Looking into the future: Endovascular intervention with intravascular ultrasound

Commentary on: Haraguchi T, et al. Impact of postprocedural minimum lumen area on clinical outcome after femoropopliteal drug-eluting stent implantation. Vasc Med 2023; 28: 412–421

Developed in the 1970s, intravascular ultrasound (IVUS) has been an important resource during the endovascular management of complex atherosclerotic arterial disease during the decades that followed. The value of the technology has been validated primarily through clinical research of coronary artery disease (CAD). During percutaneous coronary intervention (PCI) of complex CAD, IVUS imparts advantages of accurate vessel sizing and characterization of vascular calcification that optimize stent delivery and deployment.^1,2 These intraprocedural benefits have translated into meaningful reductions in post-PCI mortality risk and target vessel revascularization. ³ Despite convincing evidence exposing the limitations of angiography alone to assess vessel size and severity, endovascular treatment of peripheral artery disease (PAD) has relied nearly exclusively on digital subtraction angiography. So, has the time come for IVUS to refine the endovascular care of PAD?

In this edition of Vascular Medicine, Haraguchi and colleagues bolster the evidence for IVUS during endovascular treatment of femoropopliteal PAD. ⁴ The authors evaluated the association between IVUS-assessed minimal luminal area (MLA) and the likelihood of in-stent restenosis or aneurysmal degeneration within a subanalysis of the CAPSICUM study. ⁵ CAPSICUM was a prospective, observational study across 60 centers in Japan that included patients who received a fluoropolymer-based drug-eluting stent (FP-DES) for symptomatic femoropopliteal PAD. Patients were then evaluated 12 months after intervention with duplex ultrasound or follow-up angiography to assess the clinical endpoints. Generalized propensity score matching was used to normalize baseline covariates to assess the impact of MLA distribution on outcomes. IVUS-assessed MLA was divided into quartiles to report a dose–response function on subsequent rates of in-stent restenosis and aneurysmal degeneration. Among 718 IVUS-assessed limbs treated with FP-DES, the upper versus lower quartile MLA was associated with a 1-year restenosis rate of 8.8% versus 14.3% (odds ratio (OR) 0.58; 95% CI, 0.36 to 0.93; p = 0.024). The 1-year incidence of aneurysmal degeneration was 23.8% versus 16.8% (OR 1.55; 95% CI, 1.04 to 2.32; p = 0.031), respectively. Although limited by its observational design, this study highlights the opportunity for accurate stent sizing to reduce risk of late stenosis due to stent undersizing while avoiding vessel injury due to stent oversizing. Though validation of these findings requires future prospective study, this work suggests that point-of-care IVUS can predict and potentially impact clinical outcomes.

Indeed, a great deal of work remains to address the practical challenges posed by routine IVUS use during endovascular treatment of PAD. First, it should be acknowledged that, despite robust clinical evidence, guideline statements, and a supportive reimbursement structure, utilization of IVUS during PCI for CAD in contemporary practice remains generally low and with significant practice variation. ² Second, there is limited prospective randomized evidence of the potential benefits of IVUS on the routine endovascular care of PAD. Third, barriers to the use of IVUS in endovascular care include time, procedural cost, and uncertainty in the relevance and practical application of intravascular imaging results. The latter is perhaps the most urgent and relevant challenge to address.

Translating the benefits of IVUS from the practice of PCI to the endovascular management of PAD requires meticulous prospective clinical research with transparent study design to investigate circumstances in which the technology might be particularly effective. Among the most rigorous prospective randomized studies to date, Allan and colleagues presented a single-center analysis of 150 patients randomized to IVUS-guided versus angiographic-guided femoropopliteal intervention. ⁶ IVUS was associated with improved 1-year freedom from binary restenosis (72.4% vs 55.4%; p = 0.008), although it demonstrated no difference in clinically driven target lesion revascularization (CD-TLR) at 12 months (p = 0.776) or in rates of major adverse events between treatment groups (p = 0.593). As a notable limitation, treatment assignment did not impact stent size and the impact of IVUS on treatment strategy was not clear. In another propensity-matched observational analysis of IVUS in the care of femoropopliteal PAD, the use of IVUS was associated with a higher 5-year primary patency (65% vs 35%; p < 0.001). ⁷ IVUS resulted in significantly better assisted primary patency (p < 0.001), secondary patency (p = 0.004), freedom from any reintervention (p < 0.001), freedom from any adverse limb event (p < 0.001), and event-free survival (p < 0.001). Perhaps with a nuanced question like ‘does IVUS work,’ real-world propensity-matched data like that in this registry analysis is best capable of identifying the strengths of this technology.

So, what does it mean to use IVUS during endovascular treatment of PAD? The report by Haraguchi and colleagues evaluated IVUS-derived MLA as a predictor of late outcomes, demonstrating that a larger poststent MLA was associated with a reduced risk of restenosis. ⁴ Regardless of IVUS use, other research has established that small reference vessel diameter is a predictor for restenosis. ⁵ Interestingly, in Haraguchi et al.’s work, it is notable that the lowest rate of restenosis was within the third MLA quartile, and not the largest quartile, as might have been expected. ⁴ Therefore, additional prospective study is required to demonstrate the value of IVUS on optimizing MLA as a characteristic distinct from the reference vessel diameter. Furthermore, MLA indexed to distal lumen vessel or MLA indexed to target lesion area may provide more actionable intraprocedural targets that deserve rigorous evaluation. It is conceivable that poststent MLA may be an oversimplification of the utility of IVUS. What it means to use IVUS requires additional study in applying the intraprocedural information imparted by IVUS to maximize the benefits of the technology. IVUS excels in identifying complex disease that may benefit from enhanced vessel preparation, including atherectomy or lithotripsy angioplasty, to optimize stent sizing and deployment. IVUS may be particularly advantageous when deployed among patients with smaller reference vessel diameter or calcified lesions. For example, women often have smaller femoropopliteal vessels and underrepresented minorities have been demonstrated to have a greater anatomic lesion complexity.^8,9 Notably, these subgroups are underrepresented even among the most contemporary clinical studies. For example, the broadly anticipated and discussed BEST-CLI trial included 72% White patients and 72% male patients. ¹⁰ BASIL-2 was 82% male and 91% White patients. ¹¹ We must do better when we study IVUS in PAD. Any work that eventually rules in or rules out the value of IVUS in PAD therapies must intentionally include underrepresented subgroups to more broadly inform on the role of IVUS in PAD. IVUS may prove to provide no benefit in all-comers, but it may rescue subgroups that currently experience the worst clinical outcomes. We cannot just ask ‘does IVUS work?’ We must ask, ‘can IVUS help here?’

Haraguchi and colleagues ⁴ are commended for a rigorous analysis of observational data to refine the potential utility of IVUS on endovascular care of femoropopliteal PAD by asking a focused question about IVUS use in PAD therapies that was appropriately specific. Future studies evaluating the utility of IVUS should take care to test relevant hypotheses while rigorously controlling how IVUS is used and applied to unique patient subgroups where the benefits of the technology may be particularly relevant. Aneurysmal degeneration as an outcome may be unfamiliar to some readers, but it is an excellent outcome relevant to the technology used (i.e., FP-DES) to understand the potential role of IVUS. ⁵ Additional nuance and methodologic rigor are likely needed to study IVUS compared to what has traditionally been used to study destination therapies like stents or balloons. Such questions may provide the practical implications of IVUS on endovascular care to further guide expert consensus and appropriate use of IVUS in clinical practice.^12,13 To be sure, the answers to well-informed clinical studies of the future will help to answer the existential question of ‘does IVUS work in PAD?’