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IMPORTANCE Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT).OBJECTIVE To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT.DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted beginning May 2, 2008, and completed January 30, 2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee.MAIN OUTCOMES AND MEASURES Major bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality.RESULTS Of the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively).CONCLUSIONS AND RELEVANCE Most patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT.

Increasing D-dimer (DD) levels after discontinuation of vitamin K antagonist (VKA) therapy indicate an increased risk of recurrence of venous thromboembolism (VTE). However, after discontinuation of d irect-acting n on-VKA o ral a nti c oagulants (DOACs or NOACs) the extent of coagulation activation and its clinical impact is unknown. Blood samples were collected from consenting patients with proximal VTE at the end of anticoagulation treatment with apixaban (n = 37), dabigatran (n = 17), rivaroxaban (n = 9) or VKA (n = 184) and 4 weeks later. DD, prothrombin fragments F1 + 2 (F1 + 2) and thrombin–antithrombin complexes (TAT) were measured. All patients underwent follow-up at 12 months to establish recurrent VTE or death from any cause. Irrespective of the treatment, DD and F1 + 2 but not TAT demonstrated a similar increase between baseline and week 4. At 12 months, 18 patients (7.3%) had recurrent VTE and two (0.8%) had died. For all patients and subgroups of VKA and DOAC, positive likelihood ratios were numerically higher for baseline values but only TAT values at 4 weeks were found to be related to a small increase of outcome event likelihood (2.6; 95%CI 1.23-5.50), which was driven by VKA patients (3.1; 95%CI 1.32-7.30) and not by DOAC patients (2.27; 95%CI 0.52-9.95). For all parameters, negative likelihood ratios were not predictive. In logistic regression analysis, only ΔTAT (optimal cut-off > 178% from baseline demonstrated a significant risk increase for VTE/death (odds ratio 3.76; 95% confidence interval 1.46-9.68; p = 0.006). In conclusion, the concept of testing coagulation activation parameters may also be transferred to VTE patients at the end of DOAC therapy. For patients with an increase of TAT levels within 4 weeks after treatment discontinuation (> 178% from baseline) is associated with an increased risk for VTE recurrence or death at 12 months.

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.

Atrial fibrillation (AF) is an increasing public health issue, especially owing to an accompanying five-fold increased risk of stroke. Anticoagulants are the cornerstone of therapy for stroke prevention in AF. The clinical benefits of vitamin K antagonists (VKAs; namely warfarin) shown in randomized controlled trials (RCTs) have been challenged when used in clinical practice by issues including the need for international normalized ratio (INR) monitoring, food and drug interactions, low time in the therapeutic range in substantial numbers of patients, and serious bleeding events. Combined, these have led to both an under-initiation of VKAs and high rates of VKA discontinuation. Non-VKA oral anticoagulants (NOACs), including the oral, direct factor Xa inhibitors apixaban and rivaroxaban and the oral, direct thrombin inhibitor dabigatran, are transforming the anticoagulation landscape. These agents have shown favourable outcomes in Phase III RCTs and are licensed for the use in Europe and many other regions around the world for stroke prevention in AF. However, the safety and effectiveness of NOACs in real-world patients with AF outside RCTs is not well understood. Non-interventional studies and registries are becoming ever more important in understanding the real-life benefit–risk profile of NOACs. This review will evaluate questions that remain unanswered despite the wealth of RCT data available, and will describe a number of pivotal real-life studies that have been completed or are ongoing in the area of stroke prevention in AF, in an effort to extend our understanding of NOAC use to routine clinical practice and optimise patient care.

Data from post-authorization studies and registries are valuable in establishing the safety and effectiveness of therapies in real-life settings, particularly as physicians may have concerns about the robustness of safety data from randomized controlled trials (RCTs). Furthermore, in routine clinical practice, there may be a potential for increased adverse event reporting with new therapies, and their true safety profile may be difficult to elucidate. The non-vitamin K antagonist (VKA) oral anticoagulant (NOAC) rivaroxaban is a direct factor Xa inhibitor, first approved for the prevention of venous thromboembolism (VTE) following elective hip or knee replacement surgery in 2008, and now licensed for use in five indications in Europe in the venous and arterial thromboembolic space. A number of Phase IV, non-interventional studies, and independent registries are completed or underway that aim to further evaluate safety outcomes with rivaroxaban in everyday clinical practice. These include XAMOS (XArelto in the prophylaxis of post-surgical venous thromboembolism after elective Major Orthopaedic Surgery of the hip or knee), XANTUS (XArelto on preveNtion of sTroke and non-central nervoUS system systemic emboilism in patients with non-valvular atrial fibrillation), and XALIA (XArelto for Long-term and Initial Anticoagulation in venous thromboembolism). Results to date—from XAMOS—show that rivaroxaban has an acceptable safety profile in real-life, with outcomes that are in line with the RECORD (REgulation of Coagulation in ORthopedic surgery to prevent Deep vein thrombosis and pulmonary embolism) clinical trial programme. International and national registries are also gathering information on rivaroxaban and other NOACs. Together, this breadth of studies illustrates an ongoing commitment to understanding real-life outcomes with NOACs.

Background In phase III trials, rivaroxaban demonstrated non-inferiority over enoxaparin/warfarin to prevent recurrent venous thromboembolism (VTE), with a reduction of major bleeding. However, compared to provoked VTE, the risk-benefit ratio of rivaroxaban may be different for patients with unprovoked VTE. Methods In a retrospective claims data analysis using US MarketScan claims from 1/2012 to 12/2016, we included adults with a primary diagnosis of VTE newly-initiated on rivaroxaban or warfarin within 30-days of the incident VTE and with ≥12-months of continuous insurance benefits prior to the VTE (baseline). Patients with provoked VTE, a claim for anticoagulation during baseline or who redeemed prescriptions for ≥1 oral anticoagulant were excluded. Our primary outcomes were recurrent VTE and major bleeding at 6-months using an intention-to-treat (ITT) analysis. Three-month ITT and 12-month on-treatment (30-day permissible gap) analyses were also performed. Inverse probability-of-treatment weights based on propensity-scores and Cox regression were used to compare outcomes. Findings We identified 10,489 rivaroxaban users and 26,364 warfarin users with incident unprovoked VTE. At 6-months, rivaroxaban was associated with a hazard ratio (HR) of 0.60 (95% confidence interval [CI] = 0.54–0.67) for recurrent VTE (number-needed-to-treat: 59; 95%CI 49–76) and a HR = 0.80 (95% CI = 0.66–0.98) for major bleeding versus warfarin. Our findings remained consistent in the 3- and 12-month analyses. Interpretation Consistent with the results from the EINSTEIN phase-III trials, findings of our routine practice study suggest that, in patients with unprovoked VTE, rivaroxaban has the potential to reduce both the risk of major bleeding and recurrent VTE compared to warfarin.

The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs. ispartof: INTERNAL AND EMERGENCY MEDICINE vol:13 issue:7 pages:1051-1058 ispartof: location:Italy status: published

Postthrombotic syndrome (PTS) is a frequent complication of venous thromboembolism (VTE). Using MarketScan claims data from January 2012 to June 2015, we identified adults with a primary diagnosis code for VTE during a hospitalization/emergency department visit, ≥6 months of insurance coverage prior to the index event and newly started on rivaroxaban or warfarin within 30 days of the index VTE. Patients with

SummaryThe prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non- VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit–risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and “reallife” data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.

SummaryAtrial fibrillation (AF) patients treated with well-controlled vitamin K antagonists (VKAs) may benefit less from non-vitamin K antagonist oral anticoagulants (NOACs) because they are supposed to be at low risk of thromboembolic and bleeding complications. However, little is known about the selection, management, and outcome of such “stable” VKA patients in current practice. We assessed characteristics, VKA persistence and 12 months' outcome of AF patients selected for VKA continuation. On March 1, 2013, the Dresden NOAC registry opened recruitment of patients continuing on VKA for sites that had been actively recruiting AF patients treated with NOACs in the prior 18 months. Patient characteristics were compared with those of NOAC patients from the same sites. Four hundred twenty-seven VKA patients had a significantly lower bleeding risk profile compared with 706 patients selected for NOAC treatment. For VKA, international normalised ratio time-in-therapeutic range before enrolment was 71% and increased to 75% during a mean follow-up of 15 months. Rates of stroke/transient ischaemic attack/systemic embolism were 1.3/100 patient-years (intention-to-treat) and 0.94/100 patient-years (as-treated). On-treatment rate of ISTH major bleeding was 4.15/100 patient-years (95% CI 2.60–6.29) with a case-fatality rate of 16.3% (all-cause mortality at day 90 after major bleeding). In conclusion, in daily care, AF patients selected for VKA therapy are healthier than those treated with NOAC, demonstrate a high quality of anticoagulant control and very low stroke rates. However, despite adequate patient selection and INR control, the risk of major VKA bleeding is unacceptably high and bleeding outcome is poor.

SummaryPatients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6–12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

SummaryDirect oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Venous thromboembolism (VTE) remains a substantial clinical and health-economic burden worldwide and effective anticoagulant treatment is necessary immediately after VTE is suspected to reduce short- and long-term VTE related morbidity and mortality. For decades, low molecular weight heparin (LMWH), fondaparinux and Vitamin K antagonists (VKAs) have been the standard of anticoagulant therapy for VTE patients but these treatment options had clinically relevant drawbacks and limitations. The introduction of non-VKA oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa have resolved many of these drawbacks because these new compounds exhibit a rapid onset and offset of action, fewer food and drug interactions and a predictable anticoagulant effect. All NOACs have successfully completed their respective phase-III trial programs consisting of many large randomized controlled trials, leading to approval for acute VTE treatment around the world. Nevertheless, their introduction into daily care practice is challenging and a careful evaluation of the effectiveness and safety of NOACs in less selected cohorts outside carefully monitored clinical trials is essential. This review introduces the different types of real-world evidence (RWE) and explores the available data for VTE treatment with NOACs, based on a literature search using the key words "venous thromboembolism" or "VTE" in combination with "NOAC", "DOAC", "apixaban", "dabigatran", "edoxaban" and "rivaroxaban" on June 30; 2017, followed by data extraction from studies that reported real-world outcome data for VTE treatment with NOACs, although available evidence is almost exclusively limited to rivaroxaban.

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7–57.2 kg/m 2 ), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a "BMI paradox" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI.

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.

Direct oral anticoagulants (DOACs) have proven efficacy and safety and are approved for use in the prevention and treatment of thromboembolic events in patients with venous thromboembolism (VTE) and those with atrial fibrillation (AF). There is no clear guidance on the use of DOACs in the significant proportion of these patients who have or will develop concomitant cancer. The occurrence of nausea and vomiting in these patients, despite implementation of guideline-recommended antiemetic strategies, is a particular concern because it may affect oral drug intake and consequently outcomes with anticoagulation therapy. Here, we review recent data on the incidence and management of cancer-associated nausea and vomiting and the current evidence and guidance relating to the use of DOACs in patients with cancer. On the basis of this evidence, an international working group of experts in the fields of cancer-associated thrombosis/hemostasis, hematology, and oncology discussed key issues related to the use of DOACs in patients with VTE or AF and cancer who are at risk of nausea and vomiting and developed some consensus recommendations. We present these consensus recommendations, which outline strategies for the use and management of anticoagulants, including DOACs, in patients with VTE or AF and cancer for whom oral drug intake may pose challenges. Guidance is provided on managing patients with gastrointestinal obstruction or nausea and vomiting that is caused by cancer treatments or other cancer-related factors. The recommendations outlined in this review provide a useful reference for health care professionals and will help to improve the management of anticoagulation in patients with VTE or AF and cancer. Implications for Practice Direct oral anticoagulants (DOACs) offer several advantages over traditional anticoagulants, including ease of administration and the lack of need for routine monitoring. However, the management of patients with an indication for anticoagulation and concomitant cancer, who are at high risk of thromboembolic events, presents several challenges for administering oral therapies, particularly with regard to the risk of nausea and vomiting. In the absence of robust data from randomized trials and specific guidelines, consensus recommendations were developed for healthcare professionals regarding the use of DOACs in patients with cancer, with a focus on the management of patients who are at risk of nausea and vomiting.

The decline of renal function affects stroke risk in patients with atrial fibrillation (AF). Here, we aim to study the predictive value of the CHATwo electronic health record cohorts with AF and CKD stage III/IV were evaluated (Cohort #1 (IMS-DA, Germany): 18,539 patients with 125,149 estimated glomerular filtration rate (eGFR) measurements; Cohort #2 (IMS-THIN, United Kingdom): 18,240 patients with 133,676 eGFR measurements). The eGFR trajectories were analysed with multi-level mixed-effects regression and joint models for longitudinal and survival data.In IMS-DA, the mean baseline eGFR was 52.0ml/min/1.73mThe CHA

Direct oral anticoagulants (DOACs) have emerged as alternatives to vitamin K antagonists for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Four DOACs: dabigatran, rivaroxaban, apixaban and edoxaban, are currently available. In the absence of head-to-head clinical comparisons of DOACs, dosing regimen may influence drug choice. Areas covered: Edoxaban and rivaroxaban are administered once daily, dabigatran and apixaban twice daily. The selection of these dosage regimens is largely based on studies for the prevention or treatment of venous thromboembolism or acute coronary syndrome. Edoxaban is the only DOAC in which once and twice-daily regimens were compared in patients with NVAF; bleeding rates were higher in the twice-daily groups. Once-daily versus twice-daily regimens have a number of practical implications. Missing a once-daily dose would have a greater impact on anticoagulation. Some real world and retrospective studies found that a once-daily dosing regimen leads to better adherence and persistence to therapy, an important consideration for maintaining optimum anticoagulation. However, other studies have not found increased adherence among once daily regimens. Expert opinion: Prescription of DOACs should be tailored to the individual patient and dosing regimen is only one of the variables that should be taken into account.

Current guidelines consider outpatient treatment as an option for low-risk pulmonary embolism (PE), and risk assessment tools such as the HESTIA criteria can be used to identify PE patients who could feasibly be treated in an outpatient setting. Little is known about what proportion of patients in daily care this would comprise, and, in these patients, outcome data outside of clinical trials are scarce. To assess the proportion of PE patients receiving outpatient early discharge or in-hospital therapy, evaluate differences in patient characteristics between these subgroups and to assess clinical outcomes at 6 months. Monocentric, retrospective cohort study in 439 consecutive patients undergoing outpatient, early-discharge or in-hospital treatment for PE. Outcome data on recurrent VTE, pulmonary hypertension or death were collected from routine follow-up visits 6 months after VTE diagnosis. PE patients were treated as outpatient (OP; n = 49; 11.2 %); early-discharge (ED; n = 62; 14.1 %) or in-hospital (IH; n = 328; 74.7 %). Median duration of hospital stay in the ED and IH groups were 1 (IQR: 1) day and 9 (IQR: 7) days, respectively. Outcome event rates at 6 months were 3.9 % for recurrent VTE (95 % CI 2.3–6.1, similar between groups), 5.2 % for pulmonary hypertension (95 % CI 3.3–7.8, similar between groups) and 10.7 % for mortality (95 % CI 8.0–14.0). Mortality was significantly higher in IH patients (14.0 %; 95 % CI 10.5–18.3) compared to OP (0 %; 95 % CI 0.0–7.3) or ED (1.6 %; 95 % CI 0.0–8.7) patients. Mortality risk factors were high-risk ESC category (OR: 5.7), paraneoplastic VTE (OR: 3.0), need for oxygen supplementation (OR: 5.2), diabetes (OR: 2.5), age (OR per additional year: 1.1) and elevated INR (OR per 0.1 point increase: 1.5). No difference in the treatment groups for pulmonary hypertension during follow-up was found. Independent risk factors were thrombophilia (OR: 8.43), signs of right ventricular strain in baseline ECG (OR: 6.64) or echocardiography (RVESP > 40 mmHg OR: 2.99). 32 % of the OP or ED patients had at least one criterion of the HESTIA score that would have excluded them from outpatient treatment. In daily care, treating PE in an almost exclusively outpatient setting seems feasible and safe for up to 25 % of all PE patients. The HESTIA criteria seem to exclude up to 30 % of patients for whom outpatient or early-discharge treatment seems feasible and safe.

Summary Background Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials. Methods We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0–3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777. Findings In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28–3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66–1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21–1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34–1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [ vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03–2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37–0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15–1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08–1·31). Interpretation In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted. Funding Bayer HealthCare Pharmaceuticals and Janssen Research & Development.

Aim Vitamin-K antagonists (VKA) and non-vitamin-K dependent oral anticoagulants (NOAC) have been approved for anticoagulation in venous thromboembolism (VTE) and atrial fibrillation and patients previously treated with VKA are switched to NOAC therapy. Safety data for this switching are urgently needed.

Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119.

Background: Until recently, patients with cancer associated thrombosis (CAT) were predominantly treated with low-molecular weight heparin (LMWH) but trial data and updated guidelines suggest that direct oral anticoagulants (DOAC) may represent feasible and convenient oral alternatives. However, most data supporting this relate to 6-12 months outcomes only and long-term data in this setting are scarce Aims: To evaluate the effectiveness and safety of CAT treatment with DOAC in daily care. Patients and methods: From the multicentric Dresden NOAC Registry, long-term outcomes of a subgroup of CAT patients (active or recent cancer, defined as cancer therapy within 5 years prior to thrombosis) receiving CAT therapy with DOAC were evaluated, based on prospectively collected data and centrally adjudicated outcome events. Results: Of the 1667 VTE patients enrolled in the registry until 30th June 2019, 186 patients (11.2%) were identified to have CAT (mean age 67.3 years; 61.3% male). At enrolment, cancer was reported as active in 97 (52.2) cases and recent in 89 (47.8) cases. Solid malignancies were diagnosed in 163 (87.6%) cases were, the remaining 23 (12.4%) cases were hematologic malignancies; table 1; figure 1). Of the 97 cases with active malignancies, 43.3% had metastatic disease. CAT treatment consisted of rivaroxaban in 80 (43.0%) patients, 66 (35.5%) received edoxaban and 40 (21.5%) apixaban. During follow-up (mean 27.8 months, range 0.5 - 88.6), 14 patients experienced recurrent VTE events (7.5 %; incidence rate 3.5/100 pt. years) of which 4 occurred during DOAC treatment and 10 after discontinuation or during prolonged (>3d) DOAC interruption (figure 2a). During DOAC exposure (within 3 days of last intake), major bleeding occurred in 15 patients (8.1%; incidence rate 5.9/100 pt. years; figure 2b) and presented as gastrointestinal (GI) bleeding in 7, intracranial bleeding in 3 and in other bleeding manifestations in 5 cases. For 34 patients with GI cancer, the incidence rate for major bleeding was 13.3/100 pt. years and all four major bleedings in this group presented as upper GI bleed. 40 patients died during FU (21.5%; incidence rate 9.4/100 pt. years). Causes of death included terminal malignant disease (n=22), infection (n=6), fatal bleeding (n=4), age related death (n=3), fatal cardiovascular event (n=3), and other reasons (n=2). Conclusions: Our results now contribute long-term data of DOAC treatment for CAT. Incidence rates of recurrent VTE and major bleeding were consistent with the results from recent randomized trials in CAT. Most VTE recurrences occurred after interruption or discontinuation of DOAC, which indicates the importance of continued therapy especially for patients with active cancer. On-treatment rates of major bleeding were comparable for patients with recent or active cancer, indicating a need for an individualized risk-benefit assessment, especially since patients with recent cancer were at lower risk for VTE recurrence. Our findings of higher major bleeding rates in patients with GI cancer (both active and recent) is in line with the observations in randomized trials and supports guidelines recommendations, cautioning against DOAC use in CAT patients at high risk for bleeding, such as GI cancer patients. Disclosures Marten: Daiichi Sankyo: Honoraria; Bayer HealthCare: Honoraria. Tittl:Daiichi Sankyo: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding.

Background: Patients living with cancer who develop venous thromboembolism (VTE) have a high risk of VTE recurrence, and traditional anticoagulants (low molecular weight heparin [LMWH] or vitamin K antagonists [VKAs]) are associated with significant treatment burdens. Rivaroxaban is a direct oral anticoagulant (DOAC) that may provide a more convenient treatment option for these patients. Methods: The COSIMO study was a multinational, prospective, non-interventional, single-arm cohort study designed to collect real-world data on patient treatment satisfaction and outcomes associated with rivaroxaban treatment following ≥4 weeks of LMWH/VKA therapy for the treatment of acute VTE in patients with active cancer. Here, we report on the secondary objectives, which were to provide descriptive analyses of clinical characteristics and patterns of use of anticoagulant treatment, and to assess the safety and effectiveness of rivaroxaban in this patient population. Results: Overall, 505 patients were enrolled, and the qualifying venous thromboembolic event was deep vein thrombosis (DVT) only in 45.3% of patients, pulmonary embolism (PE) only in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients (Table). The majority of patients had solid tumors (n=449, 88.9%); 56 patients had hematological malignancies. The most common reasons to switch to rivaroxaban were patient preference/quality of life (n=310, 61.4%) and physician decision (n=174, 34.5%). A total of 150 (29.7%) patients were treated with concomitant chemotherapy and 79 (15.6%) received concomitant radiotherapy. Overall, 117 (23.2%) patients discontinued the study: 59 (11.7%) died, 21 (4.2%) withdrew consent, and 17 (3.4%) were lost to follow-up. 80.2% of patients were treated with rivaroxaban for at least 3 months, and most patients (78.6%) received rivaroxaban 20 mg once daily on study entry. Treatment-emergent adverse events (AEs) were reported: 312 (61.8%) patients had an AE (148 [29.3%] serious AEs), and 95 (18.8%) patients had a bleeding event reported, of which 18 (3.6%) patients had an adjudicated major bleeding event. Adjudicated symptomatic and incidental VTE recurrence occurred in 15 (3.0%) and 3 (0.6%) patients, respectively. Adjudicated other site thromboembolic events such as splanchnic or cerebral vein thromboses were symptomatic in 1 (0.2%) patient and incidental in 1 (0.2%) patient. Conclusions: Observed incidence rates of VTE and bleeding events in COSIMO were similar to previous studies of DOACs for VTE treatment in patients with active cancer (Young AM et al. J Clin Oncol 2018;36:2017; Raskob GE et al. N Engl J Med 2018;378:615). Study governance Bayer AG Funding The COSIMO study is funded by Bayer AG and Janssen Pharmaceuticals. Trial protocol number NCT02742623. Registered 19 April 2016. Documented approval from appropriate independent ethics committees/institutional review boards will be obtained for all participating centers prior to study start. Patients were asked to provide signed informed consent forms before joining the study. Few patients have yet completed the study, and so no data are available to share. Acknowledgements Editorial assistance was provided by Kate Weatherall of Chameleon Communications Int. Ltd. with funding from Bayer AG and Janssen Scientific Affairs, LLC. Disclosures Maraveyas: Bristol-Myers Squibb: Honoraria; Bayer AG: Honoraria, Research Funding; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Pfizer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Mantovani:Daiichi Sankyo: Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer AG: Honoraria; Fondazione Charta: Consultancy; Pfizer: Honoraria. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Cohen:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; CSL Behring: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Speakers Bureau; TRN: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; Boston Scientific: Consultancy; Guidepoint Global: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Leo Pharma: Consultancy; GLG: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Current guidelines recommend low-molecular-weight heparins (LMWH) over Vitamin K Antagonists (VKA) or Non-Vitamin K Antagonist Oral Anticoagulants (NOAC) for the treatment of cancer-associated venous thromboembolism (CAT), but also highlight that ultimately the choice of anticoagulant depends on patient-specific factors such as patient preferences, which is important for the acceptance of the treatment and, thus, for adherence and persistence. So far, little is known about the specific preferences of patients with CAT with respect to anticoagulation therapy. More specifically, the impact of dosing regimen, convenience and costs on patient preferences in CAT is poorly understood. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. Methods: Adult patients with active cancer who experienced a CAT event and for whom the decision was made to start a treatment with rivaroxaban after being treated with the standard of care anticoagulation (LMWH/VKA) for at least four weeks were included in a multinational, observational, single-arm study (COSIMO). As part of this study, a DCE was presented to the participants, who were asked to decide between complete hypothetical treatment options based on a combination of different attributes, regardless of efficacy or safety. The following attributes were preselected in a face-to-face discussion with three focus patients and in-depth interviews with four additional patients: route of administration (injection / tablet),frequency of intake (once / twice daily),need of regular controls of the International Normalized Ratio (INR) at least every 3-4 weeks (yes/no),interactions with food/alcohol (yes/no). Additionally, distance to treating physician (1 km vs. 20 km) was included as neutral comparator to express patients' overall utility in terms of a comprehensible unit. The relative importance of treatment attributes in terms of distances were calculated based on ratios between the utility estimates for each attribute. A fractional factorial design was generated resulting in nine hypothetical choice sets, supplemented by a test choice set to assess the consistency of a patient's responses. DCE data was collected by semi-structured telephone interviews, performed between week 4 and week 12 after enrollment of patients in the study and start of rivaroxaban. For each patient participating in the DCE interview, a written informed consent was obtained. Patient preferences were analyzed based on a conditional logit regression model. Results: Overall, 163 patients were included (Europe: 119; Canada: 41; Australia: 3), mean age 63.7 years, 49.1% were females and diagnosed with cancer for on average 22.4 months. Most patients in the COSIMO study changed to rivaroxaban from LMWH (> 95.0 %). The median time from diagnosis of index CAT event to conduct of DCE was 150 days (IQR 88-229). Patients strongly preferred oral administration compared to self-injections and drugs that can be taken irrespective of type of food or alcohol consumption (Figure 1). Furthermore, patients indicated slight preference for a shorter distance to the treating physician and a once daily dosing regimen compared to a twice-daily intake. The attribute "INR controls" showed no significant impact on the treatment decision. In order of patients' preference for their choice of treatment, the route of administration was by far the most important attribute for a patient's choice (73.8% of the overall decision), followed by food interactions (11.8%), the distance to treating physician (7.2%) and the intake frequency (6.5%). Accordingly, the expected utility of patients receiving an oral anticoagulation can be expressed as willingness to travel an additional distance of 192 km to the treating physician in order to avoid an injection. Conclusions Treatment related decision-making of patients with CAT, assuming equal effectiveness and safety of treatments, is predominantly driven by "route of administration", indicating a strong preference for oral intake. Disclosures Picker: Ingress-Health: Employment. Cohen:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; GLG: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; Boston Scientific: Consultancy; AbbVie: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Aspen: Consultancy, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Maraveyas:Bayer AG: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mantovani:Fondazione Charta: Consultancy; Bayer AG: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Wilke:Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pharmerit: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria.

Rivaroxaban is increasingly used to treat patients with acute venous thromboembolism (VTE), a potentially life-threatening condition. Because absorption of rivaroxaban decreases from nearly 100% to 66% under fasting conditions, it is recommended that VTE patients take rivaroxaban with a meal. However, this recommendation is based on preclinical pharmacokinetic (PK) studies in healthy volunteers. So far, no clinical evidence is available to support this recommendation. We describe a case of a compliant young patient who developed recurrent pulmonary embolism during rivaroxaban treatment. PK studies provided evidence that malabsorption of rivaroxaban 20 mg due to irregular intake of meals during shift work was the leading cause of recurrent pulmonary embolism. When the patient was instructed to take rivaroxaban with a regular meal, peak plasma concentrations increased from 115 to 318 ng mL(-1) (+ 176%). Consequently, the importance of taking rivaroxaban with food may have a greater clinical relevance than data from preclinical PK studies suggest.

Background— In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results— Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours ( P P =0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 ( P P =0.61), and no recurrent venous thromboembolism. Conclusions— In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01166997.

Aims Patients receiving novel oral anticoagulants (NOACs) frequently undergo interventional procedures. Short half-lives and rapid onset of action allow for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach are lacking. We evaluated the peri-interventional NOAC management in unselected patients from daily care. Methods and results Effectiveness and safety data were collected from an ongoing, prospective, non-interventional registry of >2100 NOAC patients. Outcome events were adjudicated using standard event definitions. Of 2179 registered patients, 595 (27.3%) underwent 863 procedures (15.6% minimal, 74.3% minor, and 10.1% major procedures). Until Day 30 ± 5 post-procedure, major cardiovascular events occurred in 1.0% of patients [95% confidence interval (95% CI) 0.5–2.0] and major bleeding complications in 1.2% (95% CI 0.6–2.1). Cardiovascular and major bleeding complications were highest after major procedures (4.6 and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events, but led to significantly higher rates of major bleeding complications (2.7%; 95% CI 1.1–5.5) compared with no bridging (0.5%; 0.1–1.4; P = 0.010). Multivariate analysis demonstrated diabetes [odds ratio (OR) 13.2] and major procedures (OR 7.3) as independent risk factors for cardiovascular events. Major procedures (OR 16.8) were an independent risk factor for major bleeding complications. However, if major and non-major procedures were separately assessed, heparin bridging was not an independent risk factor for major bleeding. Conclusion Continuation or short-term interruption of NOAC is safe strategies for most invasive procedures. Patients at cardiovascular risk undergoing major procedures may benefit from heparin bridging, but bleeding risks need to be considered.

Treatment of splanchnic vein thrombosis (SVT) is a clinical challenge due to heterogeneity of clinical presentations, increased bleeding risk, and lack of evidences from clinical trials. We performed an international registry to describe current treatment strategies and factors associated with therapeutic decisions in a large prospective cohort of unselected SVT patients. A total of 613 patients were enrolled (mean age 53.1 years, standard deviation ± 14.8); 62.6% males; the majority (468 patients) had portal vein thrombosis. Most common risk factors included cirrhosis (27.8%), solid cancer (22.3%), and intra-abdominal inflammation/infection (11.7%); in 27.4% of patients, SVT was idiopathic. During the acute phase, 470 (76.7%) patients received anticoagulant drugs, 136 patients (22.2%) remained untreated. Incidental diagnosis, single vein thrombosis, gastrointestinal bleeding, thrombocytopenia, cancer, and cirrhosis were significantly associated with no anticoagulant treatment. Decision to start patients on vitamin K antagonists after an initial course of parenteral anticoagulation was significantly associated with younger age, symptomatic onset, multiple veins involvement, and unprovoked thrombosis. Although a nonnegligible proportion of SVT patients did not receive anticoagulant treatment, the majority received the same therapies recommended for patients with usual sites thrombosis, with some differences driven by the site of thrombosis and the pathogenesis of the disease.

Summary Background Bleeding complications are common side effects of vitamin-K antagonist (VKA) therapy. Data on the in-hospital management and outcomes of these bleeding events are scarce and information is mostly derived from trial cohorts. Objectives The objective was to collect data on the management and clinical outcome of hospitalizations owing to VKA-related bleeding in real-world practice. Patients and methods We performed a multicenter observational cohort study involving 21 secondary and tertiary care hospitals in the administrative district Dresden, Saxony, Germany throughout the year 2005. All consenting patients presenting with VKA-related bleeding complications were included. No exclusion criteria applied. Data were collected at admission, at discharge and at 90 days to evaluate resource consumption, length of hospital stay and risk factors for in-hospital- and 3-month mortality. Results Two hundred and ninety patients were included (median age 74 years; 50.7% male). The main indications for VKA therapy were atrial fibrillation (63.4%), prior thromboembolism (18.6%) and mechanical heart valves (11.4%), and most common bleeding localizations were large hematoma (23.1%), upper gastrointestinal (GI) tract (17.9%) and intracranial bleeding (14.1%). On hospital admission, the median International Normalized Ratio (INR) was 3.0 (range 0.9–12.5, interquartile range [IQR] 2.1–3.9). In-hospital mortality was 7.6% with impaired renal function as the most relevant risk factor. At 90 days mortality was 14.1% and 15.3% of survivors were help-dependent. Conclusions VKA-related bleeding leading to hospitalization is associated with long hospitalization, relevant resource utilization, high mortality or persistent sequlae. Patient-related factors such as impaired renal function, chronic cardiac or pulmonary disease and dementia are predictive of in-hospital and 3-month mortality.

Objective Superficial vein thrombosis (SVT) is a common disease in clinical practice. In terms of pathophysiology and outcomes, the condition is related to venous thromboembolism, bearing a potential for severe thromboembolic complications if it is not treated adequately. A wide range of treatment approaches (including oral and injectable anticoagulants, pain medication, nondrug therapy including compression therapy, and no treatment at all) are applied in clinical practice, but there is sparse information about selection of patients for therapies, current treatment pathways, and drug use as well as outcomes. The INvestigating SIGnificant Health TrendS in the management of Superficial Vein Thrombosis (INSIGHTS-SVT) study aims to close this gap by collecting representative data on the current treatment of SVT. Methods The observational prospective study of about 1200 patients is carried out by up to 120 clinical and office-based physicians who regularly treat patients with SVT and are capable of conducting appropriate compression ultrasound diagnostics, such as vascular physicians, phlebologists, internists, vascular surgeons, and general practitioners. Patients are eligible for inclusion if they have ultrasound-confirmed acute, isolated SVT of the lower extremities. Documentation about the characteristics of the patients, diagnostics, comorbidities, and medical and nonmedical treatment is collected at baseline, at 10 ± 3 days or at approximately 45 days (depending on treatment), at approximately 3 months, and at approximately 12 months. Patients are requested to fill in quality of life questionnaires (on pain, Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms [VEINES-QOL/Sym], EuroQol-5 Dimension 5-Level [EQ-5D-5L]) at baseline and at approximately 3 months. Interventions are not stipulated by the trial protocol. Results The primary efficacy outcome is the incidence of venous thromboembolism at 3 months; the primary safety outcome is the combined incidence of major and clinically relevant bleeding events at 3 months. As quality measures, plausibility checks at data entry, queries based on statistical analyses that focus on outliers and distribution of values, monitoring visits, and adjudication procedures will be applied. Conclusions This large study is expected to provide a comprehensive picture of patients with SVT under clinical practice conditions in Germany.

Patients receiving direct-acting, non-vitamin K oral anticoagulants (NOAC) frequently undergo gastrointestinal endoscopies (GIE) but little is known on the management and outcome of these interventions. With use of data from an ongoing, prospective, noninterventional registry of NOAC patients, the management and outcome of GIE were evaluated with use of standard event definitions. Patients undergoing GIE were categorized into two subgroups: (1) scheduled GIE (scheduled appointment, no acute bleeding) and (2) unscheduled GIE (unscheduled including management of acute gastrointestinal bleeding). The rates of major bleeding complications, cardiovascular complications, and all-cause death within 30 days after the procedure were evaluated. Between October 1, 2011, and March 31, 2015, 492 patients underwent a total of 713 GIE (44.5% gastroscopies, 53.0% colonoscopies, 2.5% endoscopic retrograde cholangiopancreatography procedures), with 70.0% being scheduled procedures and 30.0% being unscheduled procedures. Endoscopies were performed within 24 h after the last NOAC intake in 45 of 713 cases (6.3%), between 24 and 48 h after the last intake in 336 cases (47.1%), and after NOAC therapy interruption for more than 48 h in 213 cases (29.9%). Heparin bridging therapy was used in 180 of 713 procedures (25.3%) and predominantly (170/180; 94.4%) in cases of NOAC therapy interruption for longer than 72 h. Until day 30 after the procedure, the event rates were 1.4% for cardiovascular events and 0.7% for major bleeding events. Continuation or short-term interruption of NOAC therapy seems to be a safe strategy for GIE. Heparin bridging therapy is predominantly used in cases of prolonged NOAC therapy interruption.

SummaryProspective trials have shown that rivaroxaban thromboprophylaxis is superior over low-molecular-weight heparin (LMWH) in patients undergoing hip and knee replacement surgery. However, patients treated under trial conditions are different from unselected routine patients, which may affect efficacy and safety of thromboprophylaxis. The objective was to evaluate the efficacy and safety of rivaroxaban or LMWH thromboprophylaxis in unselected patients undergoing hip and knee replacement surgery in daily care. In a monocentric, retrospective cohort study in 5,061 consecutive patients undergoing hip and knee replacement surgery a comparison of LMWH (hospital standard in 2006–2007) and rivaroxaban (since 2009) was made with regard to rates of symptomatic VTE, bleeding and surgical complications and length of hospital stay. Rates of symptomatic VTE were 4.1 % (LMWH) and 2.1 % (rivaroxaban; p=0.005) with rates for distal DVT 2.5 vs. 1.1 % (p

Non-vitamin K dependent oral anticoagulants (NOACs) significantly decrease overall major bleeding rates compared with vitamin K antagonists (VKAs) but there is conflicting evidence regarding the relative risk of gastrointestinal bleeding. Since data regarding the types, the management, and the outcome of NOAC-associated gastrointestinal bleeding are scarce, we aimed to fill this gap by comparing cases of gastrointestinal bleeding associated with NOAC, VKA, or antiplatelet therapy.All major gastrointestinal bleeding events documented in the prospective Dresden NOAC registry were identified, and bleeding location, lesion type, endoscopic treatment, use of blood and coagulation factor transfusion, length of stay, and in-hospital mortality were compared with historical data from a large cohort of consecutive gastrointestinal bleeding patients.In the 143 NOAC therapy cases, upper gastrointestinal tract bleeding was seen in 44.1%, lower gastrointestinal tract bleeding was seen in 42.0%, and no lesion could be identified in the remaining 14.0%. In contrast, upper gastrointestinal tract bleeding was commoner in the 185 VKA therapy cases (53.0%) and in the 711 antiplatelet therapy cases (68.1%). Among cases with upper gastrointestinal tract bleeding during VKA or antiplatelet therapy, 54.1% and 61.4% respectively presented with ulcers, compared with 27.0% for NOAC therapy. In contrast, hemorrhoid bleeding was the predominant lesion type for lower gastrointestinal tract bleeding with NOAC therapy, with a rate of 33.3%, compared with 10.6% with VKA therapy and 8.7% with antiplatelet therapy. NOAC-associated gastrointestinal bleeding resulted in comparatively low resource consumption, shorter hospitalization, and low in-hospital mortality (1.6%) compared with gastrointestinal bleeding historically seen with use of VKAs (in-hospital mortality 5.6%) or antiplatelet agents (in-hospital mortality 11.9%).Gastrointestinal bleeding in NOAC recipients is different from that seen with VKA or antiplatelet therapy and has a better short-term prognosis.

Background Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label. Objectives The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT. Methods In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings. Results Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed “true“ HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux. Conclusions Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238)

International audience; BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P

Background The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown. Objectives This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications. Methods The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated. Results Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79). Conclusions Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743)

SummaryRandomised controlled trials (RCTs) are considered the gold standard of clinical research as they use rigorous methodologies, detailed protocols, pre-specified statistical analyses and well-defined patient cohorts. However, RCTs do not take into account the complexity of real-world clinical decision-making. To tackle this, real-world data are being increasingly used to evaluate the long-term safety and effectiveness of a given therapy in routine clinical practice and in patients who may not be represented in RCTs, addressing key clinical questions that may remain. Real-world evidence plays a substantial role in supporting the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in clinical practice. By providing data on patient profiles and the use of anticoagulation therapies in routine clinical practice, real-world evidence expands the current awareness of NOACs, helping to ensure that clinicians are well-informed on their use to implement patient-tailored clinical decisions. There are various issues with current anticoagulation strategies, including under- or overtreatment and frequent monitoring with VKAs. Real-world studies have demonstrated that NOAC use is increasing (Dresden NOAC registry and Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF]), as well as reaffirming the safety and effectiveness of rivaroxaban previously observed in RCTs (XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation [XANTUS] and IMS Disease Analyzer). This article will describe the latest updates in real-world evidence across a variety of methodologies, such as non-interventional studies (NIS), registries and database analyses studies. It is anticipated that these studies will provide valuable clinical insights into the management of thromboembolism, and enhance the current knowledge on anticoagulant use and outcomes for patients.

Background: To determine predictors of clinical outcome after endovascular interventions of crural arteries in patients with peripheral arterial disease. Patients and methods: We prospectively followed 154 limbs in 147 patients treated with below the knee endovascular interventions for critical limb ischemia (52 %) and severe claudication (48 %). Patient-immanent, hemodynamic-procedural and anatomic determinants of outcome were analyzed. Outcome was defined as event-free survival from the combined endpoint freedom from re-intervention, major amputation and death. Results: Cumulative event-free survival after 12 months was 65.1 %. During follow-up 42 patients (27.3 %) required re-intervention, 8 (5.2 %) underwent major amputation and 5 (3.2 %) died. In univariate analyses, the presence of critical limb ischemia, multilevel disease, age > 72 years, impaired renal function, and long lesions (> 65 mm) were significant determinants of the study endpoint. The anatomic location of the lesion, distal patency of treated artery below the ankle, cardiovascular risk factors or concomitant cardiovascular diseases, and the type of postinterventional antithrombotic treatment did not influence outcome. Conclusions: Below-knee interventions resulted in acceptable procedural mid-term results and high rates of amputation free survival. Multilevel disease, long lesions and impaired renal function were indicative of a worse outcome.

SummaryRivaroxaban, the first direct factor-Xa inhibitor anticoagulant, has been approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for stroke prophylaxis in patients with non-valvular atrial fibrillation and for the treatment of deep vein thrombosis. There is no requirement for coagulation monitoring with rivaroxaban in routine clinical practice. However, in certain clinical circumstances such as life-threatening bleeding or an emergency operation the measurement of the thromboplastin time with a sensitive reagent will deliver first information. A quantitative determination of rivaroxaban plasma concentration is possible using an anti-factor Xa assay.In the case of a patient under long-term anticoagulation with rivaroxaban requiring an elective surgery, a discontinuation of rivaroxaban 20 to 30 hours before the operation is sufficient to normalize the associated bleeding risk, as long as the renal and liver function is normal. A longer interval should be taken into consideration, when the patient presents a renal and liver impairment or is of a higher age. In the event of an emergency operation effective rivaroxaban concentrations might be present. Nevertheless, we advise against using a prophylactic dose of factor concentrates. Recommendations: From a clinical perspective, in the event of a minor bleeding we recommend a temporary discontinuation of rivaroxaban, whereas for clinically relevant major or severe bleeding events a mechanical compression or a limited surgical i. e. interventional treatment is required. Supportive measures such as the administration of blood products or tranexamic acid might be beneficial. In addition to haemodynamic supportive measures life threatening bleeding events demand a comprehensive haemostasis management, as well as the application of PCC.

Summary. Background: The accuracy of screening ultrasound for venous thrombosis in asymptomatic patients is still a matter of debate. The VENUS study evaluated the accuracy of centrally adjudicated venous ultrasound against venography in patients after major orthopedic surgery and found the sensitivity of ultrasound to be poor for both proximal and distal deep vein thrombus (DVT). Objectives: To evaluate whether thrombus characteristics such as location or size influence the diagnostic performance of centrally adjudicated venous ultrasound. Methods: All false negative sonograms of the VENUS study were re-evaluated against the corresponding venograms. Discrepancies were categorized into types of diagnostic failures. Within these categories, thrombus characteristics such as location, length or size of thrombus were evaluated. Results: One hundred and twelve pairs of discrepant ultrasound and venography documents were compared with 28 pairs with concordant results. Discrepancies were caused by local documentation failure (37.5%), failure of the ultrasound method (43.7%) and failure of the central adjudication process (18.7%). The overall size of thrombi was small, which caused about 40% of all sonographic failures with a detection threshold of five Marder points, a thrombus length of 9.5 cm and a number of 3.5 pathological compression manoeuvres. Proximal or distal location of DVT did not affect thrombus detection. Conclusion: If centrally adjudicated ultrasound is to be used in future VTE screening trials, training of local sonographers and central adjudicators needs to be intensified, because asymptomatic DVTs seem to be small and ultrasound sensitivity depends on the number of pathological compression manoeuvres documented in the ultrasound document. In contrast, distal or proximal thrombus location itself does not influence sensitivity.

Currently, few topics in the field of anticoagulant therapy are as intensely discussed as the question: which is the best new oral anticoagulant? The most advanced substances in this field are the oral direct factor Xa-inhibitors rivaroxaban, apixaban and edoxaban and the oral direct thrombin inhibitor dabigatran. All of these substances are currently being tested in very similar phase III trials or are in the process of approval. In these trials, open-label or double-blind double-dummy designs are being used to evaluate the efficacy and safety in prevention and treatment of venous thromboembolism or stroke prevention in atrial fibrillation in several thousands of patients. As a consequence, an intense discussion of the advantages and disadvantages of open-label or double-blind trials is currently under way and interpretation of trial results is often focused on this matter. In general, a blinded trial is regarded as being less subject to bias than an open trial because it minimizes the impact of knowledge of treatment allocation on post-randomized treatment decisions and on reporting of outcomes. However, a blinded trial is not always feasible. Thus, in some respects, the two trial designs offer complementary strengths and weaknesses. This review addresses the risks of bias for internal and external validity of open-label and double-blind anticoagulation trials to help to objectify this debate.

Background: The optimal duration of anticoagulation following an incident provoked venous thromboembolism (VTE) remains unclear. Two randomized trials have shown extended duration rivaroxaban use in patients experiencing an unprovoked or provoked VTE can reduce patients' risk of recurrent thrombosis without a significant increased risk of major bleeding compared to placebo or aspirin. Objectives: We sought to evaluate the real-world effectiveness and safety of prolonged anticoagulation with rivaroxaban following an incident provoked VTE. Methods: Using claims data from the US Truven MarketScan databases from November 1, 2012 through March 31, 2017, we identified adult patients with a primary discharge diagnosis of VTE (deep vein thrombosis and/or pulmonary embolism) during a hospitalization or emergency department visit, who had a provoking (major or minor, persistent or transient) risk factor, at least 3-months of continuous rivaroxaban treatment and ≥12-months of continuous medical and prescription insurance benefits prior to their incident VTE. Patients were categorized as either continuing rivaroxaban or discontinuing anticoagulation (no anticoagulation or antiplatelet agents, with or without aspirin) after the initial 3-months of rivaroxaban treatment (index date). Differences in baseline covariates between cohorts were adjusted for using inverse probability-of-treatment weights (IPTW) based on propensity-scores (residual standardized differences Results: Among patients experiencing an incident provoked VTE and treated with rivaroxaban for the first 3-months (N=4,990), continued rivaroxaban use beyond 3-months [median (25%, 75% range) duration of additional rivaroxaban use = 3 (2, 5) months] was associated with a 44% lower hazard of recurrent VTE without significantly altering major bleeding risk when compared to anticoagulation discontinuation with or without aspirin use (Table). The highest risk of recurrent thrombosis following provoked VTE (3.1% in the discontinued anticoagulation cohort) appeared to occur in patients with a minor persisting risk factor; with continued rivaroxaban use associated with a significant 73% reduction in recurrent VTE. Conclusions: Although the absolute incidence of recurrence was low, our study suggests continuing rivaroxaban after the initial 3-month period was associated with a decreased risk of recurrent VTE, particularly in those with a minor persisting risk factor. The observed reduction in recurrent VTE with prolonged rivaroxaban use was not associated with a significantly increased risk of major bleeding. Disclosures Coleman: Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Honoraria, Research Funding. Turpie:Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Speakers Bureau. Beyer-Westendorf:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.

Purpose Frailty predicts poorer outcomes in patients receiving anticoagulation. We assessed the effectiveness and safety of rivaroxaban vs warfarin in frail patients experiencing venous thromboembolism. Methods Using US MarketScan claims data from January 2012-December 2016, we identified frail patients (using the Johns Hopkins Claims-Based Frailty Indicator score) who had ≥1 primary hospitalization/emergency department visit diagnosis codes for venous thromboembolism, received rivaroxaban or warfarin as their first outpatient oral anticoagulant within 30 days of the index event, and had ≥12 months of insurance prior to the index venous thromboembolism. Differences in baseline covariates between cohorts were adjusted using inverse probability of treatment weights based on propensity scores. The primary endpoint was the composite of recurrent venous thromboembolism or major bleeding. Patient claims were tracked for up to 12 months after the index venous thromboembolism or until endpoint occurrence oral anticoagulant discontinuation/switch, insurance disenrollment, or end of follow-up. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Results Of 58,089 incident venous thromboembolism patients identified, 6869 (1365 rivaroxaban and 5504 warfarin users) were classified as frail. Rivaroxaban reduced patients' hazard of the composite of recurrent venous thromboembolism or major bleeding (HR 0.75; 95% CI, 0.57-0.98) and recurrent venous thromboembolism alone (HR 0.65; 95% CI, 0.44-0.97) compared with warfarin. No significant difference in major bleeding was observed between cohorts (HR 0.88; 95% CI, 0.61-1.27). Conclusions Frail patients experiencing a venous thromboembolism and given rivaroxaban experience less recurrent venous thromboembolism, with at least as good bleeding outcomes, as patients prescribed warfarin.