ADMINISTER II

2024

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.

Collaborators

Contact person:

Dr. Mark Schuuring

mark.schuuring@utwente.nl

Principal investigators

Dr. Mark Schuuring

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The GENIUS II (Generating Evidence-Based Pharmaceutical Targets and Drugs for Atherosclerosis) consortium is dedicated to studying atherosclerosis, the primary pathological condition underlying cardiovascular diseases. The consortium aims to translate identified druggable targets for atherosclerosis intervention into clinical applications. Gender specificity is a key consideration in all our studies. Our consortium's talent program is structured to provide young researchers with insights into the opportunities and challenges of cardiovascular drug development.
The Research
GENIUS II research integrates knowledge of dyslipidemia and associated immune responses. Our work is organized into distinct work packages that correspond to the logical steps in drug development. Each selected target from GENIUS I is strategically incorporated into this framework. Our investigations encompass in vitro and in vivo analyses to understand mechanisms, druggability, and effects on atherosclerosis.
In addition to building upon GENIUS I drug targets and leads, we leverage recent innovative advancements to identify new druggable targets within male and female atherosclerotic lesions, as well as in circulating cells. State-of-the-art molecular biology techniques, including single cell sequencing and immunophenotyping, are actively employed to dissect immunometabolic processes within atherosclerotic plaques and patients. These studies will enable us to monitor the presence of drug targets at disease sites, expediting drug design and potentially identifying gender-specific biomarkers to aid disease progression monitoring and diagnosis.
Subsequent studies involve testing the efficacy of small molecules, monoclonal antibodies, and siRNA against pre-selected targets from GENIUS I. We have identified small molecules and monoclonal antibodies for five targets, which will undergo toxicity and proof-of-pharmacology studies to progress towards drug development for cardiovascular patients. We have also identified three drugs affecting primary targets from GENIUS I and are assessing their potential to reduce atherosclerotic parameters in First-In-Human clinical trials.
Origin
This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation. The GENIUS II consortium builds on the most promising targets identified in the GENIUS I consortium, with the goal of advancing these targets towards clinical application.

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Praetorian-covid

2020

The SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the acute respiratory distress syndrome (ARDS). The reninangiotensin-system (RAS) plays an important role in the development of ARDS, with ACE2 (angiotensin-converting enzyme 2) being a key enzyme within this. The virus's spike protein binds to ACE2, facillitating cellular internalization. Downregulation of ACE2 results in the excessive accumulation of angiotensin II, which in turn increases pulmonary vascular permeability through stimulation of the angiotensin II type 1a receptor (AT1R), thereby exacerbating lung pathology associated with decreased ACE2 activity. Currently available AT1R blockers (ARBs) such as valsartan, have shown potential to block this pathological process mediated by angiotensin II.
The Focus
The primary aim of the PRAETORIAN-COVID trial is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death of COVID-19 patients.
The Research
Participants receiving active treatment are administered valsartan at a dosage titrated to blood pressure, with a maximum of 160 mg twice daily. Participants receiving placebo are provided with a matching placebo. The treatment duration was 14 days or until reaching the primary endpoint, or until hospital discharge, if applicable within 14 days.Two complementary mechanisms underpin the potential efficacy of angiotensin II type 1 receptor blockers (ARBs) in preventing acute respiratory distress syndrome (ARDS) and reducing morbidity and mortality:

ARBs block excessive angiotensin-mediated activation of the AT1R.
ARBs upregulate ACE2 expression, leading to reduced angiotensin II levels and increased production of the protective vasodilator angiotensin 1–7.

Given these mechanisms, ARBs show promise in preventing ARDS development, potentially reducing the need for intensive care unit (ICU) admission and mechanical ventilation, and ultimately lowering mortality rates associated with SARS-CoV-2 infection.

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