Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Abstract

Background: American College of Cardiology/American Heart Association guidelines advise waiting 5 to 7 days before operating on P2Y12 inhibitor-treated acute coronary syndrome patients, to allow dissipation of its antiplatelet effects. Platelet transfusion is often used to restore hemostasis during operations, but its effectiveness and optimal timing are unclear. We investigated the degree of functional gains obtained from platelet supplementation after loading and maintenance of dual antiplatelet therapy with ticagrelor and the influence of timing on this strategy.

Methods and results: After baseline platelet testing (Multiplate Analyzer and VerifyNow), cardiovascular disease patients (n=20; 56.9±7.9 years; 65% men; 75% diabetic) received dual antiplatelet therapy as a single loading dose (ticagrelor 180 mg plus aspirin 325 mg) and as daily/maintenance treatment for 5 to 7 days (maintenance therapy: ticagrelor 90 mg BID plus aspirin 81 mg QD). At 4, 6, 24, and 48 hours from (last) dosing, patients' blood samples were supplemented with concentrated platelets from healthy donors in vitro, raising platelet counts by 0% (unsupplemented control), 25%, 50%, and 75%, and the function retested. Reactivity in supplemented samples was compared with respective 0% sample and with the pretreatment baseline. Results under loading dose and maintenance therapy regimens were nearly identical. Platelet reactivity was higher (P<0.05) in nearly all supplemented samples versus respective controls. Aggregations with supplementation were 59% to 79% of baseline at 24 hours and equal to baseline at 48 hours.

Conclusions: Platelet reactivity of ticagrelor-treated patients can be restored using concentrated platelets after a loading dose/maintenance therapy in a time-dependent manner under in vitro testing. Although statistically significant improvements are evident 6 hours after (last) dosing, ≥24 hours maybe needed for clinically meaningful restoration in platelet function.

Clinical trial registration: URL: https://ichgcp.net/clinical-trials-registry/NCT02201394" title="See in ClinicalTrials.gov">NCT02201394.

Keywords: aspirin; blood platelets; diabetes mellitus; humans; ticagrelor.

© 2017 American Heart Association, Inc.

Figures

Figure 1. Study design

DAPT: Dual Anti-Platelet Therapy, PFT: Platelet function tests (ADPtest in Multiplate® Analyzer and PRUtest in VerifyNow®), PS: Platelet supplementation (addition of concentrated platelets to DAPT-treated patients’ blood samples raising platelet counts by 0% (control), 25%, 50% and 75%).

Figure 2. Time-dependent Recovery of Platelet Function without Supplementation after Ticagrelor Loading and Maintenance Therapy

Platelet reactivity (mean ± SEM) is shown before (Baseline) and after ticagrelor administration as a single loading dose and after maintenance therapy for one week. A natural recovery in platelet reactivity was observed from 6 hours onwards, in both Multiplate® and VerifyNow® testing. *p

Figure 3. Restoring Platelet Function after Ticagrelor Loading Dose

Platelet aggregation (mean ± SEM) before (Baseline) and after ticagrelor loading dose, with (25%, 50% and 75%) and without (0%) platelet supplementation is shown. Reactivity was measured using Multiplate® Analyzer ADPtest (U) and VerifyNow® (PRU). Aggregation was significantly higher in all supplemented samples vs. corresponding 0% sample except at 48 hours in VerifyNow® testing. At 48 hours, Multiplate® testing showed aggregation in all supplemented samples to be statistically no different from Baseline. *p0.05 vs. Baseline.

Figure 4. Restoring Platelet Function after Ticagrelor Maintenance Therapy

Platelet aggregation (mean ± SEM) before (Baseline) and after one week of ticagrelor maintenance therapy, with (25%, 50% and 75%) and without (0%) platelet supplementation is shown. Reactivity was measured using Multiplate® Analyzer ADPtest (U) and VerifyNow® (PRU). Aggregation was significantly higher in all supplemented samples vs. corresponding 0% sample except at 48 hours in VerifyNow® testing. At 48 hours Multiplate® testing showed aggregation in all supplemented samples to be statistically no different from Baseline. * p0.05 vs. Baseline.