Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

Abstract

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

Graphical abstract

Figure 1.

Consolidated Standards of Reporting Trials flowchart. *Informed consent/assent received. ^†The most common reasons for exclusion were: absent or inadequate/incomplete transcranial Doppler imaging (n = 23), abnormal liver function test results (n = 20), hemoglobin <6 g/dL (n = 18), judged unsuitable by the principal investigator (n = 12), and not having experienced at least 2 vaso-occlusive crises in the past 12 months before visit 1 (n = 12). ^‡Randomized to double-blind study treatment and received at least 1 dose of double-blind, randomized study treatment. ^§Includes patients who prematurely discontinued study treatment. ^¶Lost to follow-up: patients were only considered lost to follow-up after 3 documented failed attempts to reach the patient, and all other options of reaching the patient had been exhausted.

Figure 2.

Time to first vaso-occlusive crisis (VOC). Kaplan-Meier plot (full analysis set).

Figure 3.

Ticagrelor plasma concentration. Observed and predicted plasma concentrations (A) and relationship with number of vaso-occlusive crises (VOCs) (B). Observed and predicted platelet inhibition (C) and relationship with platelet reactivity index (D). As shown in panels A and C, predicted plasma concentrations based on HESTIA1 and HESTIA2: green line is the median, and the green area is the 5% to 95% quantiles. Because ticagrelor is given every 12 hours, the 12 hours’ postdose time point is also the immediate predose (or trough) time point. As shown in panel B, individual geometric mean ticagrelor plasma concentration at visits 2, 4, and 9: blue line is the negative binomial regression model. As shown in panel D, time-matched platelet reactivity index and ticagrelor plasma concentrations, all visits: blue line is the exposure–response model of the maximum effect the drug can have.