Pharmacodynamic Comparison of Ticagrelor Monotherapy Versus Ticagrelor and Aspirin in Patients After Percutaneous Coronary Intervention: The TEMPLATE (Ticagrelor Monotherapy and Platelet Reactivity) Randomized Controlled Trial

Thomas W Johnson, Sarah Baos, Laura Collett, James L Hutchinson, Martin Nkau, Maria Molina, Riyaad Aungraheeta, Christopher Reilly-Stitt, Ruth Bowles, Barnaby C Reeves, Chris A Rogers, Stuart J Mundell, Andreas Baumbach, Andrew D Mumford, Thomas W Johnson, Sarah Baos, Laura Collett, James L Hutchinson, Martin Nkau, Maria Molina, Riyaad Aungraheeta, Christopher Reilly-Stitt, Ruth Bowles, Barnaby C Reeves, Chris A Rogers, Stuart J Mundell, Andreas Baumbach, Andrew D Mumford

Abstract

Background To assess differences in platelet inhibition during ticagrelor monotherapy (TIC) or dual therapy with ticagrelor and aspirin (TIC+ASP) in patients after percutaneous coronary intervention using a comprehensive panel of functional tests. Methods and Results In a single-center parallel group, open label, randomized controlled trial, 110 participants were randomized to receive either TIC (n=55) or TIC+ASP (n=55) for 4 weeks. The primary outcome was the platelet aggregation response with 10 μmol/L thrombin receptor activation peptide-6 (TRAP-6). The secondary outcomes were platelet aggregation responses and binding of surface activation markers with a panel of other activators. The mean percentage aggregation for 10 μmol/L TRAP-6 was similar for the TIC and TIC+ASP groups (mean difference+4.29; 95% CI, -0.87 to +9.46). Aggregation was higher in the TIC group compared with the TIC+ASP group with 1 μg/mL (+6.47; +2.04 to +10.90) and 0.5 μg/mL (+14.00; +7.63 to +20.39) collagen related peptide. Aggregation responses with 5 μmol/L TRAP-6, 5 μmol/L or 2.5 μmol/L thromboxane A2 receptor agonist and surface activation marker binding with 5 μmol/L TRAP-6 or 0.5 μg/mL collagen related peptide were the same between the treatment groups. Conclusions Patients with PCI show similar levels of inhibition of most platelet activation pathways with TIC compared with dual therapy with TIC + ASP. However, the greater aggregation response with collagen related peptide during TIC indicates incomplete inhibition of glycoprotein VI (collagen) receptor-mediated platelet activation. This difference in pharmacodynamic response to anti-platelet medication may contribute to the lower bleeding rates observed with TIC compared with dual antiplatelet therapy in recent clinical trials. Registration Information URL: https://www.isrctn.com; Unique Identifier ISRCTN84335288.

Keywords: aspirin; dual anti‐platelet therapy; platelet activation; ticagrelor monotherapy.

Conflict of interest statement

A.M. and T.J. have received speaker, consultancy fees from Astra‐Zeneca. The remaining authors have no disclosures to report.

Figures

Figure 1. Trial design.
Figure 1. Trial design.
DAPT indicates dual antiplatelet therapy; and PCI, percutaneous coronary intervention
Figure 2. Screening, eligibility, randomization and blood…
Figure 2. Screening, eligibility, randomization and blood sampling.
ASP indicates aspirin; and TIC, ticagrelor monotherapy.
Figure 3. Platelet light transmission aggregation responses.
Figure 3. Platelet light transmission aggregation responses.
Data represent the maximum amplitude of aggregation responses (medians and interquartile ranges) at visit 1 (all patients receiving DAPT), visit 2 (4 weeks after allocation to either TIC or TIC+ASP groups) and visit 3 (all patients receiving aspirin alone). P values are 2‐tailed. A, Responses to thrombin receptor activation peptide 6 (TRAP‐6), collagen related peptide (CRP) and thromboxane A2 receptor agonist (U46619). B, Responses to adenosine diphosphate (ADP) and arachidonic acid (AA).
Figure 4. Mean treatment differences in platelet…
Figure 4. Mean treatment differences in platelet aggregation responses in blood sample 2.
The whiskers indicate the 95% CIs of the mean treatment difference estimates. Estimates less than zero indicate that the aggregation responses in TIC+ASP group were greater than in TIC group. *represents posthoc comparisons of measures. P values are 2‐tailed. AA indicates arachidonic acid; ADP, adenosine diphosphate; CRP, collagen related peptide; TRAP‐6, thrombin receptor activation peptide 6; and U46619, thromboxane A2 receptor agonist.
Figure 5. Platelet binding of the PAC…
Figure 5. Platelet binding of the PAC 1 and anti‐CD62P activation markers from blood sample 2.
A, baseline activation marker binding without agonist stimulation. B, the increase in activation marker binding after stimulation with thrombin receptor activation peptide 6 (TRAP‐6) 5 μmol/L or with collagen related peptide (CRP) 1μg/mL. The data are expressed as the median (interquartile range) of the median fluorescent intensity of binding of PAC 1 or anti‐CD62P.

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