Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

AIMS: As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. METHODS AND RESULTS: Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

Emergence of Central Sleep Apnea Events After Maxillomandibular Advancement Surgery for Obstructive Sleep Apnea.

PURPOSE: Central sleep apnea (CSA) can develop after the treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP). No studies have identified whether treatment of OSA with maxillomandibular advancement surgery (MMA) can result in CSA. The purpose of our study was to determine the incidence and clinical significance of CSA emerging after MMA surgery to treat OSA. PATIENTS AND METHODS: A retrospective review was conducted of all patients who had undergone MMA surgery for OSA at the Department of Oral and Maxillofacial Surgery at the QEII Health Sciences Centre (Halifax, NS, Canada) from 1996 through 2016. All patients with preoperative level 1 polysomnography and follow-up level 1 study results available at least 6 months postoperatively were included the present study. The pre- and postoperative central apnea index (CAI) results were compared. RESULTS: A total of 113 patients (84 men and 29 women) with an average age of 44.0 years were included in the present study. In 35 patients (31.0%), the emergence of CSA events were recorded on postoperative polysomnograms. Only 2 of the 113 patients experienced the emergence of clinically significant postoperative CSA (CAI >5). In our patient cohort, gender (P = .085), patient age (P = .238), and preoperative (P = .716) and postoperative (P = .209) Apnea-Hypopnea Index (AHI) results correlated with the postoperative development of CSA events after MMA surgery. The mean AHI values had decreased from 41.4 to 8.7 in all patients treated with MMA in our study. CONCLUSIONS: The emergence of CSA events occurred in 31% of patients after OSA treatment with MMA surgery. The rate of clinically significant CSA events emerging after MMA surgery in our study was 1.8%. These findings help to support the use of MMA surgery for OSA as a reasonable treatment alternative for patients unable to tolerate CPAP.

Automated Software System to Promote Anticoagulation and Reduce Stroke Risk: Cluster-Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Oral anticoagulants (OAC) substantially reduce risk of stroke in atrial fibrillation, but uptake is suboptimal. Electronic health records enable automated identification of people at risk but not receiving treatment. We investigated the effectiveness of a software tool (AURAS-AF [Automated Risk Assessment for Stroke in Atrial Fibrillation]) designed to identify such individuals during routine care through a cluster-randomized trial. METHODS: Screen reminders appeared each time the electronic health records of an eligible patient was accessed until a decision had been taken over OAC treatment. Where OAC was not started, clinicians were prompted to indicate a reason. Control practices continued usual care. The primary outcome was the proportion of eligible individuals receiving OAC at 6 months. Secondary outcomes included rates of cardiovascular events and reports of adverse effects of the software on clinical decision-making. RESULTS: Forty-seven practices were randomized. The mean proportion-prescribed OAC at 6 months was 66.3% (SD=9.3) in the intervention arm and 63.9% (9.5) in the control arm (adjusted difference 1.21% [95% confidence interval -0.72 to 3.13]). Incidence of recorded transient ischemic attack was higher in the intervention practices (median 10.0 versus 2.3 per 1000 patients with atrial fibrillation; P=0.027), but at 12 months, we found a lower incidence of both all cause stroke (P=0.06) and hemorrhage (P=0.054). No adverse effects of the software were reported. CONCLUSIONS: No significant change in OAC prescribing occurred. A greater rate of diagnosis of transient ischemic attack (possibly because of improved detection or overdiagnosis) was associated with a reduction (of borderline significance) in stroke and hemorrhage over 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique Identifier: ISRCTN55722437.

Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family.

UDP-Glucuronosyltransferases (UGTs) conjugate a glucuronyl group from glucuronic acid to a wide range of lipophilic substrates to form a hydrophilic glucuronide conjugate. The glucuronide generally has decreased bioactivity and increased water solubility to facilitate excretion. Glucuronidation represents an important detoxification pathway for both endogenous waste products and xenobiotics, including drugs and harmful industrial chemicals. Two clinically significant families of UGT enzymes are present in mammals: UGT1s and UGT2s. Although the two families are distinct in gene structure, studies using recombinant enzymes have shown considerable overlap in their ability to glucuronidate many substrates, often obscuring the relative importance of the two families in the clearance of particular substrates in vivo. To address this limitation, we have generated a mouse line, termed ΔUgt2, in which the entire Ugt2 gene family, extending over 609 kilobase pairs, is excised. This mouse line provides a means to determine the contributions of the two UGT families in vivo. We demonstrate the utility of these animals by defining for the first time the in vivo contributions of the UGT1 and UGT2 families to glucuronidation of the environmental estrogenic agent bisphenol A (BPA). The highest activity toward this chemical is reported for human and rodent UGT2 enzymes. Surprisingly, our studies using the ΔUgt2 mice demonstrate that, while both UGT1 and UGT2 isoforms can conjugate BPA, clearance is largely dependent on UGT1s.

Discovery of MLL1 binding units, their localization to CpG Islands, and their potential function in mitotic chromatin.

BACKGROUND: Mixed Lineage Leukemia 1 (MLL1) is a mammalian ortholog of the Drosophila Trithorax. In Drosophila, Trithorax complexes transmit the memory of active genes to daughter cells through interactions with Trithorax Response Elements (TREs). However, despite their functional importance, nothing is known about sequence features that may act as TREs in mammalian genomic DNA. RESULTS: By analyzing results of reported DNA binding assays, we identified several CpG rich motifs as potential MLL1 binding units (defined as morphemes). We find that these morphemes are dispersed within a relatively large collection of human promoter sequences and appear densely packed near transcription start sites of protein-coding genes. Genome wide analyses localized frequent morpheme occurrences to CpG islands. In the human HOX loci, the morphemes are spread across CpG islands and in some cases tail into the surrounding shores and shelves of the islands. By analyzing results of chromatin immunoprecipitation assays, we found a connection between morpheme occurrences, CpG islands, and chromatin segments reported to be associated with MLL1. Furthermore, we found a correspondence of reported MLL1-driven "bookmarked" regions in chromatin to frequent occurrences of MLL1 morphemes in CpG islands. CONCLUSION: Our results implicate the MLL1 morphemes in sequence-features that define the mammalian TREs and provide a novel function for CpG islands. Apparently, our findings offer the first evidence for existence of potential TREs in mammalian genomic DNA and the first evidence for a connection between CpG islands and gene-bookmarking by MLL1 to transmit the memory of highly active genes during mitosis. Our results further suggest a role for overlapping morphemes in producing closely packed and multiple MLL1 binding events in genomic DNA so that MLL1 molecules could interact and reside simultaneously on extended potential transcriptional maintenance elements in human chromosomes to transmit the memory of highly active genes during mitosis.

A reliable and reproducible method for repositioning 3D images to calculate changes in facial volume after orthognathic surgery.

PURPOSE: An accurate, reproducible method to calculate post-operative facial swelling in patients who have undergone orthognathic surgery is important to evaluate the effects of different therapies and surgical techniques on edema. The purpose of this study was to describe such a method and assess its reliability. MATERIALS AND METHODS: A prospective study of patients undergoing orthognathic surgery was conducted. 3D facial photographs were taken on these patients immediately postoperatively, and again at least 21 days later using the 3DMD face system (3DMD LLC., Atlanta, GA, USA). These were cropped using specific anatomic points and the difference in facial volume between the photographs was calculated. Intra-rater reliability and inter-rater reliability were assessed using the Intraclass Correlation Coefficient (ICC). RESULTS: 30 patients were included in the study for analysis. When the difference in facial swelling was calculated twice by the same rater, the mean difference between the two measurements was 4.0 ± 4.2 mL. When calculated by two separate raters, the mean difference was found to be 5.0 ± 3.8 mL. The ICCs for intra-rater and inter-rater reliability were excellent at 0.979 and 0.981 respectively. CONCLUSION: This method allows for reproducible calculation of post-operative facial swelling and could be useful to evaluate the effects of different therapies used to limit swelling and to track the resolution of swelling. It can also potentially be used as a visual aid for patient counseling during the pre-surgical visits.

Direct Oral Anticoagulant (DOAC) Dosing in Patients with Non-valvular Atrial Fibrillation (NVAF) in the United Kingdom: A Retrospective Cohort Study Using CPRD Gold Database.

INTRODUCTION: Per-label dosing of direct oral anticoagulants (DOACs) is important for the prevention of stroke and systemic embolism among patients with non-valvular atrial fibrillation (NVAF), especially those with poor renal function, advanced age, low body weight or concomitant P-glycoprotein inhibitors. The study described DOAC use and dosing patterns in patients with NVAF in the UK. METHODS: Using Clinical Practice Research Datalink (CPRD Gold), patients' profiles were described at DOAC initiation (1 January 2016-31 March 2021) and followed for a mean [standard deviation (SD)] 2 (1) years. Patients were categorised as under-dosing: received a lower dose with no indication for a reduced dose; over-dosing: received a standard dose with an indication for a reduced dose; per-label dosing, according to Summary Product Characteristics (SmPC). RESULTS: Forty thousand seven hundred forty-four adult patients with NVAF were identified (mean age: 75.3 (11.2) years; males: 55.4%); 22,827 (56.0%) initiated treatment with apixaban, 930 (2.3%) dabigatran, 5633 (13.8%) edoxaban and 11,354 (27.9%) rivaroxaban. Baseline Charlson comorbidity index ≥ 4 was 65.1%; CHA2DS2-VASc score ≥ 4 was 22.5%; HAS-BLED score ≥ 3 was 18.3%; ~ 2% had prior major bleed and 4.4% a stroke ≤ 2 years before DOAC initiation. Overall, 18.0% of patients received incorrect dosing (~ one in five). Under-dosing was highest for dabigatran (156, 16.8%) and over-dosing was highest for rivaroxaban (1084, 9.6%). Per-label dosing was highest for edoxaban (4773, 84.7%), followed by apixaban (18,756, 82.2%), rivaroxaban (9161, 80.7%) and dabigatran (732, 78.7%). Treatment persistence (no switching or discontinuation) was 79% among edoxaban users, followed by 75% for apixaban, 69% for rivaroxaban and 62% for dabigatran. About 15% of dabigatran users, 10% of rivaroxaban users, 5% of apixaban users and 4% of edoxaban users switched treatment to another DOAC during follow-up. CONCLUSION: Although most patients received per-label dosing, ~ one in five patients was incorrectly dosed with DOAC, which may lead to serious clinical consequences and increased healthcare burden.

The Importance of Appropriate Dosing of Nonvitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation.

Preventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation (AF). Several factors contribute to current dosing patterns of nonvitamin K antagonist oral anticoagulants (NOACs), including patient characteristics, comorbidities, and physician judgment. Application of NOAC doses inconsistent with the drug labels may cause patients to receive either subtherapeutic (increasing stroke risk) or supratherapeutic (increasing bleeding risk) anticoagulant levels. In clinical practice, under- or over-dosing of NOACs in patients with AF is not uncommon. This analysis of prospective and retrospective registry and database studies on NOAC use in patients with AF (with at least 250 patients in each treatment arm) showed that under-dosing may be associated with reduced effectiveness for stroke prevention, with similar or even increased bleeding than with the standard dose. This may reflect underlying conditions and patient factors that increase bleeding despite NOAC dose reduction. Such factors could drive the observed overuse of reduced NOAC dosages, often making the prescription of reduced-dose NOAC an intentional label deviation. In contrast, over-dosing more likely occurs accidentally; instead of providing benefits, it may be associated with worse safety outcomes than the standard dose, including increased bleeding risk and higher all-cause mortality rates. This review summarizes the main findings on NOAC doses usually prescribed to patients with AF in clinical practice.

Point-of-Care Testing for D-Dimer in the Diagnosis of Venous Thromboembolism in Primary Care: A Narrative Review.

Venous thromboembolism (VTE) is regarded as a significant cause of mortality and disability, affecting 1-2 per 1000 people annually, presenting with a relatively wide range of symptoms, which can pose a diagnostic challenge. Historically, people in whom VTE is suspected will have been taken to hospital for diagnosis and treatment; however, a high proportion of patients are found not to have VTE. Concerns have been expressed about potential delays in treatment, with the risk of additional morbidity and disability, and death. Diagnostic strategies are typically based on the use of a clinical prediction rule to determine the pre-test probability, complemented with a measurement of D-dimer, with confirmation by imaging assessment. This narrative review explores the literature on the use of point-of-care testing (POCT) for the measurement of D-dimer, as part of a clinical decision rule, for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the primary care setting. In the two main prospective management (validation) studies that included D-dimer POCT or similar technologies, with a total cohort of 1600 participants, DVT was ruled out in 49% of patients, with a false negative rate of 1.4%, whereas PE was ruled out in 45% of patients, with a false negative rate of 1.5%. This suggests that uptake of POCT D-dimer in primary care has the potential to reduce the number of referrals to hospitals for imaging confirmatory investigation, with consequent cost savings. Thus, adopting POCT for D-dimer in primary care can offer clinical and cost benefits, particularly when quantitative POCT assays are being used. Furthermore, POCT should be undertaken in collaboration with the local laboratories to ensure the harmonisation of D-dimer methods and quality assurance to improve the diagnosis of VTE.

Uptake of Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation in a Single Clinical Commissioning Group in England Without Restrictions to Their Use.

BACKGROUND AND OBJECTIVE: In England, the uptake of direct oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation has been slow and varied across different Clinical Commissioning Groups (CCGs). This study aimed to profile the prescribing of oral anticoagulants for stroke prevention in patients with atrial fibrillation over 3 years in a CCG without restrictions to DOACs use to understand more about organisational and/or individual barriers to the early uptake of DOACs. METHODS: Data were collected from nine general practices between 1 April 2012 and 31 March 2015 of patients who were initiated on the oral anticoagulant therapy. Data were analysed descriptively and with independent Student's t test and Chi square test to explore if there was an association between type of oral anticoagulant initiated and sex, age, type of prescriber and prior aspirin use. RESULTS: The early uptake of DOACs significantly increased over the study period (p < 0.0001; medium size effect φc = 0.372). There was no statistically significant difference between sex or age and type of oral anticoagulant initiated. Primary-care prescribers were responsible for initiating the majority of oral anticoagulants (71%; N = 257) and driving the use of DOACs (72%, N = 71). Patients switched from aspirin to an oral anticoagulant were more likely to be initiated on warfarin than a DOAC. CONCLUSIONS: The early use of DOACs, in a CCG without restrictions to their use, was embraced by primary-care prescribers in this particular CCG.

Barriers to a software reminder system for risk assessment of stroke in atrial fibrillation: a process evaluation of a cluster randomised trial in general practice.

BACKGROUND: Oral anticoagulants reduce the risk of stroke in patients with atrial fibrillation (AF), but are underused. AURAS-AF (AUtomated Risk Assessment for Stroke in AF) is a software tool designed to identify eligible patients and promote discussions within consultations about initiating anticoagulants. AIM: To investigate the implementation of the software in UK general practice. DESIGN AND SETTING: Process evaluation involving 23 practices randomly allocated to use AURAS-AF during a cluster randomised trial. METHOD: An initial invitation to discuss anticoagulation was followed by screen reminders appearing during consultations until a decision had been made. The reminders required responses, giving reasons for cases where an anticoagulant was not initiated. Qualitative interviews with clinicians and patients explored acceptability and usability. RESULTS: In a sample of 476 patients eligible for the invitation letter, only 159 (33.4%) were considered suitable for invitation by their GPs. Reasons given were frequently based on frailty, and risk of falls or haemorrhage. Of those invited, 35 (22%) started an anticoagulant (7.4% of those originally identified). A total of 1695 main-screen reminders occurred in 940 patients. In 883 instances, the decision was taken not to initiate and a range of reasons offered. Interviews with 15 patients and seven clinicians indicated that the intervention was acceptable, though the issue of disruptive screen reminders was raised. CONCLUSION: Automated risk assessment for stroke in atrial fibrillation and prompting during consultations are feasible and generally acceptable, but did not overcome concerns about frailty and risk of haemorrhage as barriers to anticoagulant uptake.

Screening of older patients for atrial fibrillation in general practice: Current evidence and its implications for future practice.

BACKGROUND: Individuals with atrial fibrillation (AF) face a fivefold increased risk of ischaemic stroke compared with those without the condition. Recent studies suggest that individuals with asymptomatic AF also face an increased risk of ischaemic stroke, but their condition is often not recognized and diagnosed until an ischaemic stroke event has occurred. Identification of individuals with undiagnosed AF at increased risk for stroke is critical in promoting optimal intervention with anticoagulants. OBJECTIVES: In this narrative review, we consider the benefits and limitations of various proposed screening strategies, whether single or multiple time-points, in addition to devices for implementation in the primary care setting. OUTCOMES: Opportunistic screening via pulse palpation with subsequent referral for 12-lead electrocardiogram testing has been shown to cost-effectively identify individuals with asymptomatic AF. Some handheld devices suitable for use in primary care settings are now available and may facilitate screening of large cohorts of individuals considered to be at increased risk of AF, such as those aged ≥65 years or those diagnosed with or undergoing monitoring for hypertension. CONCLUSIONS: It was determined that improved detection and diagnosis of AF, combined with appropriate anticoagulation strategies, will be crucial for improving stroke prevention and reducing its associated social and economic costs.

The use of anticoagulants in the management of atrial fibrillation among general practices in England.

OBJECTIVES: To investigate the use of oral anticoagulants (AC) and antiplatelet agents (AP) in the management of atrial fibrillation (AF) among patients in primary care in England. DESIGN: Epidemiological study. SETTING: 1857 general practices in England representing a practice population of 13.1 million registered patients. PATIENTS: 231,833 patients with a history of AF. MAIN OUTCOME MEASURES: The primary outcome was AC and AP use by CHADS2 score and age groups <30 years, 30-49 years, 50-64 years, 65-79 years and >79 years. RESULTS: 231,833 patients with a history of AF were identified, giving a prevalence among uploading practices of 1.76%. Prevalence of AF varied markedly between practices, related to differing practice age profiles. The total number of patients with AF in a practice was strongly predicted by the number of patients aged 65 years and over in the practice. 57.0% of the AF population had a CHADS2 score ≥2 and 83.7%≥1. 114,212 (49.3%) patients received AC therapy. AC uptake increased with increasing CHADS2 score up to a score of 3, but thereafter reached a plateau. Among 132 099 patients with a CHADS2 score ≥2, 72,211 (54.7%) received an AC, 14 987(11.3%) were recorded as having a contraindication or having declined AC therapy, leaving 44,901 (34.0%) not on AC therapy and without a recorded contraindication or recorded refusal. Among patients not prescribed an AC, 79.9% were prescribed an AP. The use of AC declined in the elderly (for CHADS2 ≥ 2, 47.4% of patients ≥80 years, compared with 64.5% for patients aged <80 years, p<0.001). By contrast, AP uptake was more prevalent among elderly patients. CONCLUSIONS: Over one-third of patients with AF and known risk factors who are eligible for AC do not receive them. There is a high use of AP among patients not receiving AC. Uptake of AC is particularly poor among patients aged 80 years and over.

Automated Risk Assessment for Stroke in Atrial Fibrillation (AURAS-AF)--an automated software system to promote anticoagulation and reduce stroke risk: study protocol for a cluster randomised controlled trial.

BACKGROUND: Patients with atrial fibrillation (AF) are at significantly increased risk of stroke. Oral anticoagulants (OACs) substantially reduce this risk, with gains seen across the spectrum of baseline risk. Despite the benefit to patients, OAC prescribing remains suboptimal in the United Kingdom (UK). We will investigate whether an automated software system, operating within primary care electronic medical records, can improve the management of AF by identifying patients eligible for OAC therapy and increasing uptake of this treatment. METHODS/DESIGN: We will conduct a cluster randomised controlled trial, involving general practices using the Egton Medical Information Systems (EMIS) Web clinical system. We will randomise practices to use an electronic software tool or to continue with usual care. The tool will a) produce (and continually refresh) a list of patients with AF who are eligible for OAC therapy--practices will invite these patients to discuss therapy at the start of the trial--and b) generate electronic screen reminders in the medical records of those eligible, appearing throughout the trial. The software will run for 6 months in 23 intervention practices. A total of 23 control practices will manage their AF register in line with the usual care offered. The primary outcome is change in proportion of eligible patients with AF who have been prescribed OAC therapy after six months. Secondary outcomes are incidence of stroke, transient ischaemic attack, other major thromboembolism, major haemorrhage and reports of inappropriate OAC prescribing in the data collection sample--those deemed eligible for OACs. We will conduct a process evaluation in parallel with the randomised trial. We will use qualitative methods to examine patient and practitioner views of the intervention and its impact on primary care practice, including its time implications. DISCUSSION: AURAS-AF will investigate whether a simple intervention, using electronic primary care records, can improve OAC uptake in a high risk group for stroke. Given previous concerns about safety, especially surrounding inappropriate prescribing, we will also examine whether electronic reminders safely impact care in this clinical area. TRIAL REGISTRATION: http://ISRCTN 55722437.