Rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study.

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non-SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36.

Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society.

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control.

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (ß = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

Venous thromboembolism and cancer: Current and future role of direct-acting oral anticoagulants.

Approximately one-fifth of all cases of venous thromboembolism (VTE) are related to cancer and anticoagulant treatment in these patients has remained a challenge. Cancer patients with VTE are at increased risk of developing recurrent VTE compared to patients without cancer, but also have a higher risk of major bleeding. In these patients, low molecular weight heparins (LMWHs) have been shown to be more effective and as safe as vitamin K-antagonists (VKAs) for the treatment of VTE. Therefore, the majority of current clinical guidelines recommend LMWHs as the treatment of choice for cancer-associated VTE. However, several issues should be considered regarding the use of LMWHs as daily subcutaneous injections, the costs or risk of heparin-induced thrombocytopenia. In recent years, direct-acting oral anticoagulants (DOACs) have shown similar efficacy and better safety profile compared to VKAs and have become the standard of care for the treatment of VTE in the general population. Because DOACs offer a simple oral treatment regimen without the need for anticoagulation control, they could be an attractive alternative to LMWH. Before DOACs become an accepted treatment option for cancer associated VTE, they have to be evaluated in a head-to-head comparison with LMWH. Data from two randomized trials comparing DOACs vs. LMWH have recently been published. In the present review, we will provide three clinically relevant questions on the use of DOACs in patients with cancer and VTE and provide an overview on recent evidence on this topic: 1) are DOACs a treatment option for the prevention of VTE in cancer patients?; 2) what is the place for DOACs in patients with cancer-associated VTE?; 3) should I use DOACs for the extended treatment of cancer-related VTE?.

Multidisciplinary approach to the management of patients with pulmonary embolism and deep vein thrombosis: a consensus on diagnosis, traditional therapy and therapy with rivaroxaban.

Despite the availability of updated guidelines for the diagnosis and treatment of venous thromboembolism (VTE), the management of this disorder in clinical practice is often not standardized, given the different degree of compliance with official recommendations by the various involved specialists. The aim of this consensus paper, as a result of a board of experts in thromboembolism, is to define strategies to improve the quality of patients' care and the efficiency of healthcare resources utilization, by means of: (a) analysis of the guidelines for diagnosis and treatment of VTE; (b) analysis of diagnostic and therapeutic algorithms currently used in clinical practice by different specialists; (c) agreement on a common algorithm for diagnosis and treatment of VTE in different clinical settings; (d) definition of the possible role of the new oral anticoagulant agents (NOAC), such as rivaroxaban, based on their potential benefits for both acute and chronic therapy. The so-called "single drug approach" (as opposed to the traditional heparin/VKA combination), which can be adopted with these drugs, makes anticoagulation more convenient for both patients and healthcare providers, without the need for a close monitoring of the hemocoagulative status, and with a concomitant reduction of length of hospitalization and treatment costs. Among NOACs, in this paper we focused on rivaroxaban only because it was the unique available NOAC in Italy for the treatment of VTE at the time the manuscript was written. Concerning rivaroxaban, the results of two phase III, randomized and controlled trials confirm the non-inferiority of this drug compared to standard therapy (enoxaparin/warfarin) for the treatment of patients with pulmonary embolism (EINSTEIN PE Study) or deep vein thrombosis (EINSTEIN DVT Study) in terms of both efficacy and safety, supporting its use as an effective therapeutic option for these disorders.

Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study.

BACKGROUND: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. METHODS AND RESULTS: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA2DS2-VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. CONCLUSIONS: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Vitamin K and non-vitamin K antagonist oral anticoagulants for non-valvular atrial fibrillation in real-life.

BACKGROUND: Current guidelines recommend vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with non-valvular atrial fibrillation (AF). METHODS: We compared the clinical features of consecutive in- and out-patients with non-valvular AF newly-treated with NOACs or on treatment with VKAs. RESULTS: Overall, 1314 patients newly-treated with NOACs and 1024 on treatment with VKAs were included in the study. The mean CHA2DS2-VASc score was 4.3±1.5 and 4.0±1.5 and the mean HAS-BLED score was 2.8±1.2 and 2.2±1.1 in the two groups, respectively (both p<0.001). Hypertension, previous stroke, female gender, vascular diseases and previous bleeding were more prevalent in NOACs patients. Renal failure, age ≥75years and congestive heart failure were more prevalent in VKAs patients. Among NOACs patients, 438 were given dabigatran, 463 rivaroxaban and 413 apixaban (33%, 35% and 31%, respectively). The mean CHA2DS2-VASc and HAS-BLED scores were higher in rivaroxaban or apixaban patients compared with dabigatran (both p<0.001) and VKAs patients (both p<0.001). A lower mean age was observed in patients newly-treated with dabigatran. Patients newly-treated with reduced doses of NOACs (599 patients, 45.5%) had a higher CHA2DS2-VASc (4.8±1.4 vs. 3.9±1.5 vs. 4.0±1.5) and HAS-BLED (2.9±1.1 vs. 2.8±1.2 vs. 2.2±1.1) scores compared with those treated with regular doses of NOACs or VKAs. CONCLUSION: Patients given rivaroxaban and apixaban in clinical practice have a higher thrombotic and hemorrhagic risk in comparison with patients given dabigatran or VKAs. A considerable proportion of patients receive reduced doses of NOACs.

Treatment of Venous Thromboembolism With New Anticoagulant Agents.

Venous thromboembolism (VTE) is a common disease associated with high risk for recurrences, death, and late sequelae, accounting for substantial health care costs. Anticoagulant agents are the mainstay of treatment for deep vein thrombosis and pulmonary embolism. The recent availability of oral anticoagulant agents that can be administered in fixed doses, without laboratory monitoring and dose adjustment, is a landmark change in the treatment of VTE. In Phase III trials, rivaroxaban, apixaban, edoxaban (antifactor Xa agents), and dabigatran (an antithrombin agent) were noninferior and probably safer than conventional anticoagulation therapy (low-molecular-weight heparin followed by vitamin K antagonists). These favorable results were confirmed in specific patient subgroups, such as the elderly and fragile. However, some patients, such as those with cancer or with intermediate- to high-risk pulmonary embolism, were underrepresented in the Phase III trials. Further clinical research is required before new oral anticoagulant agents can be considered standard of care for the full spectrum of patients with VTE.

Efficacy of Rivaroxaban for thromboprophylaxis after Knee Arthroscopy (ERIKA). A phase II, multicentre, double-blind, placebo-controlled randomised study.

Without thromboprophylaxis, knee arthroscopy (KA) carries a low to moderate risk of venous thromboembolism. Over 5 million arthroscopies are performed worldwide yearly. It was our study objective to assess the efficacy and safety of rivaroxaban for thromboprophylaxis after therapeutic KA. Patients undergoing KA in nine Italian teaching or community hospitals were allocated to once-daily rivaroxaban (10 mg) or placebo for seven days in a phase II, multicentre, double-blind, placebo-controlled randomised trial. The primary efficacy outcome was a composite of all-cause death, symptomatic thromboembolism and asymptomatic proximal DVT at three months; major bleeding represented the primary safety outcome. All patients underwent whole-leg ultrasonography at day 7(+1), or earlier if symptomatic. A total of 241 patients were randomised (122 rivaroxaban, 119 placebo), and 234 completed the study. The primary efficacy outcome occurred in 1/120 of the rivaroxaban group and in 7/114 of the placebo group (0.8 % vs 6.1 %, respectively, p=0.03; absolute risk difference, -5.3 %, 95 % CI, -11.4 to -0.8; crude relative risk 0.14, 95 % CI, 0.02 to 0.83; number-needed-to-treat=19). No major bleedings were observed. We found no association between different arthroscopic procedures and thrombotic events. Small sample size, high exclusion rate, and low number of anterior cruciate ligament reconstruction procedures are the main limitations of our study. In conclusion, a seven-day course of 10-mg rivaroxaban may be safely employed for thromboprophylaxis after KA. Whether prophylaxis after KA should be given to all patients, or to selected "high-risk" subjects, remains to be determined. A larger trial to verify our preliminary results is warranted.

Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.

Pulmonary embolism (PE) is a potentially life-threatening acute cardiovascular syndrome. However, more than 95 % of patients are haemodynamically stable at presentation, and among them are patients at truly low risk who may qualify for immediate or early discharge. The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective international multicentre single-arm phase 4 management (cohort) trial aiming to determine whether home treatment of acute low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. Patients with confirmed PE, who have no right ventricular dysfunction or free floating thrombi in the right atrium or ventricle, are eligible if they meet none of the exclusion criteria indicating haemodynamic instability, serious comorbidity or any condition mandating hospitalisation, or a familial/social environment unable to support home treatment. The first dose of rivaroxaban is given in hospital, and patients are discharged within 48 hours of presentation. Rivaroxaban is taken for at least three months. The primary outcome is symptomatic recurrent venous thromboembolism or PE-related death within three months of enrolment. Secondary outcomes include quality of life and patient satisfaction, and health care resource utilisation compared to existing data on standard-duration hospital treatment. HoT-PE is planned to analyse 1,050 enrolled patients, providing 80 % power to reject the null hypothesis that the recurrence rate of venous thromboembolism is >3 % with α≤0.05. If the hypothesis of HoT-PE is confirmed, early discharge and out-of-hospital treatment may become an attractive, potentially cost-saving option for a significant proportion of patients with acute PE.

New oral anticoagulants for the treatment of venous thromboembolism.

New oral anticoagulants, acting either as direct factor-Xa or thrombin inhibitors, have been evaluated for the acute and long-term treatment of venous thromboembolism (VTE). Dabigatran and rivaroxaban are as effective as conventional therapy (heparin/vitamin K antagonists) without safety concerns. Rivaroxaban allows a single-drug regimen even in patients with pulmonary embolism, while dabigatran requires 5-7 days of initial heparin treatment. The results of clinical trials with apixaban and edoxaban will become available in the coming months. Rivaroxaban, apixaban and dabigatran are more effective than placebo for the extended treatment of VTE. Apixaban is effective in both therapeutic and prophylactic doses. Considering both efficacy and bleeding complications, all these agents have a favorable net clinical benefit. Dabigatran is as effective and safe as warfarin for the extended treatment of VTE. It is conceivable that the new oral anticoagulants will become the standard therapy for VTE in the next years.