Introduction
Numerous studies have shown satisfactory outcomes using drug-coated balloons (DCBs) in the endovascular treatment of short femoropopliteal artery disease [
1‐
6]. These outcomes cannot be directly extrapolated to long lesions. The treatment of long lesions is known to be challenging, since long lesions are always associated with complex and calcified plaques leading to insufficient dilation and elastic recoil [
7] Long lesions of the femoropopliteal artery are very common in clinical practice, and the optimal treatment remains to be explored. Furthermore, longer balloons contain more paclitaxel, and some studies suggest this may trigger dose-related adverse events, while others found different results [
8‐
11] Therefore, the effectiveness and safety of DCBs in long lesions needs further evaluation.
The advantages of DCBs in the treatment of long lesions include inhibition of vascular intima hyperplasia without leaving anything behind, thus reducing restenosis rates and avoiding implant rupture [
12,
13]. However, few clinical results have focused on long lesions in femoropopliteal peripheral artery disease, and even fewer real-world studies have been conducted [
14‐
17]. The SFA-Long study reported a patency rate of 89.3% by Kaplan–Meier estimate at 12 months, while the primary patency in the IN.PACT Global Study Long Lesion Imaging Cohort was 91.1% [
14,
16]. Most of these trials were industry-sponsored, in which patients may be highly selected and the intervention process may be tightly controlled, suggesting an ideal effect. Real-world studies with relatively loose inclusion criteria reflect real clinical situations and can reflect the actual effectiveness of the intervention. For example, in actual clinical applications, there are various methods of vessel preparation for different types of blood vessels, and studies that strictly control vessel preparation cannot reflect the actual effectiveness [
18].
This study was designed in our 3 major medical centres to estimate the effectiveness and safety of Orchid® DCB in long lesions (≥150 mm) through a 1-year follow-up under real-world conditions.
Patients
Adult patients undergoing DCB treatment for stenotic arteriosclerotic lesions in the superficial femoral artery and/or popliteal artery were included, with stenotic or occlusive lesions for a total length of ≥ 150 mm. Multiple adjacent lesions with interval angiographically healthy segments shorter than 3 cm were considered and treated as a single lesion. The Rutherford stages ranged from 2 to 5 (claudication, resting pain or small ulcers). All included patients had inflow vessels with < 50% diameter stenosis before the treatment of femoropopliteal lesions. Patients who were allergic to paclitaxel, whose life expectancy was less than 2 years, or who had vascular surgery 6 weeks before this treatment were excluded. If there were other nonatherosclerotic vascular diseases in the target lesion, including aneurysms or vasculitis, the patients were also excluded.
Procedures and devices
All patients had a thorough clinical examination at baseline. Each patient took 100 mg/day aspirin and 75 mg/day clopidogrel for at least 7 days before surgery. If the patients had no history of aspirin or clopidogrel, they took 300 mg within 12 hours before surgery.
During the procedure, 75 IU/kg heparin was administered after sheath insertion. Thrombectomy was performed in some patients before predilation if thrombosis was suspected based on the clinical symptoms and radiographic evidence. Predilation (2 minutes) was routinely performed with uncoated balloons 0.5 to 1 mm smaller than the reference vessel. The intraluminal or subintimal approach was at the discretion of the operators. Atherectomy was performed only under necessary conditions determined by the operator; for example, the calcification was so severe or near the joint that predilation was not satisfactory. The DCBs were Orchid
® from the Acotec Scientific Company, ranging from 4-6 mm in diameter and 120-300 mm in length, and the dose of paclitaxel in Orchid
® DCBs was 3.0 µg/mm
2.[
19] The DCBs were 1.0 mm larger than the uncoated balloon in diameter and were inflated only once for 3 minutes at 6-12 atmospheres. There were lesions of approximately 400 mm, but the longest balloon accessible was 300 mm. Therefore, if two or more DCBs were needed for only one lesion, they must overlap by more than 5 mm. If there was any residual stenosis (> 30%) or flow limiting dissection, another expansion of the uncoated balloon was performed. After repeated dilation, a bailout stent was deployed during the same intervention if persistent stenosis or flow-limiting dissection still existed. The bailout stents used included Zilver Flex
® (Cook, Bjaeverskov, Denmark), Protégé Everflex
TM (Covidien, Plymouth, Minn), LifeStent
® (Bard, Tempe, AZ), and Innova
TM (Boston Scientific, Marlborough, MA). Inflow and outflow lesions were also treated during the same intervention at the discretion of the operators.
After revascularization, patients were prescribed 100 mg/day aspirin and 75 mg/day clopidogrel for at least 12 weeks. Follow-up information was obtained by telephone and the outpatient service at 3 months, 6 months, and 1 year after DCB angioplasty, including the symptoms, Rutherford classification, adverse events, ankle brachial index (ABI), and imaging results. Computed tomography angiography (CTA) and Doppler ultrasound examination (US) were recommended at 6 and 12 months and in the event of ischaemic symptoms.
Definition and study endpoints
Chronic total occlusion (CTO) was defined as the minimum lumen diameter of the target lesion being 0. Calcification of the lesions was evaluated using the PACSS scale [
20]. A moderate to severe degree was defined as calcification on two sides of the vascular walls, and one of them was longer than 5 cm. Critical limb ischaemia (CLI) was defined as the presence of ischaemic rest pain, nonhealing wounds/ulcers, or gangrene for >2 weeks with associated evidence of hypoperfusion according to the American Heart Association (AHA) guidelines [
21]. Device success was defined as successful access of the guidewire and accurate deployment of the balloons to the target lesion, while technical success was defined as both device success and residual stenosis < 30% after the endovascular procedure.
The primary endpoints in this study were primary patency, freedom from clinically driven target lesion revascularization (TLR) and major adverse events (all-cause death and major target limb amputation). Primary patency is defined as freedom from restenosis (> 50% residual lumen diameters in the target lesion under CTA, or peak systolic velocity ratio ≤ 2.4 under Doppler ultrasound examination) and freedom from clinically driven TLR. Clinically driven TLR is defined as any revascularization of the target lesion because of apparent symptoms or the imaging results mentioned above. The secondary endpoints were the change in Rutherford classification and ABI between preprocedure and follow-up.
Statistical analysis
The data were analysed on the per-protocol population. Descriptive statistics were used to estimate values and changes from baseline as the absolute frequency (percentage) for categorical variables and mean ± SD for continuous variables.
Primary patency and freedom from TLR were estimated by Kaplan–Meier analyses. Comparison of the Rutherford classification and ABI between the preprocedure and follow-up was tested through the Wilcoxon signed rank-sum test. In the univariate subgroup analysis of primary patency, the log-rank test of Kaplan–Meier survival curves was used. Variables with a p value < 0.1 were included in the multivariate analysis. Cox proportional hazards multivariate regression analysis was used to estimate the independent influence of the potential prognostic factors. Statistical significance is defined as p values < 0.05. Data were analysed with SPSS version 25.0 (SPSS, Chicago, Illinois) for Windows.
Discussion
As the effectiveness of DCBs in short femoropopliteal lesions has been sufficiently proven, DCBs are extensively used in short lesions. However, long lesions with femoropopliteal artery stenosis are very common, and the treatment is challenging. However, long-lesion studies started later, and the application of DCBs in long lesions is still limited. A study summarized the use of DCBs and drug-eluted stents (DESs) in 91,864 femoropopliteal lesions, finding that DCBs are mostly used in medium length, minimally calcified lesions, while DESs are mostly used in longer, more heavily calcified lesions [
22] Thus, the evidence for the use of DCBs in long lesions is insufficient, and their effectiveness and safety are unclear. To address this problem, the lengths of the lesions included in this study were all longer than or equal to 150 mm, which is the boundary of TASC B and C. Meanwhile, the proportion of CTOs in our study was 78.3%, which is higher than that of other long-lesion studies (for example, 49.5% in the SFA-Long study and 60.4% in the IN.PACT Global Study Long Lesion Imaging Cohort) [
14,
16]; therefore, our results better reflect the efficacy of DCBs on long and more complex lesions in the real world. Another feature of this study is that all patients were Asian, while most published studies were performed in Western countries. Potential differences between races in the composition and calcium of atherosclerotic plaques may affect the patency rate and clinical decisions [
23].
According to other Orchid
® DCB studies applied in femoropopliteal lesions, the primary patency rate of the DCB group (n = 100, bailout stent 19.0%) in the AcoArt I trial was 76.1% at 12 months and 64.6% at 24 months, significantly improving the clinical outcomes compared with the uncoated balloon group (
p < 0.001) [
24,
25]. The mean lesion length in the DCB group in the AcoArt I trial was 147 ± 110 mm, while the mean length in this study was 252.3 ± 55.4 mm. The 1-year primary patency rate in this study was 82.1%, suggesting that Orchid
® DCBs are effective in treating long lesions ≥ 150 mm at 1 year. In comparison to our results, other studies focusing on long lesions, such as the SFA-Long study, reported that the primary patency was 89.3% at 12 months by Kaplan–Meier estimations (n = 105, bailout stent 10.5%) [
14], while the 12-month primary patency rate of the IN.PACT Global Study Long Lesion Imaging Cohort was 91.1% (n = 164, bailout stent 39.4%) [
16]. There are some possible reasons why the primary patency rate in this study is slightly lower than that in the SFA-Long study and the IN.PACT Global Study Long Lesion Imaging Cohort, including different characteristics of the patients and lesions. For example, in our study, patients with Rutherford grade 4–5 accounted for 41.3%, and restenosis (in-stent and non-stented) accounted for 33.9%, higher than the other long-lesion studies. Therefore, more clinical evidence is needed comparing the effectiveness of different types of DCBs.
Among patients categorized by different clinical and lesion characteristics, subgroup analysis was performed to study the potential risk factors related to primary patency. These results suggested that subgroups categorized by renal failure and CLI showed significant differences in the patency rate at 12 months. In the Cox regression analysis, we found that these 2 variables were also independent predictors, suggesting that patients with renal failure or CLI had worse outcomes. CLI is known to be an end-stage form of peripheral artery disease with poor clinical outcomes, and thus, it is reasonable that the patency rate in the CLI group was lower. In regard to the negative effect of renal failure, many studies have confirmed the acceleration of atherosclerosis under conditions of renal failure due to vascular calcification, elevated serum phosphorous levels, and hyperparathyroidism. Even so, DCB is a superior treatment to percutaneous transluminal angioplasty (PTA) in dialysis patients with femoropopliteal disease, as demonstrated by Hsin-Hua Chou et al. [
26].
In addition, restenosis and TASC D lesions also markedly affected primary patency, but the differences were not statistically significant in this study. It is worth mentioning that recent research has found that clinical outcomes after DCB angioplasty in TASC D lesions were inferior to what had been reported and much more unsatisfactory than those in TASC A to C lesions [
27]. This result should be considered in clinical treatment, and therefore, long-lesion studies including TASC D lesions are of clinical value. Furthermore, there were also some other potential predictors of primary patency, such as female sex, obesity, lesion length and severe calcification, which were found in other studies but they require confirmation by additional clinical data [
28,
29].
Since a meta-analysis reported an increased risk of death following DCBs use in femoropopliteal artery disease [
10], the safety of DCBs has remained a hot topic. Other studies, however, have come to a different conclusion. Gray WA et al. found no significant difference in all-cause mortality between DCB and PTA over 3 years, and Schneider PA et al. obtained the same results through 5 years, comparing patients with similar characteristics [
11,
30]. In this study, the rate of all-cause death up to 1 year was 2.8% (n = 3 of 109), and none of the deaths were attributable to the DCBs. Our results suggest that DCB applications are safe in long femoropopliteal artery lesions at 1 year, similar to those of other safety studies [
11,
30,
31]. Longer-term safety results need to be confirmed by further follow-up.
Study limitations
This study is single-arm and not randomized, so we cannot compare the effectiveness of DCBs with other treatments on long femoropopliteal lesions, and selection bias is inevitable. The sample size was not large since not all patients with long lesions were treated with DCBs and many were treated with plain stents or DESs, but we increased the sample size through a multicentre study. The patients included were all Asian, and the applicability of the results to different racial groups requires further study. In addition, since the patients are from different cities and usually live far away from the research centres, longer-term follow-up is difficult.
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