A Pilot Study to Investigate Platelet Reactivity in Patients With Elevated Lipoprotein(a) and Its Response to Antiplatelet Therapy

The Lp(a)-PLAT Study is designed to close a critical evidence gap in cardiovascular prevention for the roughly 20% of the population who carry genetically determined elevations in lipoprotein(a) - a recognised pro-thrombotic and pro-atherosclerotic risk factor. Its objective is to delineate the pro-thrombotic platelet phenotype driven by high Lp(a) levels and to evaluate, through pharmacodynamic comparison, how two standard-of-care antiplatelet strategies - clopidogrel, a P2Y12 ADP-receptor inhibitor, and aspirin, a COX-1 inhibitor - differ in their capacity to attenuate this platelet hyperreactivity. This study will provide the first head-to-head mechanistic comparison of clopidogrel versus aspirin on platelet reactivity in patients with elevated plasma levels of Lp(a).

Inclusion Criteria: * Age ≥ 18 years at the time of informed consent. * Ability to provide written informed consent in accordance with Swiss Human Research Act (HRA) and ICH-GCP. * Documented plasma lipoprotein(a) \[Lp(a)\] concentration: High Lp(a) cohort: ≥ 125 nmol/L (approximately ≥ 75th percentile) Low Lp(a) comparator cohort (if applicable): \< 25-30 nmol/L * Clinically stable at the time of inclusion, with no acute cardiovascular event within the previous 3 months. * Willingness and ability to comply with all study procedures, including blood sampling and study medication intake. * For women of childbearing potential: willingness to use adequate contraception during the study period (if applicable according to local ethics requirements). Exclusion Criteria: * Cardiovascular and bleeding-related conditions Active bleeding or known bleeding disorder. History of hemorrhagic stroke or intracranial hemorrhage. High risk of bleeding as judged by the investigator. Platelet count \< 100 × 10⁹/L at screening. Known platelet function disorder. * Contraindications to study medications Known hypersensitivity or contraindication to aspirin (acetylsalicylic acid) or clopidogrel. History of aspirin-induced asthma, severe NSAID intolerance, or anaphylactic reaction to salicylates. Active peptic ulcer disease or clinically significant gastrointestinal bleeding within the past 6 months. \- Concomitant medications and interference with platelet function Current use of dual antiplatelet therapy (DAPT), oral anticoagulants (e.g., DOACs, vitamin K antagonists), or other potent antithrombotic agents that cannot be safely interrupted. Use of non-steroidal anti-inflammatory drugs (NSAIDs) within 7 days prior to study entry (unless discontinued per protocol). Use of P2Y12 inhibitors or aspirin within an insufficient washout period. - Clinical conditions Severe hepatic impairment (ALT/AST \> 3× ULN) or severe renal impairment (eGFR \< 30 mL/min/1.73 m²). Active malignancy requiring systemic chemotherapy. Known hematologic disorder affecting platelet function or coagulation. Acute infection or inflammatory condition likely to affect platelet function. \- Other exclusions Pregnancy or breastfeeding. Participation in another interventional clinical trial within the last 30 days or 5 half-lives of the investigational product, whichever is longer. Any condition that, in the opinion of the investigator, would interfere with study participation, compliance, or interpretation of results.