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AimsDiscontinuation or non-publication of trials may hinder scientific progress and violates the commitment made to research participants. We sought to identify the prevalence of discontinuation and non-publication of heart failure (HF) clinical trials.Methods and resultsWe conducted a cross-sectional search of ClinicalTrials.gov to identify all completed and discontinued HF clinical trials. We limited our search to only include trials that were completed by 31 December 2017. Trials were investigated to identify reasons for discontinuation. Informative termination was defined as trial termination due to safety or efficacy concerns. Data pertaining to the trial phase, funding, intervention, enrolment, and trial completion date were extracted for each trial. A total of 572 trials were included. Of these, 21% (n = 118) were discontinued before completion. Patient accrual was the most frequently cited reason (n = 42; 36%) for trial discontinuation, followed by informative termination (n = 16; 14%) and funding (n = 14; 12%). Overall, 24 780 patients were enrolled in trials that were terminated. Of trials that were completed and not terminated, nearly one-third (n = 131/454; 29%) were not published. Seventy-nine (24%) trials were published within 12 months, 192 (59%) within 24 months, and 252 (78%) trials within 36 months.ConclusionsDiscontinuation and non-publication of HF trials is common. This raises ethical concerns towards participants who volunteer for research and are exposed to potential risks, inconvenience, and discomfort without furthering scientific progress.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

AimsThe primary objective of this systematic review was to estimate the prevalence and temporal changes in chronic comorbid conditions reported in heart failure (HF) clinical trials.Methods and resultsWe searched MEDLINE for HF trials enrolling more than 400 patients published between 2001 and 2016.Trials were divided into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or trials enrolling regardless of ejection fraction. The prevalence of baseline chronic comorbid conditions was categorized according to the algorithm proposed by the Chronic Conditions Data Warehouse, which is used to analyse Medicare data. To test for a trend in the prevalence of comorbid conditions, linear regression models were used to evaluate temporal trends in prevalence of comorbidities. Overall, 118 clinical trials enrolling a cumulative total of 215 508 patients were included. Across all comorbidities examined, data were reported in a mean of 35% of trials, without significant improvement during the study period. Reporting of comorbidities was more common in HFrEF trials (51%) compared with HFpEF trials (27%). Among trials reporting data, hypertension (63%), ischaemic heart disease (44%), hyperlipidaemia (48%), diabetes (33%), chronic kidney disease (25%) and atrial fibrillation (25%) were the major comorbidities. The prevalence of comorbidities including hypertension, atrial fibrillation and chronic kidney disease increased over time while the prevalence of smoking decreased in HFrEF trials.ConclusionMany HF trials do not report baseline comorbidities. A more rigorous, systematic, and standardized framework needs to be adopted for future clinical trials to ensure adequate comorbidity reporting and improve recruitment of multi-morbid HF patients.

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. [ABSTRACT FROM AUTHOR]

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials. [ABSTRACT FROM AUTHOR]

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities. [ABSTRACT FROM AUTHOR]

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Although chronic kidney disease is characterized by low glomerular filtration rate (GFR) or albuminuria, estimated GFR (eGFR) is more widely utilized as a marker of risk profile in cardiovascular diseases, including heart failure (HF). The presence and magnitude of albuminuria confers a strong prognostic association in forecasting risk of incident HF as well as its progression, irrespective of eGFR. Despite the high prevalence of albuminuria in HF, whether it adds incremental prognostic information in clinical practice and serves as an independent risk marker, and whether there are any therapeutic implications of assessing albuminuria in patients with HF is less well-established. In this narrative review, we assess the potential role of albuminuria in risk profiling for development and progression of HF, strengths and limitations of utilizing albuminuria as a risk marker, its ability to serve in HF risk prediction models, and the implications of adopting albuminuria as an effective parameter in cardiovascular trials and practice. [Display omitted] • Albuminuria is prevalent in patients with heart failure and confers a strong, consistent and independent association with risk. • The causes of albuminuria in patients with heart failure are incompletely understood, as are the mechanisms linking it to disease progression and adverse outcomes. • Interventions that reduce albuminuria may potentially lower the risk of incident heart failure or prevent progression of existing heart failure. [ABSTRACT FROM AUTHOR]

Introduction: Bibliometric studies can help guide researchers and funding bodies toward fields where more research activity is warranted. Bibliometric analyses have previously been published in many specialties and sub-specialties. Our literature search did not show a bibliometric analysis on pericardial diseases. We performed a bibliometric analysis of the top 100 cited manuscripts on pericardial diseases to identify knowledge. Material and methods: Bibliometric analysis is a quantitative method to assess research performance and analyze publication trends. Web of Science was searched in April 2020 to identify the top 100 cited manuscripts in pericardial diseases. Results: Twenty-six out of the top 100 cited manuscripts were published between 2000 and 2009. These manuscripts were cited on average189 times (range: 110–743) since publication. Only two manuscripts were cited > 500 times. Among the top-ten cited manuscripts, there were 6 original articles, 1 case series, and 3 review articles. Of the 3 review articles, 2 were society guidelines. 90% of the authors had written just 1 manuscript. There were ten manuscripts with women as first authors with a significant association between gender of the first and corresponding author (odds ratio = 44, p < 0.001). Only 20% of manuscripts were funded. Most publications came from institutions in the United States (n = 40), Italy (n = 10), and Spain (n = 5). Conclusions: Our study provides an insight into the characteristics and quality of the highly cited literature in the field of pericardial diseases. This can be used to guide further research in the field of pericardial diseases. [ABSTRACT FROM AUTHOR]

Heterogeneity in the reporting of kidney function, kidney outcomes, and definitions for kidney endpoints in clinical trials makes it challenging to compare results and gauge incremental benefit of interventions across trials. We conducted a systematic review of the ascertainment of baseline kidney variables, reporting of kidney endpoints, and definitions used to characterize these endpoints in type 2 diabetes mellitus (T2DM), kidney, and heart failure (HF) trials. Medline, Scopus, and ClinicalTrials.gov were searched from January 2014 through January 2021 for large (>1000 participants) T2DM, HF, and kidney disease trials and their secondary analyses. Trial publication and supplementary appendices were searched to abstract relevant data. Thirty-three trials (16 T2DM; 10 HF; 7 kidney diseases) were included. Thirteen trials did not include patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and for trials that did, representation of this cohort ranged from 0.1% to 15%. Reporting of baseline kidney function and albuminuria remained low, especially in HF trials. Variability was observed in the definition of chronic kidney disease, sustained decline in eGFR, end-stage kidney disease, kidney death, and kidney composite endpoint across trials. eGFR slope was reported in less than half trials, with differences observed in statistical models, definition of acute or chronic slope, and follow-up duration across trials. Significant heterogeneity in reporting of kidney function and kidney outcomes in large T2DM, kidney, and HF trials underscores the need for future stakeholders to draft a consensus solution. Detailed profiling of patients at baseline, accrual of more patients with advanced kidney disease, and standardization of definitions in trials may improve the ability to compare the results across trials. [ABSTRACT FROM AUTHOR]

The SPIRRIT trial will employ a more pragmatic approach and is embedded into existing disease registries in Sweden and USA to increase patient recruitment; it is expected to enrol almost double the number of patients in SPIRIT-HF. Up till the 1980s, little was known about how to manage patients with acute myocardial infarction (AMI). 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. [Extracted from the article]

Of these patients, 55% were patients newly initiated on an SGLT-2 inhibitor, whereas 45% were patients continuing previously prescribed therapy. B This article refers to 'Use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry' by P.M. Becher I et al i ., published in this issue on pages 1012-1022. b Recent randomized controlled trials have established sodium-glucose co-transporter 2 (SGLT-2) inhibitors as a new cornerstone therapy for patients with heart failure (HF) with reduced ejection fraction (HFrEF).1 These trials showed SGLT-2 inhibitors to significantly reduce cardiovascular mortality and HF hospitalization, with consistent efficacy regardless of diabetes status.1 These benefits for traditional cardiovascular outcomes were combined with improvements in patient-reported quality of life, improvements in New York Heart Association functional class, and less progression of renal disease.1 Moreover, benefits with respect to clinical events and quality of life were seen within days to weeks of initiation, suggesting that any delay in therapy exposes patients to substantial excess risk.2,3 Combined with the other pillars of comprehensive disease-modifying quadruple therapy [angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA)], use of SGLT-2 inhibitors may reduce risk of mortality for patients with HFrEF by 73% over 2 years.4 However, as we laud SGLT-2 inhibitors as a major therapeutic advance, history has taught us that strong efficacy and safety in clinical trials are unfortunately not enough to ensure robust real-world use of life-saving therapies for HFrEF. Many of these characteristics are consistent with sodium-glucose co-transporter 2 (SGLT-2) inhibitor therapy, acknowledging that same patients may still face challenges with out-of-pocket costs and accessibility. [Extracted from the article]

Background: Despite the publication of several randomized clinical trials comparing catheter ablation (CA) with medical therapy (MT) in patients with atrial fibrillation (AF), the superiority of one strategy over another is still questioned by many. In this meta-analysis of randomized controlled trials, we compared the efficacy and safety of CA with MT for AF.Methods: We systematically searched MEDLINE, EMBASE, and other online sources for randomized controlled trials of AF patients that compared CA with MT. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular hospitalizations and recurrence of atrial arrhythmia. Subgroup analyses stratified by the presence of heart failure with reduced ejection fraction, type of AF, age, and sex were performed. Risk ratios (RRs) with 95% CIs were calculated using a random effects model, and Mantel-Haenszel method was used to pool RR.Results: Eighteen randomized controlled trials comprising 4464 patients (CA, n=2286; MT, n=2178) were included. CA resulted in a significant reduction in all-cause mortality (RR, 0.69; 95% CI, 0.54-0.88; P=0.003) that was driven by patients with AF and heart failure with reduced ejection fraction (RR, 0.52; 95% CI, 0.35-0.76; P=0.0009). CA resulted in significantly fewer cardiovascular hospitalizations (hazard ratio, 0.56; 95% CI, 0.39-0.81; P=0.002) and fewer recurrences of atrial arrhythmias (RR, 0.42; 95% CI, 0.33-0.53; P<0.00001). Subgroup analyses suggested that younger patients (age, <65 years) and men derived more benefit from CA compared with MT.Conclusions: CA is associated with all-cause mortality benefit, that is driven by patients with AF and heart failure with reduced ejection fraction. CA reduces cardiovascular hospitalizations and recurrences of atrial arrhythmia for patients with AF. Younger patients and men appear to derive more benefit from CA. [ABSTRACT FROM AUTHOR]

The number of meta-analyses published annually has increased more than 20-fold between 1994 (n = 386) and 2014 (n = 8203). In examining how much of this increase in meta-analysis publication has genuinely represented novel contributions to clinical medicine and public health, it became clear that there was an abundance of redundant and disorganized meta-analyses, creating confusion and generating considerable debate. Ironically, meta-analyses, which should prevent redundant research, have become a victim of it. Recently, 17 meta-analyses were published based on the results of only 3 randomized controlled trials that studied the role of transcatheter closure of patent foramen ovale for prevention of cryptogenic stroke. In our search of the published literature, we identified at least 10 topics that were the subject of 10 meta-analyses. In the context of overlapping meta-analyses, one questions what needs to be done to put this "runaway train" back on track. In this review we examine the practice of redundant meta-analyses and the reasons for its disturbing "popularity." The registration of systematic reviews should be mandatory in prospective registries, such as PROSPERO, and the PRISMA checklist should be updated to incorporate new evidence and mandate the reference of previously published reviews and rationale for any new study. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents remains uncertain. We compared short-term (<6-month) DAPT followed by aspirin or P2Y12 inhibitor monotherapy; midterm (6-month) DAPT; 12-month DAPT; and extended-term (>12-month) DAPT after percutaneous coronary intervention with drug-eluting stents.Methods: Twenty-four randomized, controlled trials were selected using Medline, Embase, Cochrane library, and online databases through September 2019. The coprimary end points were myocardial infarction and major bleeding, which constituted the net clinical benefit. A frequentist network meta-analysis was conducted with a random-effects model.Results: In 79 073 patients, at a median follow-up of 18 months, extended-term DAPT was associated with a reduced risk of myocardial infarction in comparison with 12-month DAPT (absolute risk difference, -3.8 incident cases per 1000 person-years; relative risk, 0.68 [95% CI, 0.54-0.87]), midterm DAPT (absolute risk difference, -4.6 incident cases per 1000 person-years; relative risk, 0.61 [0.45-0.83]), and short-term DAPT followed by aspirin monotherapy (absolute risk difference, -6.1 incident cases per 1000 person-years; relative risk, 0.55 [0.37-0.83]), or P2Y12 inhibitor monotherapy (absolute risk difference, -3.7 incident cases per 1000 person-years; relative risk, 0.69 [0.51-0.95]). Conversely, extended-term DAPT was associated with a higher risk of major bleeding than all other DAPT groups. In comparison with 12-month DAPT, no significant differences in the risks of ischemic end points or major bleeding were observed with midterm or short-term DAPT followed by aspirin monotherapy, with the exception that short-term DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding. There were no significant differences with respect to mortality between the different DAPT strategies. In acute coronary syndrome, extended-term in comparison with 12-month DAPT was associated with a reduced risk of myocardial infarction without a significant increase in the risk of major bleeding.Conclusions: The present network meta-analysis suggests that, in comparison with 12-month DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduces major bleeding after percutaneous coronary intervention with drug-eluting stents, whereas extended-term DAPT reduces myocardial infarction at the expense of more bleeding events. [ABSTRACT FROM AUTHOR]

Introduction: Selective reporting can confound the interpretation and validity of randomized controlled trials (RCT). Therefore in 2005, the International Committee of Medical Journal Editors mandated protocol registration for RCT's. Hypothesis: To investigate the consistency between trials registered with an international clinical trials registry and published primary outcomes among cardiovascular RCT's. Methods: We searched the MEDLINE database for Phase II and III Cardiovascular RCTs published beyond July 2005 through May 2018. For every registered RCT, we determined the time of registration, the measured outcome, the number of outcomes in the published article and corresponding registry. The findings obtained from registry and published article were evaluated for consistency. Results: Of the 154 RCTs identified, 134 (87.1%) were registered appropriately per ICMJE guidelines with 126 registered with clinicaltrials.gov. Of these, 73 (54.4%) registered a sample size which remained unchanged from the time of registration to publication. 100 (74.6%) RCTs were registered before enrollment, 27 (20.1%) during the study and 7 (5.2%) after completion. These single and multi-center trials were conducted in North America (42.5%), Far East (18%), Europe (18%), and internationally (18%), most of which studied drugs (88%). Primary outcomes were appropriately registered and remained unchanged at the end of the study in 121 (90.1%) RCTs. Primary outcomes involved hard endpoints in 34 (26.1%) RCTs while 99 (73.8%) reported surrogate outcomes. Most trials were funded by the industry (80.5%) and research foundations/academic institutions (17.9%). Conclusion: Despite mandatory registration, compliance with trial registration continues to lag. Selective reporting of the primary end points is present in one tenth of the phase 2 and 3 cardiovascular RCT's. [ABSTRACT FROM AUTHOR]