Author + information
- Received April 25, 2018
- Revision received July 10, 2018
- Accepted July 24, 2018
- Published online December 3, 2018.
- Yongle Xu, MDa,∗,
- Xin Jia, MDa,∗,
- Jiwei Zhang, MDb,∗,
- Baixi Zhuang, MDc,∗,
- Weiguo Fu, MDd,∗∗ (, )
- Danming Wu, MDe,
- Feng Wang, MDf,
- Yu Zhao, MDg,
- Pingfan Guo, MDh,
- Wei Bi, MDi,
- Shenming Wang, MDj and
- Wei Guo, MDa,∗ ()
- aChinese PLA General Hospital, Beijing, China
- bRenji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- cXiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- dZhongshan Hospital Fudan University, Shanghai, China
- eThe People’s Hospital of Liaoning Province, Shenyang, China
- fThe First Affiliated Hospital of Dalian Medical University, Dalian, China
- gThe First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- hThe First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- iThe Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- jThe First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Objectives The authors sought to investigate the midterm efficacy and safety of drug-coated balloon (DCB) in the treatment of severe femoropopliteal artery disease (FPAD).
Background The midterm outcome of DCB versus uncoated balloon percutaneous transluminal angioplasty (PTA) for FPAD are still debated.
Methods A total of 200 Chinese patients with FPAD were prospectively randomized into treatment with DCB or with PTA. The primary efficacy endpoints were primary patency of the target lesion, freedom from clinically driven target lesion revascularization, improved ankle-brachial index, and improved Rutherford class at 24 months. The primary safety endpoint was the rate of major adverse events.
Results The DCB group and PTA group were comparable in demographic characteristics and clinical severity at baseline. At 24-month follow-up, primary patency was better in the DCB group versus PTA group (64.6% vs. 31.4%; p < 0.001). The DCB group had a higher rate of freedom from clinically driven target lesion revascularization than the PTA group (86.5% vs. 58.9%; p < 0.001). Rutherford class and ankle-brachial index also confirmed more improvements in the DCB group (p < 0.01 and p < 0.05, respectively). There was no significant difference in major adverse events.
Conclusions The superiority of DCB versus PTA in the efficacy of FPAD treatment persists at 24-month follow-up and the safety of DCB is equivalent to that of PTA.
- drug-coated balloon
- femoropopliteal artery disease
- midterm follow-up
- percutaneous transluminal angioplasty
The first randomized controlled trials comparing drug-coated balloon (DCB) angioplasty versus standard uncoated balloon percutaneous transluminal angioplasty (PTA) were conducted in Europe and in the United States (1–4). Most studies evaluated small groups of <100 patients and a mean length of femoropopliteal artery lesions ranging from 57 to 80 mm.
For patients with atherosclerotic femoropopliteal artery disease (FPAD), endovascular therapy is recommended as the standard regimen recommended by American College of Cardiology Foundation/American Heart Association for TransAtlantic Inter-Society Consensus (TASC) lesions type A (5) and European Society of Cardiology/European Society for Vascular Surgery for femoropopliteal artery stenosis/occlusions <25 cm (6). Nevertheless, there are many open questions: How does DCB angioplasty compare with PTA angioplasty in terms of midterm and long-term outcome and safety? How effective is DCB angioplasty in patients with lesion lengths >150 mm? Is DCB angioplasty safe in the Asian population (4–6)?
The present study was conducted to answer these questions by investigating a large Asian population with a high proportion of long femoropopliteal lesions and total occlusions over a longer follow-up period.
Study design and ethical approval
A detailed description of the AcoArt I (Prospective, Multi-center and Randomized Controlled Clinical Study to Verify Effectiveness and Safety of Drug-eluting Balloon in PTA Procedure) trial design, inclusion and exclusion criteria, and outcomes at 1 year have been published previously (7). This trial is registered at ClinicalTrials.gov with the number NCT01850056.
In accordance with the study protocol, patients with Rutherford class 2 to 5 symptoms and femoropopliteal artery lesions ≤40 cm, were randomly assigned (1:1) to treatment with either an Orchid paclitaxel-coated peripheral balloon catheter (Acotec Scientific, Beijing, China) or an Admiral Xtreme peripheral balloon catheter (Medtronic, Minneapolis, Minnesota) by a central randomization computer system. The Orchid DCB is coated with paclitaxel (3 μg/mm2) and a tiny amount of magnesium stearate as an effective lubricant and dispersing agent.
The trial was conducted in accordance with the Declaration of Helsinki and the provisions for the conduct of clinical trials of medical devices issued by the China Food and Drug Administration. The study was approved by the Chinese PLA General Hospital Ethics Committee and the local ethnics committees of participating hospitals. Patients were informed about the purpose, treatment, and conduct of the study and their rights to withdraw their consent at any time.
Treatment and endovascular interventions
Details of antiplatelet therapy and of the interventional procedures with coated and uncoated balloon catheters are present in an earlier article (7). Pre-dilation of the lesion with uncoated balloon catheters was not mandatory but recommended for both groups. Post-dilatation and bailout stenting was left to the discretion of the operators in case of an unsatisfactory primary result or flow-limiting dissection. Post-procedural therapy included aspirin and clopidogrel for 6 months. Aspirin or clopidogrel was recommended for each patient beyond 6 months, but the information on medication use between 2 groups was not collected systematically. Used balloon catheters were collected and analyzed for residual paclitaxel using high-performance liquid chromatography with ultraviolet detection (8).
All patients were followed up at 6 months, 12 months, and 24 months after the interventions. The 6-month angiographic images were evaluated by the quantitative angiography center at the Chinese PLA General Hospital Vascular Center. Readers were blinded to the type of balloon used for treatment (DCB vs. PTA). The vascular ultrasound examinations performed at 12-month and 24-month follow-up were evaluated by the specialists at each hospital, who were specifically trained for this study. The Department of Ultrasound of the Chinese PLA General Hospital finally checked all ultrasound images, again without being aware of whether DCB or PTA were used for treatment.
During the 24-month follow-up period, the most important efficacy endpoints were primary patency (PP) of the target lesion, freedom from clinically driven target lesion revascularization (CD-TLR), improvement of ankle-brachial index (ABI), and improvement of Rutherford class (RU). PP was defined as freedom from CD-TLR and freedom from restenosis, defined as duplex ultrasonography peak systolic velocity ratio >2.4. The primary safety endpoint was the occurrence of major adverse events (MAEs) (death from any cause, device- or procedure-related death, and major target limb amputation).
All continuous variables are expressed as mean ± SD, and categorical variables as frequencies or percentages. Differences between the study group (DCB) and control group (PTA) were analyzed using Student's t-test and the Wilcoxon signed rank test for continuous variables and the chi-square test and Fisher exact test for categorical variables (9). PP was assessed as a time-to-event outcome with Kaplan-Meier curves, and the long-rank test was applied to compare the differences between the DCB group and the PTA group. SAS software for Window 9.4 (SAS Institute, Cary, North Carolina) was used for statistical analysis, and p < 0.05 was accepted as indicating statistical significance.
A total of 200 patients were enrolled at 10 clinical hospitals across China from April 2013 through June 2014, and each patient was randomly assigned to the control arm of the study treated with conventional uncoated balloon (PTA) catheters and the investigational arm treated with a similar DCB catheter. By June 30, 2016, 24-month follow-up was completed in all participants. Some results on the efficacy and safety of DCB versus PTA at 6 months and 12 months have been published before (7). This paper focusses on midterm (24 months) results.
Baseline demographic and lesion characteristics in the DCB group and the PTA group
Overall, patients in the 2 groups were very similar, and there were no statistically significant differences in demographic and lesion characteristics (Table 1). A total of 96 patients in the DCB group and 95 patients in the PTA group completed 24-month follow-up, corresponding to a follow-up rate of 96% versus 95%, respectively.
The PP rate over the 24-month follow-up period was significantly higher in the DCB group than in the PTA group (64.6% vs. 31.4%; log-rank p < 0.001) (Figure 1).
Freedom from CD-TLR
At 24-month follow-up, freedom from CD-TLR was 86.5% in the DCB group versus 58.9% in the PTA group (log-rank p < 0.001) (Figure 2). Average times to first TLR were 312.7 ± 11.7 days and 177.6 ± 71.4 days, respectively (p < 0.001) (Table 2).
Improvement of ABI
We evaluated the ABI at 24 months for DCB versus PTA. ABI was 0.76 ± 0.29 in the DCB group and 0.63 ± 0.31 in the PTA group. There was a significant difference between the 2 groups, and the difference was 0.13 (t = 2.188; p = 0.033) (Table 2).
Improvement of RU
We applied Rutherford classification to evaluate the clinical state after angioplasty. At 24 months, the DCB group had significantly better clinical performance than the PTA group: mean RU was 2.00 ± 1.2 in the DCB group versus 2.50 ± 1.09 in the PTA group (chi-square = 25.24; p = 0.004) (Table 2).
Subgroup analysis on PP
During 24 months follow-up, there was a significant difference ln PP between the DCB group and the PTA group in most of the subgroup analyses (Table 3), such as diabetes mellitus, low age (<75 years), short lesion (<20 cm), total occlusion and critical limb ischemia [CLI] subgroup (p < 0.05). In some subgroup analyses, including female, high age (≥75 years), and long lesion (≥20 cm), the difference in PP between the 2 groups is obvious, but not significant, because the number of patients in the subgroup was too small to evaluate the p value.
Major adverse events
The incidence of combined MAEs was 9.4% in the DCB group and 9.5% in the PTA group at 24 months. There was no significant difference between the 2 groups (Table 4).
The present study of 200 patients confirms that the superior antirestenotic efficacy of DCB over PTA for FPAD persists over 24 months without a compromise in safety. This result is in accordance with the 24-month results of the THUNDER (Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries) trial (1,10), LEVANT I (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) trial (4), and IN.PACT SFA trial (Clinical Study for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery Using the IN.PACT Admiral™ Drug-Eluting Balloon in a Chinese Patient Population) (11,12). A comparison of PP rates at 24 months in these trials and the present study is presented in Figure 3. Outcomes and incidence of events are similar in our study and those major international trials. The data consistently show that drug-coated balloon catheters are superior to uncoated balloon catheters in improving blood supply in patients with fermoropopliteal lesions. For outcome in terms of CD-TLR, our results are also in agreement with those of other recent clinical trials (Figure 4), even though average ABI is poorer than that of other clinical trials. In our study, patients in the DCB group had few reinterventions compared with DCB patients in some previously published studies. One possible reason could be that our clinical trial recruited more CLI patients than other clinical trials. Absence of rest pain or tissue loss made the CLI patient less likely to receive reintervention. Another possible reason may be a difference in patient tolerability of ischemic symptoms of femoropopliteal artery disease between China and the United States/Europe, which may be the same reason of the difference on ABI baseline in patients between our trial and other recent trials (2–4,11,12). In China, most patients would not accept the intervention procedure until the ABI was <0.5. The better outcome in the DCB group in our study is also confirmed by improvements in ABI and in the RU after 24 months. Thus, our study confirms the results of the THUNDER trial and LEVANT I trial in a much larger patient population.
Another unique feature of our study is that mean femoral artery lesion length was 147 mm, which is longer compared with the lesions treated in recent trials: 75 mm in the THUNDER trial, 81 mm in the LEVANT I trial, and 89 mm at IN.PACT.SFA trial (1–4). The 24-month results confirm that our strategy is correct and feasible. The results in our patients with long lesions confirm the efficacy of paclitaxel in treating femoropopliteal lesions.
The PP rates at 24 months in both the DCB and PTA groups were significantly lower in this trial compared with prior trials such as the THUNDER, LEVANT 1, and IN.PACT SFA trials. The underlying mechanism could be related to differences in patient population (e.g., our study population has a great prevalence of smoking rates [29% to 33%] or diabetes [54% to 57%] and hypertension [62% to 72%], longer lesion length [147 to 152 cm], higher percentage of chronic total occlusions [52% to 57%], and other risk factors). Our subgroup analysis confirmed that DCB could bring inspiring outcome on PP compared with uncoated balloons, even in the long lesion, in-stent restenosis (ISR), and total occlusion subgroups. Limited by the total sample size, subgroup analysis is not powered to interpret significant differences.
The current 24-month clinical trial sheds some lights on the default therapy for the patients with long and complex femoropopliteal artery lesions, which puzzle peripheral operators today. Our study favors the application of DCB devices in long and complex SFA lesions over PTA. One recent network meta-analysis among the 2,912 patients with FPAD supports that DCB provides better reduction in TLR rates compared with PTA and stents (13). More clinical trials and the outcomes need to be accumulated to reach consensus on the default therapy for long and complex femoropopliteal artery lesions.
There was a potential observational bias in all 10 hospitals across China because the attending surgeons cannot be blinded to the type of balloon used (a paclitaxel-coated balloon has a different color). To overcome this bias, all angiographic images and main adverse events were evaluated by a core lab team unaware of the type of balloon used.
Although subgroups analyses also showed some advantage of DCB over PTA on the improvement of PP, those results should be interpreted with caution because this trial was not powered for individual subgroups.
We did not compare outcomes between the DCB and PTA groups in terms of censored walking distance. However, there is evidence that a significant improvement in the RU is highly related to objective improvement in walking distance and quality of life (14).
This study has followed up 200 patients with femoropopliteal artery disease over 24 months. PP was better in the group treated with drug-coated balloons, and this group also required fewer repeat interventions. Long-term patency and cost-effectiveness remain to be determined.
WHAT IS KNOWN? DCBs have shown favorable midterm outcomes compared with conventional PTA.
WHAT IS NEW? This clinical trial investigated the midterm outcomes of DCB on patients with more complex femoropopliteal lesions compared with other randomized controlled trials. Some important subgroups are analyzed to show the relevant outcomes with DCBs.
WHAT IS NEXT? For some specific lesions, such as ISR lesions, long lesions, total occlusions, future, large-scale randomized controlled trials would be carried out with DCBs, especially in Chinese patients with more complex baselines.
↵∗ Drs. Xu, Jia, Zhang, and Zhuang contributed equally to this work.
This study was supported by an unrestricted grant from Acotec. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- ankle-brachial index
- clinically driven target lesion revascularization
- critical limb ischemia
- drug-coated balloon
- femoropopliteal artery disease
- in-stent restenosis
- major adverse event(s)
- primary patency
- uncoated balloon percutaneous transluminal angioplasty
- Rutherford class
- Received April 25, 2018.
- Revision received July 10, 2018.
- Accepted July 24, 2018.
- 2018 American College of Cardiology Foundation
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