Comparing the Real-World and Clinical Trial Bleeding Rates Associated with Oral Anticoagulation Treatment for Atrial Fibrillation.

Background The prevention of stroke in patients with atrial fibrillation (AF) involves the use of oral anticoagulation, commonly in the form of direct oral anticoagulants (DOACs). However, it comes with an increased risk of bleeding, and therefore, counselling patients on their individual risks is important. Although the majority of patients initiated on DOACs have been represented within the clinical trials, some cohorts are under-represented in whom clinicians cannot practice evidence-based medicine. Methods Utilising the pooled clinical trial (CT) data sourced from Medidata Enterprise Data Store, five recent open-label industry-sponsored AF trials were compared with real-world data (RWD) sourced from the HealthVerity™ Marketplace with the occurrence of bleeding events as the primary outcome of interest. Results A total of 64,421 patients were included in the analysis, with 3207 patients from the clinical DOAC trials and 61,214 patients from the RWD cohort. Overall, the patients from the RWD cohort had more co-morbidities, were older (72.2 ± 11.9 vs. 65.3 ± 10.7 years old, p < 0.001), had higher mean CHA2DS2VASc (3.98 ± 1.9 vs. 2.87 ± 1.73, p < 0.001), and HAD-BLED scores (2.13 ± 1.02 vs. 1/04 ± 0.93, p < 0.001) when compared to the trial data. When comparing the incidence of the first major bleed at 12 months post-treatment initiation, rates in the RWD cohort were significantly higher (10.69 vs. 18.97 per 100 person-years). The impact of co-morbidities such as age, CHA2DS2VASc, and HAD-BLED scores was similar in both cohorts; however, there was an under-representation of older females and more co-morbid patients within the clinical trial cohort. Conclusions DOAC-treated patients have a higher bleeding incidence rate in the RWD cohort than in clinical trials. This can be explained by the older patient age group with more complex medical h istories and higher HAS-BLED scores. The under-representation of higher-risk patients and lower proportion of females within clinical trials should be addressed to better translate clinical trial data into real-world clinical practice.

Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction.

Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.

Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa.

BACKGROUND: Factor XI (FXI) inhibition offers the promise of hemostasis-sparing anticoagulation for the prevention and treatment of thromboembolic events. Abelacimab (MAA868) is a novel fully human monoclonal antibody that targets the catalytic domain and has dual activity against the inactive zymogen Factor XI and the activated FXI. OBJECTIVES: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single dose intravenous and multiple dose subcutaneous administration of abelacimab in healthy volunteers and patients with atrial fibrillation, respectively. PATIENTS/METHODS: In study ANT-003, healthy volunteers were administered single intravenous doses of abelacimab (30-150 mg) or placebo. The ANT-003 study also included a cohort of obese but otherwise healthy subjects. In study ANT-004, patients with atrial fibrillation were administered monthly subcutaneous doses of abelacimab (120 mg and 180 mg), or placebo, for 3 months. Key PK and PD parameters, including activated partial thromboplastin time (aPTT) and free FXI levels, as well as anti-drug antibodies (ADA) were assessed. RESULTS: Following intravenous administration of abelacimab, the terminal elimination half-life ranged from 25 to 30 days. One hour after the start of the intravenous infusion greater than 99% reductions in free FXI levels were observed. Following once monthly subcutaneous administration, marked reductions from baseline in free FXI levels were sustained. Parenteral administration of abelacimab demonstrated a favorable safety profile with no clinically relevant bleeding events. CONCLUSIONS: Intravenous and multiple subcutaneous dose administration of abelacimab were safe and well tolerated. The safety, PK, and PD data from these studies support the clinical development of abelacimab.

Regular Doses of Nature: The Efficacy of Green Exercise Interventions for Mental Wellbeing.

This study investigated the efficacy of medium-term Green Exercise (GE; being physically active within a natural environment) interventions for improving wellbeing, by pooling data collected at the start and end of participants' engagement with a range of GE interventions. Hypotheses were that (i) interventions would show good efficacy for improving wellbeing in the overall sample; (ii) compared to participants reporting 'average to high' wellbeing at the start of their project, participants with 'low' starting wellbeing would report greater improvements post-intervention; and (iii) improvements would significantly differ between age groups. The pooled dataset was categorized in line with UK norms (n = 318) and analyzed using a standardized meta-analysis approach. Effect size was large: g = 0.812 (95% CI [0.599, 1.025]), and differences in wellbeing changes associated with project duration, age or sex were not statistically significant. Compared to those reporting 'average-high' starting wellbeing, participants reporting 'low' starting wellbeing exhibited greater improvements (BCa 95% CI [-31.8, -26.5]), with 60.8% moving into the 'average-high' wellbeing category. GE can play an important role in facilitating wellbeing and can provide alternative pathways for health and social care practice. Public health commissioners should consider integrating such interventions for patients experiencing low wellbeing or associated comorbidities.

What makes nature-based interventions for mental health successful?

Nature-based interventions for mental health are beginning to become more common in the UK. The evidence for their usefulness is building. Taking the 'A Dose of Nature' project in the south-west as an example, factors for making such interventions a success are described.

What approaches to social prescribing work, for whom, and in what circumstances? A protocol for a realist review.

BACKGROUND: The use of non-drug, non-health-service interventions has been proposed as a cost-effective alternative to help those with long-term conditions manage their illness and improve their health and well-being. Interventions typically involve accessing activities run by the third sector or community agencies and may also be described as non-medical referral, community referral or social prescribing. To be effective, patients need to be "transferred" from the primary care setting into the community and to maintain their participation in activities. However, it is not currently known how and why these approaches enable which people under what circumstances to reach community services that may benefit their health and well-being. METHODS: Database searches and extensive searching of grey sources will be carried out in an attempt to find evidence associated with referral and retention in social prescribing. After initial scoping searches, two main phases of searching will be conducted: (a) will focus on the identification of programme theories to illustrate how approaches to social prescribing work for different people and in different contexts and (b) will consist of targeted searches to locate evidence to refine these candidate theories into configurations of the contexts in which populations and the main mechanisms outcomes are achieved. Inclusion criteria will initially be broad in order to develop a clear picture of the ways in which social prescriptions might operate but may iteratively become more focused in response to initially identified evidence, for example, in terms of the population group. An expert advisory group consisting of professionals working in a range of organisations involved in social prescribing will be convened to check the approaches in the review and provide real-life experience of social prescribing. Findings from the review will be disseminated to commissioners, published in a peer-reviewed journal and used to help refine an intervention model for an outdoor nature-based group intervention. DISCUSSION: This realist review will explore why mechanisms of social prescribing work, for what groups of people and their impact on enrolment, attendance and adherence to programmes. The use of realist approaches to detail the social prescribing process is novel and will offer insights into effective transfer of patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039491.