It is within this evolving landscape that the SMART-CASE trial,6) which evaluated the clinical outcomes after different treatment strategies for angiographically defined intermediate stenoses (50–70% diameter stenosis), becomes particularly relevant.6) This trial enrolled 899 patients between 2009 and 2012, randomizing them to either routine PCI (aggressive group) or medical therapy (conservative group). While the 1-year outcomes published in 20176) demonstrated non-inferiority of medical therapy to PCI, the 3-year follow-up data, published in this issue, tell a different story. The extended follow-up study revealed a significantly higher incidence of major adverse cardiac events in the conservative group (13.8% vs. 9.3%, hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.00–2.21; p=0.049), driven by higher rates of ischemia-driven revascularization. Notably, the risk of cardiac death or myocardial infarction (MI) beyond 1 year was higher in the conservative group compared to the aggressive group (3.2% vs. 0.7%, HR, 4.34; 95% CI, 1.24–15.22; p=0.022).7)

While these results must be interpreted cautiously due to the limitations of the post-hoc analyses, this extended follow-up study highlights several critical points. The first point is understanding the reason behind the differences in the 3-year outcomes between the two different strategies. As discussed by authors, this may be due to the inappropriate treatment of ischemia-causing stenoses stemming from the well-documented discordance between angiographic and physiologic assessments.8) Although debates continue regarding the benefits of PCI in terms of hard endpoints for patients with stable coronary syndrome, several studies have demonstrated that PCI can reduce hard endpoints in clinically significant ischemia-causing lesions. The second point is the separation of event curves occurred after 1 year, which emphasizes the need for vigilance in the long term. More specifically, while revascularization was the primary driver of overall differences, the late-phase outcomes in cardiac death and MI became significant after 1-year, similar to the FAME 2 trial.9) All these results highlight the time-dependent effectiveness of our decision-making for the patients with coronary artery disease, a principle and limitation inherently associated with all diagnostic tests. Therefore, further studies are necessary to explore the impact of medications and changes in risk profiles overtime, as plaque characteristics change. The third point is cost-effectiveness of PCI. While PCI reduced delayed risk in this study, the associated costs—including stent implantation, bleeding risk from antiplatelet therapy, and potential stent-related complications—cannot be overlooked. If the initial PCI during the index procedure is considered an “event,” the overall event rates could be interpreted as 13.8% vs. 100% for the conservative and aggressive groups, respectively. While this kind of radical interpretation warrants caution, it highlights the need for careful consideration of PCI trials targeting vulnerable plaques or intermediate lesions. Notably, the recent cost-effectiveness analysis from the FLAVOUR trial demonstrated that FFR-guided revascularization was a dominant strategy over IVUS-guided revascularization despite the fewer PCI procedures.10) Finally, this trial results along with other recent trials focusing on the treatment strategy for vulnerable plaques underscore the need for tailored approaches. These might incorporate comprehensive physiologic assessment, imaging-guided therapy, and vigilant follow-up for disease progression. Future research should focus on refining decision-making criteria, integrating physiologic and imaging modalities, and conducting cost-effectiveness analyses to guide clinicians toward optimal, patient-centered care. The clinical application of novel artificial intelligence-enhanced approaches will facilitate this process through more convenient and less invasive methods.

The SMART-CASE trial’s extended findings are a testament to the dedication of its investigators, who deserve commendation for their long-term efforts. The study results also serve as a reminder that the management of intermediate stenoses remains a complex and evolving field. Until the jury delivers a definitive verdict, clinicians must rely on a careful balance of evidence, individualized assessment, and evolving technologies to guide treatment decisions.