Toward Better Risk Stratification After Iliofemoral Endovascular Therapy in Lower Extremity Artery Disease

Corresponding Author

Lower extremity artery disease (LEAD) is a common manifestation of systemic atherosclerosis, characterized by arterial narrowing and reduced blood flow to the lower limbs. Whereas precise clinical estimates are limited, the GBD (Global Burden of Disease) study reports that lower extremity peripheral artery disease (LEPAD), a broader term used in epidemiological research, affects over 113 million individuals worldwide, with more than 10 million new cases annually. The age-standardized incidence of LEPAD varies substantially across regions, with Asian countries typically reporting rates between 100 and 120 per 100,000 person-years.¹ Although LEAD and LEPAD are often used interchangeably, LEAD generally refers to clinically significant, symptomatic disease requiring evaluation or intervention. A recent meta-analysis estimated the global prevalence of LEAD to be approximately 9.7%, with a disproportionately higher burden of 14.5% in South and Central Asia compared to other regions.² The disproportionately high burden observed in Asia may be attributed to a combination of factors, including a high prevalence of cardiometabolic conditions, delayed recognition, and suboptimal access to early vascular interventions.

The iliofemoral segment is a common site of atherosclerotic involvement in LEAD, often leading to claudication or chronic limb-threatening ischemia (CLTI). Whereas endovascular therapy (EVT) is widely adopted for iliofemoral lesions with high technical success,³ the risk of adverse clinical outcomes post-EVT, such as all-cause mortality and major adverse cardiovascular events (MACE), remains substantial,⁴ and the prognostic relevance of baseline and evolving clinical characteristics is still insufficiently understood. Prognostic tools to guide risk stratification and postprocedural management in this context are notably limited, particularly in Asian populations, highlighting the need for robust, region-specific data to inform clinical decision-making.

In this issue of JACC: Asia, Soga et al⁵ present a multicenter cohort study investigating long-term outcomes following EVT for iliofemoral disease in over 4,000 patients with symptomatic LEAD. With a median follow-up of 3.5 years and survival data extending to 10 years, this study represents one of the largest and most durable data sets in the field. Despite high initial procedural success, long-term outcomes were sobering: all-cause survival declined to 56% at 10 years, and only about one-half of the patients remained free from MACE, underscoring the progressive nature of atherosclerotic disease in this high-risk population. Notably, follow-up rates declined substantially over time, from nearly 88% at 1 year to just 37% at 10 years, which may reflect both patient attrition due to aging and disease progression, and the lack of systematic long-term follow-up in routine care. Beyond event rates, Soga et al⁵ explored the prognostic value of a wide range of baseline clinical characteristics using both conventional and time-dependent Cox regression models. Their approach allowed for the identification of not only static predictors of risk, such as older age, advanced chronic kidney disease, heart failure, and reduced ankle-brachial index, but also dynamic risk factors whose affect evolved over time. Notably, the early prognostic weight of CLTI and cerebrovascular disease attenuated over follow-up, highlighting the temporal heterogeneity of risk in this population. The consistent association between lack of statin or renin-angiotensin system inhibitor use and adverse outcomes reinforces the importance of long-term medical therapy following revascularization. Together, these findings illustrate the complex interplay among comorbidities, pharmacotherapy, and procedural outcomes and support the need for personalized, time-sensitive risk assessment strategies in patients undergoing iliofemoral EVT.

Among the identified risk factors, several well-established predictors of adverse outcomes, such as advanced age, chronic kidney disease, heart failure, cerebrovascular disease, and coronary artery disease, were significantly associated with increased risks of all-cause mortality and MACE, aligning with previous evidence from both general and cardiovascular cohorts. Among other identified risk factors, CLTI is widely acknowledged in current LEAD management guidelines as an important clinical feature associated with adverse limb and cardiovascular outcomes.^3,6 The strong early association of CLTI with both mortality and MACE in the study by Soga et al⁵ highlights its role as a marker of early disease severity, consistent with its prominence in current guideline-based risk stratification. Notably, its predictive strength declined over time, which may reflect the stabilization of limb-related risk in the early phase or the increasing influence of other comorbidities in the long term. These findings emphasize the need for dynamic, stage-specific risk stratification that adapts to the evolving clinical trajectory.

In addition to comorbid conditions, pharmacologic treatment patterns were closely link to long-term prognosis. The lack of statin and renin-angiotensin system inhibitor use was associated with a higher risk of adverse outcomes, highlighting the importance of cardioprotective medical therapy after EVT.

Importantly, warfarin use was independently associated with a higher risk of MACE in the current study. Although the cohort in Soga et al⁵ focused specifically on LEAD, a major subtype of PAD, the findings are broadly aligned with earlier PAD trials, which similarly did not demonstrate a cardiovascular benefit of warfarin. In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial, the addition of warfarin or acenocoumarol to antiplatelet therapy in patients with PAD did not reduce the incidence of major cardiovascular events and was associated with a significantly increased risk of life-threatening bleeding, underscoring the limitations of vitamin K antagonists in this population.⁷

More recently, evidence from large randomized controlled trials, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial and the VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularisation for PAD), has demonstrated that dual inhibition with low-dose rivaroxaban and aspirin reduces both cardiovascular and limb events in PAD patients, including those undergoing lower extremity revascularization.^8,9 Although bleeding risk remains a concern, this strategy offers a safer and more effective alternative to traditional anticoagulation. Given that the treatment period in Soga et al⁵ (2004-2011) predated the widespread availability of non–vitamin K oral anticoagulants, the observed association with warfarin likely reflects historical prescribing patterns rather than the intrinsic harms of anticoagulation per se.

Several limitations should be considered. First, the study was conducted exclusively in a Japanese population. Given the recognized ethnic heterogeneity within Asian populations in cardiovascular studies,¹⁰ these findings require further validation across other Asian regions. Second, as a retrospective analysis, the study is subject to inherent biases, and residual confounding cannot be entirely excluded. Third, whereas time-dependent Cox modeling accounts for deviations from proportional hazards, it may not fully capture the true temporal dynamics of risk; future studies incorporating serial follow-up data and longitudinal modeling approaches, such as trajectory analysis,¹¹ may offer deeper insights. Lastly, the study period predates contemporary management paradigms, underscoring the need for updated evidence in current clinical contexts.

Overall, this study by Soga et al⁵ provides valuable insights into the long-term prognosis of patients with symptomatic LEAD undergoing iliofemoral EVT. Their analysis adds important evidence from an Asian population, laying the groundwork for future research aimed at refining risk stratification and optimizing long-term care strategies across diverse settings.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.