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The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76–1.34) for ischemic stroke and 0.87 (0.77–0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60–1.20) for ischemic stroke and 0.80 (0.68–0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72–1.43). Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis. • Our multinational cohort study compared DOACs vs VKAs in AF patients with liver disease. • We also compared apixaban vs rivaroxaban in the same population. • DOACs were as effective but slightly safer compared to VKAs. • Apixaban was as effective but safer compared to rivaroxaban. • The safety benefit with apixaban was not present in AF patients with cirrhosis. [ABSTRACT FROM AUTHOR]

TREATMENT FAILURE Twelve (22%) patients in the survey stopped treatment before the 6-month analysis compared to 3% reported in the trials.[[1], [3]] Nine of these patients stopped treatment due to adverse side effects. This included the validated tool for patient-reported outcome measures, the Angioedema Control Test (AECT).[6] BASELINE PROPHYLAXIS Most patients (32, 59.3%) were receiving prophylaxis prior to starting berotralstat. To the Editor, Berotralstat is an oral plasma kallikrein inhibitor, used for routine prevention of attacks of hereditary angioedema (HAE) Type 1 and Type 2. [Extracted from the article]

Background: Asthma is a common long-term condition and major public health problem. Supported self-management for asthma that includes a written personalised asthma action plan, supported by regular professional review, reduces unscheduled consultations and improves asthma outcomes and quality of life. However, despite unequivocal inter/national guideline recommendations, supported self-management is poorly implemented in practice. The IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) implementation strategy has been developed to address this challenge. The aim of this implementation trial is to determine whether facilitated delivery of the IMP2ART strategy increases the provision of asthma action plans and reduces unscheduled care in the context of routine UK primary care. Methods: IMP2ART is a parallel group, cluster randomised controlled hybrid II implementation trial. One hundred forty-four general practices will be randomly assigned to either the IMP2ART implementation strategy or control group. Following a facilitation workshop, implementation group practices will receive organisational resources to help them prioritise supported self-management (including audit and feedback; an IMP2ART asthma review template), training for professionals and resources to support patients to self-manage their asthma. The control group will continue with usual asthma care. The primary clinical outcome is the between-group difference in unscheduled care in the second year after randomisation (i.e. between 12 and 24 months post-randomisation) assessed from routine data. Additionally, a primary implementation outcome of asthma action plan ownership at 12 months will be assessed by questionnaire to a random sub-group of people with asthma. Secondary outcomes include the number of asthma reviews conducted, prescribing outcomes (reliever medication and oral steroids), asthma symptom control, patients' confidence in self-management and professional support and resource use. A health economic analysis will assess cost-effectiveness, and a mixed methods process evaluation will explore implementation, fidelity and adaptation. Discussion: The evidence for supported asthma self-management is overwhelming. This study will add to the literature regarding strategies that can effectively implement supported self-management in primary care to reduce unscheduled consultations and improve asthma outcomes and quality of life. Trial registration: ISRCTN15448074. Registered on 2 December 2019. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the preferences of people with type 2 diabetes (T2D) for treatment attributes of a glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) versus an injectable GLP-1 RA medication profile. Patients and Methods: Injection-naive people taking oral medications for T2D in the US and UK completed a web survey including a discrete choice experiment to quantify patients' preferences for five treatment attributes: delivery system, frequency of nausea, frequency of hypoglycemia, HbA1c reduction, and weight reduction. Attributes and levels were based on head-to-head clinical trial data of tirzepatide 5mg, 10mg, and 15mg versus semaglutide 1mg. Preference data were analyzed separately by country using multinomial mixed logit (MXL) models. MXL parameters were used to estimate the predicted preference for each tirzepatide dose versus semaglutide 1mg. Direct preferences for each dose of tirzepatide versus semaglutide 1mg were elicited. Results: Participants (N=620) in the US (N=301) and UK (N=319) were 50.8% and 50.5% female with mean ages of 60.7 years and 58.9 years, respectively. The order and magnitude of relative attribute importance (RAI) scores differed between countries. HbA1c reduction (26.3%) had the greatest impact on US participants' preferences, and hypoglycemia (32.8%) did among UK participants. Attribute-level marginal utility results indicated preferences for greater HbA1c improvements, the single-use pre-filled pen, lower hypoglycemia, greater weight reductions, and lower frequency of nausea. Assuming the availability of only tirzepatide or semaglutide 1mg, the predicted preference for tirzepatide (5, 10, and 15mg) in the US is 95.6% (vs 4.4% for semaglutide 1mg) and in the UK was 86.3% (vs 13.7% for semaglutide 1mg). Conclusion: HbA1c reduction, frequency of hypoglycemia, and weight reduction are key drivers of preferences among people with T2D when considering medication options. Overall, people with T2D are likely to prefer the tirzepatide over the semaglutide 1mg medication profiles. [ABSTRACT FROM AUTHOR]

Treatment for hepatitis C virus (HCV) with direct‐acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct‐acting antivirals inhibit DOAC transport through P‐glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non‐major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56–2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes (T2D) is extremely burdensome to people with T2D and associated with impaired health-related quality of life. This study explores the impact of T2D and potentially relevant outcomes for new therapies using a unique approach to in-depth qualitative interviews where people with T2D are asked to think about their future with T2D. Methods: A cross-sectional qualitative interview study among people with T2D from the USA and UK. Interviews explored their treatment journey, perceptions of their future with T2D, and the value of achieving normoglycemia (explored through presentation of two vignettes with hypothetical medications that reduced hemoglobin A1c [HbA1c] levels < 7% and < 5.7%). Results: Patients with T2D (N = 50; US n = 25; UK n = 25) were 66.0% male, had a mean body mass index (BMI) of 30.8 ± 6.3 kg/m2, and had a mean of 13.0 ± 10.0 years since diagnosis. Current diabetes treatments included diet and exercise only (8.0%), oral medications only (62.0%), oral plus injections (24.0%), and insulin only (6.0%). Despite being treated, participants reported over 25 different unmet needs related to their T2D across a broad range of domains. The most common concerns were diet, diabetes-related complications, weight changes, and psychological and emotional issues. A large majority of participants indicated that achieving lower HbA1c values would change their life. When reflecting on the value of improved glycemic control, patients primarily anticipated physical improvements and improved psychological well-being. When presented with two hypothetical treatments, about 70% of participants preferred the < 5.7% treatment option over the < 7% HbA1c treatment option. Conclusions: People with T2D have a high disease burden, a broad range of unmet needs, and extremely varied experiences and expectations on the impacts of T2D on their lives and future. Many patients indicated that achieving near normoglycemia would substantially change their lives primarily in terms of their physical and emotional health. [ABSTRACT FROM AUTHOR]

Objective: To establish weight‐based dose bands for commonly used oral medicines, given in liquid forms, for children in the UK that could be used for prescribing and administering accurate and safe drug doses. Methods: A list of commonly prescribed, oral liquid medications was established from the medication dispensing database of four UK hospitals and a primary care database. The evidence base of currently used dose regimens for each drug was identified from paediatric reference books, summary of product characteristics and the literature. Then, weight‐based dose bands were developed and a modified Delphi process was used to achieve healthcare professional consensus about the suggested dose bands for each drug. Results: Forty‐six experts in paediatric medicines participated in the Delphi process (mean years of experience 17.3 ± 9.4 [standard deviation]) and assessed 45 oral liquid drugs in total. Four categories of weight‐based dose bands were established: drugs with two dose bands (17.8%, 8/45), drugs with three dose bands (64.4%, 29/45), drugs with four dose bands (15.6%, 7/45) and drugs with five dose bands (2.2%, 1/45). The 46 participants reached consensus on all the suggested dose bands for 53.3% (24/45) of the drugs. Consensus was reached in the first round of the Delphi process for 91.7% (22/24) of the drugs and after two rounds for two drugs. No agreement was achieved on any of the suggested dose bands for 26.7% (12/45) of the drugs. Conclusion: This study provides healthcare professionals with a set of recommended weight‐based dose bands for commonly prescribed oral liquid drugs for children. These bands could establish the basis for change in clinical practice to reduce dosing errors and improve healthcare for children. [ABSTRACT FROM AUTHOR]

Andexanet alfa was employed to reverse the anticoagulant effect of direct oral anticoagulants in 3 patients who required emergent surgery for repair of type A aortic dissection. Its use was instrumental in securing haemostasis. However, we caution against the administration of Andexanet alfa prior to cardiopulmonary bypass as it can induce heparin resistance and complicate the perioperative monitoring of anticoagulation during cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

Linked article:O'Kane et al. Br J Dermatol 2021; 185:1112–1123 Cutaneous lupus erythematous (CLE) refers to a range of skin conditions with common clinical and laboratory findings. CLE is caused by a combination of genetic factors, autoantibodies and the environment, and can occur alone or as a feature of systemic lupus erythematosus (SLE). The British Association of Dermatologists put together a group that included consultant dermatologists, a consultant rheumatologist and patient representatives to review published evidence on treating adults, young people and children with CLE. The UK‐based group produced 53 recommendations, based on a review of the evidence, for the management of CLE in general practitioner clinics and in hospitals. They used an approach called the GRADE system (Grading of Recommendations Assessment, Development and Evaluation) for developing guidelines. General measures central to the management of CLE include sun protection and smoking avoidance. The possibility of drug‐induced CLE should be considered, and medications that might potentially be the culprit stopped. Where the psychological impact of CLE on a patient is significant, referral to psychological support services should be considered. Topical steroids are an appropriate first‐line medication for localized CLE. However, in active or widespread CLE, oral medications should be introduced early, with antimalarial drugs (such as hydroxychloroquine) being the first choice in most cases. The recommended patient management pathway for CLE is presented as a flow diagram to guide clinicians through options for first‐line, second‐line and third‐line treatments. Recommendations for future research and audit points (to help check the care of patients with CLE is meeting the right standards) are also included. Linked article:O'Kane et al. Br J Dermatol 2021; 185:1112–1123 [ABSTRACT FROM AUTHOR]

Many people with cancer have oral medication as part or all of their regime. This medication is primarily self administered in the community. This mini-review aimed to determine the level of compliance of adult cancer patients with oral chemotherapy and to assess the quality of the available evidence. Searches were undertaken using three electronic databases (Medline, Embase, CINAHL) for studies which evaluated the compliance of adult cancer patients with oral antineoplastic agents through self-report, pill counts, drug/metabolite levels or microelectronic monitoring system (MEMS). Articles were selected if the follow-up was higher than 80% of patients. Six papers were identified for the review. The methodological quality of the studies was poor. The sample size of the majority of them was small and the method used to measure adherence was not entirely reliable. The results of these papers were varied and contradictory. A firm conclusion can not be drawn because the studies present significant methodological flaws. The comparison of results between studies is difficult due to the lack of a gold-standard measure of adherence and a standardised definition of non-compliance. Further research in this area is needed. However it does appear that compliance is a problem in this patient group. [ABSTRACT FROM AUTHOR]