Search

OBJECTIVE: Patients with diabetes mellitus (DM) and concomitant atherosclerotic cardiovascular disease (ASCVD) must be on the most effective dose of aspirin to mitigate risk of future adverse cardiovascular events. RESEARCH DESIGN AND METHODS: ADAPTABLE, an open-label, pragmatic study, randomized patients with stable, chronic ASCVD to 81 mg or 325 mg of daily aspirin. The effects of aspirin dosing was assessed on the primary effectiveness outcome, a composite of all-cause death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome of hospitalization for major bleeding. In this prespecified analysis, we used Cox proportional hazards models to compare aspirin dosing in patients with and without DM for the primary effectiveness and safety outcome. RESULTS: Of 15,076 patients, 5,676 (39%) had DM of whom 2,820 (49.7%) were assigned to 81 mg aspirin and 2,856 (50.3%) to 325 mg aspirin. Patients with versus without DM had higher rates of the composite cardiovascular outcome (9.6% vs. 5.9%; P < 0.001) and bleeding events (0.78% vs. 0.50%; P < 0.001). When comparing 81 mg vs. 325 mg of aspirin, patients with DM had no difference in the primary effectiveness outcome (9.3% vs. 10.0%; hazard ratio [HR] 0.98 [95% CI 0.83–1.16]; P = 0.265) or safety outcome (0.87% vs. 0.69%; subdistribution HR 1.25 [95% CI 0.72–2.16]; P = 0.772). CONCLUSIONS: This study confirms the inherently higher risk of patients with DM irrespective of aspirin dosing. Our findings suggest that a higher dose of aspirin yields no added clinical benefit, even in a more vulnerable population. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were 232.71 ml for BMS-986020 and 2130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs. [ABSTRACT FROM AUTHOR]

The article focuses on the Rapid Acceleration of Diagnostics-Underserved Populations(RADx-UP) program, a consortium of health disparities research projects throughout the U.S. which aims to understand factors that led to the disproportionate burden of the COVID-19 pandemic on underserved populations. Topics covered include the goals of the RADx-UP Coordination and Data Collection Center (CDCC), and a background on the CDCC community engagement core.

Objective The Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) program is a consortium of community-engaged research projects with the goal of increasing access to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) tests in underserved populations. To accelerate clinical research, common data elements (CDEs) were selected and refined to standardize data collection and enhance cross-consortium analysis. Materials and Methods The RADx-UP consortium began with more than 700 CDEs from the National Institutes of Health (NIH) CDE Repository, Disaster Research Response (DR2) guidelines, and the PHENotypes and eXposures (PhenX) Toolkit. Following a review of initial CDEs, we made selections and further refinements through an iterative process that included live forums, consultations, and surveys completed by the first 69 RADx-UP projects. Results Following a multistep CDE development process, we decreased the number of CDEs, modified the question types, and changed the CDE wording. Most research projects were willing to collect and share demographic NIH Tier 1 CDEs, with the top exception reason being a lack of CDE applicability to the project. The NIH RADx-UP Tier 1 CDE with the lowest frequency of collection and sharing was sexual orientation. Discussion We engaged a wide range of projects and solicited bidirectional input to create CDEs. These RADx-UP CDEs could serve as the foundation for a patient-centered informatics architecture allowing the integration of disease-specific databases to support hypothesis-driven clinical research in underserved populations. Conclusion A community-engaged approach using bidirectional feedback can lead to the better development and implementation of CDEs in underserved populations during public health emergencies. [ABSTRACT FROM AUTHOR]

Abstract Background Most clinical trial publications include figures, but there is little guidance on what results should be displayed as figures and how. Purpose To evaluate the current use of figures in Trial reports, and to make constructive suggestions for future practice. Methods We surveyed all 77 reports of randomised controlled trials in five general medical journals during November 2006 to January 2007. The numbers and types of figures were determined, and then each Figure was assessed for its style, content, clarity and suitability. As a consequence, guidelines are developed for presenting figures, both in general and for each specific common type of Figure. Results Most trial reports contained one to three figures, mean 2.3 per article. The four main types were flow diagram, Kaplan Meier plot, Forest plot (for subgroup analyses) and repeated measures over time: these accounted for 92% of all figures published. For each type of figure there is a considerable diversity of practice in both style and content which we illustrate with selected examples of both good and bad practice. Some pointers on what to do, and what to avoid, are derived from our critical evaluation of these articles' use of figures. Conclusion There is considerable scope for authors to improve their use of figures in clinical trial reports, as regards which figures to choose, their style of presentation and labelling, and their specific content. Particular improvements are needed for the four main types of figures commonly used.

Background: Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex.Methods: The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (≥55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746).Results: Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ≈10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%).Conclusions: Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men. [ABSTRACT FROM AUTHOR]

Background: Kidney dysfunction is prevalent and impacts prognosis in patients with acute decompensated heart failure (ADHF). However, most previous reports were from a single hospital, limiting their generalizability. Also, contemporary data using new equation for estimated glomerular filtration rate (eGFR) are needed. Methods and results: We analyzed data from the ARIC Community Surveillance for ADHF conducted for residents aged ≥55 years in four US communities between 2005–2011. All ADHF cases (n = 5, 391) were adjudicated and weighted to represent those communities (24,932 weighted cases). The association of kidney function (creatinine-based eGFR by the CKD-EPI equation and blood urea nitrogen [BUN]) during hospitalization with 1-year mortality was assessed using logistic regression. Based on worst and last serum creatinine, there were 82.5% and 70.6% with reduced eGFR (<60 ml/min/1.73m2) and 37.4% and 26.6% with severely reduced eGFR (<30 ml/min/1.73m2), respectively. Lower eGFR (regardless of last or worst eGFR), particularly eGFR <30 ml/min/1.73m2, was significantly associated with higher 1-year mortality independently of potential confounders (odds ratio 1.60 [95% CI 1.26–2.04] for last eGFR 15–29 ml/min/1.73m2 and 2.30 [1.76–3.00] for <15 compared to eGFR ≥60). The association was largely consistent across demographic subgroups. Of interest, when both eGFR and BUN were modeled together, only BUN remained significant. Conclusions: Severely reduced eGFR (<30 ml/min/1.73m2) was observed in ~30% of ADHF cases and was an independent predictor of 1-year mortality in community. For prediction, BUN appeared to be superior to eGFR. These findings suggest the need of close attention to kidney dysfunction among ADHF patients. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to characterize the repeatability of ectopic beats, defined by premature atrial contractions (PACs) and premature ventricular contractions (PVCs), on ambulatory electrocardiogram (aECG) monitoring and evaluate the effect of length of aECG monitoring on the repeatability estimates.Methods: This analysis includes 95 randomly selected participants from the Atherosclerosis Risk in Communities Study (ARIC; 2011-2013). The participants wore a Holter monitor for two, 48-hr periods separated by a mean of 38 days following an identical, standardized protocol. We divided each 48-hr recording into 3-, 6-, 12-, and 24-hr recording periods and calculated intraclass correlation coefficients (ICCs) for PACs and PVCs and also as a percentage of the corresponding total of recorded beats per hour among these periods.Results: All participants had ≥1 PAC during the 48-hr recordings, and only two participants had no PVCs. ICCs were >0.83 for all indices and recording lengths ≥12 hrs. ICCs were intermediate for 6-hr recordings (range 0.80-0.83) and lower for 3-hr recordings (range 0.74-0.80). The ratio of the between- to within-participant variation increased with recording length.Conclusion: Repeatability of PACs and PVCs was excellent for recording lengths of 6-24 hr and fair for 3 hr. Repeatability varies over shorter duration recordings within the 48-hr recording period, and thus the present results have implications for detection algorithms for ectopic beats and can facilitate epidemiologic and clinical applications in which knowledge of measurement variability and misclassification are needed. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCT) are the gold standard for evaluating the effectiveness and safety of interventions and treatments, yet traditional clinical trials have relied on cumbersome and redundant processes such as electronic data entry which involves manual abstraction of already available electronic health record (EHR) data. This review focuses on the opportunities to expand the use of EHR data for pragmatic clinical trials using methods and lessons learned from the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, the demonstration project from PCORnet® (the National Patient-Centered Clinical Research Network). [ABSTRACT FROM AUTHOR]

Objective: Increasingly, epidemiologic studies use administrative data to identify atrial fibrillation (AF). Capture of incident AF is not well documented. We examined incidence rates and concordance of AF diagnosis based on active cohort follow-up versus surveillance of Centers for Medicare and Medicaid Services data in the Atherosclerosis Risk in Communities study. Methods: Atherosclerosis Risk in Communities cohort participants without prevalent AF enrolled in fee-for-service Medicare, with inpatient and outpatient coverage, for at least 12 continuous months between 1991 and 2009 were included. In active Atherosclerosis Risk in Communities study follow-up, annual telephone calls captured hospitalizations and deaths with incident AF diagnosis codes. For Centers for Medicare and Medicaid Services data, incident AF was defined by billed inpatient and outpatient diagnoses. Results: Of 10,134 eligible cohort participants, 738 developed AF according to both Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services data; an additional 93 and 288 incident cases were identified using only Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services data, respectively. Incidence rates per 1,000 person-years were 10.8 (95% confidence interval: 10.1–11.6) and 13.6 (95% confidence interval: 12.8–14.4) in Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services, respectively; agreement was 96%; kappa was 0.77 (95% confidence interval: 0.75–0.80). Earlier AF ascertainment by one system versus the other was not associated with any cardiovascular disease risk factors, after accounting for sociodemographic factors. Additional Centers for Medicare and Medicaid Services events did not alter observed associations between risk factors and AF. Conclusion: Among fee-for-service enrollees, AF incidence rates were slightly lower for active cohort follow-up than for Centers for Medicare and Medicaid Services surveillance, because the latter included outpatient atrial fibrillation. Concordance was high and combining the two approaches could provide a more complete picture of newly-diagnosed AF. [ABSTRACT FROM AUTHOR]

An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records.During 2005-2007, all hospitalizations were identified from 4 US communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by International Classification of Diseases discharge codes and demographics from men and women aged ≥55 years. The HF classification algorithm was automated and applied to 2729 (n=13 854 weighted hospitalizations) hospitalizations in which either brain natriuretic peptide measures or ejection fraction were documented (mean age, 75 years). There were 1403 (54%; n=7534 weighted) events classified as acute decompensated HF by the automated algorithm, and 1748 (68%; n=9276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between acute decompensated HF by physician reviewer panel and the automated algorithm was moderate (κ=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard were 0.68 (95% confidence interval, 0.67-0.69) and 0.75 (95% confidence interval, 0.74-0.76), respectively.Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared with a standardized physician reviewer panel. [ABSTRACT FROM AUTHOR]

Background: The ADAPTABLE trial (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) is the first randomized trial conducted within the National Patient-Centered Clinical Research Network to use the electronic health record data formatted into a common data model as the primary source of end point ascertainment, without confirmation by standard adjudication. The objective of this prespecified study is to assess the validity of nonfatal end points captured from the National Patient-Centered Clinical Research Network, using traditional blinded adjudication as the gold standard.Methods: A total of 15 076 participants with established atherosclerotic cardiovascular disease were randomized to two doses of aspirin (81 mg and 325 mg once daily). Nonfatal end points (hospitalization for nonfatal myocardial infarction, nonfatal stroke, and major bleeding requiring transfusion of blood products) were captured with the use of programming algorithms applied to National Patient-Centered Clinical Research Network data. A random subset of end points was independently reviewed by a disease-specific expert adjudicator. The positive predictive value of the programming algorithms were calculated separately for end points listed as primary and as nonprimary diagnoses.Results: A total of 225 end points were identified (91 myocardial infarction events, 89 stroke events, and 45 bleeding events), including 142 (63%) that were listed as primary diagnoses. Complete source documents were missing for 14% of events. The positive predictive value were 90%, 72%, and 93% for hospitalizations for myocardial infarction, stroke, and major bleeding, respectively, as compared to adjudication. When only primary diagnoses were considered, positive predictive value were 93%, 91%, and 97%, respectively. When only nonprimary diagnoses were considered, positive predictive value were 82%, 36%, and 71%.Conclusions: As compared with blinded adjudication, clinical end point ascertainment from queries of the National Patient-Centered Clinical Research Network distributed harmonized data was valid to identify hospitalizations for myocardial infarction in ADAPTABLE. The proportion of contradicted events was high for hospitalizations for bleeding and strokes when nonprimary diagnoses were analyzed, but not when only primary diagnoses were considered. [ABSTRACT FROM AUTHOR]

The article presents an overview of how to interpret figures in reports of clinical trials. A discussion of the meaning and function of flow diagrams, Kaplan-Meier plots, forest plots and repeated measure plots, is presented. The importance of assessing visual evidence as a part of treatment evidence is discussed. An overview of what makes a good statistical figure, including an emphasis on clarity and the ability to be independently interpreted, is offered. An examination of several statistical figures and charts is presented.

Background: Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture.Methods: The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions.Conclusion: This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder. [ABSTRACT FROM AUTHOR]

Background: Most clinical trial publications include figures, but there is little guidance on what results should be displayed as figures and how. Purpose: To evaluate the current use of figures in Trial reports, and to make constructive suggestions for future practice. Methods: We surveyed all 77 reports of randomised controlled trials in five general medical journals during November 2006 to January 2007. The numbers and types of figures were determined, and then each Figure was assessed for its style, content, clarity and suitability. As a consequence, guidelines are developed for presenting figures, both in general and for each specific common type of Figure. Results: Most trial reports contained one to three figures, mean 2.3 per article. The four main types were flow diagram, Kaplan Meier plot, Forest plot (for subgroup analyses) and repeated measures over time: these accounted for 92% of all figures published. For each type of figure there is a considerable diversity of practice in both style and content which we illustrate with selected examples of both good and bad practice. Some pointers on what to do, and what to avoid, are derived from our critical evaluation of these articles' use of figures. Conclusion: There is considerable scope for authors to improve their use of figures in clinical trial reports, as regards which figures to choose, their style of presentation and labelling, and their specific content. Particular improvements are needed for the four main types of figures commonly used. [ABSTRACT FROM AUTHOR]

We consider efficient study designs to estimate sensitivity and specificity of a candidate diagnostic or screening test. Our focus is the setting in which the candidate test is inexpensive to administer compared to evaluation of disease status, and the test results, available in a large cohort, can be used as a basis for sampling subjects for verification of disease status. We examine designs in which disease status is verified in a sample chosen so as to optimize estimation of either sensitivity or specificity. We then propose a sequential design in which the first step of sampling is conducted to efficiently estimate specificity. If the candidate test is determined to be of sufficient specificity, then step two of sampling is conducted to estimate sensitivity. We propose estimators based on this sequential sampling scheme, and show that the performance of these estimators is excellent. We develop sample size calculations for the sequential design, and show that this design, in most situations, compares favourably in terms of expected sample size to a fixed size design. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]