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Introduction Non-vitamin-K oral anticoagulants (NOACs) were recommended in preference to oral vitamin K antagonists (VKAs) in the 2020 updated guidelines for stroke prevention in atrial fibrillation (AF), from the European Society of Cardiology (ESC). Rivaroxaban is a NOAC that is approved in many countries worldwide for reducing the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Purpose To explore the baseline characteristics, dosing and 2-year outcomes of patients with AF treated with rivaroxaban. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international, multicenter registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Results A total of 5043 patients were enrolled into RIVER between January 2015 and June 2017. Mean (SD) age at diagnosis was 69.5 (11.0) years and 55.7% were males. Caucasian patients represented the largest proportion of patients in RIVER (80.3%), followed by Asians (5.5%) and hispanic/latino (3.7%). Almost all patients (98.5%) were prescribed a single daily dose of rivaroxaban, most commonly 20 mg (77.3%) and 15 mg (20.4%), while a 10 mg dose was prescribed in only 2.3% of patients. During the 2-year follow-up, the rates (95% CI) of all-cause mortality, stroke/SE, and major bleeding were 2.75 (2.43 to 3.12), 0.89 (0.72; 1.11), and 1.26 (1.05 to 1.52) per 100 person years, respectively (Figure 1). The most common cardiovascular cause of death was congestive heart failure (30.4%) and myocardial infarction (11.4%). Leading non-cardiovascular causes of death were malignancy (27.4%), respiratory failure (18.9%) and infections/sepsis (13.2%). Over 2 years, 710 (14.1%) of patients discontinued rivaroxaban. The corresponding proportions at 6 months and 1 year were 7.8% and 10.8%, respectively. Out of all the patients who discontinued, 62 (8.7%) restarted rivaroxaban during their follow-up (Table 1). Conclusion During 2 years of follow up in the international, prospective RIVER registry, rivaroxaban treatment for AF was associated with low rates of stroke or major bleeding. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Introduction Rivaroxaban is recommended as an option for anticoagulation in patients with nonvalvular atrial fibrillation (AF) with one or more risk factors for stroke. The approved/recommended rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is solely based on renal function: 20 mg once daily (od) for patients with a creatinine clearance [CrCl] ≥50 ml/min and 15 mg od in patients with CrCl 15–49 mL/min). Purpose To assess the patterns of rivaroxaban prescription as per the creatinine clearances levels and to assess the impact of the rivaroxaban dosing on the rate of events at 2-year follow-up in patients with AF. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard model. Results Among 3402 patients with normal renal function (CrCl ≥50 mL/min), 82.1% were prescribed the recommended rivaroxaban dose of 20 mg (od) at baseline. Among 524 patients with moderate or severe renal impairment (CrCl 15–50 mL/min), 55.3% patients received rivaroxaban 15 mg (od), 39.9% received 20 mg (od) and 4.2% 10 mg (od). Non-recommended dosing was rare in patients younger than 70 (13.5%) but more frequent in older patients (28.8%). Non-recommended low dosing was more frequent in Asians (38.9%), compared to non-Asian patients (13.8%). Regarding clinical outcomes, adjusted hazards ratios (HR, presented with 95% confidence intervals) showed that the non-recommended low dosing (15 mg od) was associated with lower risk of all-cause mortality (HR 0.63 (0.42–0.93)) and cardiovascular mortality (HR 0.32 (0.13–0.77)) and higher risk of major bleeding (HR 2.86 (1.49–5.50)) in patients with moderate to severe renal impairment (figure 1 and 2). Conclusion In patients with normal renal function, non-recommended low dose rivaroxaban was associated with increased cardiovascular mortality without reducing the risk of major bleeding compared to recommended dosing. In patients with CrCl Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the RIVER registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Venous thromboembolism (VTE) is a common, potentially preventable cause of morbidity and mortality among acute medically ill patients. More than half of VTE events in this population occur after hospital discharge. Thus, providing extended-duration VTE prophylaxis from in-hospital through the post-discharge continuum may improve the quality of care in patients at risk of VTE. Betrixaban is a new oral, once-daily factor Xa inhibitor approved by the United States (US) Food and Drug Administration (FDA) for extended-duration prophylaxis of VTE in acute medically ill patients. The clinical efficacy and safety of betrixaban in acute medically ill patients perceived to be at high risk for VTE were evaluated in a large, randomized, double-blind, active-controlled, multinational clinical trial [Acute Medically Ill VTE Prevention With Extended Duration Betrixaban (APEX)]. Patients were randomized to receive subcutaneous enoxaparin (10 ± 4 days) or oral betrixaban (35–42 days) plus matching placebos. The primary efficacy outcome was a composite of asymptomatic proximal deep vein thrombosis and symptomatic VTE; the primary safety measure was major bleeding. Extended-duration betrixaban reduced VTE events without an increase in major bleeding in the modified intent-to-treat analysis. Post hoc analyses of the APEX trial provided further evidence to support the efficacy and safety of betrixaban in reducing all-cause ischaemic stroke, fatal or irreversible ischaemic or bleeding events, as well as reducing VTE-related rehospitalization. In summary, analyses of the APEX study demonstrated a positive benefit–risk profile for extended prophylaxis of VTE with betrixaban in acute medically ill patients. This is likely to have important public health and health economic implications.

Background/Introduction Andexanet alfa (“andexanet”) was developed as a specific reversal agent for patients with major bleeding while using factor Xa (FXa) inhibitors. While thrombotic events (TEs) have been reported in patients receiving andexanet, the scope, nature, and timing of these events have not been fully characterized. Purpose The ANNEXA-4 study was a prospective, single-arm, open-label clinical trial that evaluated the safety and efficacy of andexanet in patients with acute major bleeding. In this secondary analysis, the occurrence of TEs was investigated. Methods Patients presenting with acute major bleeding within 18 hours after their last dose of FXa inhibitor were treated with andexanet. Safety outcomes, including TEs (reviewed by an adjudication committee), were evaluated at 30 days. Results Among 352 patients treated with andexanet, 34 (9.7%) experienced one or more TEs (Table). Strokes and deep vein thromboses were the most frequent TE types. Compared to patients with arterial TEs, patients with venous TEs were more likely to have been originally anticoagulated for venous thromboembolism. Median time to first TE was 10.5 days (Figure); time to event was shorter for arterial TEs than for venous TEs. TEs were nonfatal for most patients. Subgroups by age, bleed type, baseline anti-fXa activity, FXa inhibitor dose, and andexanet dose were not associated with the occurrence of TEs. Of the 34 TE patients, 26 (76.4%) had TEs before restart of any (full or prophylactic) anticoagulation; all first TEs occurred in patients not receiving oral anticoagulation. No TEs occurred after resumption of oral anticoagulation (N=100). Table 1. Thrombotic event characteristics Characteristic Result (n/N [%]) TE type Strokes 14/352 (4.0%) Deep vein thromboses 13/352 (3.7%) Myocardial infarctions 7/352 (2.0%) Pulmonary embolisms 5/352 (1.4%) Transient ischemic attacks 1/352 (0.3%) Bleed type Intracranial 23/227 (10.1%) Gastrointestinal 7/90 (7.8%) Other 4/35 (11.4%) Arterial TEs Anticoagulated for AF 17/22 (77.3%) Anticoagulated for VTE 6/22 (27.3%) Venous TEs Anticoagulated for AF 11/18 (61.1%) Anticoagulated for VTE 8/18 (44.4%) Median time to first TE 10.5 days Arterial 6 days Venous 15 days Outcome Fatal 7/34 (20.6%) Nonfatal 27/34 (79.4%) AF = atrial fibrillation; n = number of patients with TEs; N = total number of patients for each characteristic; TE = thrombotic event; VTE = venous thromboembolism. Figure 1. Thrombotic Events Over Time Conclusions In patients with FXa inhibitor-associated acute major bleeding treated with andexanet, TEs occurred a rate not unexpected given the high thrombotic risk of the population. No factors predictive of TEs were identified. Resumption of anticoagulation was associated with fewer TEs. Acknowledgement/Funding Study funded by Portola Pharmaceuticals, Inc.

Background Anticoagulation is essential to prevent recurrent venous thromboembolism (VTE) during pregnancy in women with a history of preconception VTE. However, information on the safety of anticoagulant drugs in this setting is limited. Purpose To investigate the risk of maternal and foetal adverse outcomes associated with anticoagulant exposure during pregnancy. Methods Nationwide cohort of all pregnant women in Denmark with preconception VTE, 2000–2017. We linked individual-level data from nationwide registries on anticoagulant exposure, maternal and foetal outcomes. Results Among 5,099 pregnancies in 3,246 women with preconception VTE (mean age 31 years, 41% nulliparous), 36.4% were exposed to anticoagulants during first trimester (66.4% low-molecular-weight heparin (LMWH), 31.9% VKA, and 1.8% NOAC (Table). No maternal deaths occurred. Maternal outcomes were comparable among LMWH and unexposed women, whereas recurrent VTE and foetal loss was more prevalent in VKA and NOAC exposed women. Foetal risk was lowest in unexposed and LMWH exposed, whereas preterm birth was prevalent in VKA and NOAC exposed. Table 1. Maternal and foetal outcomes in pregnant women with preconception VTE according to first trimester anticoagulant exposure Maternal outcomes No anticoagulants LMWH VKA NOAC Total pregnancies/singleton foetuses, N 3,244/2,722 1231/1,124 591/442 33 /26 Recurrent VTE, % (N) 2.7 (89) 3.3 (41) 6.4 (38) – ( Conclusion Our findings are reassuring and in support of the recommendation of LMWH for pregnant women with prior VTE. Few women were exposed to NOAC during pregnancy, and the safety of NOACs cannot be substantiated with the current level of evidence. Acknowledgement/Funding The Obel Family Foundation partly funded this research by an unrestricted grant.

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.

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.

We appreciate the comments of Stollberger et al .1 regarding our publication on the persistence with rivaroxaban therapy in the Dresden NOAC registry.2 A number of issues were addressed in their letter, some of which are directly related to our publication while others are more related to an overall concern regarding the safety of non-VKA oral anticoagulants (NOACs) such as rivaroxaban. Unfortunately, word count restrictions do not allow discussing the latter issues in detail here, especially since some of these issues were discussed with Stollberger et al. previously.3,4 More or less directly related to our manuscript are the following questions: ‘ How did the authors ascertain that the patients were indeed taking the drug? Whereas adherence to VKA is easily monitored by measuring the international normalized ratio (INR), a readily available test for rivaroxaban effect is not available. Were serum concentrations of rivaroxaban obtained among the participants of the registry? ’ First of all, Stollberger et al. need to understand that our publication related to persistence (=the …

Background: Anticoagulant therapy is often discontinued for surgical procedures. Novel oral anticoagulants (NOAC) have short half-lives and rapid onset of action, which allows for very short interruptions. However, little is known about the management and outcome of peri-interventional strategies in NOAC patients from daily care. Patients and methods: In the prospective, non-interventional Dresden NOAC registry a network of more than 230 physicians enrol eligible patients. Up to 2000 patients receive prospective follow up by phone visits by the registry office. All events are centrally adjudicated using standard definitions. Performed interventions were classified: minimal (superficial skin, mucosal, non-extraction dental), minor (percutaneous, endoscopic, dental extraction, arthroscopy or similar) and major (abdominal, thoracic, brain, pelvic, major orthopaedic and trauma surgery). Results: Until December 31th 2012, 1665 patients were registered. During follow-up (635.4 patient years) a total of 348 patients (20.7%) reported 450 interventions (table 1). 93 patients (20.7%) did not interrupt NOAC. 226 patient interrupted NOAC without heparin bridging (50.2%) and 129 received heparin bridging therapy (28.7%). Within 30 days after procedure, 5 patients experienced cardiovascular events (2 strokes, 1 TIA, 2 VTE) and 28 patients experienced bleeding complications (table 1). View this table: Table 1. Type of intervention and outcome at day 30 Conclusion: Similar to VKA patients receiving bridging therapy, bleeding complications are more common than cardiovascular events. However, rates of complications are very low, indicating that peri-interventional short-term interruption of NOAC is effective and safe. Updated results of this ongoing project will be provided at ESC. ([NCT01588119][1]) [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01588119&atom=%2Fehj%2F34%2Fsuppl_1%2FP5444.atom

Background: In the RELY trial, the novel oral anticoagulant (NOAC) dabigatran has been found to be at least as effective and safe as warfarin for stroke prevention in atrial fibrillation (SPAF). As a consequence, dabigatran has become approved in many countries. However, patients in RCT's present a selected population which is treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of dabigatran need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of dabigatran anticoagulation in AF in daily care. Patients and methods: In the prospective, non-interventional Dresden NOAC registry a network of more than 230 physicians enrol eligible patients. Up to 2000 patients receive prospective follow up by phone visits by the registry office. All events are centrally adjudicated using standard definitions. Results: Until December 31th 2012, 1665 patients were registered. Of these, 303 patients received dabigatran for SPAF (50.5% male, mean age 74.5 years, mean CHADS-Score 2.6; 61.4% newly anticoagulated). Treatment adherence was acceptable with 73.6% of patients still taking dabigatran at 9 month. 18.4% of patients were switched to other anticoagulants (side effects, incompliance, costs). In total, 9 major cardiovascular events were observed (5.8 per 100 patient years; 4 TIA, 1 stroke, 2 ACS, 1 limb ischemia, see table 1). Furthermore, 84 bleeding events occurred, of which only 5 events were major bleedings (3.2 per 100 patient years). No fatal bleeding was observed. 2 patients died (1.3 per 100 patient years), both of sudden cardiac death. View this table: Table 1. Real-life efficacy and safety of dabigatran in SPAF Conclusion: In unselected patients in daily care, dabigatran is effective and safe with low rates of cardiovascular or major bleeding events. However, about 25% of patients are switched to other anticoagulants within 9 months. Data on bleeding pattern and management will be presented.