2.1 Study design and patient population

This was a retrospective observational study at Sapporo Heart Center, Sapporo Cardio Vascular Clinic, Sapporo, Japan. From June 2018 to December 2022, 842 consecutive patients with symptomatic lower extremity artery disease underwent EVT using DCBs. In the present study, we retrospectively sought to enroll patients who had de novo femoropopliteal lesions with a Rutherford classification ranging from 2 to 6.⁶ Patients with (1) flow-limiting dissections, (2) bailout scaffolding, (3) common femoral artery lesions, and (4) restenotic lesions were excluded from this study. The patients were divided into two groups according to the presence or absence of SD after DCB angioplasty. The study protocol was approved by the ethics committee at Sapporo Heart Center (No. 20230003) and was in accordance with the Declaration of Helsinki. Written informed consent was waived because of the retrospective study design.

2.2 Endovascular procedures and medical therapy

Patients with symptomatic femoropopliteal lesions exhibiting >70% diameter stenosis and a Rutherford classification between 2 and 6 were selected for EVT. A 6-Fr sheath was inserted into the common femoral artery according to lesion location, and a 5000-IU dose of unfractionated heparin was administered to achieve an activated coagulation time >250 s. Lesion crossing was accomplished using a 0.014- or 0.018-inch guidewire, with balloon selection based on lesion morphology and location. Balloon diameter was determined using angiography or intravascular ultrasound (IVUS), and DCB angioplasty was performed to cover the entire lesion. The choice of DCBs, either low-dose DCB (Lutonix, Becton Dickinson and Ranger, Boston Scientific) or high-dose DCB (IN.PACT Admiral, Medtronic), and specialty balloons (Cutting Balloon, Boston Scientific and AngioSculpt, Philips) was determined at the operator's discretion based on lesion severity such as a long lesion, small vessel, occlusion, and calcification. If residual stenosis after DCB angioplasty exceeded 50%, the lesion was evaluated to determine whether additional treatment was indicated based on pressure gradient or IVUS evaluation. Lesions determined to require additional treatment were post-dilated with an appropriately sized balloon based on angiographic or IVUS information. Atherectomy devices were not available during the study period. Hemostasis was achieved with manual compression or device closure. After DCB angioplasty, dual antiplatelet therapy (aspirin 100 mg daily and 75 mg clopidogrel daily) was recommended for 3 months. In patients receiving anticoagulant therapy, the combination of anticoagulant and dual antiplatelet therapy was recommended for 1 month, followed by long-term anticoagulation and aspirin therapy.

2.3 Study endpoints and follow-up

The primary endpoint was 1-year primary patency, defined as target lesion patency without significant restenosis. Secondary endpoints included early restenosis and 1-year clinical events (target lesion revascularization [TLR], major adverse limb event [MALE], and all-cause death). Restenosis was defined as a peak systolic velocity ratio >2.4 on duplex ultrasonography or >50% stenosis on follow-up computed tomography angiogram.^{7, 8} Early restenosis and major amputation were defined as occurring within 30 days after the index procedure. TLR was defined as a repeat EVT or surgical bypass procedure for limbs with recurrent symptoms and restenosis. MALE was defined as a composite of major amputation or any reintervention.⁹

Patients were routinely followed up at our outpatient clinic at 1, 6, and 12 months or in the occurrence of clinical deterioration. The follow-up protocol consisted of postoperative ankle-brachial index and lower limb duplex ultrasound at each visit. If ultrasound results were inconclusive, computed tomography angiogram, digital subtraction angiography, or both were performed. The severity of dissection was graded according to the National Heart, Lung and Blood Institute classification system.¹⁰ Type A was defined as dissection with minor radiolucent areas, type B as linear dissection, type C as dissection with contrast outside the lumen, type D as spiral dissection, type E as persistent filling defects, and type F as total occlusion without distal antegrade flow (Figure 1). Flow-limiting dissection was defined as dissection with deterioration of the distal antegrade flow (flow-limiting type D, E, and F dissection). The severity of lower extremity artery disease was categorized according to the Rutherford classification as mild to severe intermittent claudication (class 1–3) and chronic limb-threatening ischemia (CLTI) with and without tissue loss (class 4–6).⁶ Lesion severity was graded according to the Trans-Atlantic Inter-Society Consensus (TASC) II classification.¹¹ Calcification laterality was determined according to the Peripheral Artery Calcification Scoring System (PACSS) classification.¹²

2.4 Statistical analysis

Continuous variables were presented as mean ± SD and compared by the unpaired t-test or the Mann–Whitney U test. Categorical variables were expressed as numbers (percentages) and compared by the chi-square test. The cumulative 1-year incidence of study endpoints was estimated by the Kaplan–Meier method and compared by the log-rank test. We included 11 variables clinically relevant covariates for 1-year patency by the Cox models (below-the-knee runoff ≤1, CLTI, small vessel ≤4.0 mm, prior heart failure, hemodialysis, PACSS grade 4, residual stenosis ≥50%, IVUS use, low-dose DCB use, specialty balloon use, and TASC II D).^{3, 4, 12} All statistical analyses were performed by two physicians (T. H. and S. K.) using SPSS statistics version 29.0 (SPSS, Inc.) and R software version 3.5.2 (R Foundation for Statistical Computing). A two-sided p < 0.05 was considered statistically significant.

3.1 Study population

Among 842 patients (912 limbs), 345 were excluded due to flow-limiting dissections (n = 10), bailout scaffolding (n = 117), common femoral artery lesions (n = 81), and restenotic lesions (n = 137). Finally, 497 patients (497 limbs) were enrolled in the present study; non-flow-limiting SD was observed in 92 patients (92 limbs) (18.5%) (Figure 2).

3.2 Baseline clinical characteristics

Baseline patient and lesion characteristics are summarized in Table 1. There were no significant differences between the SD and non-SD groups. In terms of lesion characteristics, the SD group had considerably greater lesion complexity. Table 2 presents procedural characteristics and results between the two groups. Compared with the non-SD group, the SD group showed a smaller vessel diameter and a longer lesion length with less frequency of specialty balloon use, resulting in a smaller DCB size and a longer total DCB length. After DCB angioplasty, the SD group had a higher residual restenosis rate and a lower ankle-brachial index than the non-SD groups (15.3 ± 1.8% vs. 9.6 ± 0.7, p = 0.002; 0.90 ± 0.19 vs. 0.97 ± 0.18, p < 0.001, respectively). Periprocedural complications did not differ between groups.

3.3 Impact of SD on clinical outcomes

Table 3 demonstrates clinical outcomes after DCB angioplasty in the SD and non-SD groups. The 1-year primary patency and freedom from TLR were significantly lower in the SD group than in the non-SD group (69.8% vs. 83.3%, p = 0.004; 78.7% vs. 93.0%, p = 0.007, respectively) (Figures 3 and 4). Similarly, early restenosis and 1-year clinical events (MALE and major amputation) occurred more frequently in the SD group than in the non-SD group (4.3% vs. 0.5%, p = 0.002; 24.6% vs. 11.9%, p = 0.001; 9.6% vs. 1.7%, p = 0.001, respectively). All-cause death and early major amputation were comparable in both groups.

3.4 Factors associated with restenosis after SD

CLTI (hazard ratio, 3.36 [95% confidence interval, 1.21–9.36]; p = 0.020), TASC Ⅱ D (hazard ratio, 3.97 [95% confidence interval, 1.02–15.52]; p = 0.047), and residual stenosis ≥50% (hazard ratio, 4.92 [95% confidence interval, 1.01–23.94]; p = 0.048) were associated with 1-year restenosis after SD occurrence (Table 4).

4.1 Limitations

The present study has several limitations. First, the present study was a retrospective study at a single center. Furthermore, lesion characteristics and angiographic images were not analyzed in an independent core laboratory. As such, these findings might have biased the present study results and conclusions. Second, compared with two-dimensional angiographic imaging, IVUS is a more accurate tool for detecting the presence of dissection. However, the current study performed an IVUS examination in 27.8% of all cases, which might result in underestimating SD incidence. Third, atherectomy devices were not used in the present study since they were unavailable during the study period. Fourth, given that the present study excluded cases with bailout stenting for dissection, further studies are warranted to compare the clinical outcomes between DCB and drug-eluting stents in non-flow-limiting SD. Fifth, we did not obtain information on the pressure gradient within the lesions in the present study. A combined assessment of dissection using angiographic images and pressure gradients might have provided more comprehensive information on the EVT strategy. Sixth, as the SD group was relatively small, our results should be considered hypothesis-generating. An optimal strategy for non-flow-limiting SD should be addressed shortly. Finally, extrapolating our results outside Japan requires caution because the study population consisted solely of Japanese subjects.