Cilostazol effectiveness in reducing drug-coated stent restenosis in the superficial femoral artery: The ZERO study.

PURPOSE: Drug-eluting stents (DESs) play an important role in endovascular therapy (EVT) for femoropopliteal (FP) lesions. Cilostazol improves patency after bare-metal nitinol stent (BNS) implantation for femoropopliteal lesions. This study aimed to establish whether cilostazol is effective in improving the patency of DESs and determine whether BNS or DESs with or without cilostazol are more effective in improving the 12-month patency after EVT for FP lesions.
MATERIALS AND METHODS: In this prospective, open-label, multicenter study, 85 patients with symptomatic peripheral artery disease due to de novo FP lesions were enrolled and treated with DESs with cilostazol from eight cardiovascular centers between April 2018 and May 2019. They were compared with 255 patients from the DEBATE SFA study, in which patients were randomly assigned to the BNS, BNS with cilostazol, or DES groups. The primary endpoint was the 12-month patency rate using duplex ultrasound (peak systolic velocity ratio < 2.5). This study was approved by the ethics committee of each hospital.
RESULTS: The 12-month patency rates for the BNS, BNS with cilostazol, DES, and DES with cilostazol groups were 77.6%, 93.1%, 82.8%, and 94.2%, respectively (p = 0.007). The 12-month patency rate was higher in the DES with cilostazol group than in the DES group (p = 0.044). In small vessels, the DES with cilostazol group had a higher patency rate than the DES group (100.0% vs. 83.4%, p = 0.023).
CONCLUSIONS: DES with cilostazol showed better patency than DES alone. Cilostazol improved patency after EVT with DES in FP lesions and small vessels. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (no. UMIN 000032473).

Introduction

Drug-eluting stents (DESs) play an important role in endovascular therapy (EVT) for femoropopliteal (FP) lesions. Advances in pharmaceutical technologies have improved the primary patency rate after EVT for FP lesions [1-4]. A recent trial comparing two well-established DESs showed a primary patency rate of 81%–86% at 12 months [5].

The effects of cilostazol in reducing the in-stent restenosis (ISR) rate of bare-metal nitinol stents (BNSs) for FP lesions are well recognized. Cilostazol reduces the ISR rate by nearly half in first-generation BNS and by 20% in second-generation BNS [6, 7]. Furthermore, post hoc analyses of the ZEPHYR study showed that cilostazol was strongly associated with a lower ISR rate within one year after DES implantation for FP lesions.

However, no prospective study has yet determined the efficacy of cilostazol in reducing the ISR rate of DESs for FP lesions. Furthermore, it is not known whether BNS or DES with cilostazol are more effective in reducing ISR after EVT for FP lesions. The Zilver PTX with cilostazol in the Superficial Femoral Artery (ZERO) trial was designed to address this gap in knowledge and to clarify 1) whether cilostazol is effective in reducing ISR of DES, and 2) which strategy is more effective in reducing the one-year ISR rate after EVT for FP.

Materials and methods

Study design

This was a prospective, open-label, multicenter study involving 85 patients with symptomatic peripheral artery disease due to de novo FP lesions enrolled from eight cardiovascular centers which participated DEBATE in SFA study between April 2018 and May 2019. Participants underwent stenting with a Zilver PTX stent and were treated with cilostazol (DES with cilostazol group). These patients were compared with 255 patients from the drug-eluting versus bare-metal stent implantation with or without cilostazol in the treatment of the superficial femoral artery (DEBATE SFA) study, as historical control data, in which between March 2014 and April 2016, 255 patients with symptomatic PAD due to de novo FP lesions were enrolled from 25 cardiovascular centers and randomly assigned to the BNS group (Misago stent implantation without cilostazol), BNS with cilostazol group (Misago stent implantation with cilostazol), or DES group (Zilver PTX stent implantation without cilostazol).

Written informed consent was obtained from all patients. This study was approved by the ethics committees of each participating hospital (Nagano municipal hospital 0033/2018.4.12; Shinshu university hospital 4186/2018.10.2; Nagano red cross hospital 155/2018.11.12; New Tokyo Hospital 0153-1/2018.5.28; Yamato seiwa hospital 00012/2018.6.4; Asahi general hospital 201851510/2018.5.15; Shinonoi general hospital H30-5/2020.12.21; Tokyo general hospital 64/2018.7.10) and was registered in University Hospital Medical Information Network Clinical Trials Registry, and was performed in accordance with the Declaration of Helsinki and its later amendments.

Participants

Patients with symptomatic claudication or rest pain (Rutherford 2–4) and de novo FP lesions were included. Patients with dual antiplatelet therapy after coronary DES implantation, severe heart failure precluding the use of cilostazol, FP lesion with inflow aortoiliac lesions, poor below-the-knee runoff (defined as < 1 below-the-knee runoff), anticoagulant treatment, bleeding tendency, or acute or sub-acute limb ischemia were excluded. These criteria were the same as those used in the DEBATE SFA study.

Post-procedural medical treatment

The enrolled patients (DES with cilostazol group) were treated with aspirin (100 mg/day) and cilostazol (200 mg/day) for 12 months and with clopidogrel (75 mg/day) for two months after EVT. In the DEBATE SFA study, the BNS group was treated with aspirin (100 mg/day) for 12 months and clopidogrel (75 mg/day) for one month, the BNS with cilostazol group was treated with aspirin (100 mg/day) and cilostazol (200 mg/day) for 12 months, and the PTX group was treated with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 12 months after EVT.

Endovascular procedure and lesion measurement

The decision on the approach site was left at the discretion of the physicians. In nearly all cases, a 6-French sheath was inserted into the femoral artery via the contralateral or ipsilateral approach. After 50–100 IU/kg of heparin infusion, the lesion was crossed with a 0.014- or 0.035-inch guidewire. The lesion was dilated with a semicompliant or noncompliant scoring balloon. The recommended stent size was 1 mm greater than the diameter of the distal vessel before stent implantation. Post-dilatation was performed using a noncompliant balloon with a size equivalent to the diameter of the distal vessel. The decision to use intravascular ultrasonography was made at the physician’s discretion.

The proximal and distal reference vessels and lesion length were measured from angiographic data.

Outcome assessment

Outcomes were assessed over a 12-month period. The primary outcome measure was the restenosis rate, which was determined by a peak systolic velocity ratio (PSV) ≥ 2.5 (we changed definition of PSV from >2.0 to ≥ 2.5 because that of almost all trial was ≥ 2.5 [8]), derived from duplex ultrasonography performed at the 1-, 3-, 6-, and 12-months follow-up visits. The secondary outcome measure was the occurrence of major adverse limb events (MALE), which was determined as a composite of limb-related death, target lesion revascularization (TLR), major amputation, major bleeding, and definite or probable stent thrombosis. In ISR patients, the Tosaka classification was applied to the different groups.

Statistical analysis

The sample size was estimated based on the binary restenosis rates from previous trial. An overall sample size of 90 patients was expected to have 80% power to detect a difference in 1-year ISR after Zilver PTX stenting with cilostazol compared with that without cilostazol at a 2-sided α of 0.05, assuming a binary restenosis rate of 30% in the Zilver PTX with cilostazol group and 50% in the Ziver PTX without cilostazol group. Finally, the sample size was determined 90 patients which is same as that of DEBATE SFA study. All analyses were based on the intention-to-treat principle. For baseline characteristics, continuous variables are presented as mean ± standard deviation or median (interquartile range) or percentages for dichotomous variables and were compared using the Student t-tests and chi-squared tests (asymptotic or Fisher’s exact test) for categorical variables. Statistical significance was set at p < 0.05. Primary end point were estimated at 12 months using the Kaplan-Meier method, and p-values were calculated using the log-rank test. Secondary endopoints were and estimated at 12 months using Cox proportional hazards regression models. Statistical analyses were performed using SPSS version 24 (IBM Corp., Armonk, NY, USA).

Results

Among the 85 patients, three without indication for EVT were excluded. A total of 82 patients in the DES with cilostazol group were compared with the DES (n = 85), BNS with cilostazol (n = 85), and BNS groups (n = 85) (Fig 1). Baseline and lesion characteristics were well matched among the four groups (Tables 1 and 2). Lesion characteristics across the four study groups showed many similarities: the median length of the treated segment was nearly 100 mm, 41% of the lesions were chronic total occlusion lesions, 37% of the lesions were Trans-Atlantic Inter-Society Consensus II (TASC II) C/D lesions, and 54% were found in small vessels (< 5 mm diameter). In addition, the frequency of involvement of the proximal superficial femoral artery (SFA) or popliteal artery and the distal reference vessel size were comparable among the four groups. Five (6.1%) patients died during the 12-month follow-up period in the DES with cilostazol group (1, 5, and 5 patients died in the BNS, BNS with cilostazol, and DES groups, respectively). Cilostazol treatment was continued for all patients during the 12-month follow-up period. Significant differences were found in the 12-month patency rate among the DES with cilostazol, DES, BNS with cilostazol, and BNS groups (94.2% vs. 82.8% vs. 93.1% vs. 77.6%, respectively, p = 0.007) (Fig 2).

Fig 1

Study flowchart.

Abbreviations: BNS, bare nitinol stent; DES, drug-eluting stent; EVT, endovascular therapy.

Table 1

Baseline characteristics.

Variables	BNS (n = 85)	BNS with cilostazol (n = 85)	DES (n = 85)	DES with cilostazol (n = 82)
Age (years)	73.4 ± 8.0	72.7 ± 9.1	73.1 ± 7.8	74.2 ± 9.7
Male (%)	55 (64.7)	57 (67.0)	60 (70.6)	52 (63.4)
Body mass index (kg/m2)	21.9 [19.7, 24.4]	21.6 [20.0, 23.8]	22.3 [20.1, 24.5]	23.1 [20.2, 24.8]
Hypertension (%)	73 (85.9)	69 (81.2)	68 (80.0)	64 (78.0)
Dyslipidemia (%)	49 (57.7)	52 (61.2)	52 (61.2)	49 (59.8)
Diabetes mellitus (%)	48 (56.5)	42 (49.4)	50 (58.8)	42 (51.2)
Insulin use (%)	13 (15.3)	16 (18.8)	16 (18.8)	15 (18.3)
Current smoker (%)	21 (24.7)	20 (23.5)	24 (28.2)	23 (28.1)
Previous smoker (%)	43 (50.6)	45 (52.9)	45 (52.9)	43 (52.4)
eGFR (mL/min/1.73 m2)	48.3 ± 28.5	49.3 ± 29.1	52.1 ± 28.1	43.4 ± 23.8
Hemodialysis (%)	19 (22.4)	17 (20.0)	17 (20.0)	15 (18.3)
Previous stroke (%)	20 (23.5)	15 (17.7)	19 (22.4)	11 (13.4)
CAD (%)	34 (40.0)	32 (37.7)	44 (51.8)	38 (46.3)
Previous heart failure (%)	1 (1.2)	6 (7.1)	6 (7.1)	12 (14.6)
LV dysfunction (%)	3 (3.5)	2 (2.4)	5 (5.9)	8 (9.8)
Previous bleeding (%)	0 (0.0)	3 (3.5)	4 (4.7)	3 (3.7)
Rutherford class III (%)	32 (37.6)	26 (30.6)	33 (38.8)	37 (45.1)
Rutherford class IV (%)	10 (11.8)	14 (16.5)	6 (7.1)	20 (24.4)
ABI at enrollment	0.65 [0.57, 0.75]	0.66 [0.58, 0.74]	0.68 [0.58, 0.77]	0.66 [0.56, 0.77]
Medication on discharge
Statins (%)	53 (62.4)	43 (50.6)	54 (63.5)	40 (48.8)
ACE I/ARBs (%)	55 (64.7)	44 (51.8)	45 (52.9)	43 (52.4)
β-blockers (%)	16 (18.8)	25 (29.4)	29 (34.1)	23 (28.1)
Ca-antagonists (%)	53 (62.4)	44 (51.8)	45 (52.9)	49 (59.8)
Procedure
Crossover (%)	44 (51.8)	45 (52.9)	46 (54.1)	33 (40.2)
Ipsilateral (%)	41 (48.2)	39 (45.9)	37 (43.5)	41 (50.0)
IVUS usage (%)	66 (77.7)	52 (61.2)	59 (69.4)	59 (72.0)
No. of stent implantations
1 (%)	51 (60.0)	47 (55.3)	43 (50.6)	54 (65.9)
2 (%)	27 (31.8)	31 (36.5)	25 (29.4)	15 (18.3)
3 (%)	6 (7.1)	6 (7.1)	15 (17.7)	5 (6.1)
4 (%)	1 (1.2)	0 (0.0)	1 (1.2)	0 (0.0)

Abbreviations: BNS, bare-metal nitinol stents; DES, drug-eluting stents; eGFR, estimated glomerular filtration rate; CAD, coronary artery disease; LV, left ventricular; ABI, ankle-brachial index; ACE-I, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; IVUS, intravascular ultrasonography.

Data are shown as the mean ± SD, median [interquartile range], or n (percentages).

Table 2

Lesion characteristics.

Variables	BNS (n = 85)	BNS with cilostazol (n = 85)	DES (n = 85)	DES with cilostazol (n = 82)	p-value
TASC IIC/D (%)	33 (38.8)	35 (41.2)	32 (37.7)	25 (30.5)	0.76
CTO (%)	31 (36.5)	33 (38.8)	43 (50.6)	31 (37.8)	0.45
Calcification (%)	49 (57.7)	50 (58.8)	49 (57.7)	33 (40.2)	0.29
Lesion length (mm)	96.0 [44.9, 184.0]	101.3 [45.6, 210.0]	110.5 [49.3, 249.0]	99.0 [58.8, 160.0]	0.72
Proximal diameter of the reference vessel (mm)	5.1 ± 1.1	5.3 ± 1.2	5.3 ± 1.0	5.5 ± 1.1	0.03
Distal diameter of the reference vessel (mm)	4.9 ± 0.9	5.2 ± 1.0	4.9 ± 0.8	5.0 ± 0.9	0.25
P1 involvement (%)	15 (17.7)	15 (17.7)	15 (17.7)	23 (28.1)	0.18
Proximal SFA involvement (%)	19 (22.4)	22 (25.9)	20 (23.5)	13 (15.8)	0.64
Number of below the knee runoffs, 1/2/3	26/39/20	23/42/18	19/37/27	35/26/13	0.034

Abbreviations: BNS, bare-metal nitinol stents; DES, drug-eluting stents; CTO, chronic total occlusion; P1, popliteal 1; SFA, superficial femoral artery; TASC, Trans-Atlantic Inter-Society Consensus.

Data are shown as the mean ± SD, median [interquartile range], n (percentage), or number per group (n/n/n).

Fig 2

Overall primary patency in all groups.

The 12-month patency rate differed significantly among the four groups (DES with cilostazol: 94.2% vs. BNS with cilostazol 93.1% vs. DES without cilostazol 82.8%, BNS without cilostazol 77.6%, p = 0.0007). Abbreviations: DES, drug-eluting stent; BNS, bare nitinol stent; DES, drug-eluting stent; S.E; standard error.

Comparison of the patency rate between the DES and DES with cilostazol groups

Overall, the 12-month patency rate was remarkably higher in the DES with cilostazol group than in the DES group (94.2% vs. 82.8%, p = 0.044) (Fig 3A). Furthermore, Cox proportional hazards regression models showed that cilostazol is independent predictor of reducing ISR in patients with DES adjusted by proximal diameter of the reference vessel and the below knee runoffs which factors are significantly difference between groups (HR 0.26, 95%CI 0.07–0.93; P = 0.038). MALE, all-cause death, TLR, and major bleeding were comparable between the two groups (Table 3).

Fig 3

Patency rate difference between the DES with and without cilostazol groups.

(A) Overall data. The 12-month patency rate was significantly higher in the DES with cilostazol group than in the DES group (94.2% vs. 82.8%, p = 0.044). (B) Patients with small-vessel lesions. The patency rate was significantly higher in the DES with cilostazol group than in the DES group (100.0% vs. 83.4%, p = 0.021). (C) Patients with TASC II C/D lesions. The DES with cilostazol group had a higher patency rate than the DES group, although this difference was not significant (100.0% vs. 85.7%, p = 0.101). Abbreviations: DES, drug-eluting stent; BNS, bare nitinol stent; TASC II, Trans-Atlantic Inter-Society Consensus II; S.E; standard error.

Table 3

Event rate at 1 year.

	DES+C (n = 82)	BNS (n = 85)	BNS+C (n = 85)	DES (n = 84)	DES+C vs. DES		DES+C vs. BNS+C		DES+C vs. BNS
					HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value
Male (%)	3 (3.7)	14 (16.6)	5 (6.5)	5 (6.3)	0.89 (0.20–3.98)	0.875	0.79 (0.39–1.62)	0.521	0.67 (0.44–1.02)	0.063
All-cause death (%)	5 (6.1)	1 (1.2)	6 (7.1)	5 (6.0)	1.13 (0.33–3.92)	0.844	0.94 (0.52–1.70)	0.839	1.84 (0.90–3.76)	0097
Death due to limb (%)	0 (0.0)	0 (0.0)	1 (1.2)	0 (0.0)
Major bleeding (%)	1 (1.2)	4 (4.8)	1 (1.2)	2 (2.4)	0.54 (0.05–5.97)	0.616	1.02 (0.26–4.08)	0.977	0.65 (0.32–1.36)	0.253
TLR (%)	3 (3.7)	8 (9.7)	4 (5.1)	3 (3.6)	0.81 (0.14–4.90)	0.822	0.73 (0.31–1.70)	0.458	0.65 (0.39–1.10)	0.106
Major amputation (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)

Participants in groups DES+C, BNS, BNS+C, and DES were administered DES with cilostazol, BNS, BNS with cilostazol, and DES treatment, respectively.

Abbreviations: DES, drug-eluting stents; BNS, bare-metal nitinol stents; HR, hazard ratio; MALE, major adverse limb event, defined as a composite of limb-related death, target lesion revascularization, major amputation, and major bleeding; TLR, target lesion revascularization.

Comparison of the ISR rate between the DES with cilostazol and BNS with cilostazol groups

The 12-month patency rates between the DES with cilostazol and BNS with cilostazol groups was comparable. Furthermore, MALE, all-cause death, TLR, and major bleeding were comparable between the two groups. Subgroup analysis revealed a comparable patency rate between the two groups for patients with TASC II C/D lesions (100.0% vs. 93.5%, p = 0.347) and small vessels (< 5 mm) (100.0% vs. 97.6%, p = 0.392).

Comparison of ISR types

ISR occurred in three patients, and importantly, all cases were classified as Tosaka class I in the DES with cilostazol group. The distribution of the ISR type according to the patient group was as follows: Tosaka class I occurred in 10 (44%; BNS), 8 (89%; BNS with cilostazol), and 10 (62%; DES) patients; Tosaka class II occurred in 7 (30%; BNS), 0 (0%; BNS with cilostazol), and 3 (19%; DES) patients; Tosaka class III occurred in 6 (26%; BNS), 1 (11%; BNS with cilostazol), and 3 (19%; DES) patients. The distribution of the ISR type was significantly different among the four groups (p = 0.002) (Fig 4).

Fig 4

ISR pattern of each group.

The DES with cilostazol group had no type II or III ISR compared with the other three groups. Abbreviations: ISR, in-stent restenosis, DES, drug-eluting stent.

Discussion

The ZERO study is a prospective, open-label, multicenter study designed to evaluate the patency rate of DES with cilostazol after EVT for FP lesions. Data from the DEBATE SFA study were used to compare the patency rates of DES with cilostazol and BNS, BNS with cilostazol, and DES after EVT for FP lesions.

To the best of the authors’ knowledge, the ZERO study is the first to reveal that (1) cilostazol significantly improves the DES patency rate at 12 months, (2) all patients with ISR had class I (focal) type in the DES with cilostazol group, and (3) in patients with small vessels and TASC C/D FP lesions, there was no ISR in the DES with cilostazol group at the 12-month follow-up.

Soga et al. first revealed that cilostazol significantly reduced the restenosis rate after EVT with stenting or ballooning alone for FP lesions in a prospective randomized trial [9]. Iida et al. showed that cilostazol reduced the 1-year ISR for EVT with first-generation BNS implantation for FP lesions (BNS vs. BNS with cilostazol, 49% vs. 20%, P = 0.0001). Subanalysis of the ZEPHYR study revealed that the one-year ISR rate after Zilver PTX implantation for FP lesions was significantly lower in the cilostazol group than in the non-cilostazol group by propensity score matching analysis (33% vs. 51%, P = 0.008). Patients in the ZEPHYR study had a mean lesion length of nearly 170 mm and mean reference vessel diameter of 5.0 mm; 37% had chronic total occlusions, 19% had stent restenosis lesions, 31% were on dialysis, and 29% had critical limb ischemia [10]. This included severe cases, and the patients’ baseline characteristics were heterogeneous. Therefore, the ZERO study is the first to prospectively evaluate the effectiveness of reducing the ISR of cilostazol after EVT with DES for de novo FP lesions.

Cilostazol is effective in reducing ISR for small vessels and long lesions

In patients with FP lesions, small vessels and long lesions remain the limitations of EVT. Currently, drug-coated balloons (DCBs) are the first choice for treating small vessels. In a retrospective analysis, Kamioka et al. revealed that the three-year patency rate of balloon angioplasty was superior to that of BNS stenting for FP lesions [11]. Moreover, DCBs could significantly reduce restenosis compared with balloon angioplasty in FP lesions, particularly in diabetic or female patients [12]. These findings suggest that DCB use may be a preferable strategy for reducing restenosis in small vessels. However, in cases of flow-limiting dissection after balloon dilatation, a stent is required. The ZEPHYR trial showed that DES is not suitable for small-vessel FP lesions [13]. In the present study, although DES with cilostazol was significantly superior to DES in reducing restenosis in small vessels, there was a similar patency rate between the DES with cilostazol and BNS with cilostazol groups. Therefore, the authors recommend using cilostazol when using metal stents for small-vessel FP lesions, irrespective of whether these are DES or BNS.

Longer lesions decrease the linear patency rate of BNS and DES after EVT for FP lesions [13, 14]. Zeller et al. reported that a heparin-bonded stent graft (Viabahn) was suitable for long lesions based on a one-year primary patency rate of 67% after EVT [15]. However, the present study revealed that the one-year primary patency rate after EVT with DES with cilostazol for long lesions was 100.0%, which is comparable to that of BNS with cilostazol. Based on the present data, cilostazol could maintain a high patency rate for TASC II C/D lesions treated with BNS as well as DES.

ISR pattern

The ISR distribution by type has been reported as follows: Tosaka class I, II, and II patterns were found in 29%, 38%, and 33% of cases following BNS use, respectively [16], while class I, II, and III patterns were found in 50%, 25%, and 25% of cases following DES use, respectively [17].

Furthermore, the DEBATE SFA trial showed that cilostazol reduced class II and III ISR by 0% and 11%, respectively [7]. The present study revealed that DESs with cilostazol were not associated with class II or III ISR. Type III ISR occurred more frequently, particularly with re-occlusion after balloon angioplasty. This may indicate that DES with cilostazol is effective in reducing ISR and improving the treatment of FP by EVT.

Possibility of cilostazol’s effect

Recently, paclitaxel-eluting stents (Eluvia) have demonstrated superior patency rate outcomes to polymer-free paclitaxel-coated stents (Zilver PTX) [5]. Although this study revealed an extremely high patency rate for Zilver PTX with cilostazol in FP lesions, cilostazol treatment combined with Eluvia can possibly achieve improved results compared with Zilver PTX with cilostazol.

Limitations

Our study was not a randomized controlled trial, although the authors compared the present data with historical data and used the same enrollment and exclusion criteria. Statistical matching technique was not performed due to small number of enroll patients. Furthermore, adjusted analysis was not enough due to small number of endpoints. Although the authors had no independent core laboratory to assess the initial procedure, our colleagues evaluated all angiographic data. Finally, stent fracture was one of the reasons for ISR, but the authors were unable to collect these data comprehensively and could not describe the stent fracture.

Conclusions

The patency rate was greater in patients in whom DES with cilostazol was used than in patients in whom only DES was used. Cilostazol improved the patency rate after EVT with DES for FP lesions and small vessels.

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10 Mar 2022

Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study

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- https://www.ahajournals.org/doi/10.1161/CIRCINTERVENTIONS.118.006564

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General comments:

The authors present analyses where data from an open-label study were pooled with data from a historical randomized trial.

Overall, I think these analyses have merit, though more information is needed to understand why pooling these two trials is reasonable. I believe more needs to be done with the analytic methods as well. Pooling of studies can create bias since data were collected at different times and, potentially, different places. These biases need to be addressed, or at least fully discussed to inform readers, and for me that has not been done here.

Specific comments:

1. (p.4) I believe that you mean that the data…*will be* made available.

2. (p.5) A really key part of these analyses is how comparable the DES+cilostazol patients are to the DEBATE SFA study participants. One part that it completely glossed over are the locations that people are coming from. Were the eight centers from DES+cilostazol ones that were included in DEBATE SFA? If not, are they from similar geographic areas? These sorts of questions should be answered somewhere in the manuscript.

3. (p.7) Please include further information on the sample size. For instance, how was this powered, i.e., using a particular test? What values were assumed, e.g., what effect size?

4. (p.7; Table 3) I think these analyses should be run with proportional hazards regression models (aka Cox models). There is a categorical exposure here so, best that I understand, you are running a bunch of pairwise log-rank tests. That is probably resulting in a higher type I error rate than expected.

5. In addition, the Cox model will allow you to control for other potential confounders which I think needs to be done here. Some of the baseline characteristics in table 1 suggest that including them in a model might have some impact. I am not sure whether any covariates should go into a final model, but this should at least be tried, especially given that these are pooled data.

6. Finally, in the Cox model, I think clustering by center should be accounted for in the model, probably with some sort of marginal model, e.g., via the sandwich estimator. This could also be done with a frailty.

7. You might also consider performing some sensitivity analyses in regards to the pooling, especially in terms of the centers. It's hard for me to know what to recommend here information is lacking. Maybe you could limit the data from DEBATE SFA to those that were in DES+cilostazol. Or maybe some sort of intelligent matching of centers or participants.

8. (Table 1) Significance testing for baseline imbalance in randomized trials been has regarded as unnecessary and potentially misleading (see Altman DG. Comparability of randomised groups. The Statistician 1985; 125-136; Senn, S. Testing for baseline balance in clinical trials. Statistics in Medicine 1994; 1715-1726). I recommend removing the significance testing entirely from table 1.

9. There's no page 15 and then numbering starts on page 16. (It would be nice to have the line numbers throughout the document in future submissions.)

10. (Table 3) I think this table would be easier if the arm names could be used instead of "Group 1" etc.

11. (Figure 2) These survival curves should have confidence bands on them to depict the variability in these estimates. Though, four curves with bands will make this pretty busy. You may need to break these out into panels.

12. (Figure 3) Same comment as figure 2, though with just two curves, panels shouldn't be needed.

Reviewer #2: I read with interest the manuscript #PONE-D-21-22546 by Dr Miura and colleagues entitled “Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study”.

This is a prospective, open-label, multicenter study evaluating the efficacy of cilostazol in improving the patency of DESs and determine whether BNS or DESs with or without cilostazol are more effective in improving the 12-month patency after EVT for FP lesions.

The manuscript is well written and the topic is of interest.

However, the manuscript presents several issues:

- In the “outcome assessments” sub-section, concerning the peak systolic velocity (PSV) ratio cut-off used for ISR determination, authors state “we changed definition of PSV from >2.0 to > 2.5 because that of almost all trial was > 2.5”. First, authors should at least cite the studies they are referring to. Second and most important, in the DEBATE in SFA trial, it seems that the primary end point was evaluated using a peak systolic velocity ratio <2.0, as stated in the “Outcomes Assessment” section of that study1. Since the PSV was used to determine restenosis, the primary outcome of this study, this represents a major issue of the manuscript. Please Clarify.

- When comparing cohorts with historical control data, statistical methods including a propensity score matching would improve the quality of the analysis.

- In the “Results” section, authors state that “no significant differences were found in the 12-month patency rate among the DES with cilostazol, DES, BNS with cilostazol, and BNS groups (94.2% vs. 82.8% vs. 93.1% vs. 77.6%, respectively, p = 0.007) (Figure 2)”; however, in the Figure 2 description is reported that “the 12-month patency rate differed significantly among the four groups (DES with cilostazol: 94.2% vs. BNS with cilostazol 93.1% vs. DES without cilostazol 82.8%, BNS without cilostazol 77.6%, p = 0.0007) with different p value. Please clarify.

References:

1. Miura T, Miyashita Y, Soga Y, Hozawa K, Doijiri T, Ikeda U, et al. Drug-eluting versus bare-metal stent implantation with or without cilostazol in the treatment of the superficial femoral artery. Circ Cardiovasc Interv. 2018;11(8): e006564. doi: 10.1161/CIRCINTERVENTIONS.118.006564.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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25 Apr 2022

We wish to express our appreciation to the Reviewer for their comments, which have helped us significantly improve the paper.

Reviewer #1: General comments:

The authors present analyses where data from an open-label study were pooled with data from a historical randomized trial.

Overall, I think these analyses have merit, though more information is needed to understand why pooling these two trials is reasonable. I believe more needs to be done with the analytic methods as well. Pooling of studies can create bias since data were collected at different times and, potentially, different places. These biases need to be addressed, or at least fully discussed to inform readers, and for me that has not been done here.

Specific comments:

1. (p.4) I believe that you mean that the data…*will be* made available.

Response: We appreciate the Reviewer`s comment on this point. We deleted the sentence.

2. (p.5) A really key part of these analyses is how comparable the DES+cilostazol patients are to the DEBATE SFA study participants. One part that it completely glossed over are the locations that people are coming from. Were the eight centers from DES+cilostazol ones that were included in DEBATE SFA? If not, are they from similar geographic areas? These sorts of questions should be answered somewhere in the manuscript.

Response: We thank the Reviewer`s comment on this point. The eight centers participated DEBATE in SFA study As Reviewer's comment, we described that in Materials and Methods on P 5.

3. (p.7) Please include further information on the sample size. For instance, how was this powered, i.e., using a particular test? What values were assumed, e.g., what effect size?

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we described further information on the sample size in Statistical analysis on P 7.

4. (p.7; Table 3) I think these analyses should be run with proportional hazards regression models (aka Cox models). There is a categorical exposure here so, best that I understand, you are running a bunch of pairwise log-rank tests. That is probably resulting in a higher type I error rate than expected.

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we reanalysed secondary endpoints by Cox proportional hazards regression models.

5. In addition, the Cox model will allow you to control for other potential confounders which I think needs to be done here. Some of the baseline characteristics in table 1 suggest that including them in a model might have some impact. I am not sure whether any covariates should go into a final model, but this should at least be tried, especially given that these are pooled data.

6. Finally, in the Cox model, I think clustering by center should be accounted for in the model, probably with some sort of marginal model, e.g., via the sandwich estimator. This could also be done with a frailty.

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we used Cox model to adjust other factors, especially which factors have significant difference between groups. However, because number of endpoints are not so much, we could adjust only a few predictors. We described them in Limitation on P23. Unfortunately we didn`t have the data of frailty.

7. You might also consider performing some sensitivity analyses in regards to the pooling, especially in terms of the centers. It's hard for me to know what to recommend here information is lacking. Maybe you could limit the data from DEBATE SFA to those that were in DES+cilostazol. Or maybe some sort of intelligent matching of centers or participants.

Response: We thank the Reviewer`s comment on this point. All participating centers of current study participated DEBATE in SFA study As Reviewer's comment, we described that in Materials and Methods on P 5.

8. (Table 1) Significance testing for baseline imbalance in randomized trials been has regarded as unnecessary and potentially misleading (see Altman DG. Comparability of randomised groups. The Statistician 1985; 125-136; Senn, S. Testing for baseline balance in clinical trials. Statistics in Medicine 1994; 1715-1726). I recommend removing the significance testing entirely from table 1.

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we removed significance testing.

9. There's no page 15 and then numbering starts on page 16. (It would be nice to have the line numbers throughout the document in future submissions.)

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we removed that page.

10. (Table 3) I think this table would be easier if the arm names could be used instead of "Group 1" etc.

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, we changed the arm names form to .

11. (Figure 2) These survival curves should have confidence bands on them to depict the variability in these estimates. Though, four curves with bands will make this pretty busy. You may need to break these out into panels.

Response: We really appreciate the Reviewer`s comment on this point. As Reviewer's comment, four curves with bands will make busy, and still busy to describe 95%CI outside of graph. Thus, we added standard error outside of survival curves.

12. (Figure 3) Same comment as figure 2, though with just two curves, panels shouldn't be needed.

Response: We really appreciate the Reviewer`s comment on this point. As Reviewer's comment, Figure 3 was just two curves. But they were close each other. Thus, we added standard error outside of survival curves.

Reviewer #2: I read with interest the manuscript #PONE-D-21-22546 by Dr Miura and colleagues entitled “Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study”.

This is a prospective, open-label, multicenter study evaluating the efficacy of cilostazol in improving the patency of DESs and determine whether BNS or DESs with or without cilostazol are more effective in improving the 12-month patency after EVT for FP lesions.

The manuscript is well written and the topic is of interest.

However, the manuscript presents several issues:

- In the “outcome assessments” sub-section, concerning the peak systolic velocity (PSV) ratio cut-off used for ISR determination, authors state “we changed definition of PSV from >2.0 to > 2.5 because that of almost all trial was > 2.5”. First, authors should at least cite the studies they are referring to.

Response: We thank the Reviewer`s comment on this point. As Reviewer's comment, we added the paper in which there were definition of PSV ≥ 2.5 into reference (we noticed our mistake and corrected from > to ≥ ).

Second and most important, in the DEBATE in SFA trial, it seems that the primary end point was evaluated using a peak systolic velocity ratio <2.0, as stated in the “Outcomes Assessment” section of that study1. Since the PSV was used to determine restenosis, the primary outcome of this study, this represents a major issue of the manuscript. Please Clarify.

Response: We appreciate the Reviewer`s comment on this point. As Reviewer's comment, definition of ISR in the DEBATE in SFA was PSV > 2.0. Thus, in this study, we re-analysed ISR rate with PSV ≥2.5 in DEBATE in SFA data with this study`s data.

- When comparing cohorts with historical control data, statistical methods including a propensity score matching would improve the quality of the analysis.

Response: We appreciate the Reviewer`s comment on this point. We completely agree with Reviewer's comment. Actually, we tried to analyse propensity score matching, but we coludn`t, because number of original enroll patients were small. We described in Limitation on P 23.

- In the “Results” section, authors state that “no significant differences were found in the 12-month patency rate among the DES with cilostazol, DES, BNS with cilostazol, and BNS groups (94.2% vs. 82.8% vs. 93.1% vs. 77.6%, respectively, p = 0.007) (Figure 2)”; however, in the Figure 2 description is reported that “the 12-month patency rate differed significantly among the four groups (DES with cilostazol: 94.2% vs. BNS with cilostazol 93.1% vs. DES without cilostazol 82.8%, BNS without cilostazol 77.6%, p = 0.0007) with different p value. Please clarify.

Response: We really appreciate the Reviewer`s comment on this point. As Reviewer's comment, we corrected from No significant… to Significant…. in Results on P 8.

Submitted filename: response to reviewer.docx

Click here for additional data file.

22 Jun 2022

Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study

PONE-D-21-22546R1

Dear Dr. Miura,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Salvatore De Rosa

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors edited their manuscript addressing the majority of the reviwers' comments, improving the overall quality.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

27 Jun 2022

PONE-D-21-22546R1

Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study

Dear Dr. Miura:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Salvatore De Rosa

Academic Editor

PLOS ONE