Venous thromboembolism prevention and treatment: expanding the rivaroxaban knowledge base with real-life data

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1 European Heart Journal Supplements (2015) 17 (Supplement D), D32 D41 The Heart of the Matter doi: /eurheartj/suv034 Venous thromboembolism prevention and treatment: expanding the rivaroxaban knowledge base with real-life data Jan Beyer-Westendorf 1, Alexander T. Cohen 2 *, and Manuel Monreal 3 1 University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany 2 Department of Haematological Medicine, Guy s and St Thomas NHS Foundation Trust, King s College London, Westminster Bridge Road, London SE1 7EH, UK 3 Internal Medicine Department, Germans Trias i Pujol Hospital, Badalona, Barcelona, Spain KEYWORDS Anticoagulant therapy; Direct anticoagulant; Thrombosis; Registries; Observational studies Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT), and pulmonary embolism (PE) is a potentially life-threatening disease. Patients who acquire VTE are likely to experience recurrent events or life-long morbidities such as post-thrombotic syndrome or chronic thromboembolic pulmonary hypertension. The symptoms associated with VTE are highly variable, ranging from asymptomatic making diagnosis challenging to cardiogenic shock. The benefits of anticoagulant for the prevention and treatment of VTE are well established. The clinical development of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa has revolutionized the management of VTE, owing to their favourable properties that overcome the limitations of VKAs. These agents have shown favourable outcomes in Phase III randomized controlled trials (RCTs) and are licensed for use in Europe for the prevention of VTE, and the treatment and secondary prevention of DVT and PE. Randomized controlled trials do not reflect routine clinical practice, however, and while NOACs are becoming integrated into treatment protocols, uncertainties remain as to how their benefits apply to patients seen in everyday care. This article will consider these uncertainties, along with data on rivaroxaban use from a number of key non-interventional studies and registries, namely XAMOS, ORTHO-TEP, the Dresden NOAC registry, RIETE, and PREFER in VTE. These data suggest that outcomes with NOACs such as rivaroxaban in RCTs are reproducible in real-life, making these agents a simple, effective treatment choice for a wide range of patients at risk of, or suffering from, VTE. Venous thromboembolism: a persistent clinical burden Venous thromboembolism (VTE) remains a substantial clinical and economic burden worldwide. Venous thromboembolism alone is thought to account for.1 million events or deaths annually, as shown in a modelling analysis from six European countries. 1 Risk factors for * Corresponding author. Tel: , Fax: , alexander.cohen@kcl.ac.uk VTE include trauma, major surgery, spinal cord injury, increasing age, pregnancy, cancer, acute severe medical illness, oestrogen use, and previous VTE. 2 Without adequate thromboprophylaxis, the risk of VTE is as high as 40 60% following major orthopaedic surgery. 3 The diverse presentations of VTE range from asymptomatic deep vein thrombosis (DVT) to fatal pulmonary embolism (PE). Pulmonary embolism is the most feared consequence of VTE and is responsible for 10 12% of deaths annually in European hospitals. 4 Of patients who are diagnosed with acute PE and start Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com

2 Real-life data on VTE prevention and treatment D33 treatment, 5% die from the initial PE or another PE within the next 7 days. 5 Complications of VTE include recurrent VTE, which is thought to occur in 50% of untreated patients with symptomatic proximal DVT or PE within 3 months. 6 Associated life-long morbidities include post-thrombotic syndrome (PTS) and potentially fatal chronic thromboembolic pulmonary hypertension, 5 with a cumulative incidence of 3.8% within 2 years in individuals who develop PE. 7 The benefits of anticoagulant therapy in the prevention and treatment of VTE have been well-known for many years. For example, an early trial showed an absence of PE recurrence and PE-related death in patients with PE who received heparin and acenocoumarol for 14 days, compared with five cases of PE recurrence and five PE-related deaths in those who were untreated. 8 Certain drawbacks apply with established agents such as the need for parenteral administration of low-molecular-weight heparin (LMWH) and the high cost and the long half-life of fondaparinux. 9,10 Vitamin K antagonists (VKAs) have a narrow therapeutic window [international normalized ratio (INR) ] in addition to a variable intra-patient dose response relationship, need for close monitoring and known interactions with several medications and foods. 9 The clinical development of non-vka oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa has revolutionized the management of VTE, owing to their rapid onset and offset of action, fewer food and drug interactions, predictable anticoagulant effect and absence of a need for routine coagulation monitoring The direct factor Xa inhibitors apixaban and rivaroxaban, and the direct thrombin inhibitor dabigatran have been approved for use in the European Union for (a) the prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery and (b) the treatment of acute VTE, and prevention of recurrent DVT and PE in adults, based on favourable Phase III data 14 (the direct factor Xa inhibitor edoxaban is currently being evaluated by regulatory agencies in Europe for the treatment and secondary prevention of VTE). 15 Other indications will be covered separately in this supplement. While a wealth of information is available from such randomized controlled trials (RCTs), real-life data are now taking prominence owing to the valuable information it can provide on NOAC use in unselected patients in clinical practice. Accompanying articles in this supplement will explore the importance of real-life data in more detail, and the challenges in producing data that are meaningful to healthcare professionals and patients alike. This review will assess unanswered questions in the field of VTE and consider the lessons learned to date from a number of observational studies in the context of NOAC use, namely rivaroxaban, in the primary prevention and treatment of VTE. Unanswered questions As previously mentioned, favourable clinical data from RCTs involving apixaban, rivaroxaban, and dabigatran formed the basis of regulatory approvals of these agents for the prevention and treatment of VTE. While these RCTs provide robust evidence of efficacy of NOACs in this setting, they do not provide evidence of effectiveness, i.e. the true benefit to patients in routine clinical practice. For example, there may be specific clinical situations whereby practical guidance for the use of rivaroxaban is warranted, e.g. periprocedural management, switching from one anticoagulant to another, or special patient populations. A large proportion of patients, including those at high risk of VTE, are not recruited into RCTs involving NOACs owing to the presence of exclusion criteria, e.g. severe renal impairment [creatinine clearance (CrCl) 30 ml/min], active/high bleeding risk, concomitant therapies, pregnancy, recent thrombolytic therapy, or recent trauma/major surgery. 16,17 Subgroup analyses from RCTs of rivaroxaban have delivered promising results. For example, data from the EINSTEIN DVT and PE-pooled analysis showed favourable results for rivaroxaban in fragile patients (CrCl,50 ml/ min, age.75 years, and body weight 50 kg) compared with standard therapy, where the incidence of recurrent VTE was 2.7 and 3.8%, respectively [hazard ratio (HR) ¼ 0.68; 95% confidence interval (CI) ] and the incidence of major bleeding was 1.3 and 4.5%, respectively (HR ¼ 0.27; 95% CI ). 18 Another pre-specified subgroup analysis of the EINSTEIN DVT and PE studies in patients with renal impairment showed that reduced renal function is an important risk factor for the development of recurrent VTE. 19 Rivaroxaban was shown to be noninferior to standard therapy for the reduction of recurrent VTE in this subgroup (2.1% vs. 2.3%; HR ¼ 0.89; 95% CI ; P, 0.001). Overall, rivaroxaban was associated with a significant reduction in major bleeding compared with standard therapy (1.0% vs. 1.7%; HR ¼ 0.54; 95% CI ; P ¼ 0.002). In the standard therapy group, the incidence of major bleeding increased proportionately as renal function decreased (P, 0.001), reaching 9.1% in those with severe renal impairment. There was no relationship between major bleeding and reduced renal function in the rivaroxaban group (P ¼ 0.50). 19 Approximately 20% of all VTE cases occur in patients with cancer. 20 Small numbers of patients with active cancer were included in RCTs of NOACs in VTE treatment (2 6%), and LMWH ( 3 months) remains the recommended approach in treatment guidelines. 5,27 A pre-specified pooled subgroup analysis of the EINSTEIN DVT and PE studies in patients with active cancer showed a numerically lower incidence of recurrent VTE (5.0% vs. 7.0%; HR ¼ 0.67; 95% CI ) and a significant reduction in major bleeding (2.0% vs. 5.0%; HR ¼ 0.42; 95% CI ) with rivaroxaban compared with standard therapy, respectively, in this subgroup. 28 While these subgroup analyses indicate that rivaroxaban has extensive clinical benefits, there remains a lack of evidence-based recommendations. The product label for rivaroxaban states it should be used with caution in patients with severe renal impairment (CrCl ml/ min) a dose reduction from 20 mg once-daily (OD) to 15 mg OD is warranted if the assessed risk for bleeding

3 D34 J. Beyer-Westendorf et al. outweighs the risk for recurrent DVTand PE. 11 This is based on evidence that rivaroxaban and all NOACs are excreted renally to some extent; 11 13,29 therefore, reduced renal function may result in excessive accumulation of these agents. Data in the real-life setting will be needed to supplement existing evidence on NOAC use in patients with VTE who are fragile, renally impaired or who have cancer before robust recommendations can be made. The optimal duration of anticoagulation when treating patients with DVT or PE is an ongoing topic of debate. Current guidelines recommend anticoagulation for 3 months, with extended or indefinite treatment based on the patient s benefit risk ratio, e.g. provoked or unprovoked VTE, bleeding risk, or presence of cancer. 5 Discontinuation of anticoagulation after a first episode of clinically symptomatic proximal DVT and/or PE has been shown to result in a cumulative increase in the incidence of recurrent VTE, reaching 39.9% after 10 years. 30 Indefinite treatment of acute PE is thought to reduce the risk of recurrent VTE by 90%, but this benefit is partially offset by a 1% annual risk of major bleeding. 27 Therefore, the duration of anticoagulation should be individualized according to the patient s situation. It will be beneficial to understand the real-life benefit risk profiles of NOACs administered over a range of treatment durations in different patient types. Crucially, perhaps the most obvious question that remains unanswered is: which agent provides the optimal benefit risk ratio? In the absence of rigorous head-to-head studies to discriminate between NOACs, this question is unlikely to be answered unambiguously. One contributing factor is the difference among study designs and patient characteristics, particularly in the RCTs of VTE treatment. For example, in acute VTE treatment, the RE-COVER/RE-COVER II, and Hokusai VTE trials required initial parenteral anticoagulation with LMWH or UFH for 5 days before dabigatran or edoxaban administration. 21,22,31 Treatment with apixaban and rivaroxaban in the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First- Line Therapy (AMPLIFY) and EINSTEIN trials, respectively, involved a single-drug approach a two-phase approach to treatment involved administration of the aforementioned agents (apixaban: 10 mg BID for 7 days, followed by 5 mg BID for 6 months; rivaroxaban: 15 mg BID for 21 days, followed by 20 mg OD for 6 months) Another notable differentiating factor is the variation in patient numbers with PE who were enrolled, and their anatomical extent of PE at baseline. 32 Furthermore, there is a lack of standardized bleeding definitions in RCTs, which may influence the benefit risk ratio and subsequently affect its interpretation. In RCTs of VTE prevention following major orthopaedic surgery, original major bleeding definitions were employed in the RECORD programme (clinically overt bleeding that was fatal, occurred in a critical organ, necessitated re-operation, was outside of the surgical site and was associated with a fall in haemoglobin of 2 g/dl, or required an infusion of 2 units of blood), 33 while in other NOAC trials, definitions were adapted from the International Society on Thrombosis and Haemostasis (ISTH) 34,35 and the European Medicines Agency. 36,37 In VTE treatment, RCTs involving NOACs have all employed bleeding definitions adapted from the ISTH. 14,34 Such differences make it challenging to choose the most favourable NOAC for a particular situation; however, real-life data should help to expand on the existing evidence. The experience of large-scale, observational studies may be used to support, or challenge, the findings of RCTs, providing insights for clinical scenarios that have not been explored in the clinical trial setting. A summary of key registries in the setting of VTE is presented in Table 1. Lessons from real-life studies in venous thromboembolism prevention A number of registries have been undertaken to investigate the incidence and risks of VTE and real-life clinical outcomes with thromboprophylaxis, and which together reinforce the need for effective thromboprophylaxis. Global Orthopaedic Registry (GLORY) encompassed prospective patients enrolled between 2001 and Rates of symptomatic VTE were in fact higher in real-life compared with RCTs. Almost all patients received thromboprophylaxis; however, guideline compliance was suboptimal, with thromboprophylaxis use falling over time, despite patients still having an elevated risk of VTE. 39 Data from GLORY have also been published on practice patterns, complications and functional outcomes following elective hip or knee replacement surgery. 38 International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) is a prospective cohort study in a population of over hospitalized acutely ill medical patients from 52 hospitals in 12 countries. 40 Data were collected on the clinical incidence of VTE and risk factors for VTE, 40,41 the provision of thromboprophylaxis, 40,41 and bleeding risk factors and incidence. 42 A key finding was that only 60% of patients who should have received guideline-recommended thromboprophylaxis actually received it, and this care was suboptimal. 40 Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) is a cross-sectional observational registry involving patients in 358 acute care hospitals in 32 countries. 43,44 A total of 64.4 and 41.5% of surgical and medical patients, respectively, were shown to be at risk of VTE. 45 Of those at risk, only 58.5 and 39.5% of surgical and medical patients, respectively, received guideline-recommended thromboprophylaxis. 45 These three large registries clearly indicated the general need for improvement of VTE prevention in hospitalized patients. In the NOAC era, a number of registries have evaluated real-life NOAC use for VTE prevention following major orthopaedic surgery. ORTHO-TEP is a large, single-centre, retrospective comparison of rivaroxaban with the previous standard of care (e.g. LMWH or fondaparinux) in over 5000 unselected patients undergoing elective hip or knee

4 Real-life data on VTE prevention and treatment D35 replacement surgery at the University Hospital Carl Gustav Carus in Dresden, Germany. 46,47 Data from ORTHO-TEP showed that in routine clinical practice, patients receiving rivaroxaban (which included 4.03% with a history of VTE) had significantly lower rates of VTE than both fondaparinux (2.1% vs. 5.6%, P ¼ 0.001) and LMWH (2.1% vs. 4.1%, P ¼ 0.005). 46,47 Rivaroxaban was associated with fewer overt bleeding events requiring transfusion of.2 units of red blood cells, and fewer bleeding events leading to surgical revisions compared with both fondaparinux (2.6% vs. 4.3%, P ¼ 0.02 and 0.4% vs. 1.1%, P ¼ 0.04, respectively) and LMWH (2.6% vs. 6.1%, P, and 0.4% vs. 1.3%, P ¼ 0.02, respectively). XArelto in the Prophylaxis of Post-Surgical Venous Thromboembolism After Elective Major Orthopaedic Surgery of Hip or Knee (XAMOS) is a Phase IV, non-interventional study of rivaroxaban for VTE prevention after major orthopaedic surgery (elective hip or knee replacement surgery or hip fracture surgery, where appropriate). 48 Data were collected from 252 centres across 37 countries worldwide and patients were enrolled, a proportion of whom were frail ( 20%; defined as: age.75 years, body weight 50 kg, or severe, ongoing renal impairment) or who had other comorbidities such as hypertension ( 50%), heart failure ( 2.5%), or atrial fibrillation (AF; 3%). The effectiveness and safety of rivaroxaban was compared with other pharmacological thromboprophylaxis [standard of care (SOC)] in routine clinical practice and data showed that real-life clinical outcomes with rivaroxaban were consistent with that observed in RCTs. Rivaroxaban was associated with a significant reduction in symptomatic VTE compared with SOC [0.65% vs. 1.02%, respectively; odds ratio (OR) ¼ 0.63; 95% CI ], along with a comparable incidence of treatment-emergent major bleeding (RECORD definition; 0.40% vs. 0.34%). 48 For a detailed summary of the XAMOS study, please refer to the accompanying article Continued commitment to safety: Building on the existing rivaroxaban knowledge base by Beyer-Westendorf et al. Observational data have taught us that VTE continues to be a significant risk to patients, and anticoagulation therapy with traditional agents is frequently suboptimal. With NOACs, substantial improvements have been shown in reducing the risk of VTE compared with previous SOC, along with an acceptable safety profile. With rivaroxaban, evidence shows that this can be applied to daily care. Lessons from real-life studies: venous thromboembolism epidemiology and the treatment and secondary prevention of deep vein thrombosis and pulmonary embolism Real-life data are of great importance in understanding the needs of patients in routine clinical practice, particularly owing to the fact that almost a quarter of patients with VTE have at least one exclusion criterion preventing their recruitment into RCTs. 17 In addition to registries, databases can be a vital resource in supplementing our real-life clinical knowledge. The Venous Thromboembolism Epidemiology Group (VEG) comprises a subset of general practices in England known as the General Practice Research Database that contribute to the Clinical Practice Research Datalink. 49 The VEG group provided a snapshot of the incidence of VTE in the general population in the pre-noac era. Between January 2001 and September 2011 there were initial VTE events, 47.2% of which were unprovoked. The overall incidence of a first VTE in the UK general population was 131.5/ person-years and 107.0/ person-years after excluding cancer-associated VTE. A first DVT was more common than a first PE in patients,40 years (14.8% vs. 8.4%, respectively). 49 A total of 3671 cases of recurrent VTE were identified, which translated to an incidence rate of 4.9/100 and 5.1/ 100 person-years following first DVT and first PE, respectively. Incidence rates for VTE recurrence peaked in the first 6 months following the initial VTE event (11.1/ 100 person-years) and levelled out during the 2 10 years following the initial VTE event (2.2/100 person-years), with a crude cumulative risk of 25.2% at the 10-year timepoint. Venous thromboembolism recurrence rates were highest in the age group overall; DVT recurrence rates were generally higher in males than females, and remained elevated until the age of 40 years. 49 Epidemiological data from the VEG group reinforce that VTE continues to be a significant problem, and the risk of recurrence should be recognized, even in younger patients. The Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry is an ongoing, international, prospective registry of consecutive patients with acute VTE, designed to gather and analyse data on treatment patterns and outcomes. 50,51 Registro Informatizado de Enfermedad TromboEmbólica commenced in Spain in 2001, and 6 years later the database was translated into English, aiming to expand the registry to other countries, ultimately allowing worldwide use by physicians. 50 Data from RIETE are hypothesis-generating and provide feedback from real-life clinical situations. As of December 2014, over patients from 209 centres in 24 countries have been included (RIETE Registry, data on file). As previously mentioned, initial data from RIETE showed that 24% of patients with VTE had at least one exclusion criterion preventing recruitment to RCTs of antithrombotic therapy. 17,50 These patients had a 4-fold higher rate of both fatal PE and fatal bleeding than VTE patients with no exclusion criteria, emphasizing the clinical need for studies in high-risk patients. 50 Pivotal studies have been published by RIETE investigators on the natural history of VTE, including those in patients with recent major bleeding, 52 very old age, 53 disseminated cancer, 50 extreme body weight, 50 renal insufficiency, 54 or pregnancy, 50 improving the management of these groups. Prognostic scores derived from RIETE can accurately identify VTE patients at low or high risk for adverse

5 Table 1 Pivotal real-life studies in (a) venous thromboembolism prevention and (b) treatment of acute venous thromboembolism and secondary prevention of deep vein thrombosis and pulmonary embolism D36 Registry Study design/sample size (planned or enrolled) Endpoint Treatment duration VTE prevention GLORY (Global Orthopaedic Registry) 38 IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) 40 ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) 43 ORTHO-TEP 46,47 XAMOS (XArelto in the Prophylaxis of Post- Surgical Venous Thromboembolism After Elective Major Orthopaedic Surgery of Hip or Knee) 48 Prospective study patients (13 countries) Retrospective/prospective observational study; patients (12 countries) Cross-sectional observational registry; patients (32 countries) Single-centre, retrospective study;.5000 patients in Dresden, Germany Phase IV, non-interventional study (post-authorization safety study); patients in 37 countries Not specified Not specified Not specified Primary efficacy outcome: rate of any symptomatic VTE at hospital discharge Secondary efficacy outcomes: rates of proximal or distal symptomatic DVT, symptomatic PE, or VTE-related death Primary safety outcome: rate of major bleeding using a modification of the ISTH definition Efficacy outcomes: symptomatic arterial and venous thromboembolic events Primary safety outcome: major bleeding as defined in the RECORD studies As recommended by ACCP guidelines: Patients undergoing hip or knee arthroplasty receive thromboprophylaxis with LMWH, dose-adjusted VKA, or fondaparinux for at least 10 days (Grade 1A) 57 Median duration: 5 days (USA); 7 days (other countries) As recommended by ACCP guidelines: Patients undergoing hip or knee arthroplasty receive thromboprophylaxis with LMWH, dose-adjusted VKA or fondaparinux for at least 10 days (Grade 1A) 57 According to hospital protocol, prophylaxis was recommended until Day 35 post-surgery Hip surgery: mean duration of 33.3 and 31.4 days for rivaroxaban and SOC, respectively Knee surgery: mean duration of 27 and 28 days for rivaroxaban and SOC, respectively Treatment of acute VTE and secondary prevention of DVTand PE VEG (Venous Thromboembolism Observational cohort study; Epidemiology Group) 49 patients RIETE (Registro Informatizado de Prospective registry; Enfermedad TromboEmbólica) 51 patients in 24 countries Dresden NOAC registry 55 PREFER in VTE (Prevention of Thromboembolic Events European Registry in Venous Thromboembolism) 56 Prospective, non-interventional registry;.2600 patients in Saxony, Germany Prospective, observational, multicentre study; 3546 patients across 7 countries Not specified Study endpoints: Clinically recognized (and objectively confirmed) recurrences of VTE, major and minor bleeding complications, and death Please refer to individual studies Not specified Not specified Not specified Planned NOAC anticoagulation for at least 3 months was an inclusion criterion Not specified J. Beyer-Westendorf et al.

6 Real-life data on VTE prevention and treatment D37 Table 2 Clinical characteristics and therapeutic regimens of patients treated with rivaroxaban in the Registro Informatizado de Enfermedad TromboEmbólica registry (data on file) Initial therapy (n 5 627) Long-term therapy (n ) Not specified Primary outcome measures include rate of recurrent symptomatic VTE and associated complications (e.g. PTS); bleeding events; hospitalization; anticoagulation therapy persistence Prospective, observational cohort; estimated enrolment of patients GARFIELD-VTE (Global Anticoagulant Registry in the FIELD; ClinicalTrials.gov Identifier: NCT ) Primary outcome measures: Incidence of treatment-emergent adverse events, namely major bleeding, symptomatic recurrent VTE events and all-cause mortality Prospective, non-interventional cohort study (post-authorization safety study) Europe (.20 countries), Israel and Canada XALIA (XArelto for Long-term and Initial Anticoagulation in venous thromboembolism) 58 Clinical characteristics Age (mean, years +SD) Age.75 years 94 (15%) 207 (18%) Gender (male) 350 (56%) 627 (54.5%) Body weight (mean, kg +SD) Body weight,50 kg 7 (1.1%) 16 (1.4%) Initial VTE presentation Pulmonary embolism 244 (39%) 562 (49%) Underlying diseases Cancer 44 (7.0%) 63 (7.8%) Chronic heart failure 19 (3.0%) 23 (2.8%) Chronic lung disease 34 (5.4%) 54 (6.7%) Recent major bleeding 8 (1.3%) 7 (0.9%) CrCl levels ml/min 71 (11%) 76 (9.4%) CrCl levels,30 ml/min 5 (0.8%) 9 (1.1%) Duration of therapy Mean days + SD Median days (IQR) 21 (15 21) 83 (25 166) Regimen administered Twice-daily 510 (81%) 221 (19%) Once-daily 50 (8.0%) 750 (65%) Not specified 67 (11%) 180 (16%) Mean daily dose 5 mg 0 1 (0.1%) 10 mg 1 (0.2%) 15 (1.3%) 15 mg 37 (5.9%) 49 (4.3%) 20 mg 32 (5.1%) 816 (71%) 30 mg 556 (89%) 268 (23%) 40 mg 1 (0.2%) 1 (0.1%) VTE, venous thromboembolism; CrCl, creatinine clearance; IQR, interquartile range. outcome during the course of anticoagulant therapy, to assist physicians in making prompt therapeutic decisions. 50 Since the approval of NOACs for the treatment of acute VTE and the secondary prevention of DVT and PE, RIETE investigators have been gathering data on the use of apixaban, rivaroxaban, and dabigatran in real-life. As of December 2014, 627 patients with acute VTE had received rivaroxaban as initial therapy [median 21 days, interquartile range (IQR): 15 21] and 1151 as long-term therapy (median 83 days, IQR: ) (Data on file; Table 2). Clinical characteristics were largely similar to patients participating in the EINSTEIN trials. 23,24 Interestingly, one in every two patients treated with long-term rivaroxaban therapy had received initial heparin (either unfractionated or LMWH), suggesting that many doctors may be still concerned about the use of rivaroxaban as a single-drug approach during the first days of treatment. This is surprising, even though data from both EINSTEIN DVT and PE show comparable efficacy between rivaroxaban (15 mg BID) and standard therapy

7 D38 J. Beyer-Westendorf et al. groups during the first 21 days of treatment. 23,24 Furthermore, even though the majority of patients in EINSTEIN received pre-study heparin (83.8%) for 1 day, efficacy and safety outcomes achieved with rivaroxaban did not differ significantly between those who received heparin and those who did not. 59 Data from RIETE reveal that most patients are receiving rivaroxaban BID initially (81%), and most also receive the drug as an OD dose for long-term therapy (65%), as recommended. 11 However, up to one in every three such patients were treated differently. Approximately 10% of patients receiving rivaroxaban as initial therapy received lower or higher doses than recommended in the product label (15 mg BID), while almost 30% of patients receiving long-term rivaroxaban were administered lower or higher doses than that recommended (20 mg OD). 11 Physicians should therefore be vigilant when administering doses of NOACs such as rivaroxaban in the setting of acute VTE the risk of VTE recurrence and bleeding complications would be expected to be minimized by the use of recommended doses. The Dresden NOAC registry is another large, real-life study a prospective, observational database of patients with VTE or non-valvular AF enrolled through a network of private practices and community hospitals in Saxony, Germany. A total of 2667 patients have been enrolled as of 30 June The Dresden NOAC registry has investigated a number of factors relating to real-life treatment of VTE. Treatment of acute PE with rivaroxaban in daily care (n ¼ 72) showed that patients in this analysis were older than the overall EINSTEIN PE population (67.3 vs years, respectively) and overall, 23.6% were treated for recurrent VTE. 61 Rivaroxaban was shown to be effective and well-tolerated with low rates of unplanned treatment discontinuation (,10%; Dr Beyer-Westendorf, data on file) and comparatively low thromboembolic and major bleeding event rates 61 emphasizing that, as in EINSTEIN PE, 24 rivaroxaban is a feasible choice for the treatment of selected haemodynamically stable patients with acute PE, and that prompt, effective anticoagulation is crucial. There is a lack of evidence around the safety of switching from VKA to NOAC therapy in daily care, and the outcomes may differ from those in RCTs. For patients receiving chronic anticoagulation treatment, the safety of switching anticoagulation from VKAs to dabigatran or rivaroxaban was evaluated in the Dresden NOAC registry, and showed that this approach may be easily managed in clinical practice. 62 Reasons for switching in patients with VTE (n ¼ 148) included unstable INR (58.8%), bleeding complications (14.2%), thromboembolic complications (3.4%), repeated falls (5.4%), and others (38.5%). Until Day 30 after switching, bleeding complications occurred in only one patient with VTE and there were no cardiovascular complications. Evidence suggested that almost 15% of patients with VTE did not have their INR tested before NOACs were started. In those who were tested, the median interval between INR testing and the first intake of rivaroxaban was 2 days, even though the mean INR at the end of VKA therapy was 2.4 label recommendations for switching from VKAs to rivaroxaban state that rivaroxaban can be initiated once the INR is ,62 Peri-interventional management of NOACs was evaluated in 595 patients with AF and VTE undergoing 863 procedures in the Dresden NOAC registry. 63 Due to several recruitment factors, most procedures were performed in patients receiving rivaroxaban (76%), followed by patients receiving dabigatran (23.5%) and apixaban (0.5%). A total of 148 procedures were undertaken specifically in patients with VTE. It was shown that surgical or interventional procedures are common in patients receiving NOACs, yet these mostly consist of minimal (15.6%) or minor (74.3%) procedures. In the overall analysis, both cardiovascular events and major bleeding events were significantly more common in major procedures compared with minimal or minor procedures. While cardiovascular event rates were low regardless of the use of heparin bridging, the rates of major bleeding complications were significantly higher in patients who received heparin during NOAC interruption. While some NOAC patients at cardiovascular risk who need to undergo major procedures may benefit from heparin bridging, a careful risk benefit evaluation is needed. 63 Evidence generally suggested that either continuation or short-term interruption of NOACs are appropriate strategies for most invasive procedures. 63 Another analysis from the Dresden NOAC registry evaluated bleeding rates with rivaroxaban in daily care. 55 A total of 575 of 1776 patients receiving rivaroxaban in this analysis had VTE, in whom the overall bleeding rate was 59.6/100 patient-years, and the major bleeding rate was 4.1/100 patient-years. This rate is numerically higher than major bleeding rates from the EINSTEIN trials ( 1%) 23,24 ; however, this may be explained by the different statistical approaches and by the fact that VTE patients in the Dresden NOAC registry were considerably older compared with the EINSTEIN studies, as previously mentioned. 18,63 Of all bleeding events, 66 (6.1%) were recorded as major bleeding complications but the majority of these (n ¼ 41) could be managed conservatively. Surgical or interventional treatment was only needed in 25 cases, and both prothrombin complex and fresh frozen plasma were each used in only six cases. Despite this conservative approach towards major bleeding, the case-fatality rates were low (6% at Day 90). 55 Together, these data suggest that bleeding complications with rivaroxaban in daily care are within an acceptable range and appear manageable with currently available strategies. Prevention of Thromboembolic Events - European Registry in Venous Thromboembolism (PREFER in VTE) is a large, prospective, observational, multicentre study that has enrolled 3546 patients with VTE up to July 2014 across sites in Austria, France, Germany, Italy, Spain, Switzerland, and the UK. 56 This registry will gather data on important risk factors, diagnosis pathways, and treatment modalities; healthcare resource use; patient quality of life; and treatment satisfaction. An interim analysis in 3125 patients showed the proportion of patients diagnosed and enrolled with DVT and PE to be 58.9% and 41.1%, respectively. 56 At baseline, NOAC use

8 Real-life data on VTE prevention and treatment D39 was recorded in 27.6% of patients with DVT and 22.0% of patients with PE with or without DVT. Use of these agents differed largely between countries (as high as 50% in Germany, Austria, and Switzerland); this may due to different approval dates. Furthermore, NOAC use differed owing to patient characteristics such as age, body weight, and bleeding risk. 56 Other ongoing real-life studies include Global Anticoagulant Registry in the FIELD (GARFIELD-VTE; ClinicalTrials.gov Identifier: NCT ) that will evaluate treatment patterns in the field of VTE. XArelto for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) is a post-marketing surveillance study that will investigate the effectiveness and safety of a single-drug approach with rivaroxaban compared with standard therapy in patients with DVT (results anticipated later in 2015). 58 Conclusions Venous thromboembolism, encompassing DVT and PE, presents a major clinical threat to patients. With the advent of NOACs, we are experiencing a new era of post-vka anti-thrombotic therapy. Real-life data have a major role in establishing meaningful clinical outcomes, particularly with NOACs, in the management of VTE across a wide range of patient types. While we should be cautious before suggesting changes in treatment approaches based on the findings of uncontrolled studies due to their limitations related to inherent treatment biases, well-conducted real-life studies can help highlight optimal management strategies that may contribute to the improvement of patient care in the setting of VTE. Real-life data may also be considered as hypothesis-generating, and may be of help when designing new RCTs. From a payor s perspective, such studies can also be useful for evaluating the performance of NOACs in real life, as the incidence of VTE events and bleeding events are frequently higher outside the RCT setting. Analysing a larger number of patients may provide a clearer picture of adherence and persistence to medication. Real-life data have strengthened existing evidence of the clinical benefits of rivaroxaban seen in the RECORD and EINSTEIN programmes. 23,24,64 67 Patient characteristics in the RIETE registry indicate that daily care patients may often not be represented in RCTs, which highlights the need to evaluate effectiveness, safety, and management of new treatments in large registries. Data from the Dresden NOAC registry reinforce that the use of rivaroxaban in patients with VTE is indeed feasible in certain situations, e.g. in patients undergoing invasive procedures or who are being switched from VKAs. 62,63 Low rates of treatment discontinuation were also observed with rivaroxaban in the Dresden NOAC registry, 61 and importantly, bleeding complications were within an acceptable range and could be easily managed using standard procedures. 55 Observational studies are crucial in broadening and improving our understanding of everyday clinical situations in the setting of VTE, through resolving ongoing challenges and further optimization of patient care with agents such as rivaroxaban. Acknowledgements The authors acknowledge Kelly Farrell, Peter Morrow, and Louise Muttram at Inspired Science, who provided editorial support with funding from Bayer Pharma AG. Funding Editorial support was funded by Bayer Pharma AG. Conflict of interest: J.B.W. has received honoraria and research support from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. A.T.C. has received research support from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Merck, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Sanofi, and Schering Plough. A.T.C. has received fees for consultancy, honoraria, and/or scientific Advisory Boards from Astellas, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson and Johnson, Merck, Mitsubishi Pharma, Pfizer, Portola, Sanofi, Schering Plough, Takeda, and XO1 Limited. A.T.C. has also participated in Speaker Bureaus for Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Johnson and Johnson, Pfizer, Portola, and Sanofi. M.M. has received sponsorship for RIETE through an unrestricted grant from Sanofi (in Spain) and Bayer HealthCare (outside Spain). References 1. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M, Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98: Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107(23 Suppl. 1):I Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl.):381S 453S. 4. Duru S, Kelesoglu A, Ardic S. Clinical update on pulmonary embolism. Arch Med Sci 2014;10: Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl.):e419S e494s. 6. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107(23 Suppl. 1):I22 I Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350: Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;1: Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010;121:

9 D40 J. Beyer-Westendorf et al. 10. Scottish Medicines Consortium. Fondaparinux assessment no. 287/ _06.pdf (1 June 2015). 11. Bayer Pharma AG. Xarelto summary of product characteristics. (1 June 2015). 12. Bristol-MyersSquibb. Eliquissummaryofproduct characteristics. (1 June 2015). 13. Boehringer Ingelheim. Pradaxa summary of product characteristics. (1 June 2015). 14. Beyer-Westendorf J, Ageno W. Benefit-risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism. Thromb Haemost 2015;113: European Medicines Agency. Lixiana Summary of opinion EMA/CHMP/ / library/summary_of_opinion_-_initial_authorisation/human/002629/ WC pdf (1 June 2015). 16. Dobesh PP, Fanikos J. New oral anticoagulants for the treatment of venous thromboembolism: understanding differences and similarities. Drugs 2014;74: Monreal M, Suarez C, Fajardo JA, Barba R, Uresandi F, Valle R, Rondon P. Management of patients with acute venous thromboembolism: findings from the RIETE registry. Pathophysiol Haemost Thromb 2003;33: Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, Berkowitz SD, Wells PS. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVTand PE randomized studies. Thromb J 2013;11: Bauersachs RM, Lensing AWA, Prins MH, Kubitza D, Pap AF, Decousus H, Beyer-Westendorf J, Prandoni P. Rivaroxaban versus enoxaparin/ vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J 2014;12: Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117: Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le MF, Peter N, Kearon C. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129: EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366: Agnelli G, Büller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369: Agnelli G, Büller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368: Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk NA, Zamorano JL, Zompatori M ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35: k. 28. Prins MH, Lensing AWA, Brighton TA, Lyons RM, Rehm J, Trajanovic T, Davidson BL, Beyer-Westendorf J, Pap AF, Berkowitz SD, Cohen AT, Kovacs MJ, Wells PS, Prandoni P. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014;1:e37 e Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 2012;40: Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369: Cohen AT, Imfeld S, Rider T. Phase III trials of new oral anticoagulants in the acute treatment and secondary prevention of VTE: comparison and critique of study methodology and results. Adv Ther 2014;31: Turpie AG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Misselwitz F, Bandel TJ, Homering M, Westermeier T, Kakkar AK. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011;105: Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361: Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Büller HR. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370: Eriksson BI, Dahl OE, Büller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3: Warwick D, Agnelli G, Cushner F, Friedman RJ, Fitzgerald G, Gallus A, GLORY Publication Committee. Lessons learned from the global orthopaedic registry: study design, current practice patterns, and futuredirections.amjorthop(bellemead NJ) 2010;39(9Suppl.): Warwick D, Friedman RJ, Agnelli G, Gil-Garay E, Johnson K, Fitzgerald G, Turibio FM. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br 2007;89: Tapson VF, Decousus H, Pini M, Chong BH, Froehlich JB, Monreal M, Spyropoulos AC, Merli GJ, Zotz RB, Bergmann JF, Pavanello R, Turpie AG, Nakamura M, Piovella F, Kakkar AK, Spencer FA, Fitzgerald G, Anderson FA Jr. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007;132: Spyropoulos AC, Anderson FA Jr, Fitzgerald G, Decousus H, Pini M, Chong BH, Zotz RB, Bergmann JF, Tapson V, Froehlich JB, Monreal M, Merli GJ, Pavanello R, Turpie AG, Nakamura M, Piovella F, Kakkar AK, Spencer FA. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011;140: Decousus H, Tapson VF, Bergmann JF, Chong BH, Froehlich JB, Kakkar AK, Merli GJ, Monreal M, Nakamura M, Pavanello R, Pini M, Piovella F, Spencer FA, Spyropoulos AC, Turpie AG, Zotz RB, Fitzgerald G, Anderson FA. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011;139: Bergmann JF, Cohen AT, Tapson VF, Goldhaber SZ, Kakkar AK, Deslandes B, Huang W, Anderson FA Jr. Venous thromboembolism risk and prophylaxis in hospitalised medically ill patients. The ENDORSE Global Survey. Thromb Haemost 2010;103: Kakkar AK, Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Deslandes B, Huang W, Anderson FA Jr. Venous thromboembolism risk and prophylaxis in the acute care hospital setting (ENDORSE survey): findings in surgical patients. Ann Surg 2010;251: Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, Huang W, Zayaruzny M, Emery L, Anderson FA Jr. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:

10 Real-life data on VTE prevention and treatment D Beyer-Westendorf J, Lutzner J, Donath L, Tittl L, Knoth H, Radke OC, Kuhlisch E, Stange T, Hartmann A, Gunther KP, Weiss N, Werth S. Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery: findings from the ORTHO-TEP registry. Thromb Haemost 2013;109: Beyer-Westendorf J, Lutzner J, Donath L, Radke OC, Kuhlisch E, Hartmann A, Weiss N, Werth S. Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry. J Thromb Haemost 2012;10: Turpie AG, Haas S, Kreutz R, Mantovani LG, Pattanayak CW, Holberg G, Jamal W, Schmidt A, van EM, Lassen MR. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111: Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014;112: Tzoran I, Brenner B, Papadakis M, Di MP, Monreal M. VTE registry: what can be learned from RIETE? Rambam Maimonides Med J 2014;5:e Coordinating Center for the RIETE Registry. Computerized Registry of Patients with Venous Thromboembolism (RIETE). (1 June 2015). 52. Nieto JA, De Tuesta AD, Marchena PJ, Tiberio G, Todoli JA, Samperiz AL, Monreal M. Clinical outcome of patients with venous thromboembolism andrecentmajorbleeding: findingsfromaprospective registry (RIETE). J Thromb Haemost 2005;3: López-JiménezL, Montero M, Gonzalez-Fajardo JA, Arcelus JI, Suarez C, Lobo JL, Monreal M. Venous thromboembolism in very elderly patients: findings from a prospective registry (RIETE). Haematologica 2006;91: Monreal M, Falga C, Valle R, Barba R, Bosco J, Beato JL, Maestre A. Venous thromboembolism in patients with renal insufficiency: findings from the RIETE Registry. Am J Med 2006;119: Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, Michalski F, Köhler C, Werth S, Sahin K, Tittl L, Hänsel U, Weiss N. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124: Agnelli G, Bauersachs R, Gitt A, Laeis P, Mismetti P, Monreal M, Willich S, Cohen A. The current use of non-vka oral anticoagulants (NOACs) for the treatment of VTE in Europe PREFER in VTE. Eur Heart J 2014; 35(suppl.): Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl.):338S 400S. 58. Ageno W, Mantovani LG, Haas S, Kreutz R, Haupt V, Schneider J, Turpie AG. XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis. Thromb J 2014; 12: Prandoni P, Prins MH, Cohen AT, Müller K, Pap AF, Tewes MC, Lensing AW. Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboembolism in the EINSTEIN DVT and EINSTEIN PE studies. Acad Emerg Med 2015;22: Michalski F, Werth S, Köhler C, Tittl L, Daschkow K, Beyer-Westendorf J. Centrally adjudicated cause of death during NOAC treatment results of the prospective Dresden NOAC registry (NCT ). Blood 2014; 124: Köhler C, Werth S, Tittl L, Beyer-Westendorf J. Acute treatment of pulmonary embolism with rivaroxaban real life data from the prospective Dresden NOAC registry (NCT ). Blood 2013;122: Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Rollig D, Schreier T, Tittl L, Thieme C, Hänsel U, Köhler C, Werth S, Kuhlisch E, Stange T, Roder I, Weiss N. Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care results from the Dresden NOAC registry. Br J Clin Pharmacol 2014;78: Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Köhler C, Werth S, Kuhlisch E, StangeT, ThiemeC, Daschkow K, Weiss N. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014;35: Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358: Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372: Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373: