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The need for increased pragmatism in cardiovascular clinical trials
Abstract
The majority of cardiovascular randomized controlled trials (RCTs) test interventions in selected patient populations under explicitly protocol-defined settings. Although these 'explanatory' trial designs optimize conditions to test the efficacy and safety of an intervention, they limit the generalizability of trial findings in broader clinical settings. The concept of 'pragmatism' in RCTs addresses this concern by providing counterbalance to the more idealized situation underpinning explanatory RCTs and optimizing effectiveness over efficacy. The central tenets of pragmatism in RCTs are to test interventions in routine clinical settings, with patients who are representative of broad clinical practice, and to reduce the burden on investigators and participants by minimizing the number of trial visits and the intensity of trial-based testing. Pragmatic evaluation of interventions is particularly important in cardiovascular diseases, where the risk of death among patients has remained fairly stable over the past few decades despite the development of new therapeutic interventions. Pragmatic RCTs can help to reveal the 'real-world' effectiveness of therapeutic interventions and elucidate barriers to their implementation. In this Review, we discuss the attributes of pragmatism in RCT design, conduct and interpretation as well as the general need for increased pragmatism in cardiovascular RCTs. We also summarize current challenges and potential solutions to the implementation of pragmatism in RCTs and highlight selected ongoing and completed cardiovascular RCTs with pragmatic trial designs.
... This emphasizes the importance of the concept of pragmatism in contemporary study designs which we considered in this work. Pragmatic designs are conducted under conditions that are broadly representative of routine clinical care (Usman et al., 2022). The main goal of pragmatic designs is to inform decision makers by using experiment conditions that are relevant to and representative of real-world scenarios (Sepehrvand et al., 2019). ...
... Yet, the degree of pragmatism remains insufficient and efforts should be geared towards incorporating pragmatism in experimental designs related to cardiovascular treatment research. To be more specific, in the setting of cardiovascular diseases, there is an increased push towards the need for pragmatic study designs that accurately represent real-world settings and clinical scenarios (Harrington et al., 2022;Usman et al., 2022). Our study is one of these efforts. ...
... Our study is one of these efforts. Most of cardiovascular-related published literature are experimented under explicitly protocol-defined settings (Usman et al., 2022). These extremely controlled conditions allow study design optimization to maximize internal validity while limiting the generalizability to real-world clinical settings. ...
Abstract
Purpose: Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach.
Methods: Dissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV-vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f2) and difference (f1) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R2adj). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes.
Results: The dissolution profiles were not similar at pH 4.5 (f2=45.43, f1=18.97) and pH 6.8 (f2=31.47, f1=32.94). CT best fitted with Higuchi (pH 1.2: R2adj=0.9990), Weibull (pH 4.5: R2adj=0.9884), and Korsmeyer-Peppas (pH 6.8: R2adj=0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R2adj=0.9986), logistic (pH 4.5: R2adj=0.9839) and first-order (pH 6.8: R2adj=0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p=0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets.
Conclusion: Crushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube.
Keywords: Clinical pharmacokinetics; Crushing effect; Dissolution; Metoprolol; Pharmacokinetics.
... The challenges of embedding trials in health care systems may be offset by the gains in efficiency from the use of existing workforce and routinely collected data via EHRs or administrative databases; registries and administrative databases for randomization and data collection are critical assets that could move forward the design of implementation trials. A trade-off may be fidelity to the intervention and data accuracy, particularly when using endpoints that are disease specific or that require adjudication.26 HYBRID EFFECTIVENESS-IMPLEMENTATION TRIALSInstead of implementation being an afterthought when trial results are evident, it could be an early consideration in the design of pivotal phase 3 studies. ...
... Implementation trials are similar, but distinct from quality improvement studies, which use iterative processes and cycles of change to improve care. Implementation trials are often pragmatic,26 testing interventions within the complexities and variations of routine clinical care. Allocation is typically unblinded. ...
... Allocation is typically unblinded. The estimated treatment effect of interventions in pragmatic trials is often smaller than in explanatory trials, the latter of which deliver interventions with high fidelity, in controlled environments, and among selective patients most likely to benefit from the intervention.26 Implementation trials may also be vulnerable to bias toward the null due to suboptimal fidelity to the intervention, which is often a complex health service intervention; thus, despite randomization, there may be a role for a secondary per-protocol analysis.APPROACH TO DESIGNING EFFECTIVENESS-IMPLEMENTATION TRIALSA thoughtful implementation trial should fulfill an unmet health care need and engage relevant stakeholders-health care system decision makers, clinicians, researchers, and patients-in the design of the intervention and trial(Figure 2). ...
Heart failure (HF) is a leading cause of death and disability in older adults. Despite decades of high-quality evidence to support their use, guideline-directed medical therapies (GDMTs) that reduce death and disease burden in HF have been suboptimally implemented. Approaches to closing care gaps have focused largely on strategies proven to be ineffective, whilst effective interventions shown to improve GDMT uptake have not been instituted. This review synthesizes implementation interventions that increase the uptake of GDMT, discusses barriers and facilitators of implementation, summarizes conceptual frameworks in implementation science that could improve knowledge uptake, and offers suggestions for trial design that could better facilitate end-of-trial implementation. We propose an evidence-to-care conceptual model that could foster the simultaneous generation of evidence and long-term implementation. By adopting principles of implementation science, policymakers, researchers, and clinicians can help reduce the burden of HF on patients and health care systems worldwide.
... PCTs have the potential to enable evidence generation during routine care, helping to conduct more efficient and representative trials. 18 Through examining the comparative effectiveness of existing interventions that have demonstrable variation in practice, many evidence gaps may be addressed. The use of oral fluid restriction in patients who are treated pharmacologically for fluid overload in the setting of acute unplanned care represents one such gap. ...
... As a feasibility study, the findings shared will include trial evaluation, and whether alerts which 'nudge' clinicians to recruit patients into pragmatic, lowrisk comparative effectiveness trials, 33 are a scalable way to conduct efficient RCTs. 18 The THIRST Alert feasibility Open access study will share insights that inform the design and execution of future integrated approaches to evidence generation from routine care. ...
Introduction
Acute heart failure (HF) is a major cause of unplanned hospitalisation characterised by excess body water. A restriction in oral fluid intake is commonly imposed on patients as an adjunct to pharmacological therapy with loop diuretics, but there is a lack of evidence from traditional randomised controlled trials (RCTs) to support the safety and effectiveness of this intervention in the acute setting.This study aims to explore the feasibility of using computer alerts within the electronic health record (EHR) system to invite clinical care teams to enrol patients into a pragmatic RCT at the time of clinical decision-making. It will additionally assess the effectiveness of using an alert to help address the clinical research question of whether oral fluid restriction is a safe and effective adjunct to pharmacological therapy for patients admitted with fluid overload.
Methods and analysis
THIRST (Randomised Controlled
T
rial within the electronic
H
ealth record of an
I
nterruptive alert displaying a fluid
R
estriction
S
uggestion in patients with the treatable
T
rait of congestion) Alert is a single-centre, parallel-group, open-label pragmatic RCT embedded in the EHR system that will be conducted as a feasibility study at an National Health Service (NHS) hospital in London. The clinical care team will be invited to enrol suitable patients in the study using a point-of-care alert with a target sample size of 50 patients. Enrolled patients will then be randomised to either restricted or unrestricted oral fluid intake. Two primary outcomes will be explored (1) the proportion of eligible patients enrolled in the study and (2) the mean difference in oral fluid intake between randomised groups. A series of secondary outcomes are specified to evaluate the effectiveness of the alert, adherence to the randomised treatment allocation and the quality of data generated from routine care, relevant to the outcomes of interest.
Ethics and dissemination
This study was approved by Riverside Research Ethics Committee (Ref: 22/LO/0889) and will be published on completion.
Trial registration number
NCT05869656.
... Part of the emphasis on "real-world evidence" is the underlying assumption that studies with high generalizability and applicability would provide different treatment effect estimates than other studies. There is often the assumption that trials with non-pragmatic features that are typically done under artificial "ideal" and controlled settings with highly selected patients show stronger treatment effects on the desired endpoints [8,9]. It is often argued this may result from better adherence [8], but we recently showed that adherence-adjusted effects are often similar to other effects [10]. ...
... There is often the assumption that trials with non-pragmatic features that are typically done under artificial "ideal" and controlled settings with highly selected patients show stronger treatment effects on the desired endpoints [8,9]. It is often argued this may result from better adherence [8], but we recently showed that adherence-adjusted effects are often similar to other effects [10]. It is also possible that including fewer patients with comorbidities leads to smaller differences with regard to adverse effects and harms. ...
Background
Pragmatic trials provide decision-oriented, real-world evidence that is highly applicable and generalizable. The interest in real-world evidence is fueled by the assumption that effects in the “real-world” are different to effects obtained under artificial, controlled, research conditions as often used for traditional explanatory trials. However, it is unknown which features of pragmatism, generalizability, and applicability would be responsible for such differences. There is a need to provide empirical evidence and promote meta-research to answer these fundamental questions on the pragmatism of randomized trials and real-world evidence. Here, we describe the rationale and design of the PragMeta database which pursues this goal (www.PragMeta.org).
Methods
PragMeta is a non-commercial, open data platform and infrastructure to facilitate research on pragmatic trials. It collects and shares data from published randomized trials that either have a specific design feature or other characteristic related to pragmatism or they form clusters of trials addressing the same research question but having different aspects of pragmatism. This lays the foundation to determine the relationship of various features of pragmatism, generalizability, and applicability with intervention effects or other trial characteristics.
The database contains trial data actively collected for PragMeta but also allows to import and link existing datasets of trials collected for other purposes, forming a large-scale meta-database. PragMeta captures data on (1) trial and design characteristics (e.g., sample size, population, intervention/comparison, outcome, longitudinal structure, blinding), (2) effects estimates, and (3) various determinants of pragmatism (e.g., the use of routinely collected data) and ratings from established tools used to determine pragmatism (e.g., the PRagmatic–Explanatory Continuum Indicator Summary 2; PRECIS-2).
PragMeta is continuously provided online, inviting the meta-research community to collaborate, contribute, and/or use the database. As of April 2023, PragMeta contains data from > 700 trials, mostly with assessments on pragmatism.
Conclusions
PragMeta will inform a better understanding of pragmatism and the generation and interpretation of real-world evidence.
... 3,4 The extent of pragmatism seen in these early cardiovascular trials is rarely found in contemporary trials. 5 Increasing emphasis on the regulation of trial conduct, safety of patients, and demonstration of efficacy has led to cardiovascular trials becoming complex and resource intensive. In today's age, cardiovascular RCTs are primarily 'explanatory' in nature, i.e. they are designed to study the efficacy of interventions in 'optimized' and tightly controlled settings. ...
... While the concept of using technology to enhance pragmatism is still in infancy, a number of cardiovascular RCTs have successfully used this approach. 5 Other measures that can help increase pragmatism include identifying and curtailing lab tests, site monitoring, and data verification procedures, which do not significantly contribute to patient safety or trial integrity. ...
Up till the 1980s, little was known about how to manage patients with acute myocardial infarction (AMI). Morphine was the single most important drug for treatment, and alcohol was recommended to treat angina.¹ The International Studies of Infarct Survival (ISIS) were a series of four randomized controlled trials (RCTs) that provided evidence, which transformed the management of AMI. These trials were characterized by a ‘large and simple’ design. For example, the ISIS-1 trial, published in 1986,² was designed to include 6000 patients with AMI and randomize them to either intravenous atenolol or control and study the effect on vascular mortality. The trial had broad and non-restrictive inclusion criteria: virtually all patients with AMI in the last 12 h and no contraindications to beta-blockers were eligible. With fewer than 10 datapoints to be collected from each patient, the information could easily be recorded on a single sheet of paper. At its conclusion, the trial had enrolled 16 027 patients with AMI, and the results demonstrated a significant reduction in vascular mortality with atenolol in the treatment period (first week) and suggested that the benefit may persist up till 1 year. The trial laid the foundation for treatment with beta-blockers in AMI.
... We specifically examine the reporting of the types of CDSS, details of local implementation, and key elements of study design including models of consent and descriptions of co-interventions or quantification of alert burden where relevant. As CDSS become increasingly available, complex and intelligent (7), and their development and testing increasingly regulated, a greater understanding of the essential requirements for their design, development and delivery within RCTs is of critical importance. ...
Objectives
Conduct a systematic review of the existing evidence base pertaining to the conduct of randomised controlled trials of clinical decision support systems embedded within electronic health record systems. Further, to describe whether key features of trial design and implementation were consistently reported.
Materials and Methods
A systematic search of MEDLINE was conducted in April 2022. Three independent reviewers screened the search results. A 27-item checklist was used to extract data from the screened studies. A subgroup analysis was conducted to classify trials of clinical decision support systems based on whether they encouraged guideline adherence or represented new knowledge generating mechanisms.
Results
5,213 records were retrieved. Following screening, 106 studies were included in the review. The majority of studies evaluated active alerts seeking to improve adherence to clinical guidelines rather than generate new knowledge. Few studies quantified the existing ecosystem of decision support at the study site, or explored phenomena like alert fatigue.
Discussion
This systematic review provides a detailed analysis of the characteristics of trials evaluating clinical decision support systems. It highlights significant under-reporting of key factors which may affect the reproducibility and generalisability of trial results - particularly with respect to measurement of alert fatigue, description of the underlying digital ecosystem and additional co-interventions used within trials.
Conclusion
As clinical workflows undergo digital transformation, randomised controlled trials of clinical decision support systems require greater standardisation, in both conduct and reporting. This represents an area of expanding interest given the increasing use of artificial intelligence-enabled decision support.
... Such strategies were adopted in the Patient-Centered Care Transitions in Heart Failure (PACT-HF) RCT in 2015-2016 and Canagliflozin Impact on Health Status, Quality of Life, and Functional Status in Heart Failure (CHIEF-HF) decentralized RCT in 2020-2021, which enrolled 49 and 45% female participants, respectively 26,27,40 . Efforts to minimize research visits that gather data from patients may be of particular benefit to patients who have caregiver responsibilities, are unable to bear the cost of research visits or rely on family for transportation; such patients tend to be women, socioeconomically deprived groups and older adults, the very groups that are under-represented in trials 41 . ...
Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials). Trial communications ought to be culturally appropriate; engaging diverse people with lived experience in the co-design of some trial elements may foster this. The demographics of trialists themselves are associated with participant demographics; therefore, trial leadership must be actively diversified. Funding bodies and journals increasingly require the reporting of sociodemographic characteristics of trial participants, and regulatory bodies now provide guidance on increasing trial diversity; these steps may increase the momentum towards change. Although this Perspective focuses on the cardiovascular trial context, many of these strategies could be applied to other fields.
... The strength of evidence from these trials is intermediate of that from observational studies and RCTs. In general, all forms of bias, such as lack of generalizability, Hawthorne bias, confounding bias, user bias, and observer bias, within pragmatic clinical trials are believed to fall somewhere between those observed in observational studies and those in RCTs [26]. The design of pragmatic trials leads to its applicability to real-life situations, which is one of the biggest advantages over conventional trials. ...
Translating vascular aging research from bench to bedside presents both significant opportunities and challenges. This paper summarizes insights from a roundtable discussion at the Artery 23 conference, featuring perspectives from basic science, clinical trials, regulation, and industry. The main conclusions of the discussion are as follows: basic science research must align with clinical relevance, using appropriate animal models and standardized measurement techniques. Pragmatic and registry-based clinical trials offer viable alternatives to traditional randomized controlled trials, facilitating real-world applicability. The regulatory landscape, particularly for software medical devices, must evolve to keep pace with technological advancements like artificial intelligence. Industry efforts focus on developing devices or solutions for vascular aging assessment and treatment strategies, yet face hurdles in large-scale adoption and reimbursement. Despite significant progress, the development of pharmacological interventions to mitigate vascular aging remains a critical need. This discussion underscores the importance of interdisciplinary collaboration to overcome barriers and translate scientific discoveries into clinical practice effectively.
... broader phenotyping) [6] and utilising novel (i.e. decentralised) [7] clinical research methods to resolve areas of equipoise. ...
Left heart disease (LHD) is the most common cause of pulmonary hypertension (PH), which may be classified further as isolated post-capillary (ipcPH) or combined post- and pre-capillary PH (cpcPH). The 7th World Symposium on Pulmonary Hypertension PH-LHD task force reviewed newly reported randomised clinical trials and contemplated novel opportunities for improving outcome. Results from major randomised clinical trials reinforced prior recommendations against the use of pulmonary arterial hypertension therapy in PH-LHD outside of clinical trials, and suggested possible harm. Greater focus on phenotyping was viewed as one general strategy by which to ultimately improve clinical outcomes. This is potentially achievable by individualising ipcPH versus cpcPH diagnosis for patients with pulmonary arterial wedge pressure within a diagnostic grey zone (12–18 mmHg), and through a newly developed PH-LHD staging system. In this model, PH accompanies LHD across four stages (A=at risk, B=structural heart disease, C=symptomatic heart disease, D=advanced), with each stage characterised by progression in clinical characteristics, haemodynamics and potential therapeutic strategies. Along these lines, the task force proposed disaggregating PH-LHD to emphasise specific subtypes for which PH prevalence, pathophysiology and treatment are unique. This includes re-interpreting mitral and aortic valve stenosis through a contemporary lens, and focusing on PH within the hypertrophic cardiomyopathy and amyloid cardiomyopathy clinical spectra. Furthermore, appreciating LHD in the profile of PH patients with chronic lung disease and chronic thromboembolic pulmonary disease is essential. However, engaging LHD patients in clinical research more broadly is likely to require novel methodologies such as pragmatic trials and may benefit from next-generation analytics to interpret results.
... The pragmatism level of an RCT means how similar the intervention delivered in the setting in which the trial was conducted and the intervention delivered in the setting in which its results are applied, which plays a crucial role in clinical decision-making. 4 To help trialists comprehend the level of pragmatism of RCTs and make design decisions that serve the intended purpose of the trial in an even better fashion, the Pragmatic Explanatory Continuum Index Summary (PRECIS) tool was developed in 2008 5 and formed the updated PRECIS-2 version in 2015. 6 Several studies [7][8][9] have used the PRECIS-2 tool to assess the pragmatism level of trials, illustrating how current trials can help researchers gain confidence in applying the studied interventions in the real-world. ...
Background
The pragmatism levels of randomized controlled trials (RCTs) mean how similar the interventions delivered in the trial setting match those in the setting where the results will be applied. We aimed to investigate the association between the consistency of pragmatism among the characteristics of RCT design and its effect size of results in Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS).
Methods
Eight English and Chinese language databases were searched for RCTs on CHM for IBS. Six reviewers independently assessed the pragmatism of trials using the pragmatic-explanatory continuum indicator summary 2 (PRECIS-2) tool. The consistency of pragmatism levels among the characteristics of RCT design was calculated using the coefficient of variation. Linear regression models were adopted to explore influence factors of the pragmatism of RCTs.
Results
78 RCTs were included. The level of consistency in the pragmatism for RCT's design was significantly correlated with the effect size of the results (binary outcome, r = -0.413; P = 0.005; continuous outcome, r = -0.779, P < 0.001). PRECIS-2 score was higher in trials with individualized interventions than fixed interventions (3.29 [0.32] vs 2.90 [0.32]; Cohen's d relative effect size, 0.52; P < 0.001) and in standard or usual-treatment-controlled trials than placebo-controlled (3.05 [0.37] vs 2.83 [0.28]; Cohen's d relative effect size, 0.32; P = 0.048).
Conclusion
The consistency of pragmatism level across the 9 domains of the PRECIS-2 tool in CHM IBS RCTs was positively correlated with the effect size of the results.
... As the International Society for Pharmacoeconomics and Outcomes Research has proposed, pragmatic effectiveness trials are the best vehicles for economic studies 20 . However, one of the inevitable limitations of pragmatic design is that increasing nonadherence to the trial protocol, and even the use of electronic health records, results in inconsistent data collection and missing data [19][20][21] . Missing data may seriously compromise the credibility of causal inferences from pRCTs 22 . ...
Objectives
To assess the reporting quality of missing data in economic evaluations conducted alongside pragmatic randomized controlled trials (pRCTs).
Design
Cross-sectional survey.
Setting
Data were extracted from PubMed and OVID (Embase, CENTRAL, HTA database, and NIH EED) from January 1, 2010, to April 24, 2022. Economic evaluations conducted with pRCTs were included and secondary analyses, abstracts, comments, letters, notes, editorials, protocols, subgroup analyses, pilot and feasibility trials, post-hoc analyses, and reviews were excluded. Two groups of two independent reviewers identified the relevant articles, and data were extracted from three groups of two reviewers.
Main outcome measures
Descriptive analyses were performed to assess characteristics of the included studies, missingness in the included studies, and handling of missing data.
Results
A total of 715 studies were identified, of which 152 met the inclusion criteria. Overall, 113 articles reported missing data, 119 reported missing costs, and 132 reported missing effects. More than 50% (58/113) of the articles reported the proportion or quantity of overall missingness, and 64.71% and 54.55% reported missing costs and effects, respectively. The proportion of missingness of < 5% in the overall group was 3.45%, whereas the proportions of missing costs and effects were both lower than 10% (5.26% vs. 8.45%). In terms of the proportion of missing data, the overall missingness rate was 30.22% in 58 studies, whereas the median proportion of missing data was slightly higher than that of the missing effects (30.92% vs. 27.78%). For details on dealing with missing data, 56 (36.84%) studies conducted a sensitivity analysis on handling missing data. Of these studies, 12.50% reported missing mechanisms, and 83.93% examined handling methods.
Conclusions
Insufficient description and reporting of missing data, along with a high proportion of missing data in pRCT-based economic evaluations, could decrease the reliability and extrapolation of conclusions, leading to misleading decision-making. Future research should include an increased sample size by fully considering the potential proportion of missing data and enhance the transparency and evidence quality of economic evaluation alongside pragmatic trials.
... Sensitivity analyses were conducted to determine the extent to which the STRESS registry-based trial design might be adapted to reduce total trial costs. The scenarios tested were in part based upon recommendations in three expert consensus publications [28][29][30]. These included [1]: reducing sample size requirements [2], accelerating patient enrollment, and [3] automating data collection. ...
Background
Registry-based trials have the potential to reduce randomized clinical trial (RCT) costs. However, observed cost differences also may be achieved through pragmatic trial designs. A systematic comparison of trial costs across different designs has not been previously performed.
Methods
We conducted a study to compare the current Steroids to Reduce Systemic inflammation after infant heart surgery (STRESS) registry-based RCT vs. two established designs: pragmatic RCT and explanatory RCT. The primary outcome was total RCT design costs. Secondary outcomes included: RCT duration and personnel hours. Costs were estimated using the Duke Clinical Research Institute's pricing model.
Results
The Registry-Based RCT estimated duration was 31.9 weeks greater than the other designs (259.5 vs. 227.6 weeks). This delay was caused by the Registry-Based design's periodic data harvesting that delayed site closing and statistical reporting. Total personnel hours were greatest for the Explanatory design followed by the Pragmatic design and the Registry-Based design (52,488 vs 29,763 vs. 24,480 h, respectively). Total costs were greatest for the Explanatory design followed by the Pragmatic design and the Registry-Based design (4,164,863 vs. $3,268,504, respectively). Thus, Registry-Based total costs were 32 % of the Explanatory and 78 % of the Pragmatic design.
Conclusion
Total costs for the STRESS RCT with a registry-based design were less than those for a pragmatic design and much less than an explanatory design. Cost savings reflect design elements and leveraging of registry resources to improve cost efficiency, but delays to trial completion should be considered.
... The findings of EHR-sourced trials, especially those conducted in populations that are likely to benefit from the results of the study, tend to be more informative about what works in the real world than are the findings of explanatory trials (RCTs) [40,55]. EHR-sourced trials are most suited to answer the question, "Will this intervention work in this population?" ...
Real world evidence is now accepted by authorities charged with assessing the benefits and harms of new therapies. Clinical trials based on real world evidence are much less expensive than randomized clinical trials that do not rely on “real world evidence” such as contained in electronic health records (EHR). Consequently, we can expect an increase in the number of reports of these types of trials, which we identify here as ‘EHR-sourced trials.’ ‘In this selected literature review, we discuss the various designs and the ethical issues they raise. EHR-sourced trials have the potential to improve/increase common data elements and other aspects of the EHR and related systems. Caution is advised, however, in drawing causal inferences about the relationships among EHR variables. Nevertheless, we anticipate that EHR-CTs will play a central role in answering research and regulatory questions.
... According to this scenario, it appears clear that a substantial number of clinical decisions are not based on robust data from RCTs, thus implying bias and uncertainty in supporting recommendations. In view of this knowledge gap, a greater investment in trials, especially in pragmatic trials able to assess the effectiveness of interventions (diagnostic or therapeutic) in routine clinical settings, with adequate representation of clinical practice is required [82]. In order to amplify the knowledge on treatments/interventions based on solid evidence, future RCTs should focus more on elderly patients, as well as female patients and patients with comorbidities such as severe chronic kidney disease, that are patient groups largely underrepresented in most of the current trials [83][84][85], but should also consider the gaps in knowledge that characterize less common diseases and assess the value of treatments feasible also in developing countries. ...
Background:
The European Society of Cardiology (ESC) clinical practice guidelines are essential tools for decision-making.
Aim:
To analyze the level of evidence (LOE) and the class of recommendations in the ESC guidelines released in the last 12 years.
Methods:
We evaluated 50 ESC guidelines released from 2011 to 2022, related to 27 topics and categorized them into seven macro-groups. We analyzed every recommendation in terms of LOE and class of recommendation, calculating their relative proportions and changes over time in consecutive editions of the same guideline.
Results:
A total of 6972 recommendations were found, with an increase in number per year over time. Among the 50 ESC guidelines, the proportional distribution of classes of recommendations was 49% for Class I, 29% for Class IIa, 15% for Class IIb, and 8% for Class III. Overall, 16% of the recommendations were classified as LOE A, 31% LOE B and 53% LOE C. The field of preventive cardiology had the largest proportion of LOE A, while the lowest was in the field of valvular, myocardial, pericardial and pulmonary diseases. The overall proportion of LOE A recommendations in the most recent guidelines compared to their prior versions increased from 17% to 20%.
Conclusions:
The recommendations included in the ESC guidelines widely differ in terms of quality of evidence, with only 16% supported by the highest quality of evidence. Although a slight global increase in LOE A recommendations was observed in recent years, further scientific research efforts are needed to increase the quality of evidence.
... Likewise, in the AAA guidelines, therapy with metformin is specifically mentioned as a potential candidate drug for imminent clinical trials. It is well known that randomized controlled trials in general often offer beneficial interventions in routine clinical practice, but regarding conservative aneurysm treatment and impact on QoL in AAA patients, there is a lack of evidence [38] . Four recent retrospective studies and a meta-analysis on metformin prescription to diabetic AAA patients revealed a significant reduction of AAA progression, rupture rate, and incidence of repair when compared to AAA patients treated with other antidiabetic drugs [18][19][20][21][22] . ...
Background:
Abdominal aortic aneurysm (AAA) is a multifactorial vascular disease associated with high morbidity and mortality. Currently, surgical intervention is the only treatment option and there is no drug therapy available for AAA. Hence, surveillance of AAA until indication for surgery may impact patient quality of life (QoL). There is a paucity of high-quality observational data on health status and QoL, particularly among AAA patients participating in randomized controlled trials. The objective of this study was to compare QoL scores of AAA patients on surveillance to those of AAA patients enrolled in the MetAAA trial.
Material and methods:
Overall, 54 MetAAA trial patients and 23 AAA patients under regular surveillance for small AAA (of a longitudinal monitoring study) were asked to complete three established and validated (in total 561 longitudinally collected) QoL questionnaires: 1) the 36-Item Short Form Health Survey (SF-36), 2) the Aneurysm Symptom Rating Questionnaire (ASRQ), and 3) the Aneurysm-Dependent Quality of Life questionnaire (ADQoL).
Results:
A superior health status and QoL was found in AAA patients participating in the MetAAA trial compared to AAA patients under regular surveillance. In detail, MetAAA trial patients showed superior general health perception (P=0.012), higher energy level (P=0.036) as well as enhanced emotional well-being (P=0.044) and fewer limitations due to general malaise (P=0.021), which was subsequently reflected in an overall superior current QoL score (P=0.039) compared to AAA patients under regular surveillance.
Conclusion:
AAA patients enrolled in the MetAAA trial showed superior health status and QoL compared to AAA patients under regular surveillance.
... This represents a challenge with the available evidence, with statistical testing for non-inferiority or equivalence being the key to overcome these knowledge gaps [52]. While acknowledging that it is improbable that randomised trials such as VEST can ever be conducted for some of these niche indications [53], pragmatic randomised trials [54] or well-designed prospective observational studies with concomitant control may still be feasible in these cohorts of patients. ...
Objectives:
To synthesise the available evidence of wearable cardioverter defibrillator (WCD) therapy as an add-on measure to optimal medical therapy (OMT) or as a replacement of hospital stay.
Methods:
An update systematic review (SR) of comparative effectiveness and safety of WCD therapy was conducted. We included randomised controlled trials (RCT), prospective comparative studies and prospective uncontrolled studies with at least 100 patients. A narrative synthesis of the evidence was conducted.
Results:
One RCT (n = 2348) and further eleven observational studies (n = 5345) fulfilled our inclusion criteria. In the only available RCT, the use of the WCD was not statistically associated with a clinical benefit on arrhythmic mortality in post-myocardial infarction (MI) patients with an ejection fraction of ≤35%. The compliance with WCD therapy was low in the RCT and high in observational studies, with ten observational studies reporting on a daily wear time between 20 and 23.5 h. The range of percentage of patients receiving at least one appropriate shock was 1-4.8% and the rate of first shock success was reported to be 100% in three studies. Serious adverse events (SAEs) such as inappropriate shocks occurred rarely, with between 0% and 2% of patients being inappropriately shocked within ten observational studies. In one of the observational studies, two patients (2%) were allergic to nickel developing skin rash and false alarms occurred in 58 patients (57%) in this study. Another registry study (n = 448) reported milder AEs, such as dermatitis and pressure marks, occurring in 0.9% and 0.2% of enrolled patients, respectively.
Conclusion:
The only available RCT failed to show superiority of add-on use of WCD in post MI patients. Observational evidence shows that the compliance with WCD is good, but the evidence is afflicted with selection bias and the inclusion of diverse mixed patient populations diluting the ability to draw indication-specific conclusions on the utility of the device. More comparative data is needed to justify continuing or expanding use of WCD therapy.
... 22 Increasing use of pragmatic trial designs could be an effective strategy to reduce enrollment barriers and facilitate recruitment of patients from underrepresented communities in clinical trials. 23 Overall, it is clear that multiple strategies, such as financial incentives or penalties tied to trial recruitment, engagement of community leaders in research design and conduct, and a commitment to the inclusion of investigators from diverse backgrounds in clinical research are needed to improve equitable representation in clinical trials. 18 , 22 Limitations There are several limitations to our study worth noting. ...
Background:
Non-Hispanic Black people in the United States have the highest prevalence of essential hypertension. Unfortunately, clinical trials often underrepresent Black patients. We aim to understand whether trial sponsorship type is associated with representation of Black participants in anti-hypertensive drug clinical trials. Then, we contextualize our findings amongst current efforts to improve diversity in clinical research populations.
Methods:
We searched ClinicalTrials.gov in May 2022 for antihypertensive drug trials. Of n=408 trials in our initial search, n=97 (23.77%) met inclusion criteria and were stratified by sponsorship type (industry versus non-industry). Standardized tests of difference were employed to compare characteristics of these trials, and linear regression was used to model change over time.
Results:
Of 97 trials reporting results from 2010-2020, there were minimal differences in the percent of Black patients enrolled in anti-hypertensive clinical trials by sponsorship type. Both industry and non-industry sponsored studies had high rates of non-reporting, with slightly more non-reporting for industry (73.2%) versus non-industry (66.67%) studies. Industry funded studies reported results to ClinicalTrials.gov within 23.3±15.0 months from completing studies, while non-industry funded trials reported within 18.9 ±10.8 months.
Conclusions:
Despite Black Americans carrying the highest burden of disease for essential hypertension, they are underrepresented in anti-hypertension clinical trials and their overall participation has decreased between 2010-2020. In addition, there is major underreporting of trial participant race. We implore researchers and funders to establish clear, meaningful targets for anti-hypertensive drug trial diversity, and improve transparency in reporting of study characteristics.
... In Pakistan the data is quite old but estimates a prevalence of 2.8 million people suffering from heart failure [3]. On the other due to better treatment facilities, mortality due to acute myocardial infarction and acute onset of cerebrovascular accident has reduced drastically because of available acute management strategies such as primary percutaneous coronary intervention (PPCI) [4][5][6]. The survival rate in patients with heart failure reduces each year from 75.9% at one year to 12.7% at 15 years [7]. ...
Introduction: Anemia is one of the potential comorbid condition in patients with acute decompensated heart failure (ADHF) which is linked to higher morbidity and mortality rates. Worldwide, its prevalence ranges from 4% to >70% in hospitalized patients with ADHF. Unfortunately data is lacking from our region and hence we aimed to conduct this study to scientifically fill the present gap by evaluating the actual burden of anemia in patients hospitalized with ADHF in a tertiary care hospital of Karachi, Pakistan. Patients and Methods: This was a hospital based study conducted in the Department of Cardiology, Tabba Heart Institute, Karachi From 1st November 2019 to 30th April 2020. A total of 203 patients with ADHF with age >35 years and <80 years were selected. A blood sample was taken to determine the hemoglobin levels and hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men were taken as cut-off for anemia. Results: Overall mean and SD of age was 63.70±10.53 years and among them most of were males (n = 116, 57.1%). The overall prevalence of anemia in patients with ADHF was quite high and 63.5% (n = 129). Only three condition, hypertension, diabetes mellitus, and current smoking habits had significant association with the occurrence of anemia in patients with ADHF, p value <0.05. Conclusion: In conclusion, the results showed that anemia is an independent risk for HF. Anemia was observed in one-third of the study population. More prevalent in male gender, elderly patients of age above 60 years, and associated with other comorbids.
Research on cardiovascular health has dramatically evolved since the mid-1900s. Observational studies evaluate the relationships between exposures and outcomes, but these types of studies are vulnerable to confounding and bias. Randomized, controlled trials are a more effective approach for establishing cause-and-effect relationships. Cardiovascular outcome trials (CVOTs) are commonly used to evaluate the impact of interventions on outcomes such as myocardial infarction and stroke. Several study design components, including blinding, comparator groups, population, outcome variables, and follow-up durations, must be considered in the design and interpretation of a CVOT.
Aim
The TRANSFORM‐HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non‐adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on‐treatment analysis inclusive of all randomized patients except those confirmed non‐adherent to study diuretic.
Methods and results
TRANSFORM‐HF was an open‐label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator‐selected dosage. This post‐hoc on‐treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non‐adherent to study diuretic. This modified on‐treatment definition was applied separately at time of hospital discharge and 30‐day follow‐up. All‐cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on‐treatment analyses at discharge and 30‐day follow‐up, respectively. There was no significant difference in all‐cause mortality between torsemide and furosemide in patients on‐treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83–1.22], p = 0.96) and at 30‐day follow‐up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81–1.27], p = 0.90). All‐cause mortality or all‐cause hospitalization was similar between torsemide and furosemide in patients who were on‐treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82–1.03]) and 30‐day follow‐up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82–1.05]). In patients who were on‐treatment at 30‐day follow‐up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86–1.14], p = 0.87).
Conclusions
In TRANSFORM‐HF, a post‐hoc on‐treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide.
Clinical Trail Registration: ClinicalTrials.gov Identifier: NCT03296813.
Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.
Background
Accurate, timely ascertainment of clinical end points, particularly hospitalizations, is crucial for clinical trials. The Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) Digital Study extended the main TAILOR-PCI trial's follow-up to 2 years, using a smartphone-based research app featuring geofencing-triggered surveys and routine monthly mobile phone surveys to detect cardiovascular (CV) hospitalizations. This pilot study compared these digital tools to conventional site-coordinator ascertainment of CV hospitalizations.
Objective
The objectives were to evaluate geofencing-triggered notifications and routine monthly mobile phone surveys' performance in detecting CV hospitalizations compared to telephone visits and health record reviews by study coordinators at each site.
Methods
US and Canadian participants from the TAILOR-PCI Digital Follow-Up Study were invited to download the Eureka Research Platform mobile app, opting in for location tracking using geofencing, triggering a smartphone-based survey if near a hospital for ≥4 hours. Participants were sent monthly notifications for CV hospitalization surveys.
Results
From 85 participants who consented to the Digital Study, downloaded the mobile app, and had not previously completed their final follow-up visit, 73 (85.8%) initially opted in and consented to geofencing. There were 9 CV hospitalizations ascertained by study coordinators among 5 patients, whereas 8 out of 9 (88.9%) were detected by routine monthly hospitalization surveys. One CV hospitalization went undetected by the survey as it occurred within two weeks of the previous event, and the survey only allowed reporting of a single hospitalization. Among these, 3 were also detected by the geofencing algorithm, but 6 out of 9 (66.7%) were missed by geofencing: 1 occurred in a participant who never consented to geofencing, while 5 hospitalizations occurred among participants who had subsequently turned off geofencing prior to their hospitalization. Geofencing-detected hospitalizations were ascertained within a median of 2 (IQR 1-3) days, monthly surveys within 11 (IQR 6.5-25) days, and site coordinator methods within 38 (IQR 9-105) days. The geofencing algorithm triggered 245 notifications among 39 participants, with 128 (52.2%) from true hospital presence and 117 (47.8%) from nonhospital health care facility visits. Additional geofencing iterative improvements to reduce hospital misidentification were made to the algorithm at months 7 and 12, elevating the rate of true alerts from 35.4% (55 true alerts/155 total alerts before month 7) to 78.7% (59 true alerts/75 total alerts in months 7-12) and ultimately to 93.3% (14 true alerts/5 total alerts in months 13-21), respectively.
Conclusions
The monthly digital survey detected most CV hospitalizations, while the geofencing survey enabled earlier detection but did not offer incremental value beyond traditional tools. Digital tools could potentially reduce the burden on study coordinators in ascertaining CV hospitalizations. The advantages of timely reporting via geofencing should be weighed against the issue of false notifications, which can be mitigated through algorithmic refinements.
Background:
Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied.
Methods:
We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data.
Results:
2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment.
Conclusions:
These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.
Healthcare disparities are a persistent societal problem. One of the contributing factors to this status quo is the lack of diversity and representativeness of research efforts, which result in non‐generalizable evidence that, in turn, provides suboptimal means to enable the best possible outcomes at the individual level. There are several strategies that research teams can adopt to improve the diversity, equity and inclusion (DEI) of their efforts; these strategies span the totality of the research path, from initial design to the shepherding of clinical data through a potential regulatory process. These strategies include more intentionality and DEI‐based goal‐setting, more diverse research and leadership teams, better community engagement to set study goals and approaches, better tailored outreach interventions, decentralization of study procedures and incorporation of innovative technology for more flexible data collection, and self‐surveillance to identify and prevent biases. Within their remit of overlooking research efforts, regulatory authorities, as stakeholders, also have the potential for a positive effect on the DEI of emerging clinical evidence. All these are implementable tools and mechanisms that can make study participation more approachable to diverse communities, and ultimately generate evidence that is more generalizable and a conduit for better outcomes. The research community has an imperative to make DEI principles key foundational aspects in study conduct in order to pursue better personalized medicine for diverse patient populations.
Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial (NCT04252287), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8–7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.
Introduction
The recent past has seen a significant increase in the number of trauma and orthopaedic randomised clinical trials published in “the big five” general medical journals. The quality of this research has, however, not yet been established.
Methods
We therefore set out to critically appraise the quality of available literature over a 10-year period (April 2010–April 2020) through a systematic search of these 5 high-impact general medical journals (JAMA, NEJM, BMJ, Lancet and Annals). A standardised data extraction proforma was utilised to gather information regarding: trial design, sample size calculation, results, study quality and pragmatism. Quality assessment was performed using the Cochrane Risk of Bias 2 tool and the modified Delphi list. Study pragmatism was assessed using the PRECIS-2 tool.
Results
A total of 25 studies were eligible for inclusion. Over half of the included trials did not meet their sample size calculation for the primary outcome, with a similar proportion of these studies at risk of type II error for their non-significant results. There was a high degree of pragmatism according to PRECIS-2. Non-significant studies had greater pragmatism that those with statistically significant results (p < 0.001). Only 56% studies provided adequate justification for the minimum clinically important difference (MCID) in the population assessed. Overall, very few studies were deemed high quality/low risk of bias.
Conclusions
These findings highlight that there are some important methodological concerns present within the current evidence base of RCTs published in high-impact medical journals. Potential strategies that may improve future trial design are highlighted.
Level of evidence
Level 1.
Background
Prevalence of atrial fibrillation (AF) continues to increase and is associated with significant cardiovascular morbidity and mortality. To inform prevention strategies aimed at reducing the burden of AF, we sought to quantify trends in cardiovascular mortality related to AF in the United States.
Methods and Results
We performed serial cross‐sectional analyses of national death certificate data for cardiovascular mortality related to AF, whereby cardiovascular disease was listed as underlying cause of death and AF as multiple cause of death among adults aged 35 to 84 years using the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research. We calculated age‐adjusted mortality rates per 100 000 population and examined trends over time, estimating average annual percentage change using the Joinpoint Regression Program. Subgroup analyses were performed by race‐sex and across 2 age groups (younger: 35–64 years; older: 65–84 years). A total of 276 373 cardiovascular deaths related to AF were identified in the United States between 2011 and 2018 in decedents aged 35 to 84 years. Age‐adjusted mortality rate increased from 18.0 (95% CI, 17.8–18.2) to 22.3 (95% CI, 22.0–22.4) per 100 000 population between 2011 and 2018. The increase in age‐adjusted mortality rate (average annual percentage change) between 2011 and 2018 was greater among younger decedents (7.4% per year [95% CI, 6.8%–8.0%]) compared with older decedents (3.0% per year [95% CI, 2.6%–3.4%]).
Conclusions
Cardiovascular deaths related to AF are increasing, especially among younger adults, and warrant greater attention to prevention earlier in the life course.
Randomised controlled trials are increasingly conducted as embedded, nested, or using cohorts or routinely collected data, including registries, electronic health records, and administrative databases, to assess if participants are eligible for the trial and to facilitate recruitment, to deliver an embedded intervention, to collect trial outcome data, or a combination of these purposes. This report presents the Consolidated Standards of Reporting Trials (CONSORT) extension for randomised controlled trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE). The extension was developed to look at the unique characteristics of trials conducted with these types of data with the goal of improving reporting quality in the long term by setting standards early in the process of uptake of these trial designs. The extension was developed with a sequential approach, including a Delphi survey, a consensus meeting, and piloting of the checklist. The checklist was informed by the CONSORT 2010 statement and two reporting guidelines for observational studies, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and the REporting of studies Conducted using Observational Routinely collected Data (RECORD) statement. The extension includes eight items modified from the CONSORT 2010 statement and five new items. Reporting items with explanations and examples are provided, including key aspects of trials conducted using cohorts or routinely collected data that require specific reporting considerations.
Pragmatic randomised clinical trials aim to directly inform clinical or health policy decision-making. Here, we systematically review methods and design of pragmatic trials of pain therapies to examine methods, identify common challenges, and areas for improvement.
Seven databases were searched for pragmatic randomised controlled clinical trials which assessed pain treatment in a clinical population of adults reporting pain. All screening steps and data extractions were performed twice. Data were synthesised descriptively and correlation analyses between pre-specified trial features and PRECIS-2 (PRagmatic – Explanatory Continuum Indicator Summary 2) ratings and attrition were performed. Protocol registration: PROSPERO-ID CRD42020178954.
Of 57 included trials, only 21% assessed pharmacological interventions, the remainder physical, surgical, psychological or self-management pain therapies. Three-quarters of the trials were comparative effectiveness designs, often conducted in multiple centres (median: 5; Q1/3: 1, 9.25) and with a median sample size of 234 patients at randomization (Q1/3: 135.5; 363.5). Although most trials recruited chronic pain patients, reporting of pain duration was poor and not well described. Reporting was comprehensive for most general items, while often deficient for specific pragmatic aspects. Average ratings for pragmatism were highest for treatment adherence flexibility and clinical relevance of outcome measures. They were lowest for patient recruitment methods and extent of follow-up measurements and appointments.
Current practice in pragmatic trials of pain treatments can be improved in areas such as patient recruitment and reporting of methods, analysis and interpretation of data. These improvements will facilitate translatability to other real-world settings – the purpose of pragmatic trials.
Objective
To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data.
Design
Meta-research study.
Data source
Studies included in the same meta-analysis in a Cochrane review.
Eligibility criteria for study selection
Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement.
Review methods
Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source.
Results
84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I ² =14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I ² =12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I ² =8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I ² =28%; registries: 0.86, 0.75 to 0.99, I ² =20%; administrative data: 0.84, 0.72 to 0.99, I ² =0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I ² =0%).
Conclusions
Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.
Implementation science is the study of methods to promote the systematic uptake of evidence based interventions into practice and policy to improve health. Despite the need for high quality evidence from implementation research, randomised trials of implementation strategies often have serious limitations. These limitations include high risks of bias, limited use of theory, a lack of standard terminology to describe implementation strategies, narrowly focused implementation outcomes, and poor reporting. This paper aims to improve the evidence base in implementation science by providing guidance on the development, conduct, and reporting of randomised trials of implementation strategies. Established randomised trial methods from seminal texts and recent developments in implementation science were consolidated by an international group of researchers, health policy makers, and practitioners. This article provides guidance on the key components of randomised trials of implementation strategies, including articulation of trial aims, trial recruitment and retention strategies, randomised design selection, use of implementation science theory and frameworks, measures, sample size calculations, ethical review, and trial reporting. It also focuses on topics requiring special consideration or adaptation for implementation trials. We propose this guide as a resource for researchers, healthcare and public health policy makers or practitioners, research funders, and journal editors with the goal of advancing rigorous conduct and reporting of randomised trials of implementation strategies. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Objective
To assess temporal trends in the association between newly diagnosed atrial fibrillation and death.
Design
Community based cohort study.
Setting
Framingham Heart Study cohort, in 1972-85, 1986-2000, and 2001-15 (periods 1-3, respectively), in Framingham, MA, USA.
Participants
Participants with no atrial fibrillation, aged 45-95 in each time period, and identified with newly diagnosed atrial fibrillation (or atrial flutter) during each time period.
Main outcome measures
The main outcome was all cause mortality. Hazard ratios for the association between time varying atrial fibrillation and all cause mortality were calculated with adjustment for time varying confounding factors. The difference in restricted mean survival times, adjusted for confounders, between participants with atrial fibrillation and matched referents at 10 years after a diagnosis of atrial fibrillation was estimated. Meta-regression was used to test for linear trends in hazard ratios and restricted mean survival times over the different time periods.
Results
5671 participants were selected in time period 1, 6177 in period 2, and 6174 in period 3. Adjusted hazard ratios for all cause mortality between participants with and without atrial fibrillation were 1.9 (95% confidence interval 1.7 to 2.2) in time period 1, 1.4 (1.3 to 1.6) in period 2, and 1.7 (1.5 to 2.0) in period 3 (P trend =0.70). Ten years after diagnosis of atrial fibrillation, the adjusted difference in restricted mean survival times between participants with atrial fibrillation and matched referents decreased by 31%, from −2.9 years (95% confidence interval −3.2 to −2.5) in period 1, to −2.1 years (−2.4 to −1.8) in period 2, to −2.0 years (−2.3 to −1.7) in period 3 (P trend =0.03).
Conclusions
No evidence of a temporal trend in hazard ratios for the association between atrial fibrillation and all cause mortality was found. The mean number of life years lost to atrial fibrillation at 10 years had improved significantly, but a two year gap compared with individuals without atrial fibrillation still remained.
Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a “digital clinical trial” involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.
There are many nonpharmacologic interventions tested in randomized clinical trials that demonstrate significant benefits for people living with Alzheimer's disease (AD) and AD‐related dementia, their care partners, or professional care providers. Nevertheless, with few exceptions, proven interventions have not been translated for delivery in real‐world settings, such as home care, primary care, hospitals, community‐based services, adult day services, assisted living, nursing homes, or other healthcare systems (HCSs). Using embedded pragmatic clinical trial (ePCT) methods is one approach that can facilitate dissemination and implementation (D&I) of dementia care interventions. The science of D&I can inform the integration of evidence‐based dementia care in HCSs by offering theoretical frameworks that capture field complexities and guiding evaluation of implementation processes. Also, D&I science can suggest evidence‐based strategies for implementing dementia care in HCSs. Although D&I considerations can inform each stage of dementia care intervention development, it is particularly critical when designing ePCTs. This article examines fundamental considerations for implementing dementia‐specific interventions in HCSs and how best to prepare for successful dissemination upstream in the context of ePCTs, thereby illustrating the critical role of the D&I Core of the National Institute on Aging Imbedded Pragmatic Alzheimer's Disease and AD‐Related Dementias Clinical Trials Collaboratory. The scientific premise of the D&I Core is that having the “end” in mind, upfront in the design and testing of dementia care programs, can lead to decision‐making that optimizes the ultimate goal of wide‐scale D&I of evidence‐based dementia care programs in HCSs. J Am Geriatr Soc 68:S28–S36, 2020 .
Objectives
Little is routinely disclosed about the costs of the pivotal clinical trials that provide the key scientific evidence of the treatment benefits of new therapeutic agents. We expand our earlier research to examine why the estimated costs may vary 100-fold.
Design
A cross-sectional study of the estimated costs of the pivotal clinical trials supporting the approval of 101 new therapeutic agents approved by the US Food and Drug Administration from 2015 to 2017.
Methods
We licensed a software tool used by the pharmaceutical industry to estimate the likely costs of clinical trials to be conducted by contract research organisations. For each trial we collected 52 study characteristics. Linear regression was used to assess the most important factors affecting costs.
Primary and secondary outcome measures
The mean and 95% CI of 225 pivotal clinical trials using varying assumptions. We also assessed median estimated costs per patient, per clinic visit and per drug.
Results
Measured as pivotal trials cost per approved drug, the 101 new molecular entities had an estimated median cost of US20 million–US19 million (IQR US33 million) per trial and US29 894–US$75 047) per patient. The largest single factor driving cost was the number of patients required to establish the treatment effects and varied from 4 patients to 8442. Next was the number of trial clinic visits, which ranged from 2 to 166. Our statistical model showed trial costs rose exponentially with these two variables (R ² =0.696, F=257.9, p<0.01).
Conclusions
The estimated costs are modest for measuring the benefits of new therapeutic agents but rise exponentially as more patients and clinic visits are required to establish a drug effect.
The PARADIGM-HF trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in PARADIGM-HF had NYHA class IV symptomology; accordingly, data that informs the use of S/V among patients with advanced HF are limited. The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) study is a 24-week prospective, multicenter, double-blinded, double-dummy, active-comparator trial to assess the safety, efficacy and tolerability of S/V compared with V in patients with advanced HFrEF. The trial planned to randomize 400 patients age ≥18 years with advanced HF, defined as an EF ≤35%, NYHA functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/mL or N-terminal-pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/mL), and ≥1 objective finding(s) of advanced HF. Following a 3-7 day open-label run-in period with S/V 24/26 mg twice daily, patients are randomized 1:1 to S/V titrated to 97/103 mg twice daily versus 160 mg V twice daily. The primary endpoint is the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints include clinical outcomes, as well as safety and tolerability. Because of the COVID-19 pandemic enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis will consist of the first 335 randomized patients, whose clinical follow-up was not severely impacted by COVID-19.
Background
In 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10‐year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017.
Methods and Results
A list of new molecular entities was abstracted from publicly available data at Drugs@Fda . Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty‐five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175–10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation‐to‐prevalence ratio, 0.52), heart failure (participation‐to‐prevalence ratio, 0.58), and acute coronary syndrome (participation‐to‐prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women ( P =0.29) or underrepresented minorities ( P =0.45) with the drug approval year.
Conclusions
Over the past decade (2008–2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.
Replacement of regular salt with potassium-enriched substitutes reduces blood pressure in controlled situations, mainly among people with hypertension. We report on a population-wide implementation of this strategy in a stepped-wedge cluster randomized trial (NCT01960972). The regular salt in enrolled households was retrieved and replaced, free of charge, with a combination of 75% NaCl and 25% KCl. A total of 2,376 participants were enrolled in 6 villages in Tumbes, Peru. The fully adjusted intention-to-treat analysis showed an average reduction of 1.29 mm Hg (95% confidence interval (95% CI) (−2.17, −0.41)) in systolic and 0.76 mm Hg (95% CI (−1.39, −0.13)) in diastolic blood pressure. Among participants without hypertension at baseline, in the time- and cluster-adjusted model, the use of the salt substitute was associated with a 51% (95% CI (29%, 66%)) reduced risk of developing hypertension compared with the control group. In 24-h urine samples, there was no evidence of differences in sodium levels (mean difference 0.01; 95% CI (0.25, −0.23)), but potassium levels were higher at the end of the study than at baseline (mean difference 0.63; 95% CI (0.78, 0.47)). Our results support a case for implementing a pragmatic, population-wide, salt-substitution strategy for reducing blood pressure and hypertension incidence. A step-wedged cluster randomized trial, carried out in six villages in Tumbes, Peru, with 2,376 participants, demonstrates population-wide reductions in blood pressure, which appear to be higher in individuals with hypertension, as well as reductions in risk of hypertension by around 50% for those without hypertension at baseline, after community-wide replacement of regular salt with a potassium-enriched alternative.
The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.
Importance
Despite considerable improvements in heart failure care, mortality rates among patients in high-income countries have changed little since the early 2000s. Understanding the reasons underlying these trends may provide valuable clues for developing more targeted therapies and public health strategies.
Objective
To investigate mortality rates following a new diagnosis of heart failure and examine changes over time and by cause of death and important patient features.
Design, Setting, and Participants
This population-based retrospective cohort study analyzed anonymized electronic health records of individuals who received a new diagnosis of heart failure between January 2002 and December 2013 who were followed up until December 2014 from the Clinical Practice Research Datalink, which links information from primary care, secondary care, and the national death registry from a subset of the UK population. The data were analyzed from January 2018 to February 2019.
Main Outcomes and Measures
All-cause and cause-specific mortality rates at 1 year following diagnosis. Poisson regression models were used to calculate rate ratios (RRs) and 95% confidence intervals comparing 2013 with 2002, adjusting for age, sex, region, socioeconomic status, and 17 major comorbidities.
Results
Of 86 833 participants, 42 581 (49%) were women, 51 215 (88%) were white, and the mean (SD) age was 76.6 (12.6) years. While all-cause mortality rates declined only modestly over time (RR comparing 2013 with 2002, 0.94; 95% CI, 0.88-1.00), underlying patterns presented explicit trends. A decline in cardiovascular mortality (RR, 0.73; 95% CI, 0.67-0.80) was offset by an increase in noncardiovascular deaths (RR, 1.22; 95% CI, 1.11-1.33). Subgroup analyses further showed that overall mortality rates declined among patients younger than 80 years (RR, 0.79; 95% CI, 0.71-0.88) but not among those older than 80 years (RR, 0.97; 95% CI, 0.90-1.06). After cardiovascular causes (898 [43%]), the major causes of death in 2013 were neoplasms (311 [15%]), respiratory conditions (243 [12%]), and infections (13%), the latter 2 explaining most of the observed increase in noncardiovascular mortality.
Conclusions and Relevance
Among patients with a new heart failure diagnosis, considerable progress has been achieved in reducing mortality in young and middle-aged patients and cardiovascular mortality across all age groups. Improvements to overall mortality are hindered by high and increasing rates of noncardiovascular events. These findings challenge current research priorities and management strategies and call for a greater emphasis on associated comorbidities. Specifically, infection prevention presents as a major opportunity to improve prognosis.
Among patients with severe secondary mitral regurgitation, the rate of death or
unplanned hospitalization for heart failure at 1 year did not differ significantly
between patients who underwent percutaneous mitral-valve repair in addition to
receiving medical therapy and those who received medical therapy alone. (Funded by
the French Ministry of Health and Research National Program and Abbott Vascular;
MITRA-FR ClinicalTrials.)
Objectives
To report reliable estimates of short term and long term survival rates for people with a diagnosis of heart failure and to assess trends over time by year of diagnosis, hospital admission, and socioeconomic group.
Design
Population based cohort study.
Setting
Primary care, United Kingdom.
Participants
Primary care data for 55 959 patients aged 45 and over with a new diagnosis of heart failure and 278 679 age and sex matched controls in the Clinical Practice Research Datalink from 1 January 2000 to 31 December 2017 and linked to inpatient Hospital Episode Statistics and Office for National Statistics mortality data.
Main outcome measures
Survival rates at one, five, and 10 years and cause of death for people with and without heart failure; and temporal trends in survival by year of diagnosis, hospital admission, and socioeconomic group.
Results
Overall, one, five, and 10 year survival rates increased by 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2000 to 48.2% in 2012), and 6.4% (from 19.8% in 2000 to 26.2% in 2007), respectively. There were 30 906 deaths in the heart failure group over the study period. Heart failure was listed on the death certificate in 13 093 (42.4%) of these patients, and in 2237 (7.2%) it was the primary cause of death. Improvement in survival was greater for patients not requiring admission to hospital around the time of diagnosis (median difference 2.4 years; 5.3 v 2.9 years, P<0.001). There was a deprivation gap in median survival of 2.4 years between people who were least deprived and those who were most deprived (11.1 v 8.7 years, P<0.001).
Conclusions
Survival after a diagnosis of heart failure has shown only modest improvement in the 21st century and lags behind other serious conditions, such as cancer. New strategies to achieve timely diagnosis and treatment initiation in primary care for all socioeconomic groups should be a priority for future research and policy.
Background
Run-in periods are occasionally used in randomized clinical trials to exclude patients after inclusion, but before randomization. In theory, run-in periods increase the probability of detecting a potential treatment effect, at the cost of possibly affecting external and internal validity. Adequate reporting of exclusions during the run-in period is a prerequisite for judging the risk of compromised validity. Our study aims were to assess the proportion of randomized clinical trials with run-in periods, to characterize such trials and the types of run-in periods and to assess their reporting.
Materials and methods
This was an observational study of 470 PubMed-indexed randomized controlled trial publications from 2014. We compared trials with and without run-in periods, described the types of run-in periods and evaluated the completeness of their reporting by noting whether publications stated the number of excluded patients, reasons for exclusion and baseline characteristics of the excluded patients.
Results
Twenty-five trials reported a run-in period (5%). These were larger than other trials (median number of randomized patients 217 vs 90, P=0.01) and more commonly industry trials (11% vs 3%, P<0.01). The run-in procedures varied in design and purpose. In 23 out of 25 trials (88%), the run-in period was incompletely reported, mostly due to missing baseline characteristics.
Conclusion
Approximately 1 in 20 trials used run-in periods, though much more frequently in industry trials. Reporting of the run-in period was often incomplete, precluding a meaningful assessment of the impact of the run-in period on the validity of trial results. We suggest that current trials with run-in periods are interpreted with caution and that updates of reporting guidelines for randomized trials address the issue.
BACKGROUND In patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown. METHODS We randomly assigned patients who had severe secondary mitral regurgitation (defined as an effective regurgitant orifice area of >20 mm² or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months. RESULTS At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56). CONCLUSIONS Among patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone.
Merck & Co., Inc. (Kenilworth, New Jersey) is investing in approaches to enrich clinical trial data and augment decision‐making through utilization of digital health technologies, outpatient sampling, and real‐time data access. As part of this strategy, a Phase 1 study was conducted to explore a few technologies of interest. In this fixed‐sequence, two‐period trial, 16 healthy subjects were administered 50‐mg once‐daily sitagliptin packaged in a bottle that electronically captured the date and time study medication was dispensed (Period 1) and in a traditional pharmacy bottle (Period 2). Dried blood spot (DBS) samples were collected for sitagliptin concentration analysis on select study days, both in‐clinic and at‐home, with collection time recorded using an electronic diary in Period 1 and by clinic staff in Period 2. Study results demonstrated the feasibility and subject acceptance of collecting digital adherence data and outpatient DBS samples in clinical trials and highlighted areas for future improvements. This article is protected by copyright. All rights reserved.
The role of real-world evidence (RWE) in regulatory, drug development, and healthcare decision-making is rapidly expanding. Recent advances have increased the complexity of cancer care and widened the gap between randomized clinical trial (RCT) results and the evidence needed for real-world clinical decisions. Instead of remaining invisible, data from the >95% of cancer patients treated outside of clinical trials can help fill this void. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
Background:
Heart failure has a disproportionate burden on patients who are Black, Indigenous, and people of color (BIPOC), but not much is known about representation of these groups in randomized controlled trials (RCTs). We explored temporal trends in and RCT factors associated with the reporting of race and ethnicity data and the enrollment of BIPOC in heart failure RCTs.
Methods:
We searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with an impact factor ≥10 between January 1, 2000 and June 17, 2020. We used the Cochran-Armitage and Jonchkeere-Terpstra tests to examine temporal trends, and multivariable regression to assess the association between trial characteristics and outcomes.
Results:
Of 414 RCTs meeting inclusion criteria, only 157 (37.9% [95% CI, 33.2%-2.8%]) reported race and ethnicity data. Among 158 200 participants in these 157 RCTs, 29 512 (18.7% [95% CI, 18.5%-18.9%]) were BIPOC. There was a temporal increase in reporting of race and ethnicity data (29.5% in 2000-2003 to 54.7% in 2016-2020, P<0.001) and in enrollment of BIPOC (14.4% in 2000-2003 to 22.2% in 2016-2020, P=0.038). Trial leadership by a woman was independently associated with twice the odds of reporting race and ethnicity data (odds ratio, 2.0 [95% CI, 1.1-3.8]; P=0.028) and an 8.4% increase (95% CI, 1.9%-15.0%; P=0.013) in BIPOC enrollment.
Conclusions:
A minority of heart failure RCTs reported race and ethnicity data, and among these, BIPOC were under-enrolled relative to disease distribution. Both reporting of race and ethnicity as well as enrollment of BIPOC increased between 2000 and 2020. After multivariable adjustment, trials led by women had greater odds of reporting race and ethnicity and enrolling BIPOC.
Registration:
URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021237497.
Aims
The PRECISE-DAPT score is recommended by guidelines for predicting out-of-hospital bleeding in patients after percutaneous coronary intervention (PCI). However, the long-term prognostic value of the PRECISE-DAPT score in patients after PCI remains unclear.
Methods and Results
We performed a prospective study of 10,724 patients who underwent PCI throughout 2013 in Fuwai hospital. The bleeding endpoint was Bleeding Academic Research Consortium 2, 3, or 5 bleeding. The ischaemic endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCE). After a 5-year follow-up, 10,109 patients were finally analysed. A total of 415 (4.11%) patients experienced bleeding, 364 (3.60%) experienced all-cause death, and 2049 (20.27%) had MACCE. Using Cox regression, the risk of bleeding (hazard ratio [HR]: 1.721, 95% confidence interval [CI]: 1.180–2.511, P = 0.005), MACCE (HR: 1.607, 95% CI: 1.347–1.917, P < 0.001), and all-cause-death (HR: 3.902, 95% CI: 2.916–5.221, P < 0.001) in patients with a high score were significantly higher than those in patients with a low score. The PRECISE-DAPT score showed prognostic value for 5-year events of bleeding (C statistic: 0.566, 95% CI: 0.537–0.594), MACCE (C statistic: 0.540, 95% CI: 0.527–0.553), and all-cause-death (C statistic: 0.673, 95% CI: 0.644–0.702).
Conclusion
After 5 years of follow-up, the PRECISE-DAPT score has a statistically significant predictive value for long-term bleeding events in Chinese PCI population, and also had some prognostic value for death and MACCE.
Background
Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain.
Methods
We conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia.
Results
A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P=0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P<0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P<0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P=0.76).
Conclusions
Among persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt. (Funded by the National Health and Medical Research Council of Australia; SSaSS ClinicalTrials.gov number, NCT02092090.)
Background
The geographic representation of investigators and participants in heart failure (HF) randomized clinical trials (RCTs) may not reflect the global burden of disease.
Aims
We assessed the geographic diversity of RCT leaders and explored associations with geographic representation of enrolled participants among impactful HF RCTs.
Methods and Results
We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with impact factor ≥10 between January 2000 and June 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to explore associations between predictors and outcomes. There were 414 eligible RCTs. Only 80 of 828 trial leaders (9.7%; 95% CI: 7.8% to 11.8%), and 453 of 4656 collaborators (9.7%; 95% CI: 8.8% to 10.6%) were from outside Europe and North America, with no change in temporal trends and greater disparities in large RCTs. The adjusted odds of trial leadership outside Europe and North America were lower with industry funding (aOR: 0.33; 95% CI: 0.15 to 0.75; P = 0.008). Among 157,416 participants in whom geography was reported, only 14.5% (95% CI: 14.3% to 14.7%) were enrolled outside Europe and North America, but odds of enrolment were ten-fold greater with trial leadership outside Europe and North America (aOR: 10.0; 95% CI 5.6–19.0; P < 0.001).
Conclusions
Regions disproportionately burdened with HF are under-represented in HF trial leadership, collaboration, and enrolment. RCT leadership outside Europe and North America is independently associated with participant enrolment in under-represented regions. Increasing research capacity outside Europe and North America could enhance trial diversity and generalizability.
Background
The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy.
Methods
Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis.
Results
A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]).
Conclusions
In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.)
Background
The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms.
Methods
One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire.
Results
The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic.
Conclusions
CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial.
Registration
URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04252287.
Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).
Objective: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD).
Background: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs.
Methods: MITIGATE is a virtual, electronic health record (EHR)-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California (KPNC) – a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE two grams by mouth twice daily with meals) vs. the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time.
Conclusion: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pre-treatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
The learning health system is a conceptual model for continuous learning and knowledge generation rooted in the daily practice of medicine. While companies such as Google and Amazon use dynamic learning systems that learn iteratively through every customer interaction, this efficiency has not materialized on a comparable scale in health systems. An ideal learning health system would learn from every patient interaction to benefit the care for the next patient. Notable advances include the greater use of data generated in the course of clinical care, Common Data Models, and advanced analytics. However, many remaining barriers limit the most effective use of large and growing health care data assets. In this review, we explore the accomplishments, opportunities, and barriers to realizing the learning health system.
Aims
To evaluate temporal trends in the enrolment of females in randomized controlled trials (RCTs) of heart failure with reduced ejection fraction (HFrEF) published in high‐impact journals, and assess RCT characteristics associated with under‐enrolment.
Methods and results
We searched MEDLINE, EMBASE and CINAHL for studies published from January 2000 to May 2019 in journals with impact factor ≥10. We included RCTs that recruited adults with HFrEF. We used a 20% threshold below the sex distribution of HFrEF to define under‐enrolment. We used multivariable logistic regression to assess trial characteristics independently associated with under‐enrolment. We included 317 RCTs. Among the 183 097 participants, mean (standard deviation) age was 63.0 (7.0) years and 25.5% were female. Females were under‐enrolled in 71.6% [95% confidence interval (CI) 66.6–76.6%] of the RCTs; enrolment did not increase significantly between 2000–2019. Sex‐related eligibility criteria [odds ratio (OR) 2.05, 95% CI 1.01–4.16; P = 0.046]; recruitment in ambulatory settings (OR 2.56, 95% CI 1.37–4.81; P = 0.003); trial coordination in North America (OR 4.44, 95% CI 1.09–18.07; P = 0.037), Europe (OR 6.79, 95% CI 1.63–27.39; P = 0.018) and Asia (OR 9.33, 95% CI 1.40–12.40; P = 0.033); drug (OR 1.76, 95% CI 1.96–7.36; P < 0.001) and device/surgical interventions (OR 1.69, 95% CI 1.16–9.43; P = 0.002); and men in first and last authorship position (OR 1.32, 95% CI 1.12–3.54; P = 0.047) were associated with under‐enrolment of females.
Conclusions
Females were under‐enrolled relative to disease distribution in a majority of high‐impact HFrEF RCTs, with no change in temporal trends between 2000 and 2019. Trial characteristics and gender of trial leaders were associated with under‐enrolment.
Older adults traditionally have been underrepresented in cardiovascular disease (CVD) trials,¹,2 requiring extrapolation of evidence from younger populations.³ In response, the National Institutes of Health (NIH) established the Inclusion Across the Lifespan Policy in January 2019 to expand representation of older adults and children in clinical research.⁴,5 The policy requires NIH studies to include individuals across the lifespan and to justify age-based exclusions. We set out to assess the early impact of this policy for the inclusion of older adults in CVD trials with a variety of funding sources.
Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making. However, over the past 4 decades, results from well-done RCTs have repeatedly contradicted practices supported by common sense and clinical observation. Common sense and clinical observation fail for several reasons: incomplete understanding of pathophysiology, biases and unmeasured confounding in observational research, and failure to understand risks and benefits of treatments within complex systems. Concerns about traditional RCT models are legitimate, but randomization remains a critical tool to understand the causal relationship between treatments and outcomes. Instead, development and promulgation of tools to apply randomization to real-world data are needed to build the best evidence base in cardiovascular medicine.
Importance
Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) therapy provided incremental survival benefit to patients with heart failure and reduced ejection fraction (HFrEF) who received guideline-directed medical therapy regardless of type 2 diabetes status in a recent clinical trial. To date, estimation of the potential benefits that could be gained from optimal implementation of SGLT2-i therapy at the population level has not been quantified.
Objective
To quantify the projected gains for deaths prevented or postponed with comprehensive implementation of SGLT2-i therapy for patients with HFrEF in the United States.
Design, Setting, and Participants
This decision analytical model, performed from September 25 to October 20, 2019, used published sources to estimate the US population of patients with HFrEF eligible for SGLT2-i therapy and the numbers needed to treat to prevent or postpone overt death. Sensitivity analyses were performed to account for the range of potential benefits.
Main Outcomes and Measures
All-cause mortality.
Results
Of the 3.1 million patients with HFrEF in the United States, 2 132 800 (69%) were projected to be candidates for SGLT2-i therapy. Optimal implementation of SGLT2-i therapy was empirically estimated to prevent up to 34 125 deaths per year (range 21 840-49 140 deaths per year). A secondary analysis excluding patients on the basis of N-terminal–pro brain natriuretic peptide levels and other trial entry criteria would yield a potential benefit of 25 594 deaths per year prevented (range, 16 380-36 855 deaths per year prevented).
Conclusions and Relevance
This study suggests that a substantial number of deaths in the United States could be prevented by optimal implementation of SGLT2-i therapy. These data support implementation of the current evidence into practice in a timely manner to achieve important public health benefits and to reduce the mortality burden of HFrEF.
Importance
Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes.
Objective
To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy.
Design, Setting, and Participants
GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP−guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019.
Main Outcomes and Measures
For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes.
Results
Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were “clinically stable” and “already at maximally tolerated therapy.” Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of β-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P < .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes.
Conclusions and Relevance
Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic.
Trial Registration
ClinicalTrials.gov Identifier: NCT01685840
Importance
Pragmatic trials test interventions using designs that produce results that may be more applicable to the population in which the intervention will be eventually applied.
Objective
To investigate how pragmatic or explanatory cardiovascular (CV) randomized clinical trials (RCT) are, and if this has changed over time.
Data Source
Six major medical and CV journals, including New England Journal of Medicine, Lancet, JAMA, Circulation, European Heart Journal, and Journal of the American College of Cardiology.
Study Selection
All CV-related RCTs published during 2000, 2005, 2010, and 2015 were identified and included.
Data Extraction and Synthesis
Included RCTs were assessed by 2 independent adjudicators with expertise in RCT and CV medicine.
Main Outcomes and Measures
The outcome measure was the level of pragmatism evaluated using the Pragmatic Explanatory Continuum Index Summary (PRECIS)–2 tool, which uses a 5-point ordinal scale (ranging from very pragmatic to very explanatory) across 9 domains of trial design, including eligibility, recruitment, setting, organization, intervention delivery, intervention adherence, follow-up, primary outcome, and analysis.
Results
Of 616 RCTs, the mean (SD) PRECIS-2 score was 3.26 (0.70). The level of pragmatism increased over time from a mean (SD) score of 3.07 (0.74) in 2000 to 3.46 (0.67) in 2015 (P < .001 for trend; Cohen d relative effect size, 0.56). The increase occurred mainly in the domains of eligibility, setting, intervention delivery, and primary end point. PRECIS-2 score was higher for neutral trials than those with positive results (P < .001) and in phase III/IV trials compared with phase I/II trials (P < .001) but similar between different sources of funding (public, industry, or both; P = .38). More pragmatic trials had more sites, larger sample sizes, longer follow-ups, and mortality as the primary end point.
Conclusions and Relevance
The level of pragmatism increased moderately over 2 decades of CV trials. Understanding the domains of current and future clinical trials will aid in the design and delivery of CV trials with broader application.
Importance
Health care services that support the hospital-to-home transition can improve outcomes in patients with heart failure (HF).
Objective
To test the effectiveness of the Patient-Centered Care Transitions in HF transitional care model in patients hospitalized for HF.
Design, Setting, and Participants
Stepped-wedge cluster randomized trial of 2494 adults hospitalized for HF across 10 hospitals in Ontario, Canada, from February 2015 to March 2016, with follow-up until November 2016.
Interventions
Hospitals were randomized to receive the intervention (n = 1104 patients), in which nurse-led self-care education, a structured hospital discharge summary, a family physician follow-up appointment less than 1 week after discharge, and, for high-risk patients, structured nurse homevisits and heart function clinic care were provided to patients, or usual care (n = 1390 patients), in which transitional care was left to the discretion of clinicians.
Main Outcomes and Measures
Primary outcomes were hierarchically ordered as composite all-cause readmission, emergency department (ED) visit, or death at 3 months; and composite all-cause readmission or ED visit at 30 days. Secondary outcomes were B-PREPARED score for discharge preparedness (range: 0 [most prepared] to 22 [least prepared]); the 3-Item Care Transitions Measure (CTM-3) for quality of transition (range: 0 [worst transition] to 100 [best transition]); the 5-level EQ-5D version (EQ-5D-5L) for quality of life (range: 0 [dead] to 1 [full health]); and quality-adjusted life-years (QALY; range: 0 [dead] to 0.5 [full health at 6 months]).
Results
Among eligible patients, all 2494 (mean age, 77.7 years; 1258 [50.4%] women) completed the trial. There was no significant difference between the intervention and usual care groups in the first primary composite outcome (545 [49.4%] vs 698 [50.2%] events, respectively; hazard ratio [HR], 0.99 [95% CI, 0.83-1.19]) or in the second primary composite outcome (304 [27.5%] vs 408 [29.3%] events, respectively; HR, 0.93 [95% CI, 0.73-1.18]). There were significant differences between the intervention and usual care groups in the secondary outcomes of mean B-PREPARED score at 6 weeks (16.6 vs 13.9; difference, 2.65 [95% CI, 1.37-3.92]; P < .001); mean CTM-3 score at 6 weeks (76.5 vs 70.3; difference, 6.16 [95% CI, 0.90-11.43]; P = .02); and mean EQ-5D-5L score at 6 weeks (0.7 vs 0.7; difference, 0.06 [95% CI, 0.01 to 0.11]; P = .02) and 6 months (0.7 vs 0.6; difference, 0.06 [95% CI, 0.01-0.12]; P = .02). There was no significant difference in mean QALY between groups at 6 months (0.3 vs 0.3; difference, 0.00 [95% CI, −0.02 to 0.02]; P = .98).
Conclusions and Relevance
Among patients with HF in Ontario, Canada, implementation of a patient-centered transitional care model compared with usual care did not improve a composite of clinical outcomes. Whether this type of intervention could be effective in other health care systems or locations would require further research.
Trial Registration
ClinicalTrials.gov Identifier: NCT02112227
Objective:
To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients.
Methods:
Twenty-three clinical trial protocols completed during 2011-2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated.
Results:
All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14-47). A median of 55% (range 38-89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1-134).
Conclusion:
Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite.
Background
Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor. Transcatheter mitral-valve repair may improve their clinical outcomes.
Methods
At 78 sites in the United States and Canada, we enrolled patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up. The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 88.0%.
Results
Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.40 to 0.70; P<0.001). The rate of freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001).
Conclusions
Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.)
With statins, the reported rate of adverse events differs widely between randomized clinical trials (RCTs) and observations in clinical practice, the rates being 1-2% in RCTs vs. 10-20% in the so-called real world. One possible explanation is the claim that RCTs mostly use a run-in period with a statin. This would exclude intolerant patients from remaining in the trial and therefore favour a bias towards lower rates of intolerance. We here review data from RCTs with more than 1000 participants with and without a run-in period, which were included in the Cholesterol Treatment Trialists Collaboration. Two major conclusions arise: (i) the majority of RCTs did not have a test dose of a statin in the run-in phase. (ii) A test dose in the run-in phase was not associated with a significantly improved adherence rate within that trial when compared to trials without a test dose. Taken together, the RCTs of statins reviewed here do not suggest a bias towards an artificially higher adherence rate because of a run-in period with a test dose of the statin. Other possible explanations for the apparent disparity between RCTs and real-world observations are also included in this review albeit mostly not supported by scientific data.
With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.
Background
Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear.
Methods
We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer.
Results
A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned.
Conclusions
Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500; ClinicalTrials.gov number, NCT00135226.)
Background:
Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. The degree to which gaps in medication use and dosing persist in contemporary outpatient practice is unclear.
Objectives:
This study sought to characterize patterns and factors associated with use and dose of HFrEF medications in current practice.
Methods:
The CHAMP-HF (Change the Management of Patients with Heart Failure) registry included outpatients in the United States with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). Patient-level factors associated with medication use were examined.
Results:
Overall, 3,518 patients from 150 primary care and cardiology practices were included. Mean age was 66 ± 13 years, 29% were female, and mean EF was 29 ± 8%. Among eligible patients, 27%, 33%, and 67% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA therapy, respectively. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (17%), ARNI (14%), and beta-blocker (28%), whereas most patients were receiving target doses of MRA therapy (77%). Among patients eligible for all classes of medication, 1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, and MRA. In adjusted models, older age, lower blood pressure, more severe functional class, renal insufficiency, and recent HF hospitalization generally favored lower medication utilization or dose. Social and economic characteristics were not independently associated with medication use or dose.
Conclusions:
In this contemporary outpatient HFrEF registry, significant gaps in use and dose of guideline-directed medical therapy remain. Multiple clinical factors were associated with medication use and dose prescribed. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.
Introduction
Heart Failure (HF) is a common cause of hospitalization in older adults. The transition from hospital to home is high-risk, and gaps in transitional care can increase the risk of re-hospitalization and death. Combining health care services supported by meta-analyses, we designed the PACT-HF transitional care model.
Methods
Adopting an integrated Knowledge Translation (iKT) approach in which decision-makers and clinicians are partners in research, we implement and test the effectiveness of PACT-HF among patients hospitalized for HF. We use a pragmatic stepped wedge cluster randomized trial design to introduce the complex health service intervention to 10 large hospitals in a randomized sequence until all hospitals initiate the intervention. The goal is for all patients hospitalized with HF to receive self-care education, multidisciplinary care, and early follow-up with their health care providers; and in addition, for high-risk patients to receive post-discharge nurse-led home visits and outpatient care in Heart Function clinics. This requires integration of care across hospitals, home care agencies, and outpatient clinics in our publicly funded health care system. While hospitals are the unit of recruitment and analysis, patients (estimated sample size of 3200) are the unit of analysis. Primary outcomes are hierarchically ordered as time to composite all-cause readmissions / emergency department (ED) visits / death at 3 months and time to composite all-cause readmissions / ED visits at 30 days. In a nested study of 8 hospitals, we measure the patient-centered outcomes of Discharge Preparedness, Care Transitions Quality, and Quality Adjusted Life Years (QALY); and the 6-month health care resource use and costs. We obtain all clinical and cost outcomes via linkages to provincial administrative databases.
Conclusions
This protocol describes the implementation and testing of a transitional care model comprising health care services informed by high-level evidence. The study adopts an iKT and pragmatic approach, uses a robust study design, links clinical trial data with outcomes held in administrative databases, and includes patient-reported outcomes. Findings will have implications on clinical practice, health care policy, and Knowledge Translation (KT) research methodology.