Study of the Long-term Effects of P2Y12 Inhibitor Monotherapy and Coagulation Markers After Percutaneous Coronary Angioplasty.

HI-TECH 2 is a prospective, investigator-initiated, single-center, open-label clinical trial designed to optimize P2Y12 inhibitor monotherapy following percutaneous coronary intervention (PCI), with a focus on achieving a predefined therapeutic window of platelet reactivity and characterizing coagulation system activation over time.

Despite widespread use of P2Y12 inhibitor monotherapy after completion of dual antiplatelet therapy (DAPT), substantial interindividual variability in pharmacodynamic response persists. Both high platelet reactivity (HPR) and low platelet reactivity (LPR) have been associated with adverse clinical outcomes, including thrombotic and bleeding events, respectively. A therapeutic window of platelet reactivity has been proposed to balance these competing risks. However, the optimal drug selection and dosing strategy to consistently achieve this window in contemporary PCI patients remain uncertain.

The study is structured in two sequential phases.

Phase 1 (dose-finding phase):

This phase aims to identify reduced-dose regimens of ticagrelor and prasugrel that achieve platelet reactivity within the predefined therapeutic range. Patients eligible for P2Y12 inhibitor monotherapy after PCI undergo serial platelet function testing using two validated assays (VerifyNow and Multiplate) at steady state. Ticagrelor and prasugrel are administered with stepwise dose reductions at predefined intervals, allowing within-subject pharmacodynamic assessment across multiple dosing regimens. The relationship between drug dose and platelet reactivity is characterized to determine the dose associated with the highest proportion of measurements within the target therapeutic window.

Phase 2 (randomized phase):

Following identification of the optimal dosing regimens in Phase 1, patients are randomized in a 1:1:1 ratio to receive clopidogrel at standard dose or ticagrelor or prasugrel at the optimized regimens. Randomization is stratified according to key clinical variables, including clinical presentation and diabetic status. Platelet function testing is performed under standardized conditions to assess pharmacodynamic response at steady state. This phase is designed to compare the proportion of patients achieving platelet reactivity within the therapeutic window across treatment groups.

In addition to platelet function assessment, a comprehensive panel of circulating biomarkers is evaluated in a predefined subset of patients to investigate the activation and persistence of coagulation pathways following PCI. These biomarkers include markers of thrombin generation, fibrinolysis, endothelial function, and platelet activation, providing mechanistic insight into the interplay between platelet inhibition and coagulation system activity in the chronic phase after PCI.

Pharmacogenetic analyses are also incorporated to explore the influence of CYP2C19 genotype and a composite ABCD-gene score on treatment response and the likelihood of achieving the therapeutic window. This component aims to assess the potential role of genotype-guided strategies in tailoring P2Y12 inhibitor therapy.

All analyses in the randomized phase are primarily conducted according to the intention-to-treat principle, with complementary per-protocol analyses to evaluate the robustness of findings. The study is powered to detect clinically relevant differences in pharmacodynamic response between treatment strategies, with adjustment for multiple comparisons.

Overall, HI-TECH 2 integrates dose optimization, randomized comparison, biomarker profiling, and pharmacogenetics to provide a comprehensive evaluation of long-term P2Y12 inhibitor monotherapy after PCI. The results are expected to inform individualized antiplatelet strategies aimed at improving the balance between thrombotic and bleeding risk in this population.

• Identification of reduced doses of ticagrelor and prasugrel achieving target platelet reactivity by Multiplate (Phase 1) [Срок оценки: During the dose-finding phase (Phase 1): at baseline and at Visit 1 (at approximately 30 days), Visit 2 (at approximately 30 days), and Visit 3 (at approximately 30 days).]
• Proportion of patients achieving platelet reactivity within the therapeutic window by Multiplate at 3 months after randomization (Phase 2) [Срок оценки: 3 months after randomization (Phase 2)]
• Platelet reactivity within the therapeutic window after loading dose and at 6 months after randomization (Phase 2) [Срок оценки: At randomization and 6 months after randomization (Phase 2)]
• Proportion of patients with high and low platelet reactivity (Phase 2) [Срок оценки: At baseline, 3 to 6 hours after the loading dose following randomization, and 1 to 2 hours after intake of the maintenance dose at approximately 3 months and 6 months. (Phase 2)]
• Major adverse cardiovascular events (MACE) (Phase 2) [Срок оценки: Up to 6 months after randomization (Phase 2)]
• BARC bleeding events (Phase 2) [Срок оценки: Up to 6 months after randomization (Phase 2)]
• Drug adherence (Phase 2) [Срок оценки: Up to 6 months after randomization (Phase 2)]
• Drug tolerability (Phase 2) [Срок оценки: Up to 6 months after randomization (Phase 2)]
• Correlation between genotype status and platelet reactivity measured by VerifyNow P2Y12 assay (Phase 2) [Срок оценки: Up to 6 months after randomization (Phase 2)]
• Change in cardiac troponin levels (Phase 2) [Срок оценки: From baseline to 6 months after randomization]
• Change in prothrombin fragment 1+2 levels (Phase 2) [Срок оценки: From baseline to 6 months after randomization]
• Change in thrombin-antithrombin (TAT) complex levels (Phase 2) [Срок оценки: From baseline to 6 months after randomization]