Implementation, Clinical Benefit and Safety of a D-Dimer-Focused Pulmonary Embolism Testing Pathway in the Emergency Department.

STUDY OBJECTIVE: Computed tomography pulmonary angiogram (CTPA) is overused during pulmonary embolism (PE) testing in the emergency department (ED), whereas prediction rules and D-dimer are underused. We report the adherence, clinical benefit, and safety of a D-dimer-only strategy to guide need for PE imaging in the ED. METHODS: This was a prospective multicenter implementation study in 2 EDs with historical and external controls. Patients with suspected PE underwent D-dimer testing and imaging (CTPA or ventilation-perfusion scan) when D-dimer levels were 500 ng/mL or more. PE was ruled out if D-dimer was less than 500 ng/mL or with negative imaging. The primary implementation outcome was the proportion of patients tested for PE in adherence with the pathway. The primary clinical benefit outcome was the proportion of patients tested for PE who received pulmonary imaging. The primary safety outcome was diagnosis of PE in the 30 days following negative PE testing postimplementation. RESULTS: Between January 2018 and June 2021, 16,155 patients were tested for PE, including 33.4% postimplementation, 30.7% preimplementation, and 35.9% in an external control site. Adherence with the D-dimer-only pathway was 97.6% (adjusted odds ratio (aOR) post- versus preimplementation 5.26 (95% confidence interval 1.70 to 16.26). There was no effect on the proportion undergoing PE imaging. Imaging yield increased aOR 4.89 (1.17 to 20.53). Two cases of PE (0.04%; 0.01% to 0.16%) were diagnosed within 30 days. CONCLUSION: In this Canadian ED study, the uptake of a D-dimer-only PE testing strategy was high. Implementation was associated with higher imaging yield and a D-dimer level of less than 500 ng/mL safely excluded PE.

Strategies to reduce out-of-pocket medication costs for Canadians with peripheral arterial disease.

BACKGROUND: Given that peripheral arterial disease (PAD) disproportionately affects people of lower socioeconomic status, out-of-pocket expenses for preventive medications are a major barrier to their use. We carried out a cost comparison of drug therapies for PAD to identify prescribing strategies that minimize out-of-pocket expenses for these medications. METHODS: Between March and June 2019, we contacted outpatient pharmacies in Hamilton, Ontario, Canada, to assess pricing of pharmacologic therapies at dosages included in the 2016 American College of Cardiology/American Heart Association guideline for management of lower extremity PAD. We also gathered pricing information for supplementary charges, including delivery, pill splitting and blister packaging. We calculated prescription prices with and without dispensing fees for 30-day brand-name and generic prescriptions, and 90-day generic prescriptions. RESULTS: Twenty-four pharmacies, including hospital-based, independent and chain, were included in our sample. In the most extreme scenario, total 90-day medication costs could differ by up to $1377.26. Costs were affected by choice of agent within a drug class, generic versus brand-name drug, quantity dispensed, dispensing fee and delivery cost, if any. CONCLUSION: By opting for prescriptions for 90 days or as long as possible, selecting the lowest-cost generic drugs available in each drug class, and identifying dispensing locations with lower fees, prescribers can minimize out-of-pocket patient medication expenses. This may help improve adherence to guideline-recommended therapies for the secondary prevention of vascular events in patients with PAD.

Developing a privacy-preserving deep learning model for glaucoma detection: a multicentre study with federated learning.

BACKGROUND: Deep learning (DL) is promising to detect glaucoma. However, patients' privacy and data security are major concerns when pooling all data for model development. We developed a privacy-preserving DL model using the federated learning (FL) paradigm to detect glaucoma from optical coherence tomography (OCT) images. METHODS: This is a multicentre study. The FL paradigm consisted of a 'central server' and seven eye centres in Hong Kong, the USA and Singapore. Each centre first trained a model locally with its own OCT optic disc volumetric dataset and then uploaded its model parameters to the central server. The central server used FedProx algorithm to aggregate all centres' model parameters. Subsequently, the aggregated parameters are redistributed to each centre for its local model optimisation. We experimented with three three-dimensional (3D) networks to evaluate the stabilities of the FL paradigm. Lastly, we tested the FL model on two prospectively collected unseen datasets. RESULTS: We used 9326 volumetric OCT scans from 2785 subjects. The FL model performed consistently well with different networks in 7 centres (accuracies 78.3%-98.5%, 75.9%-97.0%, and 78.3%-97.5%, respectively) and stably in the 2 unseen datasets (accuracies 84.8%-87.7%, 81.3%-84.8%, and 86.0%-87.8%, respectively). The FL model achieved non-inferior performance in classifying glaucoma compared with the traditional model and significantly outperformed the individual models. CONCLUSION: The 3D FL model could leverage all the datasets and achieve generalisable performance, without data exchange across centres. This study demonstrated an OCT-based FL paradigm for glaucoma identification with ensured patient privacy and data security, charting another course toward the real-world transition of artificial intelligence in ophthalmology.

Unresolved issues in the use of direct acting oral anticoagulants.

INTRODUCTION: Currently approved direct oral anticoagulants (DOACs) target thrombin or coagulation factor Xa. Administered in fixed doses without routine laboratory monitoring, DOACs have simplified the approach to oral anticoagulation, when previously the choice was limited to vitamin K antagonists (VKAs). AREA COVERED: We discuss a) unresolved issues related to optimal use of DOACs and b) new developments including the potential for FXIa inhibitors to be effective and safer anticoagulants. EXPERT OPINION: By simplifying oral anticoagulation, DOACs have facilitated the uptake of anticoagulation. The DOACs are approved for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism, and their indications are expanding to include the prevention of atherothrombosis. DOACs have now replaced vitamin K antagonists (VKAs) for most indications, but not all. DOACs are inferior to VKAs for patients with mechanical heart valves, left ventricular assist device, rheumatic atrial fibrillation, and those with antiphospholipid syndrome, and their safety and efficacy are uncertain in some populations (e.g. advanced renal and liver disease). Impediments to use include concerns for bleeding and cost. The newly developed FXIa and FXIIa inhibitors have the potential to be safer than current anticoagulants, but phase 3 trials are needed to confirm their clinical efficacy and safety.

New Therapeutic Targets for the Prevention and Treatment of Venous Thromboembolism With a Focus on Factor XI Inhibitors.

FXI (factor XI) and FXII (factor XII) have emerged as targets for new anticoagulants that have the potential to be both more efficacious and safer than the currently available direct oral anticoagulants for the prevention and treatment of venous thromboembolism. In this review, we discuss the role of FXI and FXII in the pathogenesis of venous thromboembolism, explain why FXI is a better target, and explain why FXI inhibitors have potential advantages over currently available anticoagulants. Finally, we describe the FXI inhibitors under development and discuss their potential to address unmet needs in venous thromboembolism management.

Clinical Studies with Anticoagulants that Have Changed Clinical Practice.

Anticoagulant therapy is the cornerstone of treatment and prevention of arterial and venous thromboembolism. Taking a historical perspective, starting in the 1960s, and progressing through to 2022, we discuss key clinical trials of anticoagulants that have changed clinical practice, and examine obstacles encountered in bringing these anticoagulants to the clinic. The design of some of the early studies that shaped clinical practice was poor by current standards, but their results were influential because nothing better was available. Both heparin and vitamin K antagonists had been in clinical use for several decades before well-designed trials in the 1980s optimized their dosing and enhanced their safety and efficacy. Low-molecular-weight heparin then replaced unfractionated heparin because it had a more predictable dose-response and a longer half-life, thereby allowing it to be used conveniently in out-of-hospital settings. More recently, direct oral anticoagulants became the oral anticoagulants of choice for most indications because they were shown to be at least as safe and effective as vitamin K antagonists when used in fixed doses without the need for laboratory monitoring. The design of the trials that led to the approval of the direct oral anticoagulants was excellent, but further studies are required to optimize their dosing in selected patients who were underrepresented in these trials.

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

Background: Dabigatran is effective and safe for stroke prevention in patients with atrial fibrillation and for venous thromboembolism prevention and treatment. In Canada, APO-dabigatran, a generic formulation, has been approved based on a bioequivalence study, but its bioavailability in settings of reduced gastric acidity has not been examined. Methods: Treatment With APO-Dabigatran Absorption (TADA) was an open-label crossover study in 46 healthy male volunteers, comparing the absorption of APO-dabigatran (150 mg) with vs without rabeprazole. The primary outcome was the 24-hour total dabigatran exposure as measured by area under the curve (AUC) and peak concentration (Cmax). Results: Compared with no rabeprazole pretreatment, the total dabigatran AUC (geometric mean [gmean] AUC0-tz: 567.2 vs 804 ngh/mL, and gmean AUC0-∞: 609.7 vs 804) and Cmax (gmean: 64.1 vs 104.4 ng/mL) were significantly reduced with rabeprazole. The percent gmean ratios for AUC0-tz, AUC0-∞, and Cmax (with rabeprazole vs without) were 70.5% (95% confidence interval [CI]: 51.9% to 95.7%), 71.8% (95% CI: 53.1% to 96.9%), and 61.4% (95% CI: 44.1% to 85.5%), respectively. With rabeprazole, the proportions of participants with > 50% reduction in AUC0-tz, AUC0-∞, and Cmax were 32.6%, 30.4%, and 39.1%, respectively. Conclusions: When APO-dabigatran is administered with rabeprazole, the exposure to dabigatran is reduced by about 30%, which is similar to the level observed with Pradaxa when it was co-administered with a proton pump inhibitor. However, the finding that one-third of participants had a > 50% reduction in exposure is concerning, and it highlights the need for caution in patients who have, or are at risk of, reduced gastric acidity.

Contexte: Le dabigatran est une option thérapeutique sûre et efficace pour prévenir les accidents vasculaires cérébraux chez les patients atteints de fibrillation auriculaire et pour prévenir et traiter les thromboembolies veineuses. Au Canada, APO-dabigatran (une version générique) a été homologué sur la base d'une étude de bioéquivalence, mais sa biodisponibilité en contexte d'acidité gastrique réduite n'a pas été évaluée. Méthodologie: L'étude TADA ( T reatment with A PO- D abigatran A bsorption) est une étude croisée menée en mode ouvert auprès de 46 hommes volontaires en bonne santé, afin de comparer l'absorption d'APO-dabigatran (à 150 mg) avec et sans rabéprazole. Le critère d'évaluation principal était l'exposition totale sur 24 heures au dabigatran, telle que mesurée par la surface sous la courbe (SSC) et la concentration maximale (Cmax). Résultats: Par rapport à une administration sans prétraitement par rabéprazole, une réduction significative de la SSC totale du dabigatran (moyenne géométrique [MG] SSC0-tz : 567,2 par rapport à 804 ngh/ml; MG SSC0-∞ : 609,7 par rapport à 804 ngh/ml) et de la Cmax (MG : 64,1 par rapport à 104,4 ng/ml) a été observée avec la prise de rabéprazole. Les ratios des MG en pourcentage de la SSC0-tz, de la SSC0-∞, et de la Cmax (avec et sans rabéprazole) étaient de 70,5 % (intervalle de confiance [IC] à 95 % : 51,9 % à 95,7 %), 71,8 % (IC à 95 % : 53,1 % à 96,9 %) et 61,4 % (IC à 95 % : 44,1 % à 85,5 %), respectivement. Les proportions de participants chez qui une réduction de > 50 % de la SSC0-tz, de la SSC0-∞ ou de la Cmax a été notée avec l'administration du rabéprazole s'élevaient à 32,6 %, 30,4 % et 39,1 %, respectivement. Conclusions: Lors de l'administration d'APO-dabigatran en concomitance avec le rabéprazole, l'exposition au dabigatran était réduite d'environ 30 %, une valeur comparable à la réduction observée lors de l'administration de Pradaxa en concomitance avec un inhibiteur de la pompe à protons. La réduction de > 50 % de l'exposition médicamenteuse chez le tiers des participants n'en est pas moins préoccupante et démontre la nécessité de faire preuve de prudence lorsque l'acidité gastrique est réduite ou risque d'être réduite chez un patient.

Comparison of YEARS and Adjust-Unlikely D-dimer Testing for Pulmonary Embolism in the Emergency Department.

STUDY OBJECTIVE: We prospectively assessed the diagnostic accuracy of YEARS and a modified age-adjusted clinical decision rule ("Adjust-Unlikely") for pulmonary embolism (PE) testing in the emergency department. METHODS: This study was conducted in tertiary care Canadian emergency departments. When the D-dimer was <500 ng/ml, PE was excluded. Pulmonary imaging for PE was performed when the D-dimer was ≥500 ng/ml. Patients were followed for 30 days, and PE outcomes were independently adjudicated. Physicians systematically recorded the presence or absence of YEARS items (PE most likely, hemoptysis, signs of deep venous thrombosis) prior to D-dimer testing and imaging. We analyzed the diagnostic accuracy of YEARS and the "Adjust-Unlikely" rule. Age adjustment (age x 10 in those >50 years old) was applied in patients where PE was not the most likely diagnosis and 500 ng/ml threshold when PE was most likely. RESULTS: One thousand seven hundred three patients were included, median age 62 (50, 74), 58% female, PE prevalence 8.0%. YEARS sensitivity for PE diagnosis was 92.6% (87.0, 96.0%) and specificity 45.0% (42.5, 47.5%). Adjust-Unlikely sensitivity was 100.0% (97.2, 100.0%) and specificity 32.4% (30.1, 34.8%). Posttest probability of PE in the group of patients with PE excluded by D-dimer between 500 ng/ml and the adjusted limit was 2.8% (1.6, 5.1%) for YEARS and 0.0% (0.0, 2.6%) for the "Adjust-Unlikely" rule. CONCLUSION: The "Adjust-Unlikely" rule would modestly reduce imaging and identify all cases of PE. YEARS would substantially reduce imaging but miss 1 in 14 cases of PE.

Risk of Normal Tension Glaucoma Progression From Automated Baseline Retinal-Vessel Caliber Analysis: A Prospective Cohort Study.

PURPOSE: To determine the relationship between baseline retinal-vessel calibers computed by a deep-learning system and the risk of normal tension glaucoma (NTG) progression. DESIGN: Prospective cohort study. METHODS: Three hundred and ninety eyes from 197 patients with NTG were followed up for at least 24 months. Retinal-vessel calibers (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]) were computed from fundus photographs at baseline using a previously validated deep-learning system. Retinal nerve fiber layer (RNFL) thickness and visual field (VF) were evaluated semiannually. The Cox proportional-hazards model was used to evaluate the relationship of baseline retinal-vessel calibers to the risk of glaucoma progression. RESULTS: Over a mean follow-up period of 34.36 ± 5.88 months, 69 NTG eyes (17.69%) developed progressive RNFL thinning and 22 eyes (5.64%) developed VF deterioration. In the multivariable Cox regression analysis adjusting for age, gender, intraocular pressure, mean ocular perfusion pressure, systolic blood pressure, axial length, standard automated perimetry mean deviation, and RNFL thickness, narrower baseline CRAE (hazard ratio per SD decrease [95% confidence interval], 1.36 [1.01-1.82]) and CRVE (1.35 [1.01-1.80]) were associated with progressive RNFL thinning and narrower baseline CRAE (1.98 [1.17-3.35]) was associated with VF deterioration. CONCLUSION: In this study, each SD decrease in the baseline CRAE or CRVE was associated with a more than 30% increase in the risk of progressive RNFL thinning and a more than 90% increase in the risk of VF deterioration during the follow-up period. Baseline attenuation of retinal vasculature in NTG eyes was associated with subsequent glaucoma progression. High-throughput deep-learning-based retinal vasculature analysis demonstrated its clinical utility for NTG risk assessment.

Feasibility and Potential Effectiveness of a Smartphone Zero-Time Exercise Intervention for Promoting Physical Activity and Fitness in Patients With Coronary Heart Disease: A Pilot Randomized Controlled Trial.

Background: Zero-time Exercise (ZTEx), a simple strength- and stamina-enhancing physical activity (PA) requiring no extra equipment, can potentially increase PA and fitness. This pilot trial examined the feasibility and potential effectiveness of a smartphone ZTEx intervention to promote PA and fitness in patients with coronary heart disease (CHD). Methods: A parallel-group assessor-blinded pilot randomized controlled trial was conducted on Chinese patients with stable coronary heart disease (CHD) in three cardiology clinics. The experimental group received a 15-min brief individual face-to-face session and a 12-week ZTEx instant messaging with 28 picture e-messages and a smartphone ZTEx application (ZTExApp). The control group received the same duration of individual session and number and format of e-messages, but the content was healthy eating and breathing exercise. The feasibility was assessed based on: attrition rate, usage, response rate and perception of the intervention. The outcome evaluation included primary outcome (PA), fitness, exercise self-efficacy and intention, perceived happiness and health, and quality of life. A linear mixed model was used with intention-to-treat analysis adjusting for sex, age and baseline values. A semi-structured interview was conducted to collect feedback from the experiment group. Results: One hundred thirty-nine patients (mean age 59.8 ± 6.6; 71.2% male) were randomized to the experimental group (n = 70) or control group (n = 69), and 80% (56/70) and 82% (57/69) of patients completed the 12-week follow-up assessment, respectively. The attrition rate was 18.7%. The experimental group reported that ZTEx was feasible to integrate PA into their daily life and appreciated the picture e-messages, and 95% of them sent feedback to us, but only 19.6% (13/70) of the participants entered their PA information into the e-diary of the ZTExApp. The experimental group had a significantly greater increase in time spent walking [mean difference (95% CI): 155.3 (10.1, 300.4), P = 0.04, Cohen's d = 0.34] than the control group. Conclusions: This pilot study showed using a brief ZTEx face-to-face session with picture e-messages empowered patients with CHD to integrate PA into daily life. Future definitive trials with a longer follow-up and a more user-friendly ZTExApp interface are necessary to determine the effectiveness of the smartphone ZTEx intervention in enhancing PA and related outcomes. Trial Registration: The research protocol was registered at the Hong Kong University Clinical Trials Registry (HKUCTR) on 22 Jul 2016 (Study identifier: HKUCTR-2165) and was also retrospectively registered at the National Institutes of Health (identifier number: NCT03464331) on 14 March 2018.