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

Phase 3RecruitingNCT07582835

Cardiocentro Ticino355 enrolled

Overview

Patients who undergo percutaneous coronary intervention (PCI) are commonly treated with antiplatelet therapy to prevent stent thrombosis and recurrence of events. After an initial period of dual antiplatelet therapy, long-term treatment with a single P2Y12 inhibitor (such as clopidogrel, ticagrelor, or prasugrel) is often prescribed. However, the optimal drug and dose for long-term monotherapy remain uncertain, as patients may experience either insufficient platelet inhibition (leading to ischemic events) or excessive inhibition (increasing bleeding risk). The HI-TECH 2 study aims to identify the most appropriate type and dose of P2Y12 inhibitor monotherapy to achieve a balanced level of platelet inhibition within a predefined therapeutic range. The study also seeks to better understand how blood coagulation activity evolves over time after PCI. This is a prospective, investigator-initiated, single-center, open-label study conducted in two phases. In Phase 1, patients receive stepwise reduced doses of ticagrelor or prasugrel to determine the optimal dose that most consistently achieves the desired level of platelet inhibition. In Phase 2, patients are randomly assigned to receive clopidogrel or the optimal doses of ticagrelor or prasugrel identified in Phase 1. The main question of the study is whether optimized ticagrelor or prasugrel regimens are more effective than standard-dose clopidogrel in achieving platelet inhibition within the target therapeutic window, as measured by validated platelet function tests. Additional objectives include evaluating the role of genetic factors in treatment response and assessing markers of coagulation activation over time. The results of this study may help personalize long-term antiplatelet therapy after PCI, improving the balance between reducing thrombotic risk and minimizing bleeding complications.

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥18 years * Prior (≥3 months) ACS and/or PCI * Eligible for P2Y12 inhibitor monotherapy after an uneventful DAPT course * Free from ischemic (i.e. any new episode of ACS, symptomatic restenosis, stent thrombosis, stroke, any revascularization requiring prolonged DAPT) and/or bleeding events (defined as BARC ≥ 2) for at least 3 months * Written informed consent. Exclusion Criteria: * Unconscious patients * Unable to provide written informed consent * Under judicial protection, tutorship or curatorship * Unable to understand and follow study-related instructions or unable to comply with study protocol * Known hypersensitivity or allergy to clopidogrel, ticagrelor or prasugrel * Severe hepatic impairment * Haemoglobin level \<10 g/dL or platelet count \<100 000 cells/mL * Pregnant or breastfeeding women * Life expectancy less than 1 year * Active participation in another interventional trial * Need for concomitant oral anticoagulation * History of intracranial haemorrhage (anytime), transient ischemic attack or stroke within 3 months * PCI for in-stent restenosis or stent thrombosis at index PCI or within 6 months before randomization

Outcomes

Primary Outcomes

Identification of reduced doses of ticagrelor and prasugrel achieving target platelet reactivity by VerifyNow (Phase 1)

Identification of the reduced maintenance doses of ticagrelor and prasugrel that achieve platelet reactivity within the predefined therapeutic window, defined as platelet reactivity units (PRU) \>85 and \<208, as measured by the VerifyNow P2Y12 assay. Platelet reactivity will be assessed 1 to 2 hours after intake of each dose of the P2Y12 inhibitor.

Time frame: During the dose-finding phase (Phase 1): at baseline and at Visit 1 (at approximately 30 days), Visit 2 (at approximately 60 days), and Visit 3 (at approximately 90 days).

Proportion of patients achieving platelet reactivity within the therapeutic window by VerifyNow at 3 months after randomization (Phase 2)

Proportion of patients with platelet reactivity within the predefined therapeutic window, defined as platelet reactivity units (PRU) ≥85 and ≤208, as measured by the VerifyNow P2Y12 assay. Platelet reactivity is assessed 1 to 2 hours after witnessed intake of the maintenance dose. The primary analysis includes two comparisons: ticagrelor versus clopidogrel and prasugrel versus clopidogrel.

Time frame: 3 months after randomization

Secondary Outcomes

Identification of reduced doses of ticagrelor and prasugrel achieving target platelet reactivity by Multiplate (Phase 1)

Identification of the reduced maintenance doses of ticagrelor and prasugrel that achieve platelet reactivity within the predefined therapeutic window, defined as area under the curve (AUC) ≥18 and ≤46, as measured by the Multiplate analyzer. Platelet reactivity will be assessed 1 to 2 hours after intake of each dose of the P2Y12 inhibitor.

Time frame: 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)

Proportion of patients with platelet reactivity within the predefined therapeutic window, defined as area under the curve (AUC) ≥18 and ≤46, as measured by the Multiplate analyzer. Platelet reactivity is assessed 1 to 2 hours after witnessed intake of the maintenance dose.

Time frame: 3 months after randomization (Phase 2)

Platelet reactivity within the therapeutic window after loading dose and at 6 months after randomization (Phase 2)

Proportion of patients achieving platelet reactivity within the predefined therapeutic window (PRU 85-208 by VerifyNow and/or AUC 18-46 by Multiplate) at baseline, at 3 to 6 hours after administration of the loading dose of the randomized P2Y12 inhibitor, and at 6 months follow-up, 1 to 2 hours after witnessed intake of the maintenance dose.

Time frame: At randomization and 6 months after randomization (Phase 2)

Proportion of patients with high and low platelet reactivity (Phase 2)

Proportion of patients with high platelet reactivity (HPR: PRU ≥208 or AUC ≥46) and low platelet reactivity (LPR: PRU ≤85 or AUC ≤18), as assessed by the VerifyNow P2Y12 assay and Multiplate analyzer. Measurements will be performed 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.

Time frame: 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)

Composite of death, myocardial infarction, or stroke, and individual components.

Time frame: Up to 6 months after randomization (Phase 2)

BARC bleeding events (Phase 2)

Bleeding events classified according to the Bleeding Academic Research Consortium (BARC) criteria. The BARC scale ranges from 0 to 5, where 0 indicates no bleeding and 5 indicates fatal bleeding; higher scores correspond to worse outcomes.

Time frame: Up to 6 months after randomization (Phase 2)

Drug adherence (Phase 2)

Assessment of treatment adherence measured as the proportion of prescribed doses taken over the study period, expressed as a percentage (0% to 100%), where higher percentages indicate better adherence. Adherence will be evaluated using patient self-report (e.g., medication diary) and, where available, electronic adherence monitoring systems (e.g., automatic pill counting devices).

Time frame: Up to 6 months after randomization (Phase 2)

Drug tolerability (Phase 2)

Assessment of drug tolerability based on the incidence, type, and severity of adverse events and treatment discontinuations, as documented in the annual safety report. Adverse events will be summarized descriptively; higher incidence and greater severity indicate worse tolerability.

Time frame: Up to 6 months after randomization (Phase 2)

Correlation between genotype status and platelet reactivity measured by VerifyNow P2Y12 assay (Phase 2)

Assessment of the correlation between genotype status-including variants of CYP2C19 and ABCB1, determined by genotyping assay-and platelet reactivity measured by the VerifyNow P2Y12 assay, expressed in P2Y12 Reaction Units (PRU). Correlation will be quantified using an appropriate correlation coefficient (e.g., Pearson or Spearman), ranging from -1 to +1, where values closer to ±1 indicate stronger relationships.

Time frame: Up to 6 months after randomization (Phase 2)

Change in cardiac troponin levels (Phase 2)

Change from baseline in cardiac troponin concentration, measured in ng/L using a validated immunoassay. Higher values indicate greater cardiac injury.