Abstract
Objectives
We analyzed the 2-year clinical outcomes of patients with de novo femoropopliteal (FP) lesions who underwent drug-coated balloon (DCB) angioplasty and the angiographic predictors of restenosis.
Methods
This single-center, retrospective, and observational study evaluated 129 de novo FP lesions treated with DCB angioplasty without bailout stenting. Clinical outcomes and risk factors for loss of primary patency were analyzed using univariate and multivariate Cox proportional hazards regression models.
Results
The participants were aged 48–93 (mean: 73.6 ± 9.8) years, and 31% were women. Approximately 33% of the patients were receiving regular dialysis, and 35% of the affected limbs had critical ischemia. The mean lesion length was 132 ± 96 mm, and the mean reference vessel diameter (RVD) was 4.7 ± 0.8 mm. Forty-three (33%) limbs had chronic total occlusion of the target artery segment. Fifty-seven (44%) and 72 (56%) lesions were treated with DCB angioplasty using IN.PACT Admiral and Lutonix, respectively. The primary patency and amputation-free survival at 2 years were 59.3% and 89.5%, respectively. RVD was found to be an independent predictor of loss of primary patency. Based on the receiver operating characteristic analysis, an RVD of 4.2 mm was the best predictor of loss of primary patency at 2 years.
Conclusions
The short-term clinical outcome of DCB angioplasty for de novo FP lesions was acceptable. Moreover, an RVD of <4.2 mm was an independent predictor of restenosis after DCB angioplasty.
Keywords: Drug-coated balloon angioplasty, Endovascular treatment, Femoropopliteal artery
Abbreviations
- AFS
Amputation-free survival
- AUC
Area under the ROC curve
- CI
Confidence interval
- DCB
Drug-coated balloon
- ESVS
European Society for Vascular Surgery
- HR
Hazard ratios
- NHBLI
National Heart, Lung, and Blood Institution
- PACSS
Peripheral Arterial Calcium Scoring System
- ROC
Receiver operating characteristic
- RVD
Reference vessel diameter
1. Introduction
Endovascular treatment (EVT) is less invasive and safer than surgical bypass surgery and therefore, is considered the first-line therapy for femoropopliteal (FP) lesions.1 Several randomized trials showed that the patency rate of drug-coated balloon (DCB) angioplasty was higher than that of standard balloon angioplasty among patients with FP lesions.2, 3, 4 In Japan, IN.PACT Admiral (Medtronic, Minneapolis, MN) and Lutonix (Bard, New Hope, MN) have been commercially available since 2018. DCB angioplasty was reported to be effective among Japanese patients with FP lesions.5 However, only few studies have investigated the efficacy of DCB angioplasty among Japanese in real-world settings. Therefore, we aimed to analyze the 2-year clinical outcomes of DCB angioplasty for de novo FP lesions and to investigate the angiographic predictors of restenosis.
2. Methods
2.1. Study design and patient population
This single-center, retrospective, and observational study investigated the short-term clinical outcomes of consecutive patients with de novo FP lesions who underwent DCB angioplasty. The key inclusion criteria were patients with de novo lesions with ≥70% stenosis in the superficial femoral artery or proximal popliteal artery and with symptoms of lower limb ischemia (Rutherford categories 2–6) despite receiving appropriate exercise and medical therapy. All patients received EVT, which was discussed in the team conference of vascular surgeons. Of the 143 consecutive patients with de novo FP lesions who underwent DCB angioplasty from April 2018 to August 2020 (Fig. 1), 14 were excluded due to need for bailout stenting. Finally, 104 patients (129 lesions) were evaluated.
Fig. 1.
Flowchart of participant selection. DCB drug-coated balloon, FP femoropopliteal.
2.2. Procedures
After inserting a 5.0- or 6.0-French sheath via the ipsilateral or contralateral common femoral artery, heparin (5000 IU) was initially administered, and additional heparin was injected intravenously every hour to maintain an activated coagulation time of >250 s.
Initially, percutaneous transluminal angioplasty (PTA) was performed using standard balloons with nominal diameters similar to those of the RVD. After a successful PTA without ≥50% persistent stenosis or severe dissection (types D–F based on the National Heart, Lung, and Blood Institution [NHBLI] guidelines), IN. PACT Admiral or Lutonix was selected based on the operator's discretion. Then, the device was dilated for at least 3 min.
2.3. Medical therapy
Dual antiplatelet therapy with aspirin (100 mg/day) plus clopidogrel (75 mg/day) or cilostazol (200 mg/day) was started at least 3 days before EVT. It was continually administered for at least 1 month thereafter.
2.4. Definition and study endpoints
The definitions of hypertension, dyslipidemia, diabetes mellitus, dialysis, smoking, coronary artery disease, and cerebrovascular disease were based on a previous study.6 Below-the-knee runoff was assessed via angiography after PTA. Poor runoff was defined as one or no below-the-knee vessel runoff.7 The Proposed Peripheral Arterial Calcium Scoring System (PACSS) was used to categorize the lesions.8 Severe calcification had a PACSS grade of 3 or 4. The NHBLI guidelines was used to categorize the severity of dissection after PTA according to the coronary artery dissection criteria.9 Severe dissection was defined as NHBLI types C–F.10
The primary endpoint was primary patency at 1 year. The composite endpoint was freedom from clinical-driven target lesion revascularization and restenosis. The latter was defined as binary restenosis on angiography or a peak systolic velocity ratio of ≥2.4 on duplex ultrasonography.11
The secondary endpoint was amputation-free survival (AFS) at 2 years. The AFS was defined as the time until a major amputation of the target limb or death of any cause, whichever occurred first.
2.5. Statistical analysis
Statistical analysis was performed using JMP (version 10.0.0, SAS institute, Cary, NC, the USA). Categorial variables were presented as frequencies, and continuous variables as means ± standard deviations. The cumulative incidence of study endpoints was estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent predictor of loss of primary patency. The outcomes were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Variables with a probability (p)-value of <0.05 in the univariate analysis were included in the multivariate analysis. A receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff value of the RVDs that can predict loss of primary patency at 1 year after DCB angioplasty. The cutoff was elected to provide the highest value for the sum of sensitivity and specificity. The area under the ROC curve (AUC) was used to assess the accuracy of each parameter.
3. Results
3.1. Participants’ clinical characteristics
We investigated 129 lesions. Table 1 shows the characteristics of patients and limbs. The participants were aged 48–93 (mean: 73.6 ± 9.8), and 31% were women. Moreover, approximately 33% of the patients were on regular dialysis, and 35% of the affected legs had critical limb threatening ischemia.
Table 1.
Characteristics of patients and limbs.
| Variables | |
|---|---|
| Age, years | 73.6 ± 9.8 |
| Male, % | 72 (69) |
| Body mass index, kg/m2 | 23.2 ± 4.1 |
| Diabetes mellitus, % | 72 (69) |
| Dyslipidemia, % | 64 (62) |
| Hypertension, % | 80 (77) |
| Current smoker, % | 26 (25) |
| Hemodialysis, % | 34 (33) |
| Coronary artery disease, % | 49 (47) |
| Cerebrovascular disease, % | 23 (22) |
| Aspirin, % | 83 (80) |
| Thienopyridine, % | 78 (75) |
| Cilostazol, % | 25 (24) |
| Pre ABI | 0.58 ± 0.32 |
| CLTI, % | 45 (35) |
| CTO, % | 43 (33) |
| Severe calcification, % | 54 (42) |
| Proximal popliteal involvement, % | 56 (43) |
| Poor runoff, % | 46 (36) |
| TASC Ⅱ types C/D, % | 61 (47) |
| Lesion length, mm | 132 ± 96 |
| RVD, mm | 4.7 ± 0.8 |
Values are presented as n (%) or mean ± standard deviation.
ABI ankle-brachial index, CLTI chronic limb threatening ischemia, CTO chronic total occlusion, TASC Ⅱ Trans-Atlantic Inter-Society Consensus Ⅱ, RVD reference vessel diameter.
Approximately 47% of lesions were type C/D based on the Trans-Atlantic Inter-Society Consensus (TASC) II guidelines, and 43% of lesions involved the proximal popliteal artery. The mean reference vessel diameter (RVD) and lesion length were 4.7 ± 0.8 and 132 ± 96 mm, respectively. In total, 43 (33%) limbs presented with chronic total occlusion of the target artery segment. Table 2 presents the procedural characteristics and outcomes. Moreover, 57 (44%) and 72 (56%) lesions were treated with DCB angioplasty using IN.PACT Admiral and Lutonix, respectively. The mean DCB diameter and length were 4.6 ± 0.7 and 152 ± 92 mm, respectively.
Table 2.
Procedural characteristics and outcomes.
| Variables | |
|---|---|
| Pre dilatation | |
| Balloon diameter, mm | 4.3 ± 0.8 |
| Balloon length, mm | 118 ± 86 |
| Inflation time, s | 172 ± 88 |
| Inflation pressure, atm | 12.8 ± 5.4 |
| DCB | |
| IN.PACT Admiral, % | 57 (44) |
| Lutonix, % | 72 (56) |
| No. of DCB | 1.4 ± 0.6 |
| Balloon diameter, mm | 4.6 ± 0.7 |
| Balloon length, mm | 152 ± 92 |
| Inflation time, s | 231 ± 96 |
| Inflation pressure, atm | 8.6 ± 2.7 |
| Outcomes | |
| Post ABI | 0.91 ± 0.20 |
| MLD, mm | 3.8 ± 0.9 |
| %DS, % | 18 ± 13 |
| Severe dissection, % | 24 (19) |
Values are presented as n (%) or mean ± standard deviation.
DCB drug-coated balloon, MLD minimum lumen diameter, %DS percent diameter stenosis.
3.2. Clinical outcomes
The 2-year primary patency and AFS rates were 59.3% and 89.5%, respectively (Fig. 2). There was no major amputation at the target limb or thrombosis at the target lesion site during the study period.
Fig. 2.
Kaplan–Meier curves for primary patency and AFS. (A) The primary patency rate at 2 years was 59.3%. (B) The AFS rate at 2 years was 89.5%. AFS amputation-free survival, EVT endovascular treatment.
3.3. Univariate and multivariate analyses of loss of primary patency
Univariate and multivariate analyses were performed to identify the independent predictor of loss of primary patency. The importance of RVD and use of IN.PACT Admiral were assessed via a univariate analysis and were used in the multivariate Cox regression model. As shown in Table 3, only RVD (HR = 0.42, 95% CI = 0.27–0.65, p < 0.01) was found to be an independent predictor of loss of primary patency.
Table 3.
Univariate and multivariate Cox regression analysis results for the predictors of loss of primary patency.
| Variables | Univariate analysis |
Multivariate analysis |
||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Female | 1.81 (0.97–3.38) | 0.06 | ||
| DM | 1.25 (0.63–2.49) | 0.53 | ||
| Hemodialysis | 1.49 (0.79–2.83) | 0.22 | ||
| CLTI | 2.00 (1.06–3.79) | 0.03 | 1.72 (0.90–3.28) | 0.10 |
| CTO | 1.56 (0.83–2.92) | 0.16 | ||
| Poor runoff | 1.47 (0.79–2.76) | 0.23 | ||
| RVD (per 1 mm increase) | 0.39 (0.24–0.61) | <0.01 | 0.42 (0.27–0.65) | <0.01 |
| Lesion length (per 10 mm increase) | 1.03 (1.01–1.07) | 0.03 | 1.03 (0.99–1.07) | 0.11 |
| Severe calcification | 0.71 (0.37–1.37) | 0.30 | ||
| Use of IN.PACT Admiral | 0.47 (0.24–0.90) | 0.02 | 0.48 (0.25–1.07) | 0.07 |
| Severe dissection | 2.64 (1.34–5.21) | <0.01 | 1.60 (0.77–3.31) | 0.21 |
| Post procedure %DS (per 10% increase) | 1.21 (0.93–1.57) | 0.16 | ||
HR hazard ratio, CI confidence interval, DM diabetes mellitus, CLTI chronic limb threatening ischemia, CTO chronic total occlusion, RVD reference vessel diameter, %DS percent diameter stenosis.
3.4. ROC analysis
Fig. 3 shows the outcome of the ROC analysis of RVD as a predictor of loss of primary patency at 2 years. The AUC for RVD was 0.706 (95% CI = 0.613–0.799), and an RVD of 4.2 mm was the best predictor of loss of primary patency at 2 years, which had a sensitivity of 76.1% and a specificity of 56.1%. As shown in Fig. 4, the primary patency was superior in the large vessel group (RVD: ≥4.2 mm) than in the small vessel group (RVD: <4.2 mm) based on Kaplan–Meier analysis (Log-rank test; p = 0.003).
Fig. 3.
Receiver operating characteristic analysis of reference vessel diameter for predicting the loss of primary patency. AUC area under curve, CI confidence interval.
Fig. 4.
Kaplan–Meier curves for primary patency stratified according to reference vessel diameter. RVD reference vessel diameter, EVT endovascular treatment.
4. Discussion
The main findings of the current study are as follows: (1) the one-year clinical outcomes of DCB angioplasty for de novo FP lesions were acceptable; (2) the multivariate Cox regression analysis revealed that RVD was an independent predictor of loss of primary patency; and (3) the ROC analysis showed that the best cutoff value of RVD for predicting loss of primary patency at 2 years was 4.2 mm.
Several randomized trials revealed that DCB angioplasty was more effective than standard balloon angioplasty for FP lesions.2, 3, 4 The primary patency rate at 1 year for DCB angioplasty was 65%–80%. Iida et al reported that the efficacy of DCB treatment among Japanese patients was consistent with the result of global trials (IN.PACT SFA Japan Randomized Trial).5 In contrast, the clinical outcomes of DCB treatment among Japanese in real-world settings remain unknown.
In the current study, the primary patency rate at 2 years was 59.3%. The background characteristics of patients significantly differed from those of patients in previous randomized trials. Particularly, approximately 33% of patients were receiving dialysis, and 33% presented with CTO lesions. The lesion length was as long as 130 mm. Despite a sicker patient population and complex lesion characteristics, the primary patency at 2 years was generally comparable to that of previous reports.
Several papers about the clinical outcomes of DCB angioplasty in real-world settings had already been published.12, 13, 14 In Japan, the usage of DCB is strictly restricted based on specific guidelines generated by related congresses. DCB can be used only after a successful PTA without persistent stenosis of ≥50% or severe dissection (NHBLI types D–F) because these conditions are likely associated with a higher restenosis rate.10 To the best of our knowledge, the current study first reported the 2-year clinical outcomes of DCB angioplasty in such a unique environment in Japan. Previous studies have shown that prolonged time inflation and usage of non-slip element or long balloons could prevent severe dissection.15, 16, 17
The predictors of restenosis after DCB angioplasty are not fully elucidated. AbuRhama et al reported that long lesion and total occlusion were associated with restenosis.14 In this study, more than half of patients with TASC II type C and D lesions, including complex ones, were managed with bailout stenting. Kozuki et al showed that intravascular ultrasound (IVUS)-evaluated post-procedural dissection was associated with 1-year restenosis after DCB angioplasty.18 Although IVUS is widely used in EVT in Japan, it is not common in other countries. Hence, angiographic predictors that can be used effectively in clinical practice must be assessed. The current study revealed that RVD was the only predictor of loss of primary patency, with the best cutoff value of 4.4 mm.
The current study showed that treatment with DCB for small FP lesions was challenging. Bare nitinol, drug-eluting stent, and covered stents are other clinical options for FP lesions. The patency rate of these methods may be higher than that of standard PTA.7,19,20 However, they were not highly effective for small vessel diseases.7,21,22 Further investigation should be performed to determine which device is suitable for such lesions. Currently, the leave nothing behind strategy with DCBs plays an important role in not posing limitations in future treatment.
The current study has several limitations. First, it was a single-center, retrospective, and observational study, and a small number of patients were included. Second, the selection of device was based on each operator's discretion. Hence, there was a potential bias. Finally, the angiography results and outcomes were assessed by independent observers, not by an external core laboratory.
5. Conclusion
In conclusion, the short-term clinical outcome of DCB angioplasty for de novo FP lesions was acceptable. Moreover, an RVD of <4.2 mm was an independent predictor of restenosis after DCB treatment.
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Kohei Yamaguchi and Shinsuke Mori. The first draft of the manuscript was written by Kohei Yamaguchi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of our institution (approval no. 20210054).
Consent to participate
Informed consent was obtained from all patients.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
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