OUTREACH

2021

The successful treatment of congenital heart disease (ConHD) has greatly increased the survival of children with this condition. Many of these defects require surgical or catheter interventions immediately after birth. However, complete restoration of the defect is often unachievable, a high risk of developing heart failure, arrhythmias, sudden cardiac death or blood vessel dilatation or stenosis relatively early in life.

Currently, there is a lack of personalized risk predictors and optimal clinical decision tools, highlighting an unmet need to develop new effective strategies for treating and preventing ventricular failure, arrhythmias, and large vessel diseases.

The Focus
The OUTREACH consortium focuses on specific types of congenital heart diseases (ConHD) related to outflow tract defects, such as transposition of the great arteries, congenital aortic stenosis, and tetralogy of Fallot, which collectively account for over half of all ConHD cases. The goal of OUTREACH is to reduce the risk of mortality and morbidity and improve the quality of life for these patients (both children and adults) by improving follow-up practices based on outcomes, implementing personalized risk assessment tools, and advancing therapeutic strategies.

The Research
The OUTREACH consortium integrates expertise in preclinical research, developmental biology, disease modeling, and clinical research from academic centers specializing in pediatric and adult congenital cardiology and surgery. Its objectives are:

identifying better parameters for risk assessment and early detection of heart failure or ventricular arrhythmias in ConHD patients with outflow tract defects.
Exploring efficient treatments to enhance adaptation and prevent heart failure and vascular damage in at-risk ConHD patients.

This consortium conducts extensive research involving a large cohort of ConHD patients to unravel the underlying causes and mechanisms of cardiac adaptations following surgical interventions. It investigates the molecular mechanisms responsible for outflow tract defects and evaluates whether stimulating heart regeneration in ConHD models can mitigate adverse remodeling and heart failure. Additionally, the consortium explores new non-invasive imaging techniques and blood-derived biomarkers to develop innovative risk analysis tools for clinical decision-making. In OUTREACH a nationwide registry is created for all patients (children and adults) with ConHD in the Netherlands by harmonizing existing registries KinCor and ConCor. This is an important step towards optimizing the quality of care for the ConHD population and fostering scientific research on ConHD.

Origin
The Dutch Heart Foundation and Stichting Hartekind, who collaborate within the Dutch CardioVascular Alliance, initiated an invitational grant to start and fund large-scale research aimed at earlier detection and better treatment of the consequences of congenital heart defects.

Funded

Contact person:

Prof. W.A. Helbing (Wim)

w.a.helbing@erasmusmc.nl

Principal investigators

Prof. W.A. Helbing (Wim)

w.a.helbing@erasmusmc.nl

Prof. dr. J. Bakkers (Jeroen)

j.bakkers@hubrecht.eu

Prof. dr. B.J. Bouma (Berto)

b.j.bouma@amsterdamumc.nl

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Heart failure is an escalating global health challenge, affecting over 64 million people worldwide. Despite advancements in guideline-directed medical therapy (GDMT) that significantly reduce mortality and hospitalizations, many patients still do not receive optimal medication regimens or dosages. This gap in care highlights the need for innovative, collaborative approaches to improve treatment delivery and outcomes.
The research
The ADMINISTER I study demonstrated the potential of digital care solutions to enhance medication prescription accuracy and accelerate the time required to achieve GDMT. In real-world clinical practice, optimizing medications to meet GDMT standards is a complex and time-intensive process. It requires frequent monitoring, adjustments, and multiple visits to healthcare providers, posing a significant burden on both patients and clinicians.
Building on this foundation, the ADMINISTER II consortium is a collaborative effort uniting multiple stakeholders, including healthcare providers, researchers, and (biomedical) engineers. This consortium aims to evaluate the impact of a cutting-edge digital care intervention designed to streamline medication optimization. By leveraging a robust remote monitoring infrastructure, this approach seeks to make the process more efficient, scalable, and accessible, while focusing on improving critical clinical outcomes.
This collaborative digital intervention represents a transformative step toward patient care and offers hope for better heart failure management. Insights from ADMINISTER II could pave the way for the widespread adoption of innovative, integrated solutions, benefiting patients, caregivers, and healthcare systems worldwide.
The ADMINISTER II consortium brings together the expertise of a leading Technical University, major referral hospitals, and a renowned academic center to deliver state-of-the-art digital care across a large nationwide hospital network. This unique synergy is pivotal to achieving the ambitious goals set by the Dutch Cardiovascular Alliance (DCVA): a 25% reduction in the cardiovascular burden by 2030.
By integrating cutting-edge digital infrastructure with clinical excellence, the consortium aims to significantly lower hospitalizations and mortality rates. This partnership not only accelerates the adoption of innovative digital solutions but also ensures their effective implementation in diverse healthcare settings, marking a critical step toward transforming cardiovascular care on a national scale.
The origin
The ADMINISTER II is created after successful completion of the ADMINISTER I trial.
The ADMINISTER I was fully funded by Amsterdam UMC and was a collaboration with Netherlands heart institute, UMC Utrecht, Rode Kruis hospital and CCN.
The ADMINISTER II consortium will be on a larger scale; with a larger network and multiple funders.

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DECISION

2020

Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To validate these findings, a prospective, randomized, placebo-controlled trial is required to redefine the role of digoxin in modern HF treatment.
The Focus
The primary objective of this study is to investigate whether low-level digoxin (targeting serum concentrations of 0.5-0.9 ng/mL), compared to a placebo, reduces (repeated) HF hospitalizations, (repeated) urgent HF hospital visits, and cardiovascular mortality when added to standard guideline-recommended therapies in chronic HF patients with reduced or mid-range ejection fractions (LVEF ≤50%).
The Research
This proposed trial is a national, multicenter, randomized, double-blind, placebo-controlled clinical trial involving 982 chronic HF patients aged ≥18 years, classified as NYHA II to ambulatory IV, LVEF ≤50%, and specific serum NT-proBNP concentrations based on rhythm and recent HF hospitalization status. Patients must also be on guideline-recommended therapies. The study population includes at least one-third with atrial fibrillation (AF) and one-third women to represent the real-life HF population.
Patients were randomized to receive either a low-level digoxin or a placebo in a double-blinded manner. Digoxin Teva will be administered orally, starting at doses of 0.2mg or 0.1mg (based on age, renal function, and concomitant medication). No loading dose is given to the placebo group. After 4 weeks of evaluating medication (digoxin or placebo), concentrations will be measured. Dose adjustments will be made if needed to reach the target serum digoxin concentration range of 0.5-0.9ng/mL.
The outcomes in reducing adverse cardiovascular events in patients with chronic heart failure of low-dose digoxin will be compared to the outcomes of the placebo.
The origin
This study was funded as part of the Dutch Heart Foundation's collaboration with the ZonMw GGG program on Good Use of Medicines (Goed Gebruik Geneesmiddelen) for better treatment of heart failure and atrial fibrillation, which was one of the 5 priority's that the Dutch Heart Foundation set in 2014. The DECISION study involves 38 hospitals and is led by cardiologists from UMC Groningen and the WCN.

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