Long-Term Antithrombotic Therapy After Percutaneous Coronary Intervention: Secondary Prevention Beyond One Year

The early period following percutaneous coronary intervention (PCI), particularly the first days to weeks after stent implantation, is characterized by heightened device-related thrombotic risk, and dual antiplatelet therapy (DAPT) during this phase is well established. With contemporary drug-eluting stents (DES) and abbreviated DAPT strategies, late stent-related events have become less frequent, and long-term risk increasingly reflects underlying systemic atherosclerotic disease. Beyond 12 months, the risk profile shifts further: late events increasingly reflect progressive atherosclerosis and systemic vascular disease rather than stent-related thrombosis. This review synthesizes contemporary evidence on long-term antiplatelet and antithrombotic therapy after PCI, with a focus on the period beyond one year. We evaluate the data supporting for lifelong aspirin as the traditional default strategy, as well as the emerging evidence that P2Y₁₂ inhibitor monotherapy may be superior to aspirin in selected post-PCI populations (HOST-EXAM, HOST-EXAM Extended, PANTHER, SMART-CHOICE 3). This review also examines the role of prolonged DAPT in selected high-risk patients (DAPT Trial, PEGASUS-Thrombolysis in Myocardial Infarction (TIMI) 54) and the paradigm of dual-pathway inhibition with low-dose rivaroxaban plus aspirin (COMPASS, VOYAGER-peripheral artery disease (PAD)). In addition, the review considers protease-activated receptor (PAR) antagonism (TRA 2°P-TIMI 50) and precision-based strategies, including CYP2C19 genotype-guided therapy. Special populations, such as patients with diabetes, chronic kidney disease (CKD), polyvascular disease, and those requiring concomitant oral anticoagulation, present distinct long-term management challenges. Thus, novel targets, including factor XIa inhibitors and PAR-4 antagonists, may further refine the antithrombotic approach. Overall, the optimal long-term strategy after PCI is increasingly defined not by fixed timelines but by the dynamic balance between ischemic and bleeding risk.