Pathway-Guided and Patient-Centered Therapeutic Strategies in Atherosclerotic Cardiovascular Disease

Atherosclerotic cardiovascular disease (ASCVD), encompassing coronary artery disease (CAD), cerebrovascular disease (ischemic stroke, IS; and transient ischemic attack, TIA), and peripheral artery disease (PAD) of atherosclerotic origin, remains a leading cause of morbidity and mortality worldwide despite major advances in prevention and treatment. Although atherosclerosis arises from the convergence of endothelial injury, lipid accumulation, inflammation, and thrombosis, the relative contribution of these pathogenic processes varies markedly among individuals, due to the effects of genetics, demographic, and racial factors, lifestyle behaviors and comorbidities, several of which are modifiable. The variability in the atherosclerosis underlying mechanisms results in substantial heterogeneity in clinical presentation, disease progression, and therapeutic response. Recently, ASCVD management has expanded beyond single-pathway intensification toward pathway-guided, patient-centered, multi-targeted therapeutic strategies. Over the past decade, we have witnessed the development of highly specific therapeutics, including small-molecule inhibitors, monoclonal antibodies, and RNA-based therapies, while genome-editing approaches remain at an investigational stage. Contemporary Phase 3 randomized controlled trials (RCTs) have demonstrated that several novel agents reduce cardiovascular (CV) risk, whereas others produce biological effects without improving outcomes, underscoring the need for outcome-based validation. Despite improved safety profiles and enhanced treatment adherence, the optimal integration of these therapies into clinical practice continues to evolve. In this narrative review, we evaluate evidence from established, emerging, and investigational therapeutic strategies for ASCVD prevention and treatment. We also describe the impact of endothelial-protective, lipid-lowering, anti-inflammatory, and antithrombotic, strategies on CV outcomes, with particular emphasis on differential efficacy across patient subgroups, vascular territories, and clinical settings. In addition to synthesizing evidence from contemporary clinical trials, this review proposes a novel pathway- and phenotype-based conceptual framework for individualized ASCVD management and secondary prevention. The framework integrates residual-risk phenotypes with clinical characteristics, comorbidities, vascular territory, and treatment-related considerations to support residual-risk-guided selection of complementary evidence-based therapies while balancing anticipated benefit, safety, treatment burden, and adherence.