Cardiac Safety Research Consortium Update

Direct oral anticoagulant use in the pediatric population: Defining the path forward

Written on behalf of the Cardiac Safety Research Consortium

On April 4, the Cardiac Safety Research Consortium held a think tank, titled “Non-vitamin K antagonist oral anticoagulants use in the pediatric population: Defining the path forward.” The meeting — held at Heart House, the American College of Cardiology headquarters in Washington, D.C. — included more than 60 attendees from academia, industry, regulatory authorities and medical centers in the United States, Canada and Europe.

The goal of the think tank was to define the current state of knowledge about non-vitamin K antagonist oral anticoagulants in children and to examine future approaches to confirm their safety and efficacy in this population. A key goal will be to determine whether these therapies offer the same benefits in children as in adults, where they have been shown to be equally effective or better than prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience.

The think tank agenda covered wide-ranging topics including the current landscape for use of anticoagulation in the pediatric population, regulatory considerations in using adult data for pediatric indications, the potential need for non-vitamin K antagonist oral anticoagulants in thrombosis treatment and thromboprophylaxis, regulatory requirements for trial design and practical challenges for conducting pediatric clinical trials.

Unmet needs

There remains a need to clearly define the most pressing unmet medical needs in this area. In the cardiac population in particular, non-vitamin K antagonist oral anticoagulants appear to have a promising role, yet obtaining conclusive evidence to support use has been difficult. Also, despite a long history of use of drugs such as unfractionated heparin, low molecular weight heparin and direct thrombin inhibitors, selecting a comparator is a problem due to an insufficient understanding of the mode of action of these substances. There also remain questions around whether it is possible to extrapolate from adult dosing to inform pediatric dosing, and how to select potential biomarkers to evaluate patients.

Future directions

Looking ahead, several initial steps could be taken to help extend the availability of these therapies to children. Stakeholders could collaborate to advance pediatric non-vitamin K antagonist oral anticoagulant research and development — for example, by dividing efforts across age groups between sponsors, with each company addressing a particular challenge.

It would be helpful to identify several clinically meaningful endpoints, including bleeding or clotting that is clinically significant, to collect in real-world settings. A consensus should be developed on how far adult data can be extrapolated into the pediatric population. Adolescents, who are already being incorporated into some adult trials, might be a logical starting point.

It would be useful to focus on especially underserved populations, such as hospitalized neonates with single ventricles, patients who underwent a Fontan procedure, and individuals with Kawasaki disease or a ventricular assist device. Simple, flexible clinical trial designs are needed, with simplified screening and consent processes, and a mechanism to provide information on study results to all stakeholders, including participants.

Existing trial infrastructure should be harnessed where possible, with use of standing platform trials to enable efficient, global enrollment. A review should be carried out of case report forms (CRFs) for ongoing clinical trials, to determine what data are being gathered already. A minimum core data set is needed to inform more productive discussions in areas including outcomes, biomarkers and appropriate CRF design. Preclinical studies should be considered as a way to assess efficacy, including use of devices to monitor changes in small samples of blood and animal models such as humanized mice. Finally, the options for using existing real-world evidence should be investigated, including professional society registries, such as the Society of Thoracic Surgeons’ national database or state-required registries for procedures.

Editor’s note: The Cardiac Safety Research Consortium Update is a new feature in Cardiology Today that will be published throughout the year when updates from the CSRC are available. View all updates online at Healio.com/CSRC. This feature is edited by Peter R. Kowey, MD, the Arrhythmia Disorders Section Editor for Cardiology Today. Email the Editors at cardiology@healio.com for more information.

Written on behalf of the Cardiac Safety Research Consortium

On April 4, the Cardiac Safety Research Consortium held a think tank, titled “Non-vitamin K antagonist oral anticoagulants use in the pediatric population: Defining the path forward.” The meeting — held at Heart House, the American College of Cardiology headquarters in Washington, D.C. — included more than 60 attendees from academia, industry, regulatory authorities and medical centers in the United States, Canada and Europe.

The goal of the think tank was to define the current state of knowledge about non-vitamin K antagonist oral anticoagulants in children and to examine future approaches to confirm their safety and efficacy in this population. A key goal will be to determine whether these therapies offer the same benefits in children as in adults, where they have been shown to be equally effective or better than prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience.

The think tank agenda covered wide-ranging topics including the current landscape for use of anticoagulation in the pediatric population, regulatory considerations in using adult data for pediatric indications, the potential need for non-vitamin K antagonist oral anticoagulants in thrombosis treatment and thromboprophylaxis, regulatory requirements for trial design and practical challenges for conducting pediatric clinical trials.

Unmet needs

There remains a need to clearly define the most pressing unmet medical needs in this area. In the cardiac population in particular, non-vitamin K antagonist oral anticoagulants appear to have a promising role, yet obtaining conclusive evidence to support use has been difficult. Also, despite a long history of use of drugs such as unfractionated heparin, low molecular weight heparin and direct thrombin inhibitors, selecting a comparator is a problem due to an insufficient understanding of the mode of action of these substances. There also remain questions around whether it is possible to extrapolate from adult dosing to inform pediatric dosing, and how to select potential biomarkers to evaluate patients.

Future directions

Looking ahead, several initial steps could be taken to help extend the availability of these therapies to children. Stakeholders could collaborate to advance pediatric non-vitamin K antagonist oral anticoagulant research and development — for example, by dividing efforts across age groups between sponsors, with each company addressing a particular challenge.

It would be helpful to identify several clinically meaningful endpoints, including bleeding or clotting that is clinically significant, to collect in real-world settings. A consensus should be developed on how far adult data can be extrapolated into the pediatric population. Adolescents, who are already being incorporated into some adult trials, might be a logical starting point.

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It would be useful to focus on especially underserved populations, such as hospitalized neonates with single ventricles, patients who underwent a Fontan procedure, and individuals with Kawasaki disease or a ventricular assist device. Simple, flexible clinical trial designs are needed, with simplified screening and consent processes, and a mechanism to provide information on study results to all stakeholders, including participants.

Existing trial infrastructure should be harnessed where possible, with use of standing platform trials to enable efficient, global enrollment. A review should be carried out of case report forms (CRFs) for ongoing clinical trials, to determine what data are being gathered already. A minimum core data set is needed to inform more productive discussions in areas including outcomes, biomarkers and appropriate CRF design. Preclinical studies should be considered as a way to assess efficacy, including use of devices to monitor changes in small samples of blood and animal models such as humanized mice. Finally, the options for using existing real-world evidence should be investigated, including professional society registries, such as the Society of Thoracic Surgeons’ national database or state-required registries for procedures.

Editor’s note: The Cardiac Safety Research Consortium Update is a new feature in Cardiology Today that will be published throughout the year when updates from the CSRC are available. View all updates online at Healio.com/CSRC. This feature is edited by Peter R. Kowey, MD, the Arrhythmia Disorders Section Editor for Cardiology Today. Email the Editors at cardiology@healio.com for more information.