Johns Hopkins All Children’s Hospital researcher and clinical pharmacy specialist, Amy Kiskaddon, PharmD, and a multi-institutional group of collaborators from around the world, have won the prestigious 2023 Eberhard F. Mammen ‘Most Popular’ Award. The award is bestowed annually by the publishers of the journal Seminars in Thrombosis and Hemostasis for the research paper determined by the journal’s editors to be “the most highly cited and/or downloaded article on an international scale.”

The award-winning research article is titled “Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature.” Their study synthesized data from completed clinical trials that evaluated the safety and efficacy of non-vitamin K oral anti-clotting medications (known clinically as “anticoagulants”) for treating or preventing blood clots in the veins (medically termed “venous thromboembolism [VTE]). 

The award is named for the late Eberhard F. Mammen, M.D. (1930—2008), a physician and researcher who pioneered pharmaceutical research in the field of blood clotting. While he was on the faculty at Wayne State University in Detroit, Mammen achieved worldwide recognition for his 32 years of publishing impactful research in the field, most extensively in Seminars in Thrombosis and Hemostasis.

“We feel truly privileged to receive the 2023 Mammen Award,” says Kiskaddon, who is also an assistant professor of pediatrics in the Division of Pediatric Cardiology at the Johns Hopkins University School of Medicine. “As the use of these agents in pediatrics is rapidly increasing, we hope our study will serve as an important resource for clinicians.” Kiskaddon shared lead-authorship of the study with collaborator Joshua Branstetter, PharmD, who is presently a pediatric clinical pharmacy specialist at Children’s Healthcare of Atlanta.

“This award is a ‘feather in the cap’ for both Johns Hopkins University and Johns Hopkins All Children’s Hospital,” says Neil Goldenberg, M.D., Ph.D., associate dean for research at Johns Hopkins All Children’s Hospital, chief research officer at All Children’s Research Institute, and director of the hospital’s thrombosis program. “Most importantly, by aggregating the results of multiple clinical trials performed with the latest anti-clotting medications in children, this work will help to inform current and future care of children who are at risk for, or have developed, acute VTE.”

‘Most Popular’ Study Can Aid Clinical Decision-Making

According to the study authors, VTE in children can lead to illness, disease and death. Although VTE in children is rare — recurrent VTE in pediatric patients is a problem requiring new treatments hoped to be at least as effective as “traditional” anticoagulants

The challenges accompanying “standard of care” anti-clotting therapies, especially for pediatric patients, have led to growing interest in a group of novel so-called “direct” oral anticoagulants (alternatively abbreviated as “NOACs” or “DOACs”), which differ from earlier anticoagulants like warfarin (Coumadin) that act indirectly on the clotting system by blocking the effect of a key vitamin needed for several clotting factors in the body to properly function — vitamin K.

By conducting a systematic review of the findings of clinical trials, the authors were able to synthesize the results across several trials, in regard to rates of bleeding (safety), success in preventing new VTEs (efficacy), and other aspects relevant to translating the findings of the clinical trials into clinical practice in children.

Research Methods

“Based on up-to-date queries of www.clinicaltrials.gov, we reviewed information from ongoing NOAC/DOAC clinical trials as well as data from published pediatric clinical trials that used NOACs/DOACs,” explains Kiskaddon. The number of patients receiving NOACs/DOACs in published pediatric trials totaled over 1,000 children.

The phase 1 and phase 2 trials they reviewed focused on dosing and patient safety, but the greater numbers of patients were enrolled in phase 3 trials where researchers mainly investigated the effectiveness of the drugs in preventing or treating blood clots.

Research Results

Presenting their study results, the researchers broke down clinical trial information by the number of trial participants and the age groupings of pediatric patients enrolled in studies, and also examined clinical trials results related to the four NOAC/DOACs for which clinical trials have been published or registered: Dabigatran (Pradaxa™), approved for adults in 2010 and children in 2021 (five published pediatric trials analyzed); Rivaroxaban (Xarelto™), approved for adults in 2011 and children in 2021; (three published pediatric trials analyzed); Apixaban (Eliquis™), approved for adults in 2012 (five pediatric clinical trials, one of which was ongoing); and Edoxaban (Lixiana™), approved for adults in 2015 (three ongoing or recently completed clinical trials).

Conclusions

The researchers concluded that rates of both new blood clots and significant bleeding were low across trials, supporting the current practice of utilizing these medications as an alternative to traditional anti-clotting medications in clinical practice, given also some practical advantages of the NOACs/DOACs over traditional anticoagulants.

“The findings from published NOAC trials are promising,” concludes Kiskaddon. “As additional pediatric-specific dosage forms are developed and approved for varying indications in this young patient population, additional PK/PD data and clinical experience will refine how these agents can best be utilized in numerous pediatric clinical practice settings.”