Ticagrelor does not impact patient‐reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study

Abstract

Summary Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso‐occlusion crisis ( VOC ) in sickle cell disease ( SCD ). The HESTIA 2 study ( NCT 02482298) randomised 87 adults with SCD (aged 18–30 years) 1:1:1 to twice‐daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient‐reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non‐major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary‐reported pain was detected. Potential effects on frequency of VOC s will need to be evaluated in a larger and longer study.

Recent Advances in the Treatment of Sickle Cell Disease

“…Prasugrel showed appropriate levels of anti-platelet aggregation compared to healthy patients in ex vivo studies, and was well tolerated by patients, but on a 24-month follow up, patients on the treatment arm failed to show reduction in the frequency of VOC (Heeney et al, 2016;Conran and Rees, 2017). Ticagrelor, in a phase 2b study, was well tolerated, but failed to show effect in the frequency of VOC (Kanter et al, 2019) (ClinicalTrials.gov identifier: NCT02482298). Previous studies have also showed that aspirin as an anticoagulant therapy did not provide benefit over placebo, although it is used as an analgesic in many parts of Africa (Sins et al, 2017).…”

Role of the coagulation system in the pathogenesis of sickle cell disease

“…[95][96][97] Piroxicam, ticagrelor, and ticlopidine showed modest to disappointing results in reducing the pain of VOC in SCD patients (Table 2). [98][99][100] Although these drugs were largely unsuccessful in reducing acute VOC events, they may possibly provide benefit to chronic organ damage, which has not been studied as an end point.…”

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3)

“…There were no discontinuations due to AEs, and reported AEs were mainly due to SCD and not treatment-related [40]. The HESTIA2 study randomized 87 young adults (aged 18-30 years) with SCD in a 1:1:1 ratio to ticagrelor 10 mg, ticagrelor 45 mg, or placebo BID [41]. Patients reported daily pain and analgesic use in an electronic device (eDevice) during the 4-week single-blind run-in placebo period, as well as during the 12-week randomized treatment period.…”

“…The study will comprise a screening period of 7-28 days, followed by randomization of eligible patients to double-blind treatment with either ticagrelor or matching placebo for a period of 12-24 months using an Interactive Voice/Web Response System. Body-weight adjusted ticagrelor doses (15 mg: ≥ 12 to ≤ 24 kg body weight, 30 mg: > 24 to ≤48 kg body weight, or 45 mg: > 48 kg body weight BID) have been identified based on PK/PD modeling and simulation of phase 2 data (HESTIA1 and HESTIA2) [40,41]. For any patient with weight gain during the study period exceeding the upper weight-limit bands of ≥ 27 kg or ≥ 54 kg, treatment dose will be increased according to the next higher weight band.…”

“…The predicted level of platelet inhibition with the selected doses in HESTIA3 will be 35%-80% platelet inhibition from baseline (corresponding to 180 and 55, respectively, in absolute P2Y 12 reaction units [PRU] levels assuming a baseline of 280). The platelet inhibition range is based on population PK/PD modeling analyses based on the HESTIA1 and HESTIA2 studies [40,41]. The encouraging trend in efficacy reported for prasugrel, despite a modest platelet inhibition level (mean PRU of 207 corresponding to~20% reduction from baseline) [24], motivated the inclusion of a greater level of inhibition in HESTIA3.…”