Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis.

Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135 140 of 147 104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45 524 of 59 866 participants (71%) were male. The best aortic stenosis PRS incorporated 5 170 041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.

Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

BACKGROUND: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

Investigating the ability to adhere to cardiometabolic medications with different properties: a retrospective cohort study of >500 000 patients in the USA.

OBJECTIVE: Poor medication adherence remains highly prevalent and adversely affects health outcomes. Patients frequently describe properties of the pills themselves, like size and shape, as barriers, but this has not been evaluated objectively. We sought to determine the extent to which oral medication properties thought to be influential translate into lower objectively-measured adherence. DESIGN: Retrospective cohort study. SETTING: US nationwide commercial claims database, 2016-2019. PARTICIPANTS: Among patients initiating first-line hypertension, diabetes or hyperlipidaemia treatment based on clinical guidelines, we measured pill size, shape, colour and flavouring, number of pills/day and fixed-dose combination status as properties. OUTCOME MEASURES: Outcomes included discontinuation after the first fill (ie, never filling again over a minimum of 1-year follow-up) and long-term non-adherence (1-year proportion of days covered <0.80). We estimated associations between each property and outcomes, by therapeutic class (eg, statins), with multivariable logistic regression. RESULTS: Across 604 323 patients, 14.6% discontinued after filling once (ie, were non-persistent), and 54.0% were non-adherent over 1-year follow-up. Large pill size was associated with non-adherence, except for thiazides (eg, metformin adjusted OR (aOR): 1.12, 95% CI: 1.06 to 1.18). Greater pill burden was associated with a higher risk of non-adherence across all classes (eg, metformin aOR: 1.58, 95% CI: 1.53 to 1.64 for two pills/day). Taking less than one pill/day was also associated with higher risk of non-adherence and non-persistence (eg, non-persistence statin aOR: 1.29, 95% CI: 1.20 to 1.38). Pill shape, colour, flavouring and combination status were associated with mixed effects across classes. CONCLUSIONS: Pill burden and pill size are key properties affecting adherence for almost all classes; others, like size and combination, could modestly affect medication adherence. Clinical interventions could screen patients for potential intolerance to medication and potentially implement more convenient dosing schedules.

Breathless nights and heart flutters: Understanding the relationship between obstructive sleep apnea and atrial fibrillation.

There is an extraordinary and increasing global burden of atrial fibrillation (AF) and obstructive sleep apnea (OSA), two conditions that frequently accompany one another and that share underlying risk factors. Whether a causal pathophysiologic relationship connects OSA to the development and/or progression of AF, or whether shared risk factors promote both conditions, is unproven. With increasing recognition of the importance of controlling AF-related risk factors, numerous observational studies now highlight the potential benefits of OSA treatment in AF-related outcomes. Physicians are regularly faced with caring for this important and increasing population of patients despite a paucity of clinical guidance on the topic. Here, we review the clinical epidemiology and pathophysiology of AF and OSA with a focus on key clinical studies and major outstanding questions that should be addressed in future studies.

Neutrophil-lymphocyte ratio and clinical outcomes in 19,697 patients with atrial fibrillation: Analyses from ENGAGE AF- TIMI 48 trial.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is the ratio between neutrophil and lymphocyte counts measured in peripheral blood. NLR is easily calculable based on a routine blood test available worldwide and may reflect systemic inflammation. However, the relationship between NLR and clinical outcomes in atrial fibrillation (AF) patients is not well-described. METHODS: We calculated NLR at baseline in ENGAGE AF-TIMI 48, a randomized trial comparing edoxaban versus warfarin in patients with AF followed for 2.8 years (median). The association of baseline NLR with major bleeding events, major adverse cardiac events (MACE), cardiovascular death, stroke/systemic embolism, and all-cause mortality were calculated. RESULTS: The median baseline NLR in 19,697 patients was 2.53 (interquartile range 1.89-3.41). NLR was associated with major bleeding events (HR 1.60; 95% CI 1.41-1.80), stroke/systemic embolism (HR 1.25; 95% CI, 1.09-1.44), MI (HR 1.73; 95% CI 1.41-2.12), MACE (HR 1.70; 95% CI 1.56-1.84), CV (HR 1.93; 95% CI 1.74-2.13) and all-cause mortality (HR 2.00; 95% CI 1.83-2.18). The relationships between NLR and outcomes remained significant after adjustment for risk factors. Edoxaban consistently reduced major bleeding. MACE, and CV death across NLR groups vs. warfarin. CONCLUSIONS: NLR represents a widely available, simple, arithmetic calculation that could be immediately and automatically reported during a white blood cell differential measurement to identify patients with AF at increased risk of bleeding, CV events, and mortality.

Evaluation of obstructive sleep apnea among consecutive patients with all patterns of atrial fibrillation using WatchPAT home sleep testing.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and is associated with significant morbidity, mortality, and financial burden. Obstructive sleep apnea (OSA) is more common in individuals with AF and may impair the efficacy of rhythm control strategies including catheter ablation. However, the prevalence of undiagnosed OSA in all-comers with AF is unknown. DESIGN: This pragmatic, phase IV prospective cohort study will test 250-300 consecutive ambulatory AF patients with all patterns of atrial fibrillation (paroxysmal, persistent, and long-term persistent) and no prior sleep testing for OSA using the WatchPAT system, a disposable home sleep test (HST). The primary outcome of the study is the prevalence of undiagnosed OSA in all-comers with atrial fibrillation. RESULTS: Preliminary results from the initial pilot enrollment of approximately 15% (N = 38) of the planned sample size demonstrate a 79.0% prevalence of at least mild (AHI≥5) OSA or greater in consecutively enrolled patient with all patterns of AF. CONCLUSIONS: We report the design, methodology, and preliminary results of our study to define the prevalence of OSA in AF patients. This study will help inform approaches to OSA screening in patients with AF for which there is currently little practical guidance. CLINICAL TRIAL REGISTRATION: NCT05155813.

Risks of Heart Failure, Stroke, and Bleeding in Atrial Fibrillation According to Heart Failure Phenotypes.

BACKGROUND: The risks of heart failure (HF) events compared with stroke/systemic embolic events (SEE) or major bleeding (MB) in heart failure with reduced ejection fraction (HFrEF) vs heart failure with preserved ejection fraction (HFpEF) in a large atrial fibrillation (AF) population have not been well-studied. OBJECTIVES: This study sought to assess HF outcomes, according to HF history and HF phenotypes (HFrEF vs HFpEF), and compare these events with SEE and MB, among patients with AF. METHODS: We analyzed patients enrolled in the ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial. Cumulative incidence of heart failure hospitalization (HHF) or HF death was assessed and compared with the rates of fatal and nonfatal stroke/SEE and MB over a median follow-up of 2.8 years. RESULTS: Overall, 12,124 (57.4%) had a history of HF (37.7% HFrEF, 40.1% HFpEF, 22.1% with unknown ejection fraction). The rate per 100 person-years (py) of HHF or HF death (4.95; 95% CI: 4.70-5.20) was higher than of fatal and nonfatal stroke/SEE (1.77; 95% CI: 1.63-1.92) and MB (2.66; 95% CI: 2.47-2.86) among patients with HF history. HFrEF patients experienced a higher rate of HHF or HF death compared with HFpEF patients (7.15 vs 3.65; P < 0.001), while the rates of fatal and nonfatal stroke/SEE and MB were similar by HF phenotype. Patients with HF history had a higher rate of mortality after a HHF (1.29; 95% CI: 1.17-1.42) than after a stroke/SEE (0.69; 95% CI: 0.60-0.78) or after MB (0.61; 95% CI: 0.53-0.70). Overall, patients with nonparoxysmal AF had a higher rate of HF and stroke/SEE events regardless of HF history. CONCLUSIONS: Patients with AF and HF, regardless of ejection fraction, are at a higher risk of HF events with higher subsequent mortality rates than of stroke/SEE or MB. While HFrEF is associated with a higher risk of HF events than HFpEF, the risk of stroke/SEE and MB is similar between HFrEF and HFpEF.

Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation.

AIMS: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high-sensitivity troponin T (hsTnT, n = 8705), N-terminal pro-B-type natriuretic peptide (NT-proBNP, n = 8765), and growth differentiation factor-15 (GDF-15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p-interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category). CONCLUSION: Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov unique identifier NCT00781391.

Ideal Cardiovascular Health in Young Adults With Established Cardiovascular Diseases.

There has been an increase in the prevalence of cardiovascular diseases among young adults in the United States that has been attributed, in part, to a rise in overweight and obesity, use of combustible tobacco and unhealthy diet and exercise patterns. These factors are influenced further by socioeconomic status and other social determinants of health. In the My Research Legacy study, we examined ideal cardiovascular health in young adults aged 18- <50 years with cardiovascular disease using the Life's Simple 7 survey and data from digital health devices. Young adults with cardiovascular disease (n = 349) were older, had a lower socioeconomic status, a higher prevalence of risk factors, and lower Life's Simple 7 Health Scores (6.4 ± 1.5 vs. 7.1 ± 1.5, p < 0.01) compared to young adults without cardiovascular disease (n = 696). Analysis of digital health device data revealed that young adults with cardiovascular disease performed a similar number of weekly minutes of moderate and vigorous exercise as those without disease leading to similar ideal activity scores. Young adults with cardiovascular disease also shared similarities in modifiable risk factors with adults aged ≥50 years with cardiovascular disease (n = 217), including weight, dietary habits, and weekly minutes of exercise. Latent class analysis identified two phenogroups of young adults with cardiovascular disease: phenogroup 1 was characterized by more advantageous cardiovascular health factors and behaviors resulting in higher Life's Simple 7 Health Scores than phenogroup 2 (7.4 ± 1.2 vs. 5.5 ± 1.1, p < 0.01). These findings in young adults with cardiovascular disease may inform the design of behavioral and therapeutic interventions in the future to decrease cardiovascular morbidity and mortality.

Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis.

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.

Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma.

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics. Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure: Receipt of CCP. Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Edoxaban versus Warfarin in high-risk patients with atrial fibrillation: A comprehensive analysis of high-risk subgroups.

BACKGROUND: To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups. METHODS: ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial fibrillation (AF) within 12 months and CHADS2 score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin, and followed for 2.8 years (median). The primary outcome for this analysis was the net clinical outcome (NCO), a composite of stroke/systemic embolism events, major bleeding, or death. Multivariable risk-stratification analysis was used to categorize patients by the number of high-risk features. RESULTS: The annualized NCO rates in the warfarin arm were highest in patients with malignancy (19.2%), increased fall risk (14.0%), and very-low body weight (13.5%). The NCO rates increased with the numbers of high-risk factors in the warfarin arm: 4.5%, 7.2%, 9.9% and 14.6% in patients with 0 to 1, 2, 3, and >4 risk factors, respectively (Ptrend <0.001). Versus warfarin, HDER was associated with significant reductions of NCO in most of the subgroups: elderly, patients with moderate renal dysfunction, prior stroke/TIA, of Asian race, very-low body weight, concomitant single antiplatelet therapy, and VKA-naïve. With more high-risk features (0->4+), the absolute risk reductions favoring edoxaban over warfarin increased: 0.3%->2.0% for HDER; 0.4%->3.4% for LDER vs warfarin (P = .065 and P < .001, respectively). CONCLUSIONS: While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.

Ischaemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full- and half-dose edoxaban vs. warfarin: insights from ENGAGE AF-TIMI 48.

AIMS: In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30 mg) and lower dose edoxaban (30/15 mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described. METHODS AND RESULTS: Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg, or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P < 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30 mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15 mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039). CONCLUSION: Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.

Privacy-aware multi-institutional time-to-event studies.

Clinical time-to-event studies are dependent on large sample sizes, often not available at a single institution. However, this is countered by the fact that, particularly in the medical field, individual institutions are often legally unable to share their data, as medical data is subject to strong privacy protection due to its particular sensitivity. But the collection, and especially aggregation into centralized datasets, is also fraught with substantial legal risks and often outright unlawful. Existing solutions using federated learning have already demonstrated considerable potential as an alternative for central data collection. Unfortunately, current approaches are incomplete or not easily applicable in clinical studies owing to the complexity of federated infrastructures. This work presents privacy-aware and federated implementations of the most used time-to-event algorithms (survival curve, cumulative hazard rate, log-rank test, and Cox proportional hazards model) in clinical trials, based on a hybrid approach of federated learning, additive secret sharing, and differential privacy. On several benchmark datasets, we show that all algorithms produce highly similar, or in some cases, even identical results compared to traditional centralized time-to-event algorithms. Furthermore, we were able to reproduce the results of a previous clinical time-to-event study in various federated scenarios. All algorithms are accessible through the intuitive web-app Partea (https://partea.zbh.uni-hamburg.de), offering a graphical user interface for clinicians and non-computational researchers without programming knowledge. Partea removes the high infrastructural hurdles derived from existing federated learning approaches and removes the complexity of execution. Therefore, it is an easy-to-use alternative to central data collection, reducing bureaucratic efforts but also the legal risks associated with the processing of personal data to a minimum.

Exploring patient experiences coping with using multiple medications: a qualitative interview study.

OBJECTIVE: Long-term adherence to evidence-based medications in cardiometabolic diseases remains poor, despite extensive efforts to develop and test interventions and deploy clinician performance incentives. The limited success of interventions may be due to ignored factors such as patients' experience of medication-taking. Despite being potentially addressable by clinicians, these factors have not been sufficiently explored, which is particularly important as patients use increasing numbers of medications. The aim is to explore patient perspectives on medication-taking, medication properties that are barriers to adherence, and coping strategies for their medication regimen. DESIGN: Individual, in-person, semistructured qualitative interviews. SETTING: Urban healthcare system. PARTICIPANTS: Twenty-six adults taking ≥2 oral medications for diabetes, hypertension or hyperlipidaemia with non-adherence. Interviews were digitally recorded and transcribed. Data were analysed using developed codes to generate themes. Representative quotations were selected to illustrate themes. RESULTS: Participants' mean age was 55 years, 46% were female and 39% were non-white. Six key themes were identified: (1) medication-taking viewed as a highly inconvenient action (that patients struggle to remember to do); (2) negative implications because of inconvenience or illness perceptions; (3) actual medication regimens can deviate substantially from prescribed regimens; (4) certain medication properties (especially size and similar appearance with others) may contribute to adherence deviations; (5) development of numerous coping strategies to overcome barriers and (6) suggestions to make medication-taking easier (including reducing drug costs, simplifying regimen or dosing frequency and creating more palatable medications). CONCLUSION: Patients with poor adherence often find taking prescription medications to be undesirable and take them differently than prescribed in part due to properties of the medications themselves and coping strategies they have developed to overcome medication-taking challenges. Interventions that reduce the inconvenience of medication use and tailor medications to individual needs may be a welcome development.

Digital health device measured sleep duration and ideal cardiovascular health: an observational study.

BACKGROUND: Studies relying on self-reported sleep data suggest that there is an association between short and long sleep duration and less than ideal cardiovascular health. Evidence regarding the feasibility of using digital health devices to measure sleep duration and assess its relationship to ideal cardiovascular health are lacking. The objective of the present study was to utilize digital health devices to record sleep duration and examine the relationship between sleep duration and ideal cardiovascular health. METHODS: A total of 307 participants transmitted sleep duration data from digital health devices and answered the Life's Simple 7 survey instrument to assess ideal cardiovascular health. Sleep duration was defined as adequate (7 to < 9 h per night) or non-adequate (< 7 h and ≥ 9 h). RESULTS: We identified three sleep-cardiovascular health phenogroups: resilient (non-adequate sleep and ideal cardiovascular health), uncoupled (adequate sleep and non-ideal cardiovascular health) or concordant (sleep and cardiovascular health metrics were aligned). Participants in the resilient phenogroup (n = 83) had better cardiovascular health factor profiles (blood pressure, blood glucose and cholesterol levels) and behaviors (healthy weight, diet, exercise, smoking) than participants in the concordant (n = 171) and uncoupled (n = 53) phenogroups. This was associated with higher Life's Simple 7 Health Scores in the resilient phenogroup compared to the concordant and uncoupled phenogroups (7.8 ± 0.8 vs. 7.0 ± 1.4 vs. 5.6 ± 0.7, P < 0.01). CONCLUSION: This study identified three distinct sleep-ideal cardiovascular health phenogroups and highlights the advantage of incorporating sleep assessments into studies of cardiovascular health. Future studies should focus on the relationship between sleep-cardiovascular phenogroups and clinical outcomes. Clinical Trial Registration Clinicaltrials.gov NCT02958098. Date of registration: November 11, 2016.

An overview of the process, progress, and outcomes of a National Center for Accelerated Innovation: The Boston Biomedical Innovation Center Experience.

Implementation of clinically useful research discoveries in the academic environment is challenged by limited funding for early phase proof-of-concept studies and inadequate expertise in product development and commercialization. To address these limitations, the National Institutes of Health (NIH) established the National Centers for Accelerated Innovations (NCAI) program in 2013. Three centers competed successfully for awards through this mechanism. Here, we present the experience of one such center, the Boston Biomedical Innovation Center (B-BIC), and demonstrate its remarkable success at the translation of innovations to clinical application and commercialization, as well as skills development and education.