Orchid drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of femoropopliteal artery disease: 12-month result of the randomized controlled trial

Abstract

Purpose

To assess the efficacy and safety of the Orchid drug-coated balloon (coated with paclitaxel) for the treatment of femoropopliteal artery disease versus percutaneous transluminal angioplasty in Chinese population.

Methods

This is a prospective, single center, single-blinded, randomized controlled trial that randomized (1:1) 60 patients (38 men; mean age 68.7 ± 8.8) to drug-coated balloon group (n = 30) or percutaneous transluminal angioplasty group (n = 30). The primary efficacy endpoint was primary patency of the target lesion and clinically driven target lesion revascularization (CD-TLR) at 12 months. The primary safety end point was freedom from perioperative death at 30 days and freedom from limb-related death and major amputation at 12 months.

Results

Baseline characteristics were similar between the two groups. Drug-coated balloon group resulted in higher primary patency (82.8% vs. 48.3%, p = 0.005) and lower CD-TLR rates (3.5% vs. 27.6%; p = 0.001) versus percutaneous transluminal angioplasty group at 12 months. The ABI was significantly higher in drug-coated balloon group than percutaneous transluminal angioplasty group (0.86 ± 0.13 vs. 0.72 ± 0.18, p = 0.025). There were no perioperative death at 30 days, no limb-related death and no major amputation at 12 months in either group.

Conclusions

The randomized controlled trial showed superior treatment effect with drug-coated balloon versus percutaneous transluminal angioplasty, with remarkably higher patency and lower CD-TLR rates. The result is consistent with other study and demonstrates the safety and efficacy of the Orchid drug-coated balloon for the treatment of femoropopliteal artery disease.

Keywords

Femoropopliteal artery disease percutaneous transluminal angioplasty drug-coated balloon paclitaxel randomized controlled trial

Endovascular intervention has become the primary method of revascularization for superficial femoral and popliteal (femoropopliteal) artery disease.¹ Although percutaneous transluminal angioplasty (PTA) is effective in initially restoring blood flow, the rate of postoperative restenosis is as high as 60% because of neointimal proliferation.² Self-expanding nitinol stents have shown superior efficacy over PTA in the femoropopliteal artery disease,^3,4 but the dynamic stresses applied by the femoropopliteal artery may result in stent fracture^5,6or stent stenosis,⁷ so the optimal treatment method for femoropopliteal artery disease remains controversial.

Drug-coated balloon (DCB) offers a reliable approach for the prophylactic delivery of a high local concentrations of antiproliferative drugs to the artery wall,⁸ while the overall dose of paclitaxel is less than the levels that would cause systemic adverse effects.⁸ Some evidence has demonstrated the utility of different DCBs in reducing both restenosis and the need for reintervention in comparison with PTA,^9–11 but for different products, different ethnic groups, the therapeutic effect of DCBs may be different, and results from studies of a device are not generalizable to another. In the present trial, the efficacy and safety of the Orchid DCB versus standard PTA for the treatment of femoropopliteal artery disease were evaluated in a Chinese population.

Methods

Study design

Orchid China is a prospective, single center, single-blinded, randomized controlled trial (RCT) aimed at evaluating the efficacy and safety of the Orchid DCB (Acotec Scientific, Beijing, China) compared with PTA for the treatment of femoropopliteal artery disease in Chinese patients. The study was approved by local ethics committees, and was conducted in accordance with the Declaration of Helsinki, and applicable laws as specified by China government authorities. All patients signed informed consent. An independent clinical events committee (CEC) adjudicated the major adverse events, and an independent laboratory analyzed all ultrasonography and angiography images. The trial was registered on Chinese Clinical Trial Registry website (chictr.org.cn identifier ChiCTR1900023619).

Inclusion criteria

The main inclusion criteria were 18 to 85 years patients with de novo stenosis ≥70% or occlusion lesions between 40 and 200 mm long in the femoropopliteal artery, artery diameter at 4 to 8 mm, Rutherford category 2 to 5 in the target limb, and at least 1 non occluded vessel runoff to the foot.

Exclusion criteria

Key exclusion criteria were: (1) acute or subacute thrombus or aneurysm in the target vessel; (2) the guidewire failed to cross the target lesion; (3) severe flow-limiting dissections (≥grade D) or residual stenosis >70% are generated after predilation; (4) serum creatinine >2.5 mg/dL; (5) allergy to aspirin, heparin, clopidogrel, paclitaxel, or contrast agent; (6) patients with bilateral lower limb lesions need to be treated at the same time; (7) prior bypass surgery or stent implantation of the target vessel; (8) planned amputation of the target limb; and (9) life expectancy <1 years.

Sample size

A patency difference of 10% was considered to be clinically significant. Aiming at a 12-month primary patency of 80% in the DCB group and 50% in the PTA group, it was calculated that a sample size of 28 in each group was necessary, with a beta of 70% and alpha of 10%. Anticipating a loss to follow-up level of 5% to 10%, we planned to recruit at least 30 patients for each group.

Patient enrollment and randomization

After guidewire successful crossing of the lesion and predilation with a PTA balloon 1 mm smaller than the target vessel diameter, the patient was randomized into the study. Sixty patients were enrolled from June to August 2019 in our vascular surgery center, which were randomly assigned in a 1:1 ratio to two groups treatment with DCBs (Study group, Orchid DCB, n = 30) or uncoated balloons (Control group, Admiral Xtreme, n = 30) (Figure 1).

Figure 1.

Patients flow diagram.

Study device

Patients randomized to the study group were treated with Orchid DCBs, which were coated with paclitaxel at a dose of 3.0 μg/mm² in a urea excipient. Uncoated Admiral Xtreme balloons (Medtronic Inc.) were used in the control group.

Study procedures

Clopidogrel (75 mg/day) and aspirin (100 mg/day) were started three days before the treatment, then 75 mg/day clopidogrel was given for at least six months, and 100 mg/day aspirin was continued for life. The heparin dose during the treatment was 0.5 mg/kg body weight and, if required, an additional half dose was used repeatly.

After CTA or MRA suggestive of symptomatic femoropopliteal artery disease, patients underwent angiography by means of femoral access with the use of 6 F sheaths. After successful crossing of the femoropopliteal artery lesion, predilation with a standard balloon which was 1 mm smaller than the target vessel was performed immediately. Repeat angiography was then performed, and patients with flow-limiting dissections (≥grade D) or residual stenosis >70% were excluded from the study. The randomization sequence was computer generated, which were only opened after angiographic confirmation that the patient met all inclusion criteria and none of the exclusion criteria. Patients were randomly assigned in a 1:1 ratio to two groups treatment with DCBs or uncoated balloons, respectively.

The treating physicians were aware of the treatment choice because the DCBs looked different from uncoated balloons. However, according to the study protocol, the patients, follow-up investigators, laboratory personnel and evaluators, and members of the CEC were unaware of the treatment choices.

After randomization, the target vessels were dilated with either the DCBs (study group) or uncoated balloons (control group) based on the randomization sequence. The balloon length was selected to exceed 1 cm beyond the edge of the lesion. If more than two balloons were needed, the overlap zone should be at least 1 cm. Dilation time was 120 s at an 8 to 12 atm pressure. To control trail bias, provisional stenting in either group was allowed only in case of severe flow-limiting dissection (≥grade D).

Device success was defined as successful balloon expansion at the target lesion and withdrawal of the balloon with attainment of <30% residual stenosis by quantitative angiography. Procedural success was defined as a residual stenosis ≤50% for nonstented patients or ≤30% for stented patients.

Follow-up

Patients were followed after treatment at 30 days, 6 months, and 12 months, including ankle-brachial indexes (ABI), duplex ultrasonography, and assessments of quality-of-life use questionnaires.

Study end points

The primary efficacy endpoint was primary patency of the target lesion and clinically driven target lesion revascularization (CD-TLR) at 12 months, primary patency defined as freedom from CD-TLR or restenosis. CD-TLR was defined as reintervention at the target lesion due to symptoms deterioration. Restenosis was defined as a reduction in the luminal diameter >50% or peak systolic velocity ratio of ≥2.4 by duplex ultrasonography.¹² The primary efficacy end point was independently adjudicated by the blinded CEC (for CD-TLR) and by the laboratory (for restenosis).

The primary safety end point was freedom from perioperative death at 30 days and freedom from limb-related death and major amputation at 12 months.

The primary functional end point included walking impairment questionnaire (WIQ),¹³ quality-of-life measures (EQ-5D),¹⁴ and 6-min walking test.¹⁵

Statistical analysis

Continuous variables were expressed by mean ± standard deviation, and were compared by unpaired Student’s t test. Categorical variables were expressed by frequencies and percentages and compared using Chi-square test. Survival analysis was performed on the days from randomization to first event using the Kaplan–Meier method. The difference in the survival curves between groups was assessed using the log-rank test. All statistical analysis was performed at a two-sided significance level of 0.05. Statistical analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA).

Results

Baseline and procedure characteristics

During the study period, 60 patients (38 men; mean age 68.7 ± 8.8) were randomized, 30 patients to DCB group and other 30 patients to PTA group. There were no significant differences in patient populations between the two groups (Table 1).

Table 1.

Baseline patient and lesion characteristics.

	DCB (n = 30)	PTA (n = 30)	p value
Age (year)	69.2 ± 9.0	68.3 ± 8.6	0.452
Sex (M/F)	18/12	20/10	0.789
Hypertension, % (m/n)	83.3 (25/30)	90.0 (27/30)	0.706
Diabetes mellitus, % (m/n)	46.7 (14/30)	53.3 (16/30)	0.797
Hyperlipidemia, % (m/n)	80.0 (24/30)	73.3 (22/30)	0.761
Coronary artery disease, % (m/n)	46.7 (14/30)	40.0 (12/30)	0.795
Carotid artery disease, % (m/n)	20.0 (6/30)	26.7 (8/30)	0.761
Current smoker, % (m/n)	36.7 (11/30)	46.7 (14/30)	0.601
Obesity (BMI ≥30 kg/m²), % (m/n)	0 (0/30)	3.3 (1/30)	1.000
ABI	0.54 ± 0.12	0.50 ± 0.13	0.372
Lesion length (cm)	9.12 ± 8.09	9.26 ± 8.03	0.560
Reference vessel diameter(mm)	4.98 ± 0.89	4.76 ± 0.96	0.116
Diameter stenosis (preprocedure), %	83 ± 10	85 ± 9	0.723
Total occlusions, % (m/n)	63.3 (19/30)	66.7 (20/30)	0.779
Calcification	53.3 (16/30)	46.7 (14/30)	0.797
TASC II classification, % (m/n)			0.801
A	33.3 (10/30)	26.7 (8/30)
B	40.0 (12/30)	40.0 (12/30)
C	26.7 (8/30)	33.3 (10/30)
Runoff, % (m/n)			0.701
1	20.0 (6/30)	16.7 (5/30)
2	63.3 (19/30)	50 (15/30)
3	16.7 (5/30)	33.3 (10/30)
Rutherford class, % (m/n)			0.838
2	20.0 (6/30)	26.7 (8/30)
3	40.0 (12/30)	33.3 (10/30)
4	33.3 (10/30)	36.7 (11/30)
5	6.7 (2/30)	3.3 (1/30)

DCB: drug-coated balloon; PTA: percutaneous transluminal angioplasty; BMI: body mass index; ABI: ankle-brachial index; TASC: TransAtlantic Inter-Society Consensus II.

There was no difference in procedure characteristics among the groups (Table 2). Postdilation was performed 20.0% in the DCB group and 26.7% in the control group (p = 0.761). Provisional stenting was performed 3.3% in the DCB group and 6.7% in the control group (p = 0.554). Flow-limiting dissections (≥grade D) were generated 3.3% in the DCB group and 0% in the control group (p = 0.592). Diameter stenosis (postprocedure) 15.4 ± 4.7% in the DCB group and 15.8 ± 5.2% in the control group (p = 0.542).

Table 2.

Procedure characteristics.

	DCB group (n = 30)	PTA group (n = 30)	p value
Predilation, % (m/n)	100 (30/30)	100 (30/30)	>0.999
Postdilation, % (m/n)	20.0 (6/30)	26.7 (8/30)	0.761
Provisional stenting, % (m/n)	3.3 (1/30)	6.7 (2/30)	0.554
Dissections			0.592
0	33.3 (10/30)	36.7 (11/30)
A–C	63.3 (19/30)	63.3 (19/30)
D–F	3.3 (1/30)	0 (0/30)
Diameter stenosis(postprocedure), %	15.4 ± 4.7	15.8 ± 5.2	0.542
Device success, % (m/n)	100 (30/30)	100 (30/30)	>0.999
Procedural success, % (m/n)	100 (30/30)	100 (30/30)	>0.999

Efficacy outcomes

Procedural success was achieved in 100% in both groups. During the period between treatment and 12-month follow-up, 1 patient in each group was lost to follow-up, so 96.7% patients completed the 12-month follow-up in both groups (Figure 1). In the intention-to-treat population, the primary patency rate at 12 months was significantly higher with DCB group than PTA group (82.8% vs. 48.3%, p = 0.005; Table 3). The Kaplan–Meier estimate of primary patency was 83.3% for DCB compared to 50.0% for PTA (p = 0.005; Figure 2). The DCB group demonstrated lower rates of CD-TLR versus PTA group through 12 months (3.5% vs. 27.6%; p = 0.001; Table 3). The ABI was significantly higher in DCB group than PTA group (0.86 ± 0.13 vs. 0.72 ± 0.18, p = 0.025; Table 3)

Table 3.

Efficacy, safety and functional outcomes at 12 months.

	DCB (n = 30)	PTA (n = 30)	p value
12-month efficacy outcomes
Primary efficacy-primary patency, % (m/n)	82.8 (24/29)	48.3 (15/29)	0.005
CD-TLR, % (m/n)	3.5 (1/29)	27.6 (8/29)	0.001
ABI	0.86 ± 0.13	0.72 ± 0.18	0.025
12-month safety outcomes
30-day perioperative death, % (m/n)	0.0 (0/30)	0.0 (0/30)	>0.999
Target limb major amputation, % (m/n)	0.0 (0/29)	0.0 (0/29)	>0.999
Limb related death, % (m/n)	0.0 (0/29)	0.0 (0/29)	>0.999
12-month functional outcomes
Walking impairment, %	70.9 ± 25.3	71.8 ± 27.8	0.825
Change from baseline by EQ-5D Index	0.092 ± 0.142	0.085 ± 0.147	0.787
Change in 6MWT from baseline to 12 mo, m	40 ± 66	48 ± 73	0.624

TLR: target lesion revascularization; CD-TLR: Clinically driven target lesion revascularization; EQ-5D: 5-dimension health-related quality-of-life questionnaire; 6MWT: 6-min walk test.

Figure 2.

Kaplan–Meier estimates of primary patency at 12 months. The line 1 shows 83.3% patency rate for the DCB group; The line 2 shows 50.0% patency rate for the PTA group (p = 0.005).

Safety outcomes

There were no perioperative deaths, no limb-related death, and no major amputations through 12 months in either group.(Table 3). There were no paclitaxel-related adverse effects as determined by the CEC.

Functional outcomes

At 12 months, both groups showed similar improvement from baseline in all functional outcomes assessed, including WIQ, EQ-5D, and 6-min walk test. The walking impairment was 70.9 ± 25.3% for DCB group versus 71.8 ± 27.8% for PTA group (p = 0.825). The mean change in the EQ-5D index from baseline to 12 months was 0.092 ± 0.142 for DCB group versus 0.085 ± 0.147 for PTA group (p = 0.787). The improvement in walking distance was 40 ± 66 m for DCB group versus 48 ± 73 m for PTA group (p = 0.624).

Discussion

Prevention of restenosis remains a major challenge in the treatment of femoropopliteal artery disease. Paclitaxel has proven to inhibit neointimal growth and thus reduce restenosis after PTA. Several randomized trials have shown that there was significantly better primary patency at 12 months following treatment with the DCB than uncoated balloons.^11,16–18 DCB performance and pharmacokinetic profiles differ because of differences in the balloon platform, excipients, drug concentrations, coating morphology, drug solubility, and coating methods,¹⁹ so each DCB has to be evaluated separately and outcomes from one cannot be generalized to another. Furthermore, pathophysiological differences in the presentation of femoropopliteal artery disease have been reported between ethnic groups, which may adversely impact response to treatment,²⁰therefore the results of the former trials are difficult to account of the significant heterogeneity in the study populations. We designed the RCT to evaluate the efficacy and safety of the Orchid DCB in a Chinese population.

The data from the present trial showed that in Chinese patients of femoropopliteal artery disease, Orchid DCB had a greater primary patency and fewer CD-TLR compared to those treated with an uncoated balloon at 12-month follow-up. In terms of safety outcomes, no difference was observed between the two groups in the incidence of death, limb amputation, and paclitaxel-related adverse effects.

Provisional stenting was as low as 3.3% in DCB group and 6.7% in control group. Optimal PTA technique and features of the trial design, including the patients with flow-limiting dissections (≥grade D) or residual stenosis >70% were excluded from randomization after predilation, and resulted in a low rate of stent use. This was different from many other DCB trails, in which the rates of provisional stenting ranged from 14 to 50%.^3,7,9,16 In addition, the use of prolonged balloon inflations may have contributed to the low provisional rate we observed.

Interestingly, the rate of provisional stenting in the DCB group in all RCTs was lower than in the control group (4% vs. 22% for Thunder,⁹ 9% vs. 14% for FemPac,¹⁰ 20.5% vs. 34% for Pacifier,¹¹ 3% vs. 16% for Levant-I,²¹ and 6.7% vs. 26.7% for BIOLUX P-I²²) as seen in our trail (3.3% vs. 6.7%). This might reflect the higher trust in the potency superior outcomes of DCBs compared with uncoated balloons.

Many methods are available for the treatment of femoropopliteal artery disease, which are divided into two main categories: implant-based technologies such as bare metal stents²³ and drug-eluting stents;³ implant-free technologies such as atherectomy devices²⁴ and DCBs. DCBs are an attractive alternative because it improved primary patency in comparison with uncoated balloons and a reduction in the need for stents. In-stent restenosis is not only frequent but also difficult to treat. So DCBs can leave the door open to future treatment options, especially in those patients with a long life expectancy.

Limitations

The trial enrolled only a limited number of patients and restricted to Chinese patients and thus is not generalizable to other patient populations. In addition, further studies may compare the DCBs with other therapeutic options, such as atherectomy, bare-metal stents, or drug eluting stents. Longer term follow-up is needed to confirm the durability of the benefit.

Conclusions

Results from the RCT showed superior treatment effect with DCB versus PTA, with remarkably higher patency and lower CD-TLR rates. These results are consistent with other former DCB trials and demonstrate the safety and efficacy of this Orchid DCB for the treatment of femoropopliteal artery disease.

Footnotes

Authors’ contributions

Chuan-jun Liao: Conception and design, analysis and interpretation, data collection, writing the manuscript, statistical analysis.

Sheng-han Song: Analysis and interpretation, data collection.

Tan Li: Analysis and interpretation, data collection.

Yang Zhang: Analysis and interpretation, data collection.

Wang-de Zhang: Data collection, statistical analysis.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Chuan-Jun Liao

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