Causes of death in patients with atrial fibrillation anticoagulated with rivaroxaban: a pooled analysis of XANTUS.

AIMS: Anticoagulation can prevent stroke and prolong lives in patients with atrial fibrillation (AF); However, anticoagulated patients with AF remain at risk of death. The aim of this study was to investigate the causes of death and factors associated with all-cause and cardiovascular death in the XANTUS population. METHODS AND RESULTS: Causes of death occurring within a year after rivaroxaban initiation in patients in the XANTUS program studies were adjudicated by a central adjudication committee and classified following international guidance.Baseline characteristics associated with all-cause or cardiovascular death were identified. Of 11,040 patients, 187 (1.7%) died. Almost half of these deaths were due to cardiovascular causes other than bleeding (n = 82, 43.9%), particularly heart failure (n = 38, 20.3%) and sudden or unwitnessed death (n = 24, 12.8%). Fatal stroke (n = 8, 4.3%), which was classified as a type of cardiovascular death, and fatal bleeding (n = 17, 9.1%) were less common causes of death. Independent factors associated with all-cause or cardiovascular death included age, AF type, body mass index, left ventricular ejection fraction, hospitalization at baseline, rivaroxaban dose, and anaemia. CONCLUSION: The overall risk of death due to stroke or bleeding was low in XANTUS. Anticoagulated patients with AF remain at risk of death due to heart failure and sudden death. Potential interventions to reduce cardiovascular deaths in anticoagulated patients with AF, require further investigation, e.g. early rhythm control therapy and AF ablation.

Cancer-Associated ThrOmboSIs - Patient-Reported OutcoMes With RivarOxaban (COSIMO) - Baseline characteristics and clinical outcomes.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolic events, which contribute to significant morbidity and mortality. Direct oral anticoagulants may provide a convenient treatment option for these patients. OBJECTIVES: To assess clinical characteristics and outcomes of patients with active cancer changing to rivaroxaban after ≥4 weeks of standard therapy for the treatment of venous thromboembolism (VTE) in clinical practice. This analysis focused on secondary outcomes of Cancer-associated thrOmboSIs - Patient-reported outcoMes with rivarOxaban (COSIMO). PATIENTS: COSIMO was a multinational, prospective, noninterventional, single-arm cohort study. Overall, 505 patients received at least one dose of rivaroxaban; 96.6% changing from low-molecular-weight heparin, 1.6% from a vitamin K antagonist, and 1.8% from fondaparinux. RESULTS: Most patients had solid tumors (n = 449; 88.9%) and approximately half of these patients had metastases. The qualifying venous thromboembolic event was deep vein thrombosis (DVT) in 45.3% of patients, pulmonary embolism (PE) in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients. Approximately 75.1% of patients received rivaroxaban for at least 3 months; 150 (29.7%) patients received concomitant chemotherapy during the study. VTE recurrence, major bleeding, nonmajor bleeding, and major adverse cardiovascular events occurred in 18 (3.6%), 18 (3.6%), 81 (16.0%), and 12 (2.4%) patients, respectively. CONCLUSIONS: In patients with CAT who changed to rivaroxaban treatment after ≥4 weeks of standard therapy, the observed incidence proportions of recurrent VTE and bleeding events were in keeping with the recognized effectiveness and safety profile of rivaroxaban for the treatment of CAT.

Investigation of Electromechanical Properties on 3-D Printed Piezoelectric Composite Scaffold Structures.

Piezoelectric composites with 3-3 connectivity gathered attraction due to their potential application as an acoustic transducer in medical imaging, non-destructive testing, etc. In this contribution, piezoelectric composites were fabricated with a material extrusion-based additive manufacturing process (MEX), also well-known under the names fused deposition modeling (FDM), fused filament fabrication (FFF) or fused deposition ceramics (FDC). Thermoplastic filaments were used to achieve open and offset printed piezoelectric scaffold structures. Both scaffold structures were printed, debinded and sintered successfully using commercial PZT and BaTiO3 powder. For the first time, it could be demonstrated, that using the MEX processing method, closed pore ferroelectric structure can be achieved without pore-former additive. After ceramic processing, the PZT scaffold structures were impregnated with epoxy resin to convert them into composites with 3-3 connectivity. A series of composites with varying ceramic content were achieved by changing the infill parameter during the 3D printing process systematically, and their electromechanical properties were investigated using the electromechanical aix PES device. Also, the Figure of merit (FOM) of these composites was calculated to assess the potential of this material as a candidate for transducer applications. A maximum for the FOM at 25 vol.% of PZT could be observed in this study.

Anticoagulation Treatment in Cancer-Associated Venous Thromboembolism: Assessment of Patient Preferences Using a Discrete Choice Experiment (COSIMO Study).

INTRODUCTION: Clinical guidelines recommend anticoagulation therapy for the treatment of cancer-associated venous thromboembolism (VTE), but little is known about preferences. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. METHODS: Adult patients with cancer-associated VTE who switched to direct oral anticoagulants were included in a single-arm study (COSIMO). Patients were asked to decide between hypothetical treatment options based on a combination of the following attributes: route of administration (injection/tablet), frequency of intake (once/twice daily), need for regular controls of the international normalized ratio (INR) at least every 3 to 4 weeks (yes/no), interactions with food/alcohol (yes/no), and distance to treating physician (1 vs. 20 km) as an additional neutral attribute. DCE data were collected by structured telephone interviews and analyzed based on a conditional logit regression. RESULTS: Overall, 163 patients (mean age 63.7 years, 49.1% female) were included. They strongly preferred oral administration compared with self-injections (importance of this attribute for overall treatment decisions: 73.8%), and a treatment without dietary restrictions (11.8%). Even if these attributes were less important (7.2% and 6.5%, respectively), patients indicated a preference for a shorter distance to the treating physician and once-daily dosing compared with twice-daily intake. "Need for regular controls of INR at least every 3 to 4 weeks" showed no significant impact on the treatment decision (0.7%). CONCLUSION: This study showed that treatment-related decision making in cancer-associated VTE, assuming comparable effectiveness and safety of anticoagulant treatments, is predominantly driven by "route of administration," with patients strongly preferring oral administration.

Impact of gender: Rivaroxaban for patients with atrial fibrillation in the XANTUS real-world prospective study.

BACKGROUND: The XANTUS study (NCT01606995) demonstrated low rates of stroke and major bleeding in patients with atrial fibrillation (AF) receiving rivaroxaban in clinical practice for the prevention of thromboembolic events (N = 6784). HYPOTHESIS: Because previous real-world studies have not reported gender-dependent responses to rivaroxaban treatment, this sub-analysis of the XANTUS study investigated the effect of gender on outcomes. METHODS: The centrally adjudicated outcomes were compared between genders. Primary outcomes were major bleeding and all-cause death. Secondary outcomes included symptomatic thromboembolic events. Multivariable Cox regression analysis was performed to assess the effect of risk factors on outcomes between genders. RESULTS: A total of 2765 female and 4016 male patients were included in the analysis. Baseline characteristics were generally similar. No nominally significant interaction between gender and risk factors for the study outcomes was observed. Rates of major bleeding, all-cause death and symptomatic thromboembolic events in patients with non-valvular AF receiving rivaroxaban for stroke prevention were similar in men and women; no significant differences in risk factors for these outcomes were observed between genders. CONCLUSIONS: Further research is needed to better characterize the relative importance of different risk factors on outcomes in men vs women and to determine whether gender differences exist in patients treated with non-vitamin K antagonist oral anticoagulants.

Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study.

AIMS: In Europe, the approved rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is 20 mg once daily (o.d.), with 15 mg o.d. recommended in patients with creatinine clearance (CrCl) 15-49 mL/min. Non-recommended doses are prescribed in real-world practice. This analysis of the XANTUS study assessed outcomes associated with non-recommended dosing and patient characteristics that may have impacted dose choice. METHODS AND RESULTS: Baseline characteristics and 1 year outcomes were compared in 4464/6784 patients with known CrCl, receiving recommended or non-recommended rivaroxaban doses; 3608 (80.8%) patients received recommended doses (mean CHADS2 score 1.9) and 856 (19.2%) non-recommended doses (mean CHADS2 score 2.5). Incidence rate (events/100 patient-years) for the composite of treatment-emergent adjudicated major bleeding, stroke/systemic embolism, and death was 7.5 [95% confidence interval (CI) 5.7-9.8] and 4.8 (95% CI 4.1-5.7) with non-recommended and recommended doses, respectively [hazard ratio (HR) 1.55, 95% CI 1.2-2.1; P = 0.004]. Incidence rates for the components of the composite were 3.7 and 2.6, 1.4 and 0.9, and 3.5 and 1.9, respectively. Adjustment for baseline characteristics showed similar rates of the composite outcome (HR 1.06, 95% CI 0.77-1.45; P = 0.719). Multivariable analysis identified age, anaemia, congestive heart failure, diabetes mellitus, CrCl, lower body weight, AF type, and vascular disease as predictors of non-recommended dosing. CONCLUSION: Non-recommended rivaroxaban dosing was associated with less favourable outcomes, possibly due to baseline characteristics, in addition to renal function, that may also affect physicians' dosing decisions. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01606995.

Real-world vs. randomized trial outcomes in similar populations of rivaroxaban-treated patients with non-valvular atrial fibrillation in ROCKET AF and XANTUS.

AIMS: Based on Phase III data, non-vitamin K antagonist oral anticoagulants are recommended for stroke prevention in patients with atrial fibrillation. To determine whether trial outcomes translate into similar event rates in unselected patients, this analysis compared outcomes from the real-world XANTUS study with those from the Phase III ROCKET AF study. METHODS AND RESULTS: Individual patient data from 4020 XANTUS patients were re-weighted to match the proportion of selected baseline characteristics in 7061 rivaroxaban-treated patients from ROCKET AF, using the matching-adjusted indirect comparison (MAIC) method. For the primary analysis, CHADS2 scores and gender were selected as relevant variables. Adjusted annualized incidence rates for XANTUS were calculated and compared with incidence rates from ROCKET AF-the ratio of these rates ('MAIC ratio') was used as a relative effect estimate. Rates of major bleeding [3.10%/year vs. 3.60%/year; MAIC ratio 0.86; 95% confidence interval (CI) 0.67-1.12] and stroke/non-central nervous system systemic embolism (1.54%/year vs. 1.70%/year; MAIC ratio 0.91; 95% CI 0.62-1.32) were similar between XANTUS and ROCKET AF. The rate of all-cause death was higher in XANTUS (3.22%/year vs. 1.87%/year; MAIC ratio 1.72; 95% CI 1.31-2.27), but the rates of vascular death were similar (1.83%/year vs. 1.53%/year; MAIC ratio 1.19; 95% CI 0.84-1.70). Sensitivity analyses weighted by different baseline characteristics supported these results. CONCLUSION: The low rates of major bleeding and stroke in XANTUS were consistent with results from ROCKET AF. All-cause death, but not vascular death, was higher in XANTUS, as expected in an unselected real-world population.

COSIMO - patients with active cancer changing to rivaroxaban for the treatment and prevention of recurrent venous thromboembolism: a non-interventional study.

BACKGROUND: Around 20% of venous thromboembolism (VTE) cases occur in patients with cancer. Current guidelines recommend low molecular weight heparin (LMWH) as the preferred anticoagulant for VTE treatment. However, some guidelines state that vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are acceptable alternatives for long-term therapy in some patients if LMWHs are not available. LMWHs and VKAs have a number of drawbacks that can increase the burden on patients. DOACs, such as rivaroxaban, can ameliorate some burdens and may offer an opportunity to increase patient satisfaction and health-related quality of life (HRQoL). The Cancer-associated thrOmboSIs - patient-reported outcoMes with rivarOxaban (COSIMO) study is designed to provide real-world information on treatment satisfaction in patients with active cancer who switch from LMWH or VKA to rivaroxaban for the treatment of acute VTE or to prevent recurrent VTE. METHODS: COSIMO is a prospective, non-interventional, single-arm cohort study that aims to recruit 500 patients in Europe, Canada and Australia. Adults with active cancer who are switching to rivaroxaban having received LMWH/VKA for the treatment and secondary prevention of recurrent VTE for at least the previous 4 weeks are eligible. Patients will be followed for 6 months. The primary outcome is treatment satisfaction assessed as change in the Anti-Clot Treatment Scale (ACTS) Burdens score at week 4 after enrolment compared with baseline. Secondary outcomes include treatment preferences, measured using a discrete choice experiment, change in ACTS Burdens score at months 3 and 6, and change in HRQoL (assessed using the Functional Assessment of Chronic Illness Therapy - Fatigue questionnaire). COSIMO will collect data on patients' medical history, patterns of anticoagulant use and incidence of bleeding and thromboembolic events. Study recruitment started in autumn 2016. CONCLUSIONS: COSIMO will provide information on outcomes associated with switching from LMWH or VKA therapy to rivaroxaban for the treatment or secondary prevention of cancer-associated thrombosis in a real-life setting. The key goal is to assess whether there is a change in patient-reported treatment satisfaction. In addition, COSIMO will facilitate the evaluation of the safety and effectiveness of rivaroxaban in preventing recurrent VTE in this patient population. TRIAL REGISTRATION: NCT02742623. Registered 19 April 2016.

Global Prospective Safety Analysis of Rivaroxaban.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. OBJECTIVES: This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. METHODS: A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. RESULTS: Overall, 11,121 patients were included (mean age 70.5 ± 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient-years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). CONCLUSIONS: This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban-treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788).

Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE.

Venous thromboembolism (VTE) is associated with numerous complications and high mortality rates. Patients with cancer are at high risk of developing cancer-associated thrombosis (CAT), and VTE recurrence is common. Evidence supporting use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in patients with cancer is lacking - direct comparisons between NOACs and low-molecular-weight heparin (LMWH) are needed, along with patient-reported outcomes. Cancer Associated thrombosis - expLoring soLutions for patients through Treatment and Prevention with RivarOxaban (CALLISTO) is an international research programme exploring the potential of the direct, oral factor Xa inhibitor rivaroxaban for the prevention and treatment of CAT, supplementing existing data from EINSTEIN DVT and EINSTEIN PE. Here, we focus on four CALLISTO studies: A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism Prophylaxis in Ambulatory Cancer Participants receiving Chemotherapy (CASSINI), Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D), Rivaroxaban in the Treatment of Venous Thromboembolism in Cancer Patients - a Randomized Phase III Study (CONKO-011) and a database analysis. Optimal anticoagulation duration for VTE treatment has always been unclear. Following favourable results for rivaroxaban 20 mg once-daily (Q. D.) for secondary VTE prevention (EINSTEIN EXT), EINSTEIN CHOICE is assessing rivaroxaban safety and (20 mg Q. D. or 10 mg Q. D.) vs acetylsalicylic acid (ASA), and will investigate whether an alternative rivaroxaban dose (10 mg Q. D.) could offer long-term VTE protection. It is anticipated that results from these studies will provide important answers and expand upon current evidence for rivaroxaban in VTE management.

Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation.

The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets regulators of the cell division cycle for degradation by the 26S proteasome. Discovered as a key regulator of mitosis, the APC/C has more recently been recognized to also play a limiting role in the control of G(0) maintenance, G(1)/S-transition and DNA-replication. Human cytomegalovirus (HCMV) has been shown to interfere with cell cycle regulation at different levels. It can induce an S phase-prone proliferation program in quiescent cells but at the same time this virus directly inhibits competitive cellular DNA replication. Here we show, that human cytomegalovirus (HCMV) inactivates the G(0)/G(1) APC/C rapidly after infection of quiescent fibroblasts, resulting in the untimely stabilization of APC/C substrates. APC/C inactivation is caused by the dissociation of its positive regulator, Cdh1. Surprisingly, this dissociation is independent from known Cdh1 inhibitors, Emi1 and Cyclin A, suggesting that APC/C-Cdh1 inhibition by HCMV is directly caused by a viral protein or an intermediate cellular factor distinct from Emi1 and Cyclin A. Thus, upon infection of quiescent cells HCMV not only activates the E2F-dependent G(1)/S transcription program but also facilitates protein accumulation of APC/C substrates by rapid Cdh1 dissociation.

Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells.

RGD peptides targeting alphav-integrins are promising ligands for the generation of vascular targeting agents. We isolated from phage display RGD motif libraries novel high-affinity cyclic RGD peptides by selection on either endothelial or melanoma cells. Although the starting sequences contained only two cysteine residues flanking the RGD motif, several of the isolated peptides possessed four cysteine residues. A high-affinity peptide (RGD10) constrained by only one disulfide bond was used to generate novel lipopeptides composed of a lipid anchor, a short flexible spacer and the peptide ligand conjugated to the spacer end. Incorporation of RGD10 lipopeptides into liposomes resulted in specific and efficient binding of the liposomes to integrin-expressing cells. In vivo experiments applying doxorubicin-loaded RGD10 liposomes in a C26 colon carcinoma mouse model demonstrated improved efficacy compared with free doxorubicin and untargeted liposomes.

Isolation from phage display libraries of lysine-deficient human epidermal growth factor variants for directional conjugation as targeting ligands.

Ligand-targeted anticancer therapeutics represent an opportunity for the selective and efficient delivery of drugs to tumours. The chemical coupling of ligands to drugs or drug carrier systems is, however, often hampered by the presence of multiple reactive groups within the ligand, for example, epsilon-NH(2) groups in lysine side chains. In this paper, we describe the isolation by phage display of human epidermal growth factor (EGF) variants without lysine and a reduced number of arginine residues. The selection on A431 carcinoma cells also revealed that R41 is indispensable for EGF binding activity as all EGF variants contained an arginine residue at this position. One EGF variant (EGFm1) with K28Q, R45S, K48S and R53S mutations was expressed in bacteria and showed an identical binding activity as wild-type EGF. EGFm1 could be labelled with fluorescein isothiocyanate demonstrating the accessibility of the N-terminal amino group for coupling reagents. Furthermore, coupling of EGFm1 to PEGylated liposomes resulted in target cell-specific binding and internalization of the liposomes. These human EGF variants should be advantageous for the generation of anticancer therapeutics targeting the EGF receptor, which is overexpressed by a wide variety of different tumours.