Recent results from the phase 3 HESTIA3 study suggest that treatment of pediatric patients with sickle cell disease (SCD) using ticagrelor did not meet its primary composite endpoint. The study results were reported in the journal Blood.1
“Platelet activation is increased at baseline in patients with SCD, and platelets are further activated during vaso-occlusive events, thus making antiplatelet therapy a potential therapeutic option,” the researchers wrote in their report. Ticagrelor is a reversible P2Y12 inhibitor that has been used as an agent to control thrombosis to prevent outcomes like myocardial infarction and stroke among adults who have coronary artery disease or cerebrovascular disease.
The multicenter, international HESTIA3 study (ClinicalTrials.gov Identifier: NCT03615924) was designed to evaluate the efficacy and safety of ticagrelor, compared with placebo in prevention of vaso-occlusive crises. The study enrolled children with SCD with hemoglobin SS (HbSS) or sickle b0 thalassemia (HbS/b0) types who were between the ages of 2 and 17 years. Participants were randomly assigned 1:1 to receive either ticagrelor or placebo, with doses based on body weight.
The primary endpoint was a composite of painful crises and/or acute chest syndrome (ACS), together reflecting vaso-occlusive crises. Key secondary efficacy end points were also studied, and these were the number and duration of painful crises, the number of ACS events, and the number of vaso-occlusive crises that led to hospitalizations or visits to the emergency department. The effect of ticagrelor on platelet activation had been evaluated as an exploratory end point.
There were 101 patients assigned to the ticagrelor treatment arm and 92 to the placebo arm. Patients had median ages of 10.0 years (range, 3.0-17.0) in the ticagrelor arm and 10.5 years (range, 3.0-17.0) in the placebo arm. At baseline, there had been 2 to 4 vaso-occlusive events in the prior 12 months among 98% of patients in the ticagrelor arm and 97% of patients in the placebo arm.
Owing to a lack of efficacy, the study was terminated early at 4 months, and the primary endpoint was not met. Patients had a median exposure duration to ticagrelor of 296.5 days.
Participants in the ticagrelor arm had an estimated yearly incidence of vaso-occlusive crises of 2.74, compared with 2.60 for the placebo arm (rate ratio, 1.06; 95% CI, 0.75-1.50; P =.7597). Analyses of secondary end points also did not reveal efficacy with ticagrelor in comparison with placebo. Additionally, at 6 months, in the ticagrelor arm, the median platelet inhibition was 34.9% prior to a dose and 55.7% at 2 hours after a dose compared with baseline.
There were 1 or more bleeding events reported among 9% of patients in either treatment arm. There were fatal adverse events reported in 3 patients in the ticagrelor arm and in 1 patient from the placebo arm.
“At present, we conclude that ticagrelor is not effective for the prevention of vaso-occlusive crises in pediatric patients with the SCD genetic traits HbSS and HbS/b0,” the study investigators wrote in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Heeney MM, Abboud MR, Githanga J, et al; on behalf of the HESTIA3 study investigators. Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study. Blood. 2022;140(13):1470-1481. doi:10.1182/blood.2021014095