Machine learning and optical coherence tomography-derived radiomics analysis to predict persistent diabetic macular edema in patients undergoing anti-VEGF intravitreal therapy.

BACKGROUND: Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME. METHODS: A retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated. RESULTS: The logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p < 0.001). OCT-omics scores were also positively correlated with the rate of decline in central subfield thickness after treatment (Pearson's R = 0.44, p < 0.001). CONCLUSION: The developed OCT-omics model accurately assesses anti-VEGF treatment response in DME patients. The model's robust performance and clinical implications highlight its utility as a non-invasive tool for personalized treatment prediction and retinal pathology assessment.

Approval, Evidence, and "Off-Label" Device Utilization: The Patent Foramen Ovale Closure Story.

BACKGROUND: Following regulatory approval, medical devices may be used "off-label." Patent foramen ovale (PFO) closure is indicated to reduce recurrent stroke but has been proposed for other indications, including migraine, transient ischemic attack, and diving decompression illness. We sought to evaluate PFO closure rates and indications relative to the timing of regulatory approval and publication of key randomized trials. METHODS: We performed a retrospective cohort study using the OptumLabs Data Warehouse of US commercial insurance enrollees from 2006 to 2019. We quantified PFO closure among individuals with ≥2 years of preprocedure coverage to establish indications, classified hierarchically as stroke/systemic embolism, migraine, transient ischemia attack, or other. RESULTS: We identified 5315 patients undergoing PFO closure (51.8% female, 29.2%≥60 years old), which increased from 4.75 per 100 000 person-years in 2006 to 6.60 per 100 000 person-years in 2019. Patients aged ≥60 years accounted for 29.2% of closures. Procedure volumes corresponded weakly with supportive clinical publications and device approval. Among patients with PFO closure, 58.6% underwent closure for stroke/systemic embolism, 10.2% for transient ischemia attack, 8.8% for migraine, and 22.4% for other indications; 17.6% of patients had atrial fibrillation at baseline; and 11.9% developed atrial fibrillation postprocedure. Those aged ≥60 years and male were less likely to undergo closure for migraine than stroke/systemic embolism. CONCLUSIONS: From 2006 to 2019, PFO closure use was consistently low and corresponded weakly with clinical trial publications and regulatory status. Nearly half of patients underwent PFO closure for indications unapproved by the Food and Drug Administration. Regulators and payers should coordinate mechanisms to promote utilization for approved indications to ensure patient safety and should facilitate clinical trials for other possible indications.

Daylight Saving Time Practice and the Rate of Adverse Cardiovascular Events in the United States: A Probabilistic Assessment in a Large Nationwide Study.

We investigated the association of daylight saving time (DST) transitions with the rates of adverse cardiovascular events in a large, US-based nationwide study. The study cohort included 36,116,951 unique individuals from deidentified administrative claims data of the OptumLabs Data Warehouse. There were 74,722 total adverse cardiovascular events during DST transition and the control weeks (2 weeks before and after) in spring and autumn of 2015-2019. We used Bayesian hierarchical Poisson regression models to estimate event rate ratios representing the ratio of composite adverse cardiovascular event rates between DST transition and control weeks. There was an average increase of 3% (95% uncertainty interval, -3% to -10%) and 4% (95% uncertainty interval, -2% to -12%) in adverse cardiovascular event rates during Monday and Friday of the spring DST transition, respectively. The probability of this being associated with a moderate-to-large increase in the event rates (estimate event rate ratio, >1.10) was estimated to be less than 6% for Monday and Friday, and less than 1% for the remaining days. During autumn DST transition, the probability of any decrease in adverse cardiovascular event rates was estimated to be less than 46% and a moderate-to-large decrease in the event rates to be less than 4% across all days. Results were similar when adjusted by age. In conclusion, spring DST transition had a suggestive association with a minor increase in adverse cardiovascular event rates but with a very low estimated probability to be of clinical importance. Our findings suggest that DST transitions are unlikely to meaningfully impact the rate of cardiovascular events.

Realtime Diagnosis from Electrocardiogram Artificial Intelligence-Guided Screening for Atrial Fibrillation with Long Follow-Up (REGAL): Rationale and design of a pragmatic, decentralized, randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risks of stroke and dementia. Early diagnosis and treatment could reduce the disease burden, but AF is often undiagnosed. An artificial intelligence (AI) algorithm has been shown to identify patients with previously unrecognized AF; however, monitoring these high-risk patients has been challenging. Consumer wearable devices could be an alternative to enable long-term follow-up. OBJECTIVES: To test whether Apple Watch, used as a long-term monitoring device, can enable early diagnosis of AF in patients who were identified as having high risk based on AI-ECG. DESIGN: The Realtime diagnosis from Electrocardiogram (ECG) Artificial Intelligence (AI)-Guided Screening for Atrial Fibrillation (AF) with Long Follow-up (REGAL) study is a pragmatic trial that will accrue up to 2,000 older adults with a high likelihood of unrecognized AF determined by AI-ECG to reach our target of 1,420 completed participants. Participants will be 1:1 randomized to intervention or control and will be followed up for 2 years. Patients in the intervention arm will receive or use their existing Apple Watch and iPhone and record a 30-second ECG using the watch routinely or if an abnormal heart rate notification is prompted. The primary outcome is newly diagnosed AF. Secondary outcomes include changes in cognitive function, stroke, major bleeding, and all-cause mortality. The trial will utilize a pragmatic, digitally-enabled, decentralized design to allow patients to consent and receive follow-up remotely without traveling to the study sites. SUMMARY: The REGAL trial will examine whether a consumer wearable device can serve as a long-term monitoring approach in older adults to detect AF and prevent cognitive function decline. If successful, the approach could have significant implications on how future clinical practice can leverage consumer devices for early diagnosis and disease prevention. CLINICALTRIALS: GOV: : NCT05923359.

Mortality and Morbidity of Heart Failure Hospitalization in Adult Patients With Congenital Heart Disease.

BACKGROUND: Little is known about outcomes following heart failure (HF) hospitalization among adults with congenital heart disease (CHD) in the United States. We aim to compare the outcomes of HF versus non-HF hospitalizations in adults with CHD. METHODS AND RESULTS: Using a national deidentified administrative claims data set, patients with adult congenital heart disease (ACHD) hospitalized with and without HF (ACHDHF+, ACHDHF-) were characterized to determine the predictors of 90-day and 1-year mortality and quantify the risk of mortality, major adverse cardiac and cerebrovascular events, and health resource use. Cox proportional hazard regression was used to compare ACHDHF+ versus ACHDHF- for risk of events and health resource use. Of 26 454 unique ACHD admissions between January 1, 2010 and December 31, 2020, 5826 (22%) were ACHDHF+ and 20 628 (78%) were ACHDHF-. The ACHD HF+ hospitalizations increased from 6.6% to 14.0% (P<0.0001). Over a mean follow-up period of 2.23 ± 2.19 years, patients with ACHDHF+ had a higher risk of mortality (hazard ratio [HR], 1.86 [95% CI, 1.67-2.07], P<0.001), major adverse cardiac and cerebrovascular events (HR, 1.73 [95% CI, 1.63-1.83], P<0.001) and health resource use including rehospitalization (HR, 1.09 [95% CI, 1.05-1.14], P<0.001) and increased postacute care service use (HR, 1.56 [95% CI, 1.32-1.85], P<0.001). Cardiology clinic visits within 30 days of hospital admission were associated with lower 90-day and 1-year all-cause mortality (odds ratio [OR], 0.62 [95% CI, 0.49-0.78], P<0.001; OR, 0.69 [95% CI, 0.58-0.83], P<0.001, respectively). CONCLUSIONS: HF hospitalization is associated with increased risk of mortality and morbidity with high health resource use in patients with ACHD. Recent cardiology clinic attendance appears to mitigate these risks.

Risk of cervical intraepithelial neoplasia grade 3 or more diagnoses for human papillomavirus16/18-positive women by cytology and co-infection status.

BACKGROUND: Human papillomavirus (HPV) 16 and 18 cause approximately 70% of cervical cancer cases. The aim of this study was to evaluate whether co-infected with other HPV genotypes will affect the risk of cervical carcinogenesis in HPV16/18 positive-women. METHODS: In this cross-sectional study, cervical cytology and histological classifications from women who tested positive for HPV 16/18 and underwent colposcopy within 6 months, between January 2010 and May 2021 were obtained from West China Second University Hospital of Sichuan University. MAIN OUTCOMES AND MEASURES: Immediate risk of cervical intraepithelial neoplasia grade 3 or more diagnoses (CIN 3+). RESULTS: A total of 7940 HPV 16/18-positive women were included, with a median age of 40 years (range 25-84 years). Among them, 2710 (34.1%) were infected with multiple genotypes, 6533 (82.28%) had cytology results and 2116 (26.65%) women were diagnosed with CIN 3+. The effects of HPV 16/18 coinfecting with other HPV on CIN3 + risk varied with specific HPV genotypes. After adjusting for cofactors, compared to single HPV 16 infection, the CIN 3 + risk was significantly reduced in women infected with HPV 16 + other high-risk HPV (hrHPV) [odds ratio (OR) = 0.621, 95% confidence interval (CI) 0.511-0.755], HPV 16 + low-risk HPV (lrHPV) (OR = 0.620, 95% CI 0.436-0.883), and HPV 16 + lrHPVs + other hrHPVs (OR = 0.248, 95% CI 0.157-0.391). The prevalence of CIN 3 + was associated with increased severity of cytologic abnormalities in HPV 16/18-positive women and peaked at cytology HSIL + (89.9% and 82.3%), which held a substantially greater risk than that of NILM (OR = 65.466, 95% CI 50.234-85.316). CONCLUSIONS: In this cross-sectional study of HPV 16/18-positive women, the effects of multiple infection were likely complicated and varied with specific HPV genotypes. The coinfection of HPV 16 and other genotypes of HPV except HPV 18 was associated with decreased CIN 3 + risk. Cytologic results were informative when HPV 16/18 was positive. It might be reasonable to recommend expedited treatment for patients with HPV 16/18 positive and HSIL + cytology in the Chinese population.

Physicians' perspectives on percutaneous left atrial appendage occlusion for patients with atrial fibrillation.

BACKGROUND: There has been an increasing uptake of transcatheter left atrial appendage occlusion (LAAO) for stroke reduction in atrial fibrillation. OBJECTIVES: To investigate the perceptions and approaches among a nationally representative sample of physicians. METHODS: Using the American Medical Association Physician Masterfile, we selected a random sample of 500 physicians from each of the specialties: general cardiologists, interventional cardiologists, electrophysiologists, and vascular neurologists. The participants received the survey by mail up to three times from November 9, 2021 to January 14, 2022. In addition to the questions about experiences, perceptions, and approaches, physicians were randomly assigned to 1 of the 4 versions of a patient vignette: white man, white woman, black man, and black woman, to investigate potential bias in decision-making. RESULTS: The top three reasons for considering LAAO were: a history of intracranial bleeding (94.3%), a history of major extracranial bleeding (91.8%), and gastrointestinal lesions (59.0%), whereas the top three reasons for withholding LAAO were: other indications for long-term oral anticoagulation (87.7%), a low bleeding risk (77.0%), and a low stroke risk (65.6%). For the reasons limiting recommendations for LAAO, 59.8% mentioned procedural risks, 42.6% mentioned "limiting efficacy data comparing LAAO to NOAC" and 32.8% mentioned "limited safety data comparing LAAO to NOAC." There was no difference in physicians' decision-making by patients' race, gender, or the concordance between patients' and physicians' race or gender. CONCLUSIONS: In the first U.S. national physician survey of LAAO, individual physicians' perspectives varied greatly, which provided information that will help customize future educational activities for different audiences. CONDENSED ABSTRACT: Although diverse practice patterns of LAAO have been documented, little is known about the reasoning or perceptions that drive these variations. Unlike prior surveys that were directed to Centers that performed LAAO, the current survey obtained insights from individual physicians, not only those who perform the procedures (interventional cardiologists and electrophysiologists) but also those who are closely involved in the decision-making and referral process (general cardiologists and vascular neurologists). The findings identify key evidence gaps and help prioritize future studies to establish a consistent and evidence-based best practice for AF stroke prevention.

Fertility loss: negative effects of environmental toxicants on oogenesis.

There has been a global decline in fertility rates, with ovulatory disorders emerging as the leading cause, contributing to a global lifetime infertility prevalence of 17.5%. Formation of the primordial follicle pool during early and further development of oocytes after puberty is crucial in determining female fertility and reproductive quality. However, the increasing exposure to environmental toxins (through occupational exposure and ubiquitous chemicals) in daily life is a growing concern; these toxins have been identified as significant risk factors for oogenesis in women. In light of this concern, this review aims to enhance our understanding of female reproductive system diseases and their implications. Specifically, we summarized and categorized the environmental toxins that can affect oogenesis. Here, we provide an overview of oogenesis, highlighting specific stages that may be susceptible to the influence of environmental toxins. Furthermore, we discuss the genetic and molecular mechanisms by which various environmental toxins, including metals, cigarette smoke, and agricultural and industrial toxins, affect female oogenesis. Raising awareness about the potential risks associated with toxin exposure is crucial. However, further research is needed to fully comprehend the mechanisms underlying these effects, including the identification of biomarkers to assess exposure levels and predict reproductive outcomes. By providing a comprehensive overview, this review aims to contribute to a better understanding of the impact of environmental toxins on female oogenesis and guide future research in this field.

Assessing the use of observational methods and real-world data to emulate ongoing randomized controlled trials.

BACKGROUND/AIMS: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. METHODS: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). RESULTS: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. CONCLUSION: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

Clinical Trials Overview: From Explanatory to Pragmatic Clinical Trials.

Clinical trials have been the bedrock of research to evaluate the safety and efficacy of new medical, surgical, or other interventions. Traditional "explanatory" clinical trials have aimed to explain a biological cause (new treatment) and effect (patient outcome) while controlling for many factors that might impact the evaluation, such as restricted eligibility criteria, frequent follow-up visits, and multiple clinical and laboratory measures. Despite the benefits of a well-controlled clinical trial, compromises have been made that can limit who might benefit from a new intervention, can increase complexity of the conduct of a trial, or that lead to excessively long durations of trials. An alternative approach to evaluate the effectiveness of an intervention is based on "pragmatic" clinical trials, which consider how an intervention affects a patient's condition in the real world, accounting for how to optimize an intervention within the operations of busy and diverse clinical practices. Although we describe explanatory and pragmatic trial designs as separate approaches, there is a continuum of approaches that intersect. Some key points are the need to maintain scientific rigor, increase efficiency of clinical trials operations, ensure that trial results can be generalized to a broad spectrum of patients, and balance the needs of real-world clinical care. Pragmatic trials can leverage technology and telecommunication strategies of decentralized trials to further reach underrepresented and underserved patients to close the health disparity gaps.

Application of Innovative Subject Recruitment System for Batch Enrollment: A Pilot Study.

INTRODUCTION: Using a digital process that leverages electronic health records (EHRs) can ease many of the challenges presented by the traditional enrollment process for clinical trials. We tested if automated batch enrollment using a technology-enabled subject recruitment system (TESRS) enhances recruitment while preserving representation of research subjects for the study population in our study setting. METHODS: An ongoing community-based prospective adult cohort study was used to randomize 600 subjects who were eligible by age and residential address to TESRS (n = 300) and standard mailing method (n = 300), respectively, for 3 months. Then, TESRS was initiated and included automatic identification of patients' preference for being contacted (online patient portal vs postal mail) from EHRs and automatic sending out of invitation letters followed by completion of a short online survey for checking eligibility and the digital consent process if eligible. We compared (1) median time to consent from invitation sent out per subject and total subjects recruited after a 3-month recruitment period, (2) the estimated study staff's time, and (3) representation of sociodemographic characteristics (e.g., age, sex, race, SES measured by HOUSES index, and rural residence) between subjects recruited via TESRS and those via traditional mailing methods. RESULTS: Median age of randomized subjects (n = 600) was 63 years with 52.0% female and 89.2% non-Hispanic White. Over a 3-month period, results showed consent rate via TESRS was 13% (39/297) similar to 11% (31/295) via standard mailing. However, recruitment was significantly faster with the TESRS approach (median 7 vs 26 days) given the study staff's effort. Study staff's time saved by using TESRS compared to standard mailing approach was estimated at 40 min per subject (equivalent to 200 h for 300 subjects). No significant differences in characteristics of research subjects from the study population were found. CONCLUSION: Our study demonstrated the utility of TESRS as a subject recruitment digital technology which significantly enhanced the recruitment effort while reducing the study staff burden of recruitment while maintaining the consistency of characteristics of recruited subjects. The strategy and support for implementing and testing TESRS in other study settings should be considered.

Effectiveness of Transcatheter Closure of Patent Foramen Ovale in Clinical Practice.

Background Transcatheter closure of patent foramen ovale (PFO) has reduced the risk of recurrent stroke in patients with cryptogenic strokes in randomized clinical trials. Whether PFO closure in clinical practice is associated with similar benefit remains unknown. Methods and Results We identified patients with PFO and a history of ischemic stroke or transient ischemic attack who were treated with PFO closure or medical therapy in the OptumLabs database. The primary end point was recurrent ischemic stroke or systemic embolization. Secondary outcomes included mortality, all stroke, transient ischemic attack, and major bleeding. A total of 6668 propensity-matched patients were included (PFO closure n=4111; medical therapy n=2557). The incidence of stroke or systemic embolization per 100 person-years was 2.38 after PFO cohort and 2.99 with medical therapy (hazard ratio [HR], 0.85 [95% CI, 0.68-1.05], P=0.13). Mortality was lower in the PFO closure cohort (1.78 versus 2.59 per 100 person-years: HR, 0.69 [95% CI, 0.55-0.87], P=0.002). Falsification end points showed that this difference is unlikely to be completely explained by residual confounders. There were no significant differences between the groups in secondary end points including intracranial hemorrhage and major bleeding except for an increase in nonintracranial hemorrhage bleeding among patients treated with oral anticoagulation (1.42 versus 2.16 per 100 person-years: HR, 0.69 [95% CI, 0.48-0.99], P=0.043). The main end point was consistent in subanalyses including patients <60 years of age, patients with prior stroke, and those treated after the publication of the positive PFO trials in 2017. Conclusions In contemporary US practice, PFO closure is not associated with lower rates of recurrent ischemic stroke or systemic embolization compared with medical therapy. Potential reasons for this discrepancy warrant further investigation.

Comparative Effectiveness of Anticoagulants in Patients With Cancer-Associated Thrombosis.

Importance: Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored. Objectives: To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting. Design, Setting, and Participants: This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021. Exposures: The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin. Main Outcomes and Measures: Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs. Results: This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs. Conclusions and Relevance: In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.

Contemporary trends and barriers to oral anticoagulation therapy in Non-valvular atrial fibrillation during DOAC predominant era.

There is a need to reassess contemporary oral anticoagulation (OAC) trends and barriers against guideline directed therapy in the United States. Most previous studies were performed before major guideline changes recommended direct oral anticoagulant (DOAC) use over warfarin or have otherwise lacked patient level data. Data on overuse of OAC in low-risk group is also limited. To address these knowledge gaps, we performed a nationwide analysis to analyze current trends. This is a retrospective cohort study assessing non-valvular AF identified using a large United States de-identified administrative claims database, including commercial and Medicare Advantage enrollees. Prescription fills were assessed within a 90-day follow-up from the patient's index AF encounter between January 1, 2016, and December 31, 2020. Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, moderate-, and high-risk groups (according to CHA2DS2-VASc score). An over (29.6%) and under (52.2%) utilization of OAC was reported in low- and high-risk AF patients. A considerably high frequency for warfarin use was also noted among high-risk group patients taking OAC (33.1%). The results suggest that anticoagulation use for stroke prevention in the United States is still comparable to the pre-DOAC era studies. About half of newly diagnosed high-risk non-valvular AF patients remain unprotected against stroke risk. Several predictors of OAC and DOAC use were also identified. Our findings may identify a population at risk of complications due to under- or over-treatment and highlight the need for future quality improvement efforts.

Identifying treatment heterogeneity in atrial fibrillation using a novel causal machine learning method.

BACKGROUND: Lifelong oral anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent stroke. Over the last decade, multiple new oral anticoagulants (OACs) have expanded the number of treatment options for these patients. While population-level effectiveness of OACs has been compared, it is unclear if there is variability in benefit and risk across patient subgroups. METHODS: We analyzed claims and medical data for 34,569 patients who initiated a nonvitamin K antagonist oral anticoagulant (non-vitamin K antagonist oral anticoagulant (NOAC); apixaban, dabigatran, and rivaroxaban) or warfarin for nonvalvular AF between 08/01/2010 and 11/29/2017 from the OptumLabs Data Warehouse. A machine learning (ML) method was applied to match different OAC groups on several baseline variables including, age, sex, race, renal function, and CHA2DS2 -VASC score. A causal ML method was then used to discover patient subgroups characterizing the head-to-head treatment effects of the OACs on a primary composite outcome of ischemic stroke, intracranial hemorrhage, and all-cause mortality. RESULTS: The mean age, number of females and white race in the entire cohort of 34,569 patients were 71.2 (SD, 10.7) years, 14,916 (43.1%), and 25,051 (72.5%) respectively. During a mean follow-up of 8.3 (SD, 9.0) months, 2,110 (6.1%) of patients experienced the composite outcome, of whom 1,675 (4.8%) died. The causal ML method identified 5 subgroups with variables favoring apixaban over dabigatran; 2 subgroups favoring apixaban over rivaroxaban; 1 subgroup favoring dabigatran over rivaroxaban; and 1 subgroup favoring rivaroxaban over dabigatran in terms of risk reduction of the primary endpoint. No subgroup favored warfarin and most dabigatran vs warfarin users favored neither drug. The variables that most influenced favoring one subgroup over another included Age, history of ischemic stroke, thromboembolism, estimated glomerular filtration rate, Race, and myocardial infarction. CONCLUSIONS: Among patients with AF treated with a NOAC or warfarin, a causal ML method identified patient subgroups with differences in outcomes associated with OAC use. The findings suggest that the effects of OACs are heterogeneous across subgroups of AF patients, which could help personalize the choice of OAC. Future prospective studies are needed to better understand the clinical impact of the subgroups with respect to OAC selection.

Screening for peripartum cardiomyopathies using artificial intelligence in Nigeria (SPEC-AI Nigeria): Clinical trial rationale and design.

BACKGROUND: Artificial intelligence (AI), and more specifically deep learning, models have demonstrated the potential to augment physician diagnostic capabilities and improve cardiovascular health if incorporated into routine clinical practice. However, many of these tools are yet to be evaluated prospectively in the setting of a rigorous clinical trial-a critical step prior to implementing broadly in routine clinical practice. OBJECTIVES: To describe the rationale and design of a proposed clinical trial aimed at evaluating an AI-enabled electrocardiogram (AI-ECG) for cardiomyopathy detection in an obstetric population in Nigeria. DESIGN: The protocol will enroll 1,000 pregnant and postpartum women who reside in Nigeria in a prospective randomized clinical trial. Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. Women aged 18 and older, seen for routine obstetric care at 6 sites (2 Northern and 4 Southern) in Nigeria will be included. Participants will be randomized to the study intervention or control arm in a 1:1 fashion. This study aims to enroll participants representative of the general obstetric population at each site. The primary outcome is a new diagnosis of cardiomyopathy, defined as left ventricular ejection fraction (LVEF) < 50% during pregnancy or within 12 months postpartum. Secondary outcomes will include the detection of impaired left ventricular function (at different LVEF cut-offs), and exploratory outcomes will include the effectiveness of AI-ECG tools for cardiomyopathy detection, new diagnosis of cardiovascular disease, and the development of composite adverse maternal cardiovascular outcomes. SUMMARY: This clinical trial focuses on the emerging field of cardio-obstetrics and will serve as foundational data for the use of AI-ECG tools in an obstetric population in Nigeria. This study will gather essential data regarding the utility of the AI-ECG for cardiomyopathy detection in a predominantly Black population of women and pave the way for clinical implementation of these models in routine practice. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05438576.

Outcomes of Early Rhythm Control Therapy in Patients With Atrial Fibrillation and a High Comorbidity Burden in Large Real-World Cohorts.

BACKGROUND: A recent subanalysis of the EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) suggests a stronger benefit of early rhythm control (ERC) in patients with atrial fibrillation and a high comorbidity burden when compared to patients with a lower comorbidity burden. METHODS: We identified 109 739 patients with newly diagnosed atrial fibrillation in a large United States deidentified administrative claims database (OptumLabs) and 11 625 patients in the population-based UKB (UK Biobank). ERC was defined as atrial fibrillation ablation or antiarrhythmic drug therapy within the first year after atrial fibrillation diagnosis. Patients were classified as (1) ERC and high comorbidity burden (CHA2DS2-VASc score ≥4); (2) ERC and lower comorbidity burden (CHA2DS2-VASc score 2-3); (3) no ERC and high comorbidity burden; and (4) no ERC and lower comorbidity burden. Patients without an elevated comorbidity burden (CHA2DS2-VASc score 0-1) were excluded. Propensity score overlap weighting and cox proportional hazards regression were used to balance patients and compare groups for the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction as well as for a primary composite safety outcome of death, stroke, and serious adverse events related to ERC. RESULTS: In both cohorts, ERC was associated with a reduced risk for the primary composite outcome in patients with a high comorbidity burden (OptumLabs: hazard ratio, 0.83 [95% CI 0.72-0.95]; P=0.006; UKB: hazard ratio, 0.77 [95% CI, 0.63-0.94]; P=0.009). In patients with a lower comorbidity burden, the difference in outcomes was not significant (OptumLabs: hazard ratio, 0.92 [95% CI, 0.54-1.57]; P=0.767; UKB: hazard ratio, 0.94 [95% CI, 0.83-1.06]; P=0.310). The comorbidity burden interacted with ERC in the UKB (interaction- P=0.027) but not in OptumLabs (interaction-P=0.720). ERC was not associated with an increased risk for the primary safety outcome. CONCLUSIONS: ERC is safe and may be more favorable in a population-based sample of patients with high a comorbidity burden (CHA2DS2-VASc score ≥4).

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

BACKGROUND: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations. METHODS: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization. RESULTS: A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis. CONCLUSIONS: In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).

Cardiovascular Events Among Survivors of Sepsis Hospitalization: A Retrospective Cohort Analysis.

Background Sepsis is associated with an elevated risk of late cardiovascular events among hospital survivors. Methods and Results We included OptumLabs Data Warehouse patients from 2009 to 2019 who survived a medical/nonsurgical hospitalization lasting at least 2 nights. The association between sepsis during hospitalization, based on explicit and implicit discharge International Classification of Diseases, Ninth Revision (ICD-9)/Tenth Revision (ICD-10) diagnosis codes, with subsequent death and rehospitalization was analyzed using Kaplan-Meier survival analysis and multivariable Cox proportional-hazards models. The study population included 2 258 464 survivors of nonsurgical hospitalization (5 396 051 total patient-years of follow-up). A total of 808 673 (35.8%) patients had a sepsis hospitalization, including implicit sepsis only in 448 644, explicit sepsis only in 124 841, and both in 235 188. Patients with sepsis during hospitalization had an elevated risk of all-cause mortality (adjusted hazard ratio [HR], 1.27 [95% CI, 1.25-1.28]; P<0.001), all-cause rehospitalization (adjusted HR, 1.38 [95% CI, 1.37-1.39]; P<0.001), and cardiovascular hospitalization (adjusted HR, 1.43 [95% CI, 1.41-1.44]; P<0.001), especially heart failure hospitalization (adjusted HR, 1.51 [95% CI, 1.49-1.53]). Patients with implicit sepsis had higher risk than those with explicit sepsis. A sensitivity analysis using the first hospitalization yielded concordant results for cardiovascular hospitalization (adjusted HR, 1.78 [95% CI, 1.76-1.78]; P<0.001), as did a propensity-weighted analysis (adjusted HR, 1.52 [95% CI, 1.50-1.54]; P<0.001). Conclusions Survivors of sepsis hospitalization are at elevated risk of early and late post-discharge death as well as cardiovascular and non-cardiovascular rehospitalization. This hazard spans the spectrum of cardiovascular events and may suggest that sepsis is an important cardiovascular risk factor.

The Digitization and Decentralization of Clinical Trials.

Now, more than ever, digital technology has made its way into the daily lives of billions across the globe, and the widespread use of this technology has also allowed a digital window into consumers' and patients' daily lives, respectively. In a similar way, the practice of medicine has digitally evolved with the application of electronic health records and development of wearable/portable consumer-based medical devices (eg, Apple Watch ECG and Kardia Mobile by AliveCor). Alongside the increased use of digital technology in clinical care (eg, telehealth and wearable arrhythmia detection), clinical investigators have harnessed this powerful stockpile of data to gain insight into what happens to patients beyond the clinic walls. In this thematic review, we show the impact of digital advancements on the clinical trial process from recruitment and enrollment to interventions and data collection. We also show the pragmatism of this decentralized process and how it will mitigate the limitations of conventional randomized controlled trials. Finally, while pushing the boundaries of tech, we also describe a few limitations of this rapidly growing field to understand better what gaps need to be bridged in the future.