Drug-Coated Balloon for the Treatment of Small Vessel Coronary Artery Disease　― A Randomized Non-Inferiority Trial ―

Abstract

Background: Drug-coated balloons (DCB) have shown promising results for the treatment of in-stent restenosis (ISR) and small vessel disease (SVD). However, data comparing the treatment efficacy of different DCBs are limited.

Methods and Results: AGENT Japan is a prospective randomized controlled trial that compares the Agent balloon coated with a low-dose formulation of paclitaxel (2 μg/mm²) to the SeQuent Please paclitaxel-coated balloon (3 μg/mm²) for the treatment of SVD. Patients with target lesion length ≤28 mm and reference diameter between ≥2.00 and <3.00 mm were randomized 2 : 1 for treatment with Agent (n=101) or SeQuent Please (n=49). This trial also includes a separate single-arm substudy evaluating the clinical safety and effectiveness of Agent in patients with ISR. The primary endpoint of 6-month target lesion failure (TLF) was observed in 3.0% of Agent and 0.0% of SeQuent Please patients (difference=3.0%; 97.5% upper confidence bound [UCB]=9.57%, which is less than the prespecified margin of 13.2%; P_{non-inferiority}=0.0012). There were no deaths or thrombosis, and angiographic and quality-of-life outcomes were comparable between groups. The AGENT Japan ISR substudy (n=30) primary endpoint was met because the one-sided 97.5% UCB for 6-month TLF (3.3%) was significantly less than the study success criterion of 15.1% (97.5% UCB=9.8%; P<0.0001).

Conclusions: Data from this study demonstrate good clinical outcomes with the Agent DCB when used to treat patients with SVD or ISR.

Drug-eluting stents (DES) are commonly used in patients presenting with coronary lesions, including small vessels (SV). However, percutaneous coronary intervention (PCI) of SV is clinically challenging due to vessel size and difficulties with device delivery. There is also an increased risk of restenosis and major adverse cardiovascular events (MACE) after stenting.^1,2

Management of in-stent restenosis (ISR) with DCBs is gaining widespread attention due to its ability to homogeneously transfer an antiproliferative drug to the affected artery without using a permanent metal implant.^3–5 This subsequently may reduce the associated risk of thrombosis, and allow for a shorter duration of dual antiplatelet therapy (DAPT) in patients who are at a high risk of bleeding.⁶ Over the past decade, the use of DCB in patients with ISR and SV disease (SVD) has shown promising results.^7,8 Due to mounting evidence, the German⁹ and Asia Pacific¹⁰ consensus groups recommend DCB treatment for ISR, de novo lesions in small coronary arteries, and bifurcation lesions. Moreover, the third report of the International DCB Consensus group recently updated guidelines to include a DCB-only approach as a valid treatment alternative to DES for SVD.¹¹

Agent (Boston Scientific Corporation), a percutaneous transluminal coronary angioplasty device, consists of a semicompliant balloon coated with paclitaxel blended in an inactive excipient. There are limited data comparing clinical outcomes in patients with SVD undergoing treatment with 2 different DCBs. The aim of the present study was to investigate the safety and efficacy of the Agent DCB in Japanese patients with SVD and ISR.

Methods

Study Design and Patient Selection

AGENT Japan is a prospective multicenter single-blinded randomized controlled study comparing the long-term clinical and safety outcomes of the Agent and SeQuent Please (B. Braun Melsungen AG) paclitaxel-coated balloons for the treatment of SV de novo native lesions. This trial also includes a separate single-arm substudy with the objective of establishing the safety and effectiveness of Agent in patients with ISR of a lesion previously treated with either a DES or bare metal stent (BMS).

Briefly, patients aged ≥20 years with a target lesion located in a native coronary artery (SV study) or ISR of a previously treated lesion (ISR substudy) that was ≤28 mm in length were enrolled. Eligible patients had a reference vessel diameter (RVD) between ≥2.00 and <3.00 mm for the SV study and between ≥2.00 and ≤4.00 mm for the ISR substudy, as well as visually estimated target lesion stenosis ≥75 and <100%. Patients with left main disease, saphenous vein or arterial graft disease, complex bifurcation, severe calcification, or thrombus in the target vessel were excluded. Patients who met the SV study selection criteria and underwent successful predilation of the target lesion were randomized 2:1 to Agent or SeQuent Please. Randomization was stratified by study site and a computer-generated list of random treatment allocations was used to assign subjects to treatments. Random permuted blocks of varying sizes were used to ensure an approximate balance of treatment allocation within each site.

This study was approved by the institutional review board at each site prior to enrollment and complied with the principles of the Declaration of Helsinki, Good Clinical Practice (GCP), Order for Enforcement of the Pharmaceutical and Medical Device Law and all applicable local and federal regulations. The AGENT Japan study is registered at ClinicalTrials.gov (ID: NCT04058990).

Device Description and Procedure

The Agent device consists of a semicompliant balloon catheter, which is coated with a low-dose formulation of paclitaxel (2 μg/mm²) blended with an inactive excipient acetyl-tri-n-butyl citrate (ATBC).¹² The control devices used in the SV study were the SeQuent Please and SeQuent Please Neo DCBs, which are coated with 3 μg/mm² paclitaxel in an X-ray contrast agent called iopromide. Sites were allowed to treat patients with SeQuent Please Neo only after its approval in Japan.

DAPT with aspirin and a P2Y₁₂ inhibitor was prescribed for a minimum of 3 months after the procedure. Clinical follow-up was required at hospital discharge, 30 days, 6 months, 1 year and then annually between 2 and 5 years after the index procedure. Protocol-specified coronary angiography was required at baseline and at the 6-month follow-up. An office visit is required for follow-up at 6 months and 1, 2, and 3 years. Follow-up at 30 days and 4 and 5 years may be performed via telephone interview if the subject is unable to return for an office visit.

Study Endpoints

The primary endpoint was the rate of target lesion failure (TLF) at 6 months after the procedure, defined as any ischemia-driven target lesion revascularization (TLR), myocardial infarction (MI; Q-wave and non–Q-wave) related to the target vessel, or cardiac death. Additional prespecified clinical endpoints of target vessel failure (TVF; a composite of ischemia-driven TVR, MI related to the target vessel, or cardiac death), all-cause death, MI (third universal definition),¹³ target vessel revascularization (TVR), and thrombosis related to the target lesion (Academic Research Consortium definition)¹³ will be evaluated through 5 years of follow-up. A clinical events committee reviewed and adjudicated all deaths, TVR, TLR, MI, and thrombosis related to the target lesion. The functional status of general health-related quality of life was measured by changes in EQ-5D scores at hospital discharge, 6 months, and 1, 2, and 3 years after the procedure.

Quantitative coronary analysis (QCA) was performed at baseline, post-procedure and at 6 months. Angiographic endpoints included minimum lumen diameter, late lumen loss, percentage diameter stenosis, and binary restenosis. An independent core laboratory evaluated all baseline and follow-up angiograms (Beth Israel Deaconess Medical Center, Boston, MA, USA). Technical success was defined as the ability to cross and dilate the lesion to achieve residual angiographic stenosis no greater than 30%, as confirmed by the angiographic core laboratory. Clinical procedural success was defined as technical success with no death or MI within 24 h of the index procedure.

Statistical Analysis

The primary endpoint of 6-month TLF in the SV study was powered for non-inferiority. Specifically, Agent would be considered non-inferior to SeQuent Please if the one-sided 97.5% upper confidence bound (UCB) for the difference in TLF between groups was <13.2% (non-inferiority margin). This corresponds to a P value of <0.025 from a 1-sided Farrington-Manning score test in the intention-to-treat (ITT) patient population. Assuming a 6-month TLF rate of 3.1% in both groups,¹⁴ an estimated 150 patients (100 Agent, 50 SeQuent Please) would provide ≥95% power to demonstrate non-inferiority with a margin of 13.2% and a 1-sided test significance level of 2.5%, while accounting for 3% attrition rate.

The AGENT Japan ISR substudy assessed the primary endpoint of 6-month TLF vs. a prespecified study success criterion of 15.1%, which was based on results from the SeQuent Please DCB Japanese study.¹⁵ A 1-group Clopper-Pearson exact test was used to test whether the 6-month TLF rate for the Agent device was less than the study success criterion. Given an expected TLF rate between 3% and 7% and a success criterion of 15.1%, a minimum of 30 patients was planned to be enrolled after adjusting for attrition (4%).

Cumulative event rates were evaluated by the Kaplan-Meier method. Continuous and discreet variables are reported as the mean±SD and as percentages (%), respectively. P values were obtained using Student’s t-test (continuous variables) and the Chi-squared or Fisher exact tests (discreet variables). Statistical analyses were conducted using SAS^® Version 9.2 (SAS Institute, Cary, NC, USA).

Results

SV Study

The AGENT Japan SV study enrolled 150 patients at 14 sites in Japan. Specifically, 101 subjects were randomized to the Agent DCB group and 49 to the SeQuent Please DCB group (Figure 1). Six-month clinical follow-up was completed in 99% of Agent and 100% of SeQuent Please DCB-treated patients.

Figure 1.

AGENT Japan enrollment and follow-up. *One subject was randomized to the SeQuent Please drug-coated balloon (DCB) but was treated with the Agent DCB due to investigative site error. ISR, in-stent restenosis; RCT, randomized control trial; SV, small vessel.

Baseline clinical and quantitative coronary angiographic lesion characteristics were well balanced between treatment arms (Table 1). The mean age was 68 years, and women accounted for 26% of Agent and 22% SeQuent Please patients (P=0.66). Diabetes was present in 36% and 35% of Agent and SeQuent Please patients, respectively (P=0.91). By QCA, mean RVD in the Agent arm was 2.19±0.37 mm, compared with 2.22±0.34 mm in the SeQuent Please arm (P=0.74). Mean lesion length in the Agent and SeQuent Please arms was 12.58±5.94 and 13.38±5.70 mm, respectively (P=0.44), and bifurcation lesions were present in 40% and 41% of subjects, respectively (P=0.89; Table 1).

Table 1. Baseline Clinical and Angiographic Characteristics

	Small vessel study			ISR substudy
	SeQuent Please (N=49 patients)	Agent (N=101 patients)	P value	Agent (N=30 patients)
Baseline characteristics
Male sex	77.6 (38)	74.3 (75)	0.66	86.7 (26)
Age (years)	67.73±10.38 (49)	68.37±10.62 (101)	0.73	68.50±11.71 (30)
BMI (kg/m2)	25.49±3.87 (49)	24.86±3.96 (101)	0.36	26.08±4.71 (30)
Medical history
Current smoker	10.2 (5)	21.8 (22)	0.08	20.0 (6)
Diabetes	34.7 (17)	35.6 (36)	0.91	43.3 (13)
Hyperlipidemia	95.9 (47)	88.1 (89)	0.15*	96.7 (29)
Hypertension	73.5 (36)	76.2 (77)	0.71	80.0 (24)
Coronary artery disease	65.3 (32)	56.4 (57)	0.30	100 (30)
Myocardial infarction	28.6 (14)	30.7 (31)	0.79	56.7 (17)
Previous PCI	61.2 (30)	57.4 (58)	0.66	100 (30)
Angina status
Stable	91.8 (45)	97.0 (98)	0.22*	96.7 (29)
Unstable	8.2 (4)	3.0 (3)	0.22*	3.3 (1)
Peripheral vascular disease	2.0 (1)	6.9 (7)	0.27*	10.0 (3)
Silent ischemia	10.2 (5)	5.1 (5)	0.30*	0.0 (0)
History of multivessel disease	57.1 (28)	47.5 (48)	0.27	60.0 (18)
Congestive heart failure	2.0 (1)	11.9 (12)	0.06*	10.0 (3)
NYHA classification
I	0.0 (0)	58.3 (7)	0.46*	66.7 (2)
II	100 (1)	8.3 (1)	0.15*	0.0 (0)
III	0.0 (0)	8.3 (1)	1.00*	33.3 (1)
IV	0.0 (0)	8.3 (1)	1.00*	0.0 (0)
Target lesion characteristicsA
No. lesions	49	101		30
Target vessel treated
LAD	22.4 (11)	27.7 (28)	0.49	60.0 (18)
LCx	51.0 (25)	42.6 (43)	0.33	16.7 (5)
RCA	26.5 (13)	29.7 (30)	0.69	23.3 (7)
RVD (mm)	2.22±0.34 (49)	2.19±0.37 (101)	0.74	2.63±0.59 (30)
MLD (mm)	0.71±0.27 (49)	0.70±0.28 (101)	0.87	0.96±0.45 (30)
DS (%)	68.02±10.52 (49)	68.23±10.95 (101)	0.91	64.15±12.01 (30)
Lesion length (mm)	13.38±5.70 (49)	12.58±5.94 (100)	0.44	15.27±6.41 (30)
<10	32.7 (16)	40.0 (40)	0.38	23.3 (7)
10–20	55.1 (27)	46.0 (46)	0.30	50.0 (15)
>20	12.2 (6)	14.0 (14)	0.77	26.7 (8)
Eccentric lesion	81.6 (40)	86.1 (87)	0.47	86.7 (26)
Bifurcation	40.8 (20)	39.6 (40)	0.89	30.0 (9)
Modified ACC/AHA B2/C	67.3 (33)	70.3 (71)	0.71	76.7 (23)
Pre-procedure TIMI flow 3	95.9 (47)	99.0 (100)	0.25*	96.7 (29)

Intention-to-treat analysis. Values are % (n) or the mean±SD. P values are 2-sided and from Student’s t-tests for continuous variables or the Chi-squared or Fisher’s exact (*) tests for discrete variables. ^AAs determined by the angiographic core laboratory. ACC/AHA, American College of Cardiology/American Heart Association; BMI, body mass index; DS, diameter stenosis; ISR, in-stent restenosis; LAD, left anterior descending; LCx, left circumflex; MLD, minimum lumen diameter; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; RCA, right coronary artery; RVD, reference vessel diameter; TIMI, Thrombolysis in Myocardial Infarction.

Periprocedural variables and post-procedural angiographic outcomes were similar between treatment arms (Table 2). Both technical and clinical success rates were 66.3% in the Agent arm and 77.6% in the SeQuent Please arm (P=0.16). Eleven (22.4%) patients in the SeQuent Please arm and 34 (33.7%) patients in the Agent arm had a post-procedure diameter stenosis >30% (core laboratory adjudicated), which was counted towards technical failure. Figure 2 shows the cumulative frequency distributions of in-lesion percentage diameter stenosis and late lumen loss. At 6 months, in-lesion binary restenosis occurred in 5.1% and 10.4% of patients in the Agent and SeQuent Please arms, respectively (P=0.30; Table 2), and in-lesion minimum lumen diameter was 1.72±0.38 and 1.65±0.41 mm (P=0.38), respectively. As indicated in Table 3, DAPT (aspirin plus a P2Y₁₂ inhibitor) use at 3 months was comparable between the Agent and SeQuent Please arms (87.1% vs. 93.9%, respectively; P=0.21). However, a significantly greater number of patients treated with SeQuent Please remained on DAPT at 6 months (59.4% vs. 77.6%; P=0.03).

Table 2. Procedural and Angiographic Outcomes

	Small vessel study			ISR substudy
	SeQuent Please (N=49 patients, 49 lesions)	Agent (N=101 patients, 101 lesions)	P value	Agent (N=30 patients, 30 lesions)
Procedural
Time from sheath placement to last guide catheter removal (min)	45.69±19.35 (49)	41.45±15.69 (101)	0.15	37.13±10.71 (30)
Pre-dilatationA (%)	100 (49)	100 (101)	Undef	100 (30)
Post-dilatationA (%)	0.0 (0)	1.0 (1)	1.00*	0.0 (0)
Study device deployment inflation timeA/device (s)	61.06±25.51 (54)	57.48±19.45 (101)	0.33	49.17±16.09 (30)
Maximum pressure overallA (atm)	12.65±3.63 (49)	11.40±3.06 (101)	0.03	14.77±4.90 (30)
Post-procedural
Technical success	77.6 (38)	66.3 (67)	0.16	93.3 (28)
Clinical procedural success	77.6 (38)	66.3 (67)	0.16	93.3 (28)
Technical failureB	22.4 (11)	33.7 (34)	0.16	6.7 (2)
RVD (mm)	2.21±0.34 (49)	2.21±0.36 (101)	0.95	2.64±0.58 (30)
MLD (mm)
In-lesion/in-stentC	1.67±0.30 (49)	1.69±0.33 (101)	0.73	2.10±0.46 (30)
In-segment	1.71±0.32 (49)	1.72±0.35 (101)	0.88	2.17±0.47 (30)
Acute gain
In-lesion/in-stentC	0.97±0.31 (49)	0.99±0.37 (101)	0.65	1.14±0.33 (30)
In-segment	1.00±0.34 (49)	1.02±0.38 (101)	0.79	1.22±0.37 (30)
DS (%)
In-lesion/in-stentC	23.63±13.23 (49)	23.04±10.51 (101)	0.77	20.26±6.88 (30)
In-segment	21.83±14.37 (49)	21.77±11.02 (101)	0.98	17.39±7.66 (30)
TIMI Flow 3	100 (49)	100 (101)	Undef	100 (30)
6 months
RVD (mm)	2.20±0.36 (48)	2.22±0.36 (99)	0.84	2.59±0.50 (29)
MLD (mm)
In-lesion/in-stentC	1.65±0.41 (48)	1.72±0.38 (99)	0.38	1.99±0.49 (29)
In-segment	1.70±0.41 (48)	1.75±0.40 (99)	0.47	2.04±0.50 (29)
Late loss (mm)
In-lesion/in-stentC	0.03±0.34 (48)	−0.03±0.34 (99)	0.31	0.07±0.29 (29)
In-segment	0.02±0.35 (48)	−0.04±0.36 (99)	0.33	0.10±0.32 (29)
DS (%)
In-lesion/in-stentC	24.52±16.03 (48)	22.34±12.91 (99)	0.38	23.34±10.27 (29)
In-segment	22.25±16.47 (48)	20.58±14.01 (99)	0.52	21.46±10.98 (29)
Binary restenosis
In-lesion/in-stentC	10.4 (5)	5.1 (5)	0.30*	3.4 (1)
In-segment	8.3 (4)	5.1 (5)	0.47*	3.4 (1)
TIMI Flow 3	100 (48)	100 (99)	Undef	100 (29)

Intention-to-treat analysis. Values are % (n) or the mean±SD. P values are 2-sided and from Student’s t-test for continuous variables or the Chi-squared or Fisher’s exact (*) test for discrete variables. ^ABy target lesion. ^BIncludes angiographic core laboratory-adjudicated post-procedure DS >30%. ^CIn-stent analysis (ISR substudy). Undef, undefined. Other abbreviations as in Table 1.

Figure 2.

Angiographic endpoints at 6 months determined using quantitative coronary angiography. Cumulative frequency distributions of (A) percentage diameter stenosis (in-lesion) and (B) late lumen loss (in-lesion) in the Agent drug-coated balloon (DCB) vs. SeQuent Please DCB groups before and after the procedure, and at 6 months.

Table 3. Antiplatelet Medications Through 6 Months

	Small vessel study			ISR substudy
	SeQuent Please (N=49 patients)	Agent (N=101 patients)	P value	Agent (N=30 patients)
Aspirin
Discharge	100.0 (49)	98.0 (99)	1.00*	100.0 (30)
30 days	98.0 (48)	95.0 (96)	0.66*	100.0 (30)
3 months	95.9 (47)	94.1 (95)	1.00*	96.6 (28)
6 months	89.8 (44)	77.2 (78)	0.06	89.7 (26)
DAPT
Discharge	98.0 (48)	95.0 (96)	0.66*	100.0 (30)
30 days	95.9 (47)	92.1 (93)	0.50*	100.0 (30)
3 months	93.9 (46)	87.1 (88)	0.21	96.6 (28)
6 months	77.6 (38)	59.4 (60)	0.03	75.9 (22)

Intention-to-treat subjects. Values are % (n). *P values are 2-sided from Fisher’s exact test; P values without an asterisk are from the Chi-squared test. DAPT, dual antiplatelet therapy (aspirin and one of clopidogrel, ticlopidine, prasugrel or ticagrelor); ISR, in-stent restenosis.

The AGENT Japan SV study primary endpoint was met: non-inferiority of Agent compared with SeQuent Please was demonstrated with a difference of 3.0% and a 1-sided 97.5% UCB of 9.57%, which was less than the prespecified non-inferiority margin of 13.2% (P_{non-inferiority}=0.0012). Specifically, TLF to 6 months was observed in 3 subjects treated with Agent and in none of the SeQuent Please-treated subjects in the ITT population (Figure 3). There were no differences in the rates of individual components of TLF through 6 months (Table 4). Additional clinical endpoints presented in Table 4 were low and comparable between arms. One patient in the Agent arm had a periprocedural MI related to the target vessel and underwent TLR; 2 additional patients underwent TLR that was treated with PCI (165 and 173 days after the index procedure). There were no deaths or thrombosis related to the target lesion in either treatment arm. Agent and SeQuent Please DCBs were associated with similar improvements in quality of life from baseline to 6 months, as assessed using the EQ-5D questionnaire (Supplementary Table 1).

Figure 3.

Primary endpoint of target lesion failure (TLF) at 6 months. (A) Non-inferiority of the Agent drug-coated balloon (DCB) to the SeQuent Please DCB in the AGENT SV Study. The plot on the right shows the difference in TLF between Agent and SeQuent Please (black circle) with the error bar indicating the 1-sided 97.5% upper confidence bound (UCB) The P value for non-inferiority testing is from the Farrington-Manning test. (B) TLF in the Agent DCB group of the in-stent restenosis (ISR) substudy was compared to a study success criterion of 15.1%. The 1-sided 97.5% UCB is indicated by the error bar. The 1-sided P value was calculated using Asymptotic test.

Table 4. Clinical Outcomes Through 6 Months

	Small vessel study			ISR substudy
	SeQuent Please (N=49 patients)	Agent (N=101 patients)	P value	Agent (N=30 patients)
Death	0.0 (0)	0.0 (0)	Undef	3.3 (1)
Cardiac death	0.0 (0)	0.0 (0)	Undef	3.3 (1)
Non-cardiac death	0.0 (0)	0.0 (0)	Undef	0.0 (0)
Myocardial infarction	0.0 (0)	1.0 (1)	1.00*	3.3 (1)
Q-Wave	0.0 (0)	0.0 (0)	Undef	0.0 (0)
Non Q-Wave	0.0 (0)	1.0 (1)	1.00*	3.3 (1)
Related to target vessel	0.0 (0)	1.0 (1)	1.00*	3.3 (1)
TVR	0.0 (0)	3.0 (3)	0.55	0.0 (0)
TLR	0.0 (0)	3.0 (3)	0.55	0.0 (0)
TLF	0.0 (0)	3.0 (3)	0.55	3.3 (1)
TVF	0.0 (0)	3.0 (3)	0.55	3.3 (1)
Thrombosis related to target lesion	0.0 (0)	0.0 (0)	Undef	0.0 (0)

Intention-to-treat subjects. Values are % (n). Time-to-event analysis: *P values are two-sided from Fisher’s exact test; P values without * are from the Chi-square test. Target vessel failure (TVF) was defined as the composite of any ischemia-driven target vessel revascularization (TVR), myocardial infarction related to the target vessel, or cardiac death. ISR, in-stent restenosis; TLF, target lesion failure; TLR, target lesion revascularization; Undef, undefined.

ISR Substudy

Thirty subjects were enrolled and treated with the Agent DCB at 9 sites in Japan. Clinical follow-up at 6 months was available for all patients (Figure 1). Baseline and lesion characteristics are presented in Table 1. Briefly, the mean age of subjects was 69 years, 13% were female, 43% had diabetes, and 57% had prior MI.

Angiographic core laboratory-adjudicated RVD was 2.63±0.59 mm and mean lesion length was 15.27±6.41 mm (Table 1). The ISR length was 11.03±4.68 mm; 67% and 33% of patients underwent first treatment for ISR of a lesion previously treated with a DES and BMS, respectively (Supplementary Table 2). As indicated in Table 2, both technical and clinical procedural success rates were high with Agent (93.3%). Six-month in-stent binary restenosis was 3.4%, late loss was 0.07±0.29 mm, and percentage diameter stenosis was 23.34±10.27%. DAPT usage decreased from 96.6% at 3 months to 75.9% at 6 months (Table 3).

The AGENT Japan ISR substudy primary endpoint of 6-month TLF was observed in 3.3% of Agent-treated patients and the 1-sided 97.5% UCB was 9.8%, significantly less than the study success criterion of 15.1% (P<0.0001; Figure 3). One patient had a non-Q-wave MI related to the target vessel 59 days after the procedure and died. This was adjudicated as a cardiac-related death. None of the patients experienced definite/probable thrombosis related to the target lesion through 6 months (Table 4). There were general improvements in quality of life scores from discharge to 6 months (Supplementary Table 3).

Discussion

AGENT SV is the first randomized trial comparing outcomes of Agent versus SeQuent Please paclitaxel-coated balloons in patients undergoing treatment for SVD. The data demonstrate non-inferiority of Agent to SeQuent Please for the primary endpoint of TLF at 6 months. There were no deaths or device thrombosis, and the rates of target vessel-related MI and TLR were not significantly different between treatment arms. Late lumen loss and binary restenosis rate were low and comparable at the 6-month angiographic follow-up. The substudy also met its primary endpoint of 6-month TLF and demonstrated good clinical outcomes among ISR patients treated with the Agent DCB.

DESs are used in the vast majority of PCI procedures. However, data from preclinical studies have shown that the permanent presence of a polymer may result in vascular inflammation and recurrent narrowing in the stented portion of the vessel.¹⁶ Permanently caging the affected artery with a metal implant may potentially disturb the normal anatomy and cause an inflammatory reaction to the polymer or stent struts. The risk of restenosis with DES increases further in SVD, which affects approximately one-third of patients with symptomatic coronary artery disease.^2,17 Over the past decade, angioplasty balloons coated with the antiproliferative drug paclitaxel have been used as an alternative therapeutic option in certain patient populations where stent implantation is not desirable or is potentially less effective. Treatment with a DCB may be particularly advantageous in patients at high bleeding risk, in whom a shorter duration of DAPT is desirable.¹⁸ Importantly, DCBs allow drug delivery without the need for a permanent metal implant and potentially reduce the proliferation of neointimal smooth muscle cells and associated complications (e.g., thrombosis).¹⁹ In the present study, Agent, with a drug dose density of 2 μg/mm², demonstrated comparable clinical safety and efficacy to the 3-μg/mm² paclitaxel dose in SeQuent Please in small coronary vessels. Moreover, angiographic and clinical outcomes data from the ISR substudy also showed favorable outcomes with Agent. In preclinical studies, Agent showed comparable vascular responses to Pantera Lux, which contains 3 μg/mm² paclitaxel blended in butyryl tri-hexyl citrate excipient.²⁰ In addition, paclitaxel tissue concentrations at the treatment site were equivalent, despite differences in the drug dose densities.²⁰ Data from preclinical testing conducted by Boston Scientific have shown equivalent safety and drug release profiles between Agent and SeQuent Please (unpubl. data). These data suggest that Agent, with its unique ATBC coating, can transfer sufficient paclitaxel into the vessel wall for the prevention of restenosis without causing toxicity.

Several studies have shown promising results with DCB in patients with ISR,^7,21 but randomized data for SV coronary lesions are limited. The BASKET-SMALL 2 (The Basel Kosten Effektivitäts Trial—drug-coated balloons versus drug-eluting stents in small vessel interventions) trial demonstrated non-inferiority of SeQuent Please DCB (paclitaxel eluting) compared with DES (everolimus or paclitaxel eluting) for the occurrence of 1-year MACE (8.0% vs. 8.0%; P=0.0217) and comparable rates of TVR (3.4% vs. 4.5%; P=0.4375).²² In the BELLO (Balloon Elution and Late Loss Optimization) trial, the 6-month TLR rate in the DCB arm was 4.4%,²³ consistent with the TLR rate of 3.3% reported here. The 1-year rates of TLR in the RESTORE SVD²⁴ (4.4%) and PICCOLETO II (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment)²⁵ (5.6%) trials were favorable in patients with SVD who were treated with a paclitaxel-eluting balloon, with no incidence of device-related thrombosis. In a recently conducted all-comer observational registry,²⁶ the primary endpoint of 1-year TLF was comparable between patients treated with a 2.0-mm DCB and those treated with a DES (7.0% vs. 8.2%; P=0.73). In addition, a meta-analysis that included data from 4 randomized trials and 3 observational studies demonstrated similar safety and efficacy of DCB vs. DES, as well as favorable outcomes compared with plain old balloon angioplasty (POBA), in patients with SVD.⁸ The rate of TLR was statistically significant with DCB vs. POBA (1.5% vs. 8.0% [P=0.03]; mean follow-up 7.0±1.5 months) and comparable with DES (5.5% vs. 5.9% [P=0.97]; mean follow-up 14.5±10.0 months).

The ISR substudy of AGENT Japan demonstrates good clinical outcomes following treatment with Agent in patients with ISR of a lesion previously treated with a stent. The 6-month angiographic endpoints are comparable to those reported in the Agent ISR randomized trial.²¹ Notably, there were no device-related thrombotic events in the Agent arm in either study. In a pooled analysis from 2 randomized (ISAR-DESIRE [Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis] 3 and ISAR-DESIRE 4) trials, Pantera Lux versus SeQuent Please paclitaxel-coated balloons showed similar rates of TLR (21.7% vs. 22.0% of patients; P=0.91; P_adjusted=0.93) and target lesion thrombosis (0.0% vs. 0.7%; P=0.34, P_adjusted=0.93) at 1 year, even after adjusting for baseline differences.²⁷

Study Limitations

The 6-month outcomes from the AGENT Japan SV study and ISR substudy demonstrate low rates of adverse cardiac events and no thrombosis with the Agent DCB. However, potential limitations to this study must be noted. The primary endpoint of 6-month TLF was met, but the SV study was not powered to detect differences in individual components of TLF. The moderately small sample size may have limited the ability to measure infrequent clinical adverse outcomes (e.g., thrombosis). In addition, the data do not necessarily apply to more complex patients, who were excluded from this study based on the protocol’s inclusion/exclusion criteria. The AGENT Japan substudy includes a non-randomized ISR patient cohort and uses a study success criterion; therefore, directly comparing these results to outcomes with other DCBs is challenging. Agent IDE, an ongoing multicenter randomized controlled trial, will further evaluate the safety and efficacy of the Agent DCB in patients with ISR.¹² Finally, current follow-up is limited to 6 months; longer follow-up data may better differentiate between the 2 DCBs with different structural design and paclitaxel doses.

Conclusions

AGENT Japan is the first randomized controlled trial comparing 2 different DCBs in patients with SVD. The data demonstrate non-inferiority of the Agent paclitaxel-coated balloon (2 μg/mm² paclitaxel) relative to SeQuent Please (3 μg/mm² paclitaxel) for the occurrence of 6-month TLF. In addition, procedural and clinical outcomes and quality of life scores were comparable between DCBs. The AGENT Japan ISR substudy showed good clinical outcomes in patients treated with Agent and met the prespecified primary endpoint at 6 months, with no incidence of thrombosis. These data support the safety and efficacy of the Agent DCB for the treatment of both de novo small vessels and ISR.

Acknowledgments

The authors thank Pooja Bhatt, PhD (Boston Scientific Corporation [BSC]) and Sachiyo Sato (BSC Japan K.K.) for assistance with manuscript preparation and trial management, respectively.

Sources of Funding

The AGENT Japan trial was sponsored and funded by Boston Scientific Corporation Japan K.K.

Disclosures

K.A. has received honoraria from Terumo, Japan Lifeline, Bristol Myers Squibb, Japan Medtronic, Abbott Medical Japan, and Biotronik Japan. J.S. has received honoraria from Abbott, Terumo, and Nipro. K.K. has received honoraria and research and scholarship grants from Boston Scientific Corporation (BSC) Japan K.K., and is a member of Circulation Journal’s Editorial Team. J.Y. has received honoraria from Abbott and endowments from Abbott, BSC Japan K.K., Medtronic, and Terumo. P.U. and D.J.A. are full-time employees and shareholders of BSC. The remaining authors have no conflicts of interest to disclose.

IRB Information

This study was approved by Mirai Iryo Research Center Inc. (Reference no. 024-19-07 and 012-19-02) and Tokyo Women’s Medical University Institutional Review Board (Reference no. NR1001).

Data Availability

The deidentified participant data for this clinical trial will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0584

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