Antithrombotic Therapy After PCI in High-Risk Cardiovascular Patients: Navigating Complexity Beyond Guidelines

Antithrombotic therapy is a cornerstone of contemporary cardiovascular management, substantially reducing thrombotic complications across a wide spectrum of cardiovascular conditions. However, the application of antithrombotic strategies in routine clinical practice remains challenging. Many patients commonly encountered in real-world settings—including elderly individuals, patients with multimorbidity, active malignancy, or advanced chronic kidney disease—are underrepresented in randomized clinical trials. Consequently, current guideline recommendations, although evidence-based, may not fully capture the complexity of these populations. In daily practice, clinicians are often required to balance competing risks of thrombosis and bleeding in patients characterized by multiple comorbidities, polypharmacy, and varying degrees of frailty, particularly when more than one indication for antithrombotic therapy coexists, such as atrial fibrillation in patients undergoing percutaneous coronary intervention. In this critical narrative review, we address key high-risk scenarios—frailty, advanced chronic kidney disease, active cancer, and atrial fibrillation in patients undergoing recent percutaneous coronary intervention—where standard antithrombotic strategies require special consideration. We critically appraise the limitations of existing bleeding risk scores and propose practical considerations for tailoring dual antiplatelet therapy duration, minimizing triple therapy, selecting antithrombotic combinations, and reassessing risk over time to optimize net clinical benefit.