Rivaroxaban and dabigatran reduced the risk for venous thromboembolism in children, according to three studies presented at the International Society on Thrombosis and Haemostasis Congress.
EINSTEIN - J r trial
In this phase 3 trial, Christoph Male, MD, pediatric cardiologist, associate professor of pediatrics and deputy chair for research in the division of pediatric cardiology at the Medical University of Vienna, and colleagues analyzed data from 500 children with acute VTE.
“The trial examined for the first time whether a direct oral anticoagulant could alleviate the burden of blood clots in young patients,” Male said in a press release from Janssen. “The EINSTEIN-Jr study with rivaroxaban represents a significant advance for pediatric VTE treatment.”
Children were assigned 20-mg equivalent doses of rivaroxaban (n = 335; Xarelto, Janssen) that were adjusted for body weight or a comparator (n = 165) and were treated for 3 months. Those younger than 2 years who had VTE related to a catheter were treated for 1 month. Events that were assessed in both treatment groups included bleeding and symptomatic recurrent VTE.
Imaging was performed at baseline and at the end of the treatment period, in addition to pharmacodynamic and pharmacokinetic data.
Recurrent VTE occurred in 1.2% of patients assigned rivaroxaban vs. 3% of those assigned the comparator (HR = 0.4; 95% CI, 0.11-1.41). Thrombotic burden improved more in the rivaroxaban group compared with the comparator group.
Clinically relevant bleeding was seen in 3% of children assigned rivaroxaban and 1.9% of those assigned the comparator.
There were similar estimates of absolute and relative efficacy and safety in both groups when compared with adults.
Pharmacokinetic parameters for rivaroxaban showed that plasma levels in these patients were equivalent to adults in VTE trials that evaluated the efficacy of rivaroxaban. Both pharmacodynamic and pharmacokinetic data were closely related.
“VTE affects people of all ages, which is why we are committed to advancing new research and uncovering ways for Xarelto to help people in need,” James List, MD, PhD, global therapeutic area head for Janssen Research and Development, said in the release. “The EINSTEIN-Jr results offer important insights on the efficiency and safety of Xarelto in managing blood clots in our youngest patients.
In this study that assessed the effects of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) in children, Manuela Albisetti, MD, of the department of hematology at University Children’s Hospital in Zurich, and colleagues analyzed data from 220 children with VTE who were initially treated with unfractionated heparin or low-molecular-weight heparin. Children were assigned dabigatran etexilate or standard of care for 3 months. Children from both groups received standard of care for 4 weeks after the 3-month treatment period.
The combined efficacy endpoint was death related to VTE, recurrence of VTE and thrombus resolution. Other endpoints assessed in this study included pharmacokinetic and pharmacodynamic parameters, bleeding events and adverse events.
Dabigatran was noninferior to standard of care regarding freedom from recurrent VTE (weighted difference = –0.06; 90% CI, –0.14 to 0.02). Both groups had similar rates of freedom from any bleeding events (HR = 1.37; 95% CI, 0.79-2.39).
There was a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time. A nonlinear relationship was also seen between dabigatran plasma concentration and activated partial thromboplastin time. Both of these relationships were consistent in all age groups.
“The DIVERSITY study is the first study comparing a direct oral anticoagulant to report efficacy, safety and [pharmacokinetic-pharmacodynamic] relationships in children,” Albisetti and colleagues wrote. “The study demonstrates the appropriateness of an age- and body-weight-adjusted dosing algorithm for [dabigatran etexilate] in children between 0 [and] 18 years of age.”
Dabigatran etexilate for secondary prevention
In another study that analyzed the safety of dabigatran etexilate for secondary prevention of VTE in children, Leonardo R. Brandão, MD, MSc, staff hematologist at The Hospital for Sick Children in Toronto and associate professor and instructor at the University of Toronto, and colleagues analyzed data from an estimated 200 patients with a confirmed diagnosis of VTE who were treated with standard of care for at least 3 months. These patients also completed treatment from the DIVERSITY study.
In this study, patients were treated with dabigatran etexilate twice per day for up to 12 months. Patients were then treated with standard of care if they had ongoing risk factors.
The primary endpoint was VTE recurrence, mortality and any bleeding events at 6 and 12 months. Secondary endpoints included pharmacokinetic and pharmacodynamic parameters, post-thrombotic syndrome and adverse events.
There were low rates of recurrent VTE (probability of freedom = 0.988; 95% CI, 0.951-0.997) and post-thrombotic syndrome at 1 year (probability of freedom = 0.974; 95% CI, 0.916-0.992). Two girls had recurrent VTE during the first 6 months, and three boys had post-thrombotic syndrome between 6 and 12 months.
There was a linear relationship between total dabigatran plasma concentration and both thrombin time and ecarin clotting time. A nonlinear relationship was also seen between total dabigatran plasma concentration and activated partial thromboplastin time. These relationships were consistent in all age groups and were similar to adults.
“This is the first study of a direct oral anticoagulant for secondary VTE prevention in children reporting favorable results on safety with a [pharmacokinetic-pharmacodynamic] relationship of [dabigatran etexilate] comparable to adults,” Brandão and colleagues wrote.
“There is a tremendous unmet need for treatments to help manage the risk of venous thromboembolism in pediatric patients,” Mohamed Eid, MD, MPH, MHA, vice president of clinical development and medical affairs at Boehringer Ingelheim Pharmaceuticals, said in a press release from the company. “We are proud to share the results of these studies, which we believe will help enhance our understanding of the role of anticoagulants in managing venous thromboembolism in pediatric patients.” – by Darlene Dobkowski
Albisetti M, et al. OC 57.3.
Brandão LR, et al. OC 57.1.
Male C, et al. LB 01.5. All presented at: International Society on Thrombosis and Haemostasis Congress; July 6-10, 2019; Melbourne, Australia.
Disclosures: The EINSTEIN-Jr trial was sponsored by Bayer AG and Janssen Research and Development. The DIVERSITY trial and the study on the safety of dabigatran etexilate for secondary prevention of venous thromboembolism in children were funded by Boehringer Ingelheim. Male reports he is on the steering or advisory board for Bayer, Bristol-Myers Squibb and Pfizer and an investigator of Boehringer Ingelheim. Albisetti reports she received research support from Bayer, Biogen, Boehringer Ingelheim and Shire and was on the scientific advisory board for Boehringer Ingelheim, Daiichi Sankyo and Sobi. List is an employee of Janssen Research and Development. Eid is an employee of Boehringer Ingelheim. Cardiology Today could not confirm relevant financial disclosures for Brandão at the time of publication.