Oral Factor Xa Inhibitor Rivaroxaban Research Articles

Is There an Alternative Oral Anticoagulation to Vitamin-K-Antagonists for Patients with Mechanical Aortic Valve Replacement? - A Literature Review.

Current guidelines exclusively recommend vitamin-K-antagonists (VKA) as anticoagulation for patients after mechanical aortic valve replacement due to the increased postoperative risk of valve thrombosis and thrombo-embolism. Strict and regular assessments are mandatory during VKA therapy to ensure a potent anticoagulatory effect within the desired range. From the patients' perspective, VKA are associated with relevant interactions and side effects reducing the quality of life and contributing to a high number of patients not achieving the optimal therapeutic target. Direct oral anticoagulants (DOAC) have replaced VKA therapy in the past for several indications, e.g., atrial fibrillation. However, it is still unclear if DOACs could replace VKA therapy in patients after mechanical aortic valve replacement. While the PROACT-Xa study did not show a sufficient anticoagulatory effect of apixaban plus aspirin compared to VKA therapy in patients after mechanical aortic valve replacement, the direct thrombin inhibitor dabigatran and the oral factor Xa inhibitors apixaban and rivaroxaban showed promising results in comparable patient cohorts in smaller studies and case reports. Factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients after mechanical aortic valve replacement. Therefore, factor Xa inhibitors or factor XI inhibitors could provide a potent alternative to VKA for patients after a mechanical aortic valve replacement.

Recommendations for the use of andexanet alfa in the management of bleeding in patients on oral factor Xa inhibitors in Switzerland: Guideline from the Working Party Hemostasis of the Swiss Society of Hematology

Anticoagulants are essential in preventing and treating thrombosis. Unfortunately, their use is accompanied by an enhanced risk of bleeding. Since the introduction of direct oral anticoagulants (DOACs), the risk of major bleeding has been reduced but not eliminated. Major bleeding events related to the use of factor Xa inhibitors can be challenging to manage. In recent years, four-factor prothrombin complex concentrates have been used in patients with severe bleeding taking oral direct factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). Andexanet alfa (OndexxyaTM, AstraZeneca AG) is a specially designed recombinant version of human factor Xa that acts as a decoy receptor to reverse the effects of factor Xa inhibitors. Since 2 December 2020, andexanet alfa has been used in Switzerland for adult patients receiving apixaban or rivaroxaban when reversal of anticoagulation is required because of life-threatening or uncontrolled bleeding. However, the use of andexanet alfa remains a challenge owing to its cost, the reported thrombotic complications and the fact that its efficacy mainly relates to intracranial haemorrhage. Moreover, the use of nonspecific reversal agents together with andexanet alfa is controversial. The present recommendations on the use of andexanet alfa in the management of bleeding in patients on factor Xa inhibitors in Switzerland were developed by a group of Swiss experts from the Working Party Hemostasis of the Swiss Society of Hematology. These recommendations aim to provide support to clinicians in their decision-making in the management of patients with major bleeding receiving factor Xa inhibitors.

Real world prescribing practices of apixaban or rivaroxaban lead-in doses for the treatment of venous thromboembolism in hospitalized patients.

The oral factor Xa inhibitors (OFXAi) apixaban and rivaroxaban are increasingly utilized for the treatment of venous thromboembolism (VTE) with recommended initial higher dose 7- and 21-day lead-in regimens, respectively. In patients receiving initial parenteral anticoagulation, it remains unknown if the full recommended higher dose OFXAi lead-in regimens are warranted, or if days can be subtracted. We aimed to describe when clinicians may deviate from recommended lead-in durations and evaluate clinical outcomes in these scenarios. This is a retrospective, observational study of patients 18years or older who were treated with rivaroxaban or apixaban for acute pulmonary embolism (PE) or symptomatic proximal deep vein thrombosis (DVT) that received parenteral anticoagulation for at least 24h before transitioning to the OFXAi. Among our cohort of 171 patients with acute VTE who received parenteral anticoagulation for a median of 48h, 134 (78%) were prescribed a full OFXAi lead-in and 37 (22%) were prescribed a reduced lead-in. Patients in the reduced lead-in group were older with more cardiac comorbidities and antiplatelet use. There were four recurrent thromboembolic events within 3months, two in the reduced lead-in group and two in the full lead-in group (5% vs. 2%, p = 0.206). Bleeding within 3months occurred in 9 (5%) patients, with 6 events occurring in the reduced lead-in group and 3 events in the full lead-in group (16% vs. 2%, p = 0.004). Prescribing patterns of OFXAi lead-in therapy duration are variable in patients receiving initial parenteral anticoagulation. Larger cohorts are needed to better define the safety and efficacy of lead-in reduction.

Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Patients with a mechanical heart valve need a lifelong anticoagulation due to the increased risk of valve thrombosis and thrombo-embolism. Currently, vitamin K antagonists (VKA) are the only approved class of oral anticoagulants, but relevant interactions and side effects lead to a large number of patients not achieving the optimal therapeutic target international normalized ration (INR). Therefore, steady measurements of the INR are imperative to ensure potent anticoagulation within a distinctive range. Direct oral anticoagulants (DOACs) with newer agents could serve as a possible alternative to VKAs in this patient cohort. DOACs are approved for several indications, e.g., atrial fibrillation (AF). They only have a minor interaction potential, which is why monitoring is not needed. Thereby, DOACs improve the livability of patients in need of chronical anticoagulation compared with VKAs. In contrast to dual platelet inhibition using aspirin in combination with an ADP receptor antagonist and the direct thrombin inhibitor dabigatran, the oral factor Xa inhibitors apixaban and rivaroxaban show promising results according to current evidence. In small-scale studies, factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients with mechanical heart valves. Finally, DOACs seem to represent a feasible treatment option in patients with mechanical heart valves, but further studies are needed to evaluate clinical safety. In addition to the ongoing PROACT Xa trial with apixaban in patients after aortic On-X valve implantation, studies in an all-comer collective with rivaroxaban could be promising.

Cancer-associated thrombosis - treatment and prevention with direct oral factor Xa inhibitors.

Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in patients with cancer. Moreover, management of VTE is frequently connected with complications, namely risk of recurrent VTE and bleeding. Low molecular weight heparins (LMWH) therapy administrated for 3-6 months is currently considered a standard for the treatment of cancer-associated VTE (CA-VTE). Direct oral factor Xa inhibitors (FXaI) apixaban, edoxaban and rivaroxaban have emerged as a new possibility for long-term antithrombotic therapy for VTE. These agents expose several advantages in individuals with cancer, and might overcome several disadvantages connected with LMWH therapy. First clinical studies with oral FXaI for the treatment of CA-VTE with very promising results were recently published. The article summarizes current data regarding the use of oral FXaI in the treatment of CA-VTE.

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients Treated for Venous Thromboembolism

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without the need for routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (15 mg twice daily [BID] for 21 days followed by 20 mg once daily [OD] for up to 12 months) in the phase 3 EINSTEIN-DVT (NCT00440193) and EINSTEIN-PE (NCT00439777) trials (BID period, N = 4130; OD period, N = 3953). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the concentration-time curve, maximum concentration [Cmax] and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by application of an adjustment function based on a linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in phase 2/3 rivaroxaban studies. Composite efficacy outcomes were: (1) objectively-documented recurrent DVT, or fatal or non-fatal PE; and (2) recurrent DVT, fatal or non-fatal PE, or death from any cause. Safety outcomes were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding. Relationships between exposure/clinical risk factors and outcomes were evaluated using logistic regression for the 21-day BID dosing period and Cox regression for the subsequent OD dosing period.Results: Of the estimated exposure parameters, Ctrough displayed the strongest associations for efficacy and safety during both dosing periods. The first and second composite efficacy outcomes occurred in 1.0% and 1.1% of patients, respectively, in the BID period, and 1.0% and 1.6% of patients, respectively, in the OD period. Individual predicted Ctrough was significantly associated with the first efficacy outcome in both dosing periods (Table 1), and with recurrent DVT, fatal or non-fatal PE, or death from any cause in the BID period only (Figure 1, Table 1). Patients with reduced creatinine clearance (CrCL; < 50 mL/min) were more likely than patients with CrCL > 80 mL/min to develop one of the composite efficacy outcomes during the BID and OD dosing periods (Figure 1, Table 1). Active malignancy at randomization was significant for the second efficacy endpoint in the OD period (hazard ratio 5.31 [95% CI: 2.97-9.51]). Major bleeding and major and NMCR bleeding occurred in 0.4% and 4.3% of patients, respectively, in the BID period and in 0.6% and 6.0% of patients, respectively, in the OD period. None of the investigated exposure metrics was a significant predictor of major bleeding or major and NMCR bleeding in either dosing period. Clinical variables including a history of bleeding, low baseline hemoglobin and non-steroidal anti-inflammatory drug use were, however, significant predictors of bleeding events (Table 2). CrCL was not a significant predictor of bleeding events.Conclusions: Estimated rivaroxaban exposure was significantly associated with efficacy outcomes but not with bleeding outcomes in patients with DVT or PE enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Clinical risk factors had a substantial impact on outcomes. Based on these findings, it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban treatment in patients with venous thromboembolism. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Weitz:Daiichi-Sankyo: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Fox:AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AG: Employment; Bayer AB: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in the Prevention of Venous Thromboembolism after Elective Hip or Knee Replacement Surgery

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for venous thromboembolism prevention (VTE-P) after elective total hip replacement (THR) or total knee replacement (TKR) surgery to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (10 mg once daily [OD] for ≤35 days after THR or ≤14 days after TKR) in the phase 3 REgulation of Coagulation in ORthopedic Surgery to prevent DVT and PE (RECORD) trials (efficacy population, n = 4246; safety population, n = 6097). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the plasma concentration-time curve, maximum concentration and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by applying an adjustment function based on the linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in the phase 2/3 rivaroxaban studies. The composite efficacy outcome was total VTE (any objectively-documented asymptomatic or symptomatic deep vein thrombosis [proximal and/or distal], non-fatal pulmonary embolism and death). Safety endpoints were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding occurring (1) ≤3 days after surgery (days 1-4) and (2) >3 days after surgery (after day 4). The relationships between exposure/clinical risk factors and outcomes in terms of event rates were evaluated using logistic regression models.Results: The model-estimated rivaroxaban exposures are summarized in the Table. In the final model, age and creatinine clearance were included as forced variables for all endpoints. Exposure was not found to be a significant predictor of total VTE, major bleeding (days 1-4 and after day 4), or of the composite safety endpoint of major and NMCR bleeding during days 1-4. For major and NMCR bleeding after day 4, a statistically significant exposure-response relationship was observed, with Ctrough displaying the strongest association. The odds ratios (ORs) associated with Ctrough in the 5th and 95th percentiles versus the median were 0.82 (95% confidence interval [CI]: 0.77-0.87) and 1.68 (95% CI: 1.21-2.33), respectively. The relationship was shallow, with a predicted absolute increase in major and NMCR bleeding of ~1% at the 5th percentile of Ctrough to 2% at the 95th percentile (Figure). No clinical risk factors were predictors of total VTE or of major bleeding (days 1-4 and after day 4), or of major and NMCR bleeding after day 4. Male versus female sex (OR: 3.05; 95% CI: 1.92-4.93) and geographical region (OR: 1.63; 95% CI: 0.98-2.70, for the USA/Canada vs Western Europe) were significant predictors (p < 0.00001 and p <0.001, respectively) of major and NMCR bleeding during days 1-4.Conclusions: An exposure-response relationship for total VTE and major bleeding events was not observed in patients enrolled in the RECORD trials despite significant reductions in VTE with rivaroxaban versus the comparator enoxaparin, indicating a favorable benefit-risk ratio over the range of rivaroxaban concentrations observed with the 10 mg OD fixed dose. Exposure, and particularly Ctrough, was the predominant predictor of major and NMCR bleeding after day 4. These data are consistent with rivaroxaban phase 2 VTE-P studies, in which no significant dose-response relationship was observed for total VTE, but post-operative bleeding events increased dose dependently over the ranges of rivaroxaban doses of 5-40 mg OD and 2.5-30 mg twice daily. Based on these findings it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban for VTE prevention after THR and TKR. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Fox:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Weitz:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AB: Employment; Bayer AG: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

Survival and quality of life after early discharge in low-risk pulmonary embolism

Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

联合或者单独使用利伐沙班治疗青斑样血管病三例

Livedoid vasculopathy is a rare chronic ischemic necrotic skin disease caused by microvascular thrombosis in superficial vascular plexuses. Effective treatments are lacking. Efficacy of anticoagulants has been clinically proven in the treatment of this disease, but the administration route and adverse reactions limit their extensive application. The new oral factor Xa inhibitor rivaroxaban, which has many advantages, such as no need for coagulation monitoring, few adverse reactions and convenient oral administration, can be used in the prevention and treatment of thrombosis and post-thrombotic ulcers. In this article, 3 patients with livedoid vasculopathy were treated with rivaroxaban alone or in combination, and satisfactory efficacy was obtained. Key words: Skin diseases, vascular; Anticoagulants; Treatment outcome; Livedoid vasculopathy; Rivaroxaban

Direct Oral Anticoagulants: Novel Approach for the Treatment of Thrombosis in Pediatric Patients?

Venous thromboembolism (VTE) is a rare, but life-threatening disease in those who have not reached their adulthood. This condition is usually treated with heparin or low molecular weight heparins which require parenteral administration and, in case of unfractionated heparin, also frequent laboratory monitoring and dose adjustment. Direct oral anticoagulants (DOACs)-direct thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban-are currently frequently used for the prevention and treatment of VTE in adult population. In fact, these agents offer several advantages compared to traditional agents, such as oral route of administration, short on-set and off-set of action, predictable pharmacologic profile with low risk of food and drug interactions, and no need for routine laboratory assessment of anticoagulant activity. However, clinical experience with these directly acting oral anticoagulants in pediatric population is very limited as these drugs had been tested and are used mostly in adult individuals. This article reviews the current data from pre- and post-marketing studies reporting the use of DOACs for the treatment of VTE in pediatric patients.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

AbstractThe noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

Treatment Challenges in Venous Thromboembolism: An Appraisal of Rivaroxaban Studies.

Venous thromboembolism (VTE) presents a continuing clinical burden to healthcare systems and there are patient groups for whom VTE management is challenging. Depending on the patient profile, the optimal duration of anticoagulation for VTE treatment can be unclear. EINSTEIN CHOICE was a Phase III, randomized, double-blind trial that compared the safety and efficacy of two once-daily (od) doses of the direct, oral factor Xa inhibitor rivaroxaban (20 and 10 mg) with acetylsalicylic acid (ASA; 100 mg daily) for prevention of recurrent VTE. Extended therapy with rivaroxaban at either dose was more effective than ASA at preventing recurrent VTE without increasing bleeding risk. Another group that is challenging to treat in the context of VTE is patients with cancer-associated thrombosis. Cancer is associated with a hypercoagulable state, while cancer treatment itself may increase VTE risk. Evidence supporting the use of non-vitamin K antagonist oral anticoagulants in patients with cancer is growing through specifically designed studies. Cancer Associated thrombosis-expLoring soLutions for patIentS through Treatment and prevention with rivarOxaban (CALLISTO) is an international research program exploring the role of rivaroxaban for the prevention and treatment of cancer-associated thrombosis. Here, we present overviews of three CALLISTO studies: PRO-LAPS II, CASTA-DIVA and COSIMO. Currently available and anticipated results from studies in a variety of patients at risk of or with VTE will provide valuable insights and seek to optimize future VTE management.

Managing transitions from oral factor Xa inhibitors to unfractionated heparin infusions.

Published evidence regarding the effects of oral factor Xa inhibitors on anticoagulation monitoring tests is reviewed with a focus on monitoring concerns that can arise during transitions to i.v. heparin therapy. Assays that measure inhibition of factor Xa activity (i.e., anti-Xa assays) are widely used in U.S. institutions to monitor i.v. heparin therapy and, in some cases, for monitoring other types of anticoagulation therapy. Clinicians have raised concerns that the use of anti-Xa assays to monitor heparin levels in hospitalized patients who must be transitioned from oral factor Xa inhibitor therapy to i.v. unfractionated heparin (UFH) infusions could yield unquantifiable or inaccurate results, leading to unnecessary UFH dose reductions and potential treatment failures; the manufacturer labeling of oral factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) does not provide specific guidance on this issue. Results of a literature review indicated that residual effects of oral factor Xa inhibitor use can result in substantial interference with the currently available chromogenic anti-Xa assays but negligible to moderate effects on global coagulation assays, which measure activated partial thromboplastin time (aPTT) or prothrombin time. Therefore, during the transition from an oral factor Xa inhibitor to i.v. UFH therapy, it may be prudent to consider an aPTT assay for anticoagulation monitoring. The use of oral factor Xa inhibitors appears to affect the accuracy of anti-Xa assay results, with results of global coagulation assays affected to a lesser degree.

Novel Approach to Management of Localised Intravascular Coagulopathy in Extensive Low Flow Venous Malformations Using Rivaroxaban

Introduction: Extensive low flow venous malformations, such as Klippel Trenaunay Syndrome (KTS), are rare conditions. Abnormal blood flow in these structures leads to activation of coagulation, sometimes referred to as localised intravascular coagulopathy (LIC). This results in spontaneous, sometimes painful, thrombus formation and fibrinolysis as indicated by raised D-dimer levels.In some cases the LIC can be so severe that it leads to a consumptive coagulopathy with bleeding complications. It is important to assess for this, particularly as many of these patients undergo corrective surgeries. It has been noted that low fibrinogen and, more recently, low FXIII levels correlate with severity of LIC and bleeding risk in these cases while other coagulation factors and platelet counts seem to be unaffected.There is very little published evidence to help with antithrombotic and haemostatic management of these rare and complex patients. Anticoagulation with low-molecular-weight heparin (LMWH) has been used to reduce LIC and consumptive coagulopathy on a case-by-case basis to either manage thrombotic events or reduce bleeding risk. The main issues with long term use of LMWH are that it can result in reduction of bone density and impact on quality of life due to requirement for daily administration of subcutaneous injections. An oral agent would be preferable but vitamin K antagonists, such as warfarin, have been found to be not as effective. Direct oral anticoagulants (DOACs) are being increasingly used as an alternative anticoagulant in more common conditions, such as atrial fibrillation and venous thromboembolism. These could be a potential alternative in this rare group of patients.Aims: We present the use of direct oral factor Xa inhibitor rivaroxaban (off-label) as a novel treatment option for LIC and consumptive coagulopathy in three patients with extensive low flow venous malformations. Serial measurements of D-dimer, fibrinogen and factor XIII levels were used as surrogate markers for the severity of LIC.Methods: Patients managed with rivaroxaban at our tertiary centre were identified retrospectively by the lead consultant. All had a diagnosis of extensive venous malformation with laboratory features of LIC, defined by at least one of the following parameters: high D-dimer levels, low fibrinogen (Clauss), low FXIII levels with the latter only being monitored for the last two years since its clinical significance was realised. Case notes and laboratory results were reviewed.Results: Three patients fulfilled the inclusion criteria (Table 1). Mean age was 29 years. Two cases had KTS, the third had an extensive low flow venous malformation on the back. All cases received prior LMWH. Rivaroxaban (10-20mg once daily) was administered for between 6 weeks and 23 months.In all patients there was an improvement in laboratory parameters (Table 1). D-dimer levels were reduced by 66, 97 and 69% (Cases 1 - 3 respectively). A low fibrinogen increased by 1.1, 0.5 and 0.6 g/L on rivaroxaban (Cases 1 - 3 respectively), with all patients maintaining a level above 1 g/L. Results for FXIII were only available for Case 3: the level more than doubled on rivaroxaban treatment.All patients had a normal platelet count.In addition good clinical response was observed in the two patients with painful phleboliths and venous thromboembolism.No adverse effects were seen in this small cohort.Conclusions: This is the first case series reporting the successful use of rivaroxaban in extensive low flow venous malformations for the management of LIC and consumptive coagulopathy. Our findings suggest that this novel approach can provide good control of laboratory parameters and clinical symptoms and is more convenient for patients. The optimal dose and duration of therapy remains to be defined. In light of these findings other DOACs may also have a role in the treatment of these conditions. [Display omitted] DisclosuresMathias:Bayer: Speakers Bureau. Drebes:Bayer: Consultancy; Bayer: Other: Educational Grant.

PO-36 - Thrombin Inhibition Preoperatively (TIP) in early breast cancer, the first clinical trial of NOACs as an anti-cancer agent: trial methodology

Breast cancer is associated with a 3-4 fold increased risk of VTE. These patients have a 4-fold lower survival than those remaining free of VTE, implying VTE is a surrogate marker for aggressive cancer. Tumour expression of thrombin pathway markers are increased in the oestrogen receptor negative (ER-), high Ki67, more aggressive breast cancer subtypes. In in vitro and in vivo studies, the thrombin pathway promotes cancer growth and metastases, highlighting the potential role of the thrombin pathway as a therapeutic target in cancer. To determine whether 14days of a preoperative oral Factor Xa inhibitor (Rivaroxaban) in oestrogen receptor negative early breast cancer patients results in inhibition of tumour proliferation as determined by a reduction in tumour Ki67 from baseline (pre-treatment) to 14days post treatment start (at time of surgical excision). The TF-VIIa-FXa complex activates Protease Activated Receptor (PAR)2 to induce angiogensis, growth factors and tumour cell migration. Thrombin, in part via PAR1, induces angiogenesis, tumour cell proliferation as well as in vivo metastasis. In early breast cancer, TF and PAR2 expression is increased in the stroma, particularly in the more aggressive ER-, high Ki67 (proliferation) cancers. Rivaroxaban is an orally active direct Factor Xa inhibitor. Through inhibition of the TF-FVIIa-FXa complex, it can downregulate TF-FVIIa-FXa activation of PAR2, and inhibit conversion of prothrombin to thrombin. We hypothesise that 14days of Rivaroxaban will reduce breast cancer proliferation, as a surrogate marker for anti-cancer efficacy, in early breast cancer patients awaiting resectional surgery. Trial methodology: A multi-centre phase II preoperative 'Window-of Opportunity' randomised controlled trial of Rivaroxaban compared to no treatment in ER-, stage I-III early breast cancer patients. Patients will be randomised 1:1:1 (Rivaroxaban 20mg od: Rivaroxaban 10mg od: no treatment) and receive 14 (+/-3) days of treatment in the window between diagnosis and surgery. Randomisation will be blinded to pathologists, but not to patients or clinicians. Primary analysis will be based on the two Rivaroxaban arms being combined to form a Rivaroxaban: no treatment, 2:1 trial design, with change in Ki67 from baseline (pre) to post Rivaroxaban/no treatment (post) being the primary endpoint, and the no treatment arm acting as a reference group. Subgroup analysis of the Rivaroxaban arm (20mg od:10mg od) will allow assessment of dose-response. Funder: National Institute for Health Research Eudract No: 2014-004909-33 REC Number: 15/NW/0406 UKCRN ID: 19731 Expected commencement: January 2016. For further information please contact Chief Investigator: cliona.kirwan@manchester.ac.uk.

Spotlight on real-world evidence for the treatment of DVT: XALIA.

Venous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

Exploring unmet needs in venous and arterial thromboembolism with rivaroxaban.

The vast clinical research programme for the direct, oral factor Xa inhibitor rivaroxaban has generated a wealth of data since the first rivaroxaban approval in 2008 for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery. While rivaroxaban is widely used across a spectrum of seven indications, there is continuous commitment to investigating its wider benefits in new indications and attempts to refine current evidence. Key data from recently completed randomised controlled trials (RCTs) have shown that rivaroxaban is a feasible anticoagulation option for patients with non-valvular atrial fibrillation (NVAF) undergoing cardioversion or catheter ablation. Now, a number of Phase II and III RCTs are underway that seek to uncover further roles for rivaroxaban in patients at risk of thrombosis and aim to improve quality of life. This article will introduce and provide context for these RCTs in the contemporary management of arterial and venous thromboembolism in the following underserved areas: Patients with both NVAF and acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI); patients with embolic stroke of undetermined source (ESUS); patients who require transcatheter aortic valve replacement (TAVR); patients with acute or chronic coronary artery disease (CAD; including those with heart failure [HF]); those at risk of or suffering from cancer-associated thrombosis (CAT) and those requiring long-term anticoagulation. It is hoped that this collection of studies provides clarity around the use of rivaroxaban as a fundamental component of antithrombotic therapy in an array of clinical situations.

Erratum to Barco et al. "Home treatment of patients with lowrisk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the Hot-PE Trial" (Thromb Haemost 2016; 116: 191-197).

[This corrects the article DOI: 10.1160/TH16-01-0004.].

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.

Controversy Surrounding ROCKET-AF: A Call for Transparency, But Should We Be Changing Practice?

Controversy Surrounding ROCKET-AF: A Call for Transparency, But Should We Be Changing Practice?