New Clinical Study Shows Continuing Promise of Cangrelor for Use in Shunt Thrombosis Prevention in Neonates After Cardiac Surgery

January 28, 2021

For the last five years, Thomas G. Diacovo, MD, division chief of the UPMC Newborn Medicine Program and director of neonatal cardiovascular research at UPMC Children’s Hospital of Pittsburgh, has led new clinical studies to combat the development of acute thromboembolic events (ATE) in neonates who require surgical palliation for complex congenital heart conditions.

Rates of thrombosis in postoperative neonatal cardiac patients, and in particular those requiring placement of a systemic to pulmonary artery shunt, are the highest of all pediatric patients treated in specialized centers. The current literature indicates a prevalence of shunt thrombosis ranging from 17% to 34%, with correspondingly high rates of morbidity and mortality. 

Many anticoagulation agents have been developed for adults over many decades, going back to aspirin's synthesis in the mid-1800s, which have proven to be extremely successful in preventing clot formation in adults and saving lives. However, virtually none of these agents have been tested in pediatric patients. Therefore, there is limited understanding of their efficacy, safety, pharmacodynamics, and optimal dosage in this patient population.

Platelet function in neonates also has been understudied. The availability and development of technologies to rapidly assess platelet response in pediatric patients to various agonists and antagonists has lagged in development. Dr. Diacovo and colleagues’ research has begun to upend this suboptimal treatment paradigm with new findings, technological advances, and animal models leading to important new clinical trials in human subjects.

Clinical Trial Details and Results

In January, Dr. Diacovo and colleagues’ published findings from their most recent phase 1 clinical trial1 examining the use of the P2Y12 receptor inhibitor, cangrelor, in neonates after surgery for complex congenital heart lesions. The clinical study, published in the Journal of Thrombosis and Haemostasis, is the first to study the pharmacokinetics and pharmacodynamics of cangrelor in a cohort of neonatal congenital heart surgery patients who received either a systemic-to-pulmonary artery shunt, right ventricle-to-pulmonary artery shunt, or ductal stenting. In all cases, cangrelor was administered in various doses (cohort 1 = 0.5 μg/kg/min; cohort 2 = 0.25 μg/kg/min) across the entire cohort (n = 15).

“The primary aim of our study was designed to determine the most efficacious dose of cangrelor to inhibit platelet function to similar degrees as in adult patients treated with cangrelor to prevent clots, and at the same time avoid or limit the risk of bleeding events while also examining the time required to reverse the effects of cangrelor after stopping infusions. Another interesting part of this study was the inclusion and assessment of a microfluidic assay requiring only minute quantities of blood to examine pharmacodynamic properties of the dosing,” says Dr. Diacovo.

In terms of pharmacodynamics, the study's endpoint was a > 90% reduction in platelet function in more than 60% of the patients. This goal was achieved in the cohort of patients receiving the 0.5 μg/kg/min dose, but not at the lower dose of 0.25 μg/kg/min. Only 29% of patients in the lower dose cohort achieved a > 90% reduction in platelet function. Patients receiving the 0.5 μg dose also had far greater platelet inhibition levels than neonates receiving combined aspirin/clopidogrel therapy postsurgery, as currently reported in the literature.

“The majority of our patients – 70% – had undetectable levels of cangrelor within 10 minutes after the infusion, and their platelet function returned to a normal level one hour after infusion, indicating fast-acting reversibility," says Dr. Diacovo.

Furthermore, no drug-induced bleeding events occurred in either of the patient cohorts nor were there any thromboembolic events recorded in any individuals up the point of discharge from the hospital.

“While our study was not powered or designed to test whether cangrelor infusions postsurgery can reduce the incidence of shunt thrombosis, we have learned a tremendous amount from this study pointing to cangrelor’s potential to do just that. The pharmacodynamic and pharmacokinetic data ascertained by this study is critical to what should be the next phase of our studies – clinical efficacy and safety data. From our preclinical studies2 through this phase 1 investigation, cangrelor looks as if it could be a promising therapeutic for these critically ill neonates. Still, we will need to prove that down the road in a controlled trial. We are optimistic and hard at work on developing a protocol for a multi-national, multi-institutional phase 2b/3 trial," says Dr. Diacovo.

References

1. Vargas D, Zhou H, Yu X, Diamond S, Yeh J, Allada V, Krishnamurthy G, Price M, Allen B, Alexander J, Schmidhofer J, Kreutzer J, Vincent J, Morell V, Bacha E, Diacovo T. Cangrelor PK/PD Analysis in Post-Operative Neonatal Cardiac Patients at Risk for Thrombosis. J Thromb Haemost. 2021 Jan; 19(1): 202-211.

2. Kaza EA, Egalka MC, Zhou H, Chen J, Evans D, Prats J, Li R, Diamond SL, Vincent JA, Bacha EA, Diacovo TG. P2y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease. JACC Basic Transl Sci. 2017; 2(4): 465-476.