 (87%)402 (90%)
      Mean LMWH dose (IU/kg/day)177 ± 72
      p<0.05.
      166 ± 68
      LMWH dose ≥150 IU/kg/day531 (77%)
      p<0.01.
      302 (69%)
      Unfractionated heparin54 (7.4%)23 (5.2%)
      Fondaparinux17 (2.3%)11 (2.5%)
      Inferior vena cava filter14 (1.9%)8 (1.8%)
      Long-term therapy
      Vitamin K antagonists523 (75%)
      p<0.001.
      266 (63%)
      Low-molecular-weight heparin160 (23%)
      p<0.001.
      149 (35%)
      Days of treatment (mean, SD)242 ± 257213 ± 215
      Days of treatment (median, IQR)169 ± 214
      p<0.05.
      133 ± 163
      VTE, venous thromboembolism.
      low asterisk p < 0.05.
      p < 0.01.
      p < 0.001.
      Most patients in both subgroups received low molecular weight heparin (LMWH) (87% and 90%) as initial therapy for VTE, and significantly more patients who discontinued the antiplatelet agents received higher doses of LMWH (77% vs. 69%; p < 0.01) (Table 1).
      Of note, more patients continuing with antiplatelet drugs switched to vitamin K antagonists (VKA) (Table 1), while patients discontinuing antiplatelet drugs received a longer course of anticoagulation (169 ± 214 days vs. 133 ± 163; p < 0.05).
      During anticoagulation, patients on antiplatelet therapy presented a higher rate of major adverse outcomes, including lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p < 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p < 0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p < 0.01), but no differences in the rate of major bleeding or recurrent VTE were observed (Table 2). A higher number of ischemic events (18 vs. 8), recurrent VTE (16 vs. 8) and overall deaths (97 vs. 32) occurred later (≥15 days) in the treatment of patients who received both antiplatelet and anticoagulant therapy (Table 3).
      Table 2Clinical outcome during the course of anticoagulation. Findings expressed as events per 100 patient-years and 95% confidence intervals.
      Antiplatelet drugs withdrawnAntiplatelet drugs continued
      Events,

      No
      Events per 100

      patient-years
      Events,

      No
      Events per 100

      patient-years
      Patients, No729449
      Years of treatment483263
      Myocardial infarction10.21 (0.01–1.02)10.38 (0.02–1.88)
      Ischemic stroke30.62 (0.16–1.69)51.90 (0.70–4.21)
      Amputation of lower limb10.21 (0.01–1.02)
      p<0.01.
      62.28 (0.92–4.74)
      Any ischemic event112.28 (1.20–3.96)
      p<0.05.
      155.70 (3.31–9.20)
      Major bleeding285.80 (3.93–8.27)176.46 (3.89–10.1)
      Recurrent VTE132.69 (1.50–4.49)114.18 (2.20–7.27)
      Recurrent PE51.04 (0.38–2.29)62.28 (0.93–4.74)
      Recurrent DVT81.66 (0.77–3.15)51.90 (0.70–4.21)
      Fatal bleeding51.04 (0.38–2.29)10.38 (0.02–1.88)
      Fatal PE30.62 (0.16–1.69)20.76 (0.13–2.51)
      Fatal myocardial infarction10.21 (0.01–1.02)0
      Fatal ischemic stroke020.76 (0.13–2.51)
      Fatal lower limb ischemia010.38 (0.02–1.88)
      Fatal ischemic events10.21 (0.01–1.02)31.14 (0.29–3.10)
      Overall death6713.9 (10.8–17.5)
      p<0.01.
      6223.6 (18.2–30.0)
      Abbreviations: PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism.
      p < 0.001.
      low asterisk p < 0.05.
      p < 0.01.
      Table 3Number of adverse events that occurred in first two weeks after VTE diagnosis and later in treatment in patients who continued antiplatelet treatment.
      Days of treatment
      15 days15 days
      Myocardial infarction11
      Ischemic stroke26
      Amputation of a lower limb34
      Any ischemic event818
      Major bleeding2025
      Recurrent VTE816
      Recurrent PE47
      Recurrent DVT49
      Fatal bleeding24
      Fatal PE50
      Fatal myocardial infarction02
      Fatal ischemic stroke11
      Fatal lower limb ischemia01
      Fatal ischemic events13
      Overall death3297
      Matched analysis showed patients on antiplatelet therapy to have a significantly higher rate of lower limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes, including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in the rate of major bleeding (Table 4).
      Table 4Odds ratio for clinical outcome during the course of anticoagulation, according to antiplatelet treatment (continued vs. withdrawn), before and after matching.
      Pre-matchingPost full matching
      Outcome
      Myocardial infarction1.63 (0.10–26.0)0.43 (0.02–7.69)
      Ischemic stroke2.73 (0.65–11.5)1.11 (0.24–5.02)
      Amputation of lower limb9.86 (1.18–82.2)
      p<0.05.
      15.3 (1.02–229)
      p<0.05.
      Any ischemic event2.07 (0.96–4.45)1.23 (0.53–2.85)
      Major bleeding0.99 (0.53–1.82)0.89 (0.45–1.75)
      Recurrent VTE1.38 (0.61–3.12)1.06 (0.43–2.61)
      Recurrent PE1.96 (0.60–6.46)1.49 (0.42–5.30)
      Recurrent DVT1.02 (0.33–3.12)0.75 (0.21–2.76)
      Fatal bleeding0.32 (0.04–2.78)0.38 (0.04–3.65)
      Fatal PE1.08 (0.18–6.50)0.89 (0.14–5.80)
      Fatal ischemic events4.90 (0.51–47.2)1.92 (0.19–19.4)
      Overall death1.53 (1.06–2.21)
      p<0.05.
      1.35 (0.91–2.00)
      Composite outcome1.72 (1.21–2.43)
      p<0.01.
      1.46 (1.02–2.11)
      p<0.05.
      Composite outcome with VTE complications1.72 (1.23–2.39)
      p<0.01.
      1.46 (1.03–2.06)
      p<0.05.
      DVT, deep vein thrombosis; PE, pulmonary embolism.
      Composite outcome = death or ischemic events.
      Composite outcome with VTE complications = death or ischemic events or recurrent PE or DVT.
      p < 0.001.
      low asterisk p < 0.05.
      p < 0.01.

      4. Discussion

      Patients receiving antiplatelet therapy due to prior arterial disease may develop VTE [
      • Goldhaber S.Z.
      Pulmonary embolism.
      ]. Physicians and patients are facing a challenge, since VTE should be treated with anticoagulants and concomitant antiplatelet therapy may increase the risk for bleeding. Current literature has not thoroughly addressed this question. Our data reveal that in real life one in every 3 such patients continued with both therapies and that this approach was not associated with an increased risk for bleeding, recurrent VTE, ischemic events or death.
      Our findings differ from those in recent trials demonstrating an increased rate of bleeding complications in patients concomitantly receiving anticoagulant and antiplatelet therapy, which reached 9.1% patients/year [
      • Denas G.
      • Padayattil Jose S.
      • Gresele P.
      • Erba N.
      • Testa S.
      • De Micheli V.
      • et al.
      Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study.
      ]. A plausible explanation for this difference could be attributed to a relatively short period of follow-up (up to 8 months) in our study and to the fact that most patients, assumed to be at a higher risk for bleeding in our series, would probably discontinue antiplatelet treatment at baseline.
      In our study, the rate of bleeding in both groups was similar, despite their high age (76 ± 11 and 74 ± 11), a finding that correlates with recent publications reporting a better outcome in octogenarian patients with atrial fibrillation and coronary events who were discharged with combined anticoagulant and antiplatelet treatment [
      • Caballero L.
      • Ruiz-Nodar J.M.
      • Marin F.
      • Roldan V.
      • Hurtado J.A.
      • Valencia J.
      • et al.
      Oral anticoagulation improves the prognosis of octogenarian patients with atrial fibrillation undergoing percutaneous coronary intervention and stenting.
      ]. Recurrent VTE was found to be the same in both groups, despite different treatment regimens, which could be explained by a relatively short follow-up.
      On the contrary, the higher rate of ischemic events observed in patients that maintained antiplatelet treatment may be explained by the fact that they were sicker and more likely to develop ischemic events. Moreover, some of these patients may be resistant to antiplatelet treatment and therefore could have demonstrated active ischemic disease despite concomitant therapy [
      • Hennekens C.H.
      • Schror K.
      • Weisman S.
      • FitzGerald G.A.
      Terms and conditions: semantic complexity and aspirin resistance.
      ]. In addition, antiplatelet treatment failure can be related to many other reasons, including patients' failure to take their medications appropriately or to drug–drug interactions [
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • Reeves M.J.
      • Barber K.
      • DeFranco A.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      ,
      • Webster S.E.
      • Payne D.A.
      • Jones C.I.
      • Hayes P.D.
      • Bell P.R.
      • Goodall A.H.
      • et al.
      Anti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomy.
      ,
      • Faraday N.
      • Yanek L.R.
      • Mathias R.
      • Herrera-Galeano J.E.
      • Vaidya D.
      • Moy T.F.
      • et al.
      Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1.
      ,
      • Catella-Lawson F.
      • Reilly M.P.
      • Kapoor S.C.
      • Cucchiara A.J.
      • DeMarco S.
      • Tournier B.
      • et al.
      Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.
      ,
      • Capone M.L.
      • Sciulli M.G.
      • Tacconelli S.
      • Grana M.
      • Ricciotti E.
      • Renda G.
      • et al.
      Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects.
      ].
      The number of composite outcomes incorporating all-cause death, arterial events and VTE was higher among patients that continued antiplatelet treatment. This can be explained by the fact that such patients have a higher rate of thrombotic risk factors, e.g., postoperative state and cancer. Other possible explanations are a longer treatment with anticoagulants in patients who discontinued antiplatelet therapy and higher doses of LMWH (Table 1), and a more potent treatment with VKA [
      • Hurlen M.
      • Abdelnoor M.
      • Smith P.
      • Erikssen J.
      • Arnesen H.
      Warfarin, aspirin, or both after myocardial infarction.
      ,
      • van Es R.F.
      • Jonker J.J.
      • Verheugt F.W.
      • Deckers J.W.
      • Grobbee D.E.
      Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial.
      ,
      • Wong C.K.
      • White H.D.
      Rivaroxaban for the treatment of acute coronary syndromes.
      ] which could account in part for the observed survival advantage.
      The limitations of the current study include the retrospective nature of the analysis of consecutively recruited patients, a relatively short follow-up period, lack of information regarding the specific antiplatelet regimen used or the international normalized ratio (INR) values and time in therapeutic range (TTR).

      5. Conclusion

      Based on our results, the combination of antiplatelet drugs with anticoagulants used for a short-term treatment of VTE does not increase the risk for bleeding.

      Conflict of interest statement

      The authors have no conflicts to declare.

      Acknowledgements

      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 20.9% 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.

      Appendix A.

      Tabled 1
      Coordinator of the RIETE Registry:Dr. Manuel Monreal (Spain)
      RIETE Steering Committee Members:Dr. Hervè 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

      Appendix B. Members of the RIETE Group

      SPAIN: Andújar V, Arcelus JI, Auguet T, Barba R, Barrón M, Barrón-Andrés B, Bascuñana J, Blanco-Molina A, Bueso T, Casado I, Casillas C, Conget F, del Molino F, del Toro J, Falgá C, Fernández-Capitán C, Font L, Gallego P, García-Bragado F, Gómez V, González J, González-Bachs E, Guijarro R, Guil M, Gutiérrez J, Hernández L, Hernández-Huerta S, Jara-Palomares L, Jaras MJ, Jiménez D, Jiménez R, Lobo JL, López-Jiménez L, López-Montes L, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Llutart J, Madridano O, Marchena PJ, Martín M, Martín-Antorán JM, Mellado M, Monreal M, Nauffal D, Nieto JA, Ogea JL, Otero R, Pagán B, Pedrajas JM, Peris ML, Porras JA, Pons I, Riera-Mestre A, Rivas A, Rodríguez-Dávila MA, Román P, Roncero A, Rosa V, Ruiz-Giménez N, Ruiz J , Sabio P, Sahuquillo JC, Samperiz A, Sánchez R, Sánchez Muñoz-Torrero JF, Soler S, Suriñach JM, Tiberio G, Tirado R, Tolosa C, Trujillo-Santos J, Valero B, Valle R, Vela J, Vidal G, Villalobos A, Vilella V, ARGENTINA: Malfante P, Villagra M, Vivero F, BELGIUM: Verhamme P, Peerlinck K, CZECH REPUBLIC: Malý R, Hirmerova J, Kaletova M, FRANCE : Bertoletti L, Bura-Riviere A, Farge-Bancel D, Grange C, Hij A, Mahe I, Merah A, Quere I, GERMANY: Schellong S, GREECE: Babalis D, Papadakis M, Tzinieris I, ISRAEL: Braester A, Brenner B, Tzoran I, Zeltser D, ITALY: Apollonio A, Barillari G, Ciammaichella M, Di Micco P, Duce R, Guida A, Maida R, Mattei L, Pace F, Piovella C, Pesavento R, Poggio R, Prandoni P, Rota L, Schenone A, Tonello D, Tufano A, Visonà A, Zalunardo B, PORTUGAL: Santos M, REPUBLIC OF MACEDONIA: Bosevski M, Kovacevic D, SWITZERLAND: Alatri A, Bounameaux H, Calanca L, Mazzolai L. VENEZUELA: Serrano JC.

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