Symptoms Burden as a Clinical Outcomes Assessment in Heart Failure Patients With Atrial Fibrillation.

Background: Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period.

Objectives: The authors sought to develop and validate a method of measuring symptom burden of AF in a HF population.

The Case for Access to Data Monitoring Committee Charters.

AbstractClinical trials investigating novel or high-risk interventions often use data monitoring committees (DMCs) to ensure that the participants' best interests are safeguarded. The typical DMC charter describes procedures by which the DMC operates, including important details concerning organizational structure, membership, meeting frequency, statistical monitoring guidelines, and contents of DMC reports for interim review. These charters, however, are not routinely publicly available; in some cases, their access could be important to the interpretation of trial results.

Training the Next Generation of Data Monitoring Committee Members: An Initiative of the Heart Failure Collaboratory.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members.

Guidance for Healthcare Providers on Newest Guidelines for Over-the-Counter Drug Treatment of Mild Symptoms of COVID-19.

On January 18, 2024, the US Centers for Disease Control and Prevention issued their most recent guidelines for over-the-counter drugs for coronavirus disease 2019 (COVID-19). Specifically, the organization stated that "Most people with COVID-19 have mild illness and can recover at home. You can treat symptoms with over-the-counter medicines, such as acetaminophen (Tylenol) or ibuprofen (Motrin, Advil), to help you feel better.

Training New DMC Members: A Call to Action.

Historically, clinical trialists developed DMC expertise and experience with "on the job training". Clinical trialists have recognized a large and growing gap between the demand and supply of trained DMC members due in part to the huge increase in ongoing clinical trials. A critical need exists to increase the supply of DMC trained clinicians and biostatisticians.

Bringing data monitoring committee charters into the sunlight.

Clinical trials investigating novel or high risk interventions, or studying vulnerable participants, often use a data monitoring committee to oversee the progress of the trial. The data monitoring committee serves both an ethical and a scientific function, by protecting the interests of trial participants while ensuring the integrity of the trial results. A data monitoring committee charter, which typically describes the procedures by which data monitoring committees operate, contains details about the data monitoring committee's organizational structure, membership, meeting frequency, sequential monitoring guidelines, and the overall contents of data monitoring committee reports for interim review.

The Data Monitoring Committee: A Collective or a Collection?

In this commentary, we urge that a Data Monitoring Committee (DMC) should operate as a collective, that is, as a unitary whole. In so doing, its recommendations should emerge through a consensus development process, not through a vote of the members. The summary notes of its closed session, that is, its minutes, should report the recommendations of the DMC and, if necessary, the justification for those recommendations; it should not attribute opinions to individual members.

Dapagliflozin in heart failure with improved ejection fraction: a prespecified analysis of the DELIVER trial.

With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial ( NCT03619213 ), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF >40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to >40%.

Experiences of the Data Monitoring Committee for the RECOVERY trial, a large-scale adaptive platform randomised trial of treatments for patients hospitalised with COVID-19.

Aim: To inform the oversight of future clinical trials during a pandemic, we summarise the experiences of the Data Monitoring Committee (DMC) for the Randomised Evaluation of COVID therapy trial (RECOVERY), a large-scale randomised adaptive platform clinical trial of treatments for hospitalised patients with COVID-19.

Methods And Findings: During the first 24 months of the trial (March 2020 to February 2022), the DMC oversaw accumulating data for 14 treatments in adults (plus 10 in children) involving > 45,000 randomised patients. Five trial aspects key for the DMC in performing its role were: a large committee of members, including some with extensive DMC experience and others who had broad clinical expertise; clear strategic planning, communication, and responsiveness by the trial principal investigators; data collection and analysis systems able to cope with phases of very rapid recruitment and link to electronic health records; an ability to work constructively with regulators (and other DMCs) to address emerging concerns without the need to release unblinded mortality results; and the use of videoconferencing systems that enabled national and international members to meet at short notice and from home during the pandemic when physical meetings were impossible.

Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

Background: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.

Objectives: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.

Methods: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo.

Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER.

Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)).

Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age: The DELIVER Trial.

Background: The prevalence of heart failure with mildly reduced or preserved ejection fraction markedly increases with age, with older individuals disproportionately facing excess risk for mortality and hospitalization.

Methods: The DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) randomized patients with New York Heart Association functional class II-IV and left ventricular ejection fraction >40% to either dapagliflozin or placebo for a median follow-up period of 2.3 years.

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.

Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy.

The effect of cardiac resynchronization without a defibrillator on morbidity and mortality: an individual patient data meta-analysis of COMPANION and CARE-HF.

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm. The aim of this study was to identify patient characteristics that predict the effect, specifically, of CRT pacemakers (CRT-P) on all-cause mortality or the composite of hospitalization for heart failure or all-cause mortality.

Methods And Results: We conducted an individual patient data meta-analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization-Heart Failure (CARE-HF) trials.

The challenges of data safety monitoring for a pragmatic study: Lessons from the ADAPTABLE study.

Data monitoring committees (DMCs) play a critical role in protecting the safety of participants and integrity of clinical studies. While there are well-established DMC guidelines for traditional, randomized controlled trials, the clinical trial community is still in the search for best practices in data and safety monitoring in pragmatic clinical trials. ADAPTABLE was a large, open label, pragmatic, randomized controlled trial, harnessing real world data from multiple sources and studying the comparative effectiveness of the two most common dosages of aspirin in patients with atherosclerotic cardiovascular disease.

Baseline Characteristics of Patients With HF With Mildly Reduced and Preserved Ejection Fraction: DELIVER Trial.

Objectives: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials.

Background: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF).

Methods: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo.

Ivermectin in COVID-19: The Case for a Moratorium on Prescriptions.

In treatment or prevention of COVID-19, ivermectin is not approved by the United States (US) Food and Drug Administration (FDA). Nonetheless, in the US, prescriptions of ivermectin by healthcare providers have increased > tenfold from 3589 per week pre-COVID-19 to 39,102. Ivermectin is FDA approved for animals to treat parasites and for humans to treat intestinal strongyloidiasis and onchocerciasis orally, and ectoparasites and skin conditions topically.

Primary care providers should prescribe aspirin to prevent cardiovascular disease based on benefit-risk ratio, not age.

Recent guidelines restricted aspirin (ASA) in primary prevention of cardiovascular disease (CVD) to patients <70 years old and more recent guidance to <60.In the most comprehensive prior meta-analysis, the Antithrombotic Trialists Collaboration reported a significant 12% reduction in CVD with similar benefit-risk ratios at older ages. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four trials were added to an updated meta-analysis.

Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials.

Background: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials.

Methods: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials.

Data monitoring committee interim reports: We must get there soon!

Currently, too many Data Monitoring Committee Reports for interim review of trial progress are quite inadequate for Data Monitoring Committees to make informed decisions about risks and benefits. Immediate serious improvement is necessary for Data Monitoring Committees to meet their ethical, clinical, and scientific responsibility to trial participants, investigators, sponsors, and participating institutions. To achieve this critical goal, all parties involved in the Data Monitoring Committee process including sponsors, investigators, Data Monitoring Committee members, and the independent statistical reporting group need to have a better understanding of the structure, function, and needs of a Data Monitoring Committee and the content of a Data Monitoring Committee Report.