Aims
Treatment response to vericiguat, based on baseline N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA ...trial population by post hoc analysis of combined lower three quartiles Q1–Q3 vs. the upper quartile Q4.
Methods and results
VICTORIA participants with available baseline NT‐proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1–Q3 (NT‐proBNP: Q1, ≤1556 pg/mL; Q2, >1556–2816 pg/mL; and Q3, >2816–5314 pg/mL), patients in Q4 (NT‐proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P < 0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1–Q3, patients in Q4 had higher mean Meta‐Analysis Global Group in Chronic Heart Failure risk score (27.3 ± 6.6 vs. 23.5 ± 6.4; P < 0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5 ± 25.5 vs. 65.0 ± 26.8 mL/min/1.73 m2; P < 0.0001) and haemoglobin (12.8 ± 2.0 vs. 13.6 ± 1.9 g/dL; P < 0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P = 0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P < 0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1–Q3 and Q4, respectively (P < 0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient‐years for vericiguat and placebo in Q1–Q3 hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69–0.88, P < 0.001 and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99–1.34, P = 0.070).
Serious adverse events were more frequent in NT‐proBNP Q4 (total population) compared with Q1–Q3 (38.3 vs. 32.3%; P = 0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1–Q3 (5.8 vs. 2.4%; P < 0.0001).
Conclusions
Plasma NT‐proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT‐proBNP values are probably too far advanced, suffering more co‐morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat.
Background: Assessment of reliability is one of the key components of the validation process designed to demonstrate that a novel clinical measure assessed by a digital health technology tool is ...fit-for-purpose in clinical research, care, and decision-making. Reliability assessment contributes to characterization of the signal-to-noise ratio and measurement error and is the first indicator of potential usefulness of the proposed clinical measure. Summary: Methodologies for reliability analyses are scattered across literature on validation of PROs, wet biomarkers, etc., yet are equally useful for digital clinical measures. We review a general modeling framework and statistical metrics typically used for reliability assessments as part of the clinical validation. We also present methods for the assessment of agreement and measurement error, alongside modified approaches for categorical measures. We illustrate the discussed techniques using physical activity data from a wearable device with an accelerometer sensor collected in clinical trial participants. Key Messages: This paper provides statisticians and data scientists, involved in development and validation of novel digital clinical measures, an overview of the statistical methodologies and analytical tools for reliability assessment.
Objective
To estimate the relative contribution of malaria and other potential determinants to current anaemia prevalence in Rwanda.
Methods
The database for this study was the Rwanda Demographic and ...Health Survey 2010. Haemoglobin and malaria test results, and additional exposures ascertained through mothers’ interviews, were analysed for all eligible children age 6–59 months (n = 4068), in addition to diet data available for the youngest under 5‐year‐old per household. We examined anaemia‐exposure associations through forward logistic regression, first for the overall population (n = 3685), and second, for the subpopulation with diet data (n = 1934).
Results
In the overall study population, malaria was strongly associated with anaemia (OR = 6.83, 95% CI: 2.90–16.05), but population impact was modest (population‐attributable fraction = 2.5%). Factors associated with lower odds of anaemia were recent de‐worming medication (six months; OR = 0.60, 95% CI: 0.49–0.74), female sex (OR = 0.76, 95% CI: 0.66–0.87), increasing age, residence in North Province and educated mother. Being underweight and recent fever (two weeks) were associated with higher odds. In the subpopulation with diet data, odds were lower with consumption of vitamin A‐rich foods (OR = 0.66, 95% CI: 0.50–0.88); and higher in households with many young children.
Conclusions
Malaria remains a strong determinant of anaemia for the individual child: transmission control efforts must be maintained. At population level, to further reduce anaemia prevalence, promoting regular vitamin A intake from natural sources and reducing intestinal helminths burden appear the most promising strategies to explore; exploring potential hitherto unidentified sex‐linked factors is warranted.
Objectif
Estimer la contribution relative du paludisme et d'autres déterminants potentiels à la prévalence actuelle de l'anémie au Rwanda.
Méthodes
La base de données de cette étude provient de la Surveillance Démographique et de Santé du Rwanda de 2010. Les résultats d'hémoglobine et du test du paludisme, et les expositions additionnelles constatées à travers des interviews avec les mères, ont été analysés pour tous les enfants admissibles de 6 à 59 mois (n = 4068), en plus des données sur l'alimentation disponibles pour les plus jeunes de moins de 5 ans par ménage. Nous avons examiné les associations d'exposition à l'anémie par l'analyse de régression logistique, d'abord pour la population générale (N = 3685) et ensuite pour un sous‐ensemble de la population avec des données nutritionnelles (n = 1934).
Résultats
Dans la population générale de l’étude, le paludisme était fortement associé à l'anémie (OR = 6,83, IC95%: 2,90 à 16,05), mais l'impact de la population était modeste (fraction attribuable à la population = 2,5%). Les facteurs associés à un risque plus faible de l'anémie étaient des médicaments pour le déparasitage récent (six mois; OR = 0,60, IC95%: 0,49 à 0,74), le sexe féminin (OR = 0,76, IC95%: 0,66 à 0,87), l’âge croissant, la résidence dans la Province du Nord et une mère instruite. L'insuffisance pondérale et une fièvre récente (deux semaines) étaient associées à des chances plus élevées. Dans le sous‐ensemble de la population avec des données nutritionnelles, les chances étaient plus faibles avec la consommation d'aliments riches en vitamine A (OR = 0,66, IC95%: 0,50 au 0,88) et plus élevées dans les ménages avec de nombreux jeunes enfants.
Conclusions
Le paludisme demeure un déterminant important de l'anémie pour l'enfant: les efforts de lutte contre la transmission devraient être maintenus. Au niveau de la population, afin de réduire davantage la prévalence de l'anémie, la promotion de la prise régulière de sources naturelles de vitamine A et la réduction de la charge des helminthes intestinaux semble les stratégies les plus prometteuses à explorer. La recherche des facteurs potentiels liés au sexe non identifiés jusqu'ici est justifiée.
Objetivo
Calcular la contribución relativa de la malaria y otros determinantes potenciales a la actual prevalencia de anemia en Ruanda.
Métodos
La base de datos para este estudio fue el censo demográfico y sanitario de Ruanda del 2010. Se analizaron por hogar los resultados de las pruebas de hemoglobina y malaria y las exposiciones adicionales determinadas mediante entrevistas con las madres, para todos los niños elegibles y con edades entre los 6‐59 meses (N=4068), además de datos sobre la dieta disponibles para los más jóvenes, menores de 5 años. Hemos examinado las asociaciones de exposición a la anemia mediante regresión logística, primero en la población general (N=3685) y después para la subpoblación para la que contábamos con datos sobre la dieta (N=1934).
Resultados
En el estudio de la población general, la malaria estaba fuertemente asociada con la anemia (OR=6.83, IC 95%:2.90‐16.05), pero el impacto sobre la población era modesto (fracción atribuible a la población =2.5%). Los factores asociados con la menor probabilidad de anemia eran haber tomado recientemente medicación antiparasitaria (seis meses; OR=0.60, IC 95%: 0.49‐0.74), ser del sexo femenino (OR=0.76, IC 95%:0.66‐0.87), mayor edad, tener la residencia en la Provincia del Norte y tener una madre con educación. El estar bajo de peso y haber tenido fiebre recientemente (dos semanas) estaba asociado con una mayor probabilidad. En la subpoblación con datos sobre la dieta, la probabilidad era menor con el consumo de alimentos ricos en vitamina A (OR=0.66, IC 95%: 0.50‐0.88); y mayor en hogares con muchos niños pequeños.
Conclusiones
La malaria continúa siendo un determinante importante de anemia para el individuo niño. Los esfuerzos de control de la transmisión deben mantenerse. A nivel poblacional, para reducir más la prevalencia de anemia, promover la ingesta regular de vitamina A de fuentes naturales y reducir la carga por helmintos intestinales parecen ser las estrategias más prometedoras a explorar. Se justifica la investigación de los potenciales factores ligados al sexo, no identificados hasta ahora.
ABSTRACT
The exponential growth in digital technology coupled with the global coronavirus disease 2019 pandemic is driving a profound change in the delivery of medical care and research conduct. The ...growing availability of electronic monitoring, electronic health records, smartphones and other devices and access to ever greater computational power provides not only new opportunities, but also new challenges. Artificial intelligence (AI) exemplifies the potential of this digital revolution, which also includes other tools such as mobile health (mHealth) services and wearables. Despite digital technology becoming commonplace, its use in medicine and medical research is still in its infancy, with many clinicians and researchers having limited experience with such tools in their usual practice. This article, derived from the ‘Digital Health and Artificial Intelligence’ session of the Kidney Disease Clinical Trialists virtual workshop held in September 2020, aims to illustrate the breadth of applications to which digital tools and AI can be applied in clinical medicine and research. It highlights several innovative projects incorporating digital technology that range from streamlining medical care of those with acute kidney injury to the use of AI to navigate the vast genomic and proteomic data gathered in kidney disease. Important considerations relating to any new digital health project are presented, with a view to encouraging the further evolution and refinement of these new tools in a manner that fosters collaboration and the generation of robust evidence.
Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large ( ...e.g. , ≥50%) decrease in GFR. Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. In addition, components of the end point are considered of equal importance; however, their clinical significance varies. For example, kidney function replacement therapy initiation is likely to be clinically more meaningful than GFR decline of ≥50%. By contrast, hierarchical composite end points (HCEs) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically used in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy end point.
The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point ...components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point.
The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR. However, the statistical method does not weigh the relative clinical importance of the end point components. A HCE accounts for the clinical importance of the end point components and enables combining dichotomous outcomes with continuous measures.
We developed and validated a new HCE for kidney disease progression, performing post hoc analyses of seven major Phase 3 placebo-controlled trials that assessed the effects of canagliflozin, dapagliflozin, finerenone, atrasentan, losartan, irbesartan, and aliskiren in patients with CKD. We calculated the win odds (WOs) for treatment effects on a kidney HCE, defined as a hierarchical composite of all-cause mortality; kidney failure; sustained 57%, 50%, and 40% GFR declines from baseline; and GFR slope. The WO describes the odds of a more favorable outcome for receiving the active compared with the control. We compared the WO with the hazard ratio (HR) of the primary kidney outcome of the original trials.
In all trials, treatment effects calculated with the WO reflected a similar direction and magnitude of the treatment effect compared with the HR. Clinical trials incorporating the HCE would achieve increased statistical power compared with the established composite end point at equivalent sample sizes.
In seven major kidney clinical trials, the WO and HR provided similar direction of treatment effect estimates with smaller HRs associated with larger WOs. The prioritization of clinical outcomes and inclusion of broader composite end points makes the HCE an attractive alternative to the established kidney end point.
The performance of electronic health record (EHR) screening for heart failure with preserved ejection fraction (HFpEF) is variable. We sought to characterize HFpEF populations identified by different ...EHR screening strategies and associated outcomes.
We retrospectively analyzed 9,263 consecutive patients from an academic referral center who underwent both echocardiography and right heart catheterization (RHC) within six months of each other between January 2008 - December 2018. Three EHR-based screening strategies identified patients with HFpEF using ICD-9/10 codes (n=5,274), H2FpEF score ≥6 and ejection fraction (EF) ≥50% (n=1,730), and RHC criteria of pulmonary capillary wedge ≥15 mmHg and EF ≥50% (n=2,224). Primary outcomes of interest were incident heart failure hospitalizations (HFH) and all-cause mortality over 10 years. For each HFpEF definition, cumulative mortality event rates were estimated as a function of follow-up time with the use of the Kaplan-Meier method and incident HFH rates by a nonparametric cumulative incidence function estimator accounting for all-cause mortality as a competing risk. Overall population who underwent RHC were 61.5 (±14.7) years old, 44% female, and 73% Caucasian/White. Of 6,353 patients who met any HFpEF criteria, 33% satisfied ≥2 HFpEF screening methods. Female sex was more common among RHC-based HFpEF (55%) compared to other methods (47% for H2FpEF and 43% for ICD). Atrial fibrillation was substantial higher among HFpEF identified by the H2FPEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Cumulative incidence rates for HFH and all-cause mortality are shown in Figure.
Differences in EHR-based HFpEF definitions identifies populations with varying baseline characteristics and outcomes. These data have implications for EHR screening for HFpEF.
Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory focused on recommendations ...for meaningful change and use of actigraphy as an end point in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy.
Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID Medline, PubMed, and Cochrane Review. Data on trial characteristics and results were collected.
We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was high overall. All trials had the primary outcomes reflecting measures of either physical activity (n = 8), sleep (n = 2), or both (n = 1). Five trials evaluated response to pharmacologic therapies compared with placebo, 3 evaluated physical activity interventions, 2 evaluated group or cognitive therapy, and 1 evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n = 5) demonstrated a significant improvement of actigraphy-based primary end point measurements.
There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials.
La mesure des paramètres physiologiques au moyen de l'actigraphie permet la conception des essais cliniques sur l'insuffisance cardiaque (IC) centrés sur les patients. Récemment, le consortium Heart Failure Collaboratory (HFC) a élaboré des recommandations pour un changement important et l'utilisation de l'actigraphie comme critère d’évaluation des essais cliniques sur l'IC. Nous visions à évaluer les essais contrôlés randomisés (ECR) qui ont quantifié l'incidence des interventions en cas d'IC à l'aide de l'actigraphie.
En suivant une stratégie d'examen systématique, nous avons évalué l'utilisation de l'actigraphie dans des ECR sur l'IC. Les études ont été ciblées en effectuant des recherches électroniques dans les bases de données Embase, OVID MEDLINE, PubMed et Cochrane. Les données sur les caractéristiques et les résultats des essais ont été recueillies.
Nous avons repéré 11 ECR portant sur 1 455 participants en tout. Le risque de biais dans les essais inclus était élevé dans l'ensemble. Tous les essais comportaient des critères d’évaluation principaux qui reflétaient les mesures de l'activité physique (n = 8), du sommeil (n = 2), ou les deux (n = 1). Cinq essais ont évalué la réponse à des traitements pharmacologiques comparativement à un placebo, trois ont évalué des interventions axées sur l'activité physique, deux ont évalué une thérapie de groupe ou cognitive, et un a évalué une stratégie de ventilation pendant le sommeil. La taille des échantillons variait de 30 à 619 participants. Il y avait une hétérogénéité importante en ce qui concerne le type de dispositif, l'emplacement du dispositif sur le corps et le traitement des données manquantes sur l'actigraphie. La durée de la surveillance variait de 48 heures à 12 semaines. Aucune étude sur l’évaluation de traitements pharmacologiques (n = 5) n'a mis en évidence une amélioration significative des mesures relatives aux critères d’évaluation principaux effectuées à l'aide de l'actigraphie.
Il y a une hétérogénéité importante dans l'utilisation, la méthodologie et les résultats des ECR sur l'IC ayant recours à l'actigraphie. Nos résultats soulignent la nécessité d’élaborer, de normaliser et de valider des critères d’évaluation propres à l'actigraphie pour les essais cliniques sur l'IC.
Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the ...understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population.
We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years.
There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations.
Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.
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