Abstract
Aim: The present study investigated the effects of additional cilostazol administration on the 12-month risk of restenosis after femoropopliteal heparin-bonded stent graft implantation.
Methods: This study was a sub-analysis of the Viabahn stent graft placement for femoropopliteal disease reQUIring endovaScular tHerapy (VANQUISH) study, which was a prospective multicenter study investigating patients who received Viabahn stent graft (W.L. Gore & Associates, Flagstaff, AZ, USA) and dual-antiplatelet therapy with aspirin and a thienopyridine. The comparison of clinical outcomes between subgroups with and without cilostazol treatment were performed using the propensity score-matching method to minimize the intergroup differences in baseline characteristics.
Results: Cilostazol-treated patients had a lower 12-month proportion of restenosis than cilostazol-free patients (8.2% vs 27.3%). The odds ratio of cilostazol for the 12-month restenosis was 0.27 [95% CI, 0.08 to 0.97] (p=0.045). Furthermore, the cumulative incidence rates of surgical reconstruction, target lesion revascularization and acute thrombotic occlusion (p values by the log-rank test) were 2.6% versus 1.8% (P=0.43), 5.3% versus 20.5% (P=0.067), and 0.0% versus 11.8% (P=0.0499), respectively. The rates of surgical reconstruction and target lesion revascularization (TLR) were not significantly different between both groups.
Conclusions: Our study revealed the clinical impact of additional cilostazol treatment on the risk of restenosis and acute thrombotic occlusion following heparin-bonded stent graft implantation, while TLR and surgical reconstruction were not significantly different.
Introduction
In the new era of management of femoropopliteal (FP) pathologies, current guidelines recommend the use of drug-eluting stents and drug-coated balloons, which can inhibit restenosis and improve the patency outcomes1-3). Whereas, the application of heparin-bonded stent graft is limited to complex and/or long occlusive lesions3). Several studies demonstrated durable patency of heparin-bonded stent graft in complex FP lesions4-6). A randomized trial revealed superior outcomes of heparin-bonded stent graft compared to bare nitinol stent (BNS)7) and comparable outcomes with surgical bypass therapy8). These findings affected the update of recent guidelines, which conditionally recommend the use of an endovascular-first approach for complex FP lesions1). In contrast, the appropriate regimen of antithrombotic therapy remains unclear following heparin-bonded stent graft implantation because acute thrombotic occlusion is substantially encountered in clinical practice despite continuing antithrombotic treatments recommended by the instruction for use (IFU)9).
Cilostazol has a multifaceted effect in the treatment of peripheral artery disease (PAD)10), which improves the distance covered by patients with intermittent claudication while walking because of a vasodilatory effect11). Cilostazol reduces the restenosis rate after vascular intervention by suppressing the chances of neointimal hyperplasia12, 13). However, whether cilostazol reduces the restenosis rate following heparin-bonded stent graft implantation for FP lesions remains unclear. Therefore, this study evaluated the effects of cilostazol treatment on the 12-month risk of restenosis in patients having FP lesions and undergoing heparin-bonded stent graft implantation for symptomatic PAD.
Methods
Research Design and Patient Population
We analyzed the clinical database of the Viabahn stent graft placement for femoropopliteal disease reQUIring endovaScular tHerapy (VANQUISH) study. The VANQUISH study was a prospective multicenter observational study that registered adult patients aged ≥ 20 years undergoing intravascular ultrasound (IVUS)-supported FP endovascular therapy with Viabahn stent graft with a heparin bioactive surface (W.L. Gore & Associates, Flagstaff, AZ, USA) for symptomatic atherosclerotic PAD (Rutherford category 1-6). Patients from 19 cardiovascular centers across Japan were enrolled who were assessed between March 2017 and December 2018 and scheduled for a one-year follow-up. Registration was performed before the heparin-bonded stent graft implantation. The indications for revascularization were patients with symptomatic PAD and FP lesions with ≥ 50% stenosis and length ≥ 10 cm evaluated by using duplex ultrasound/computed tomographic angiography/diagnostic angiography. The decision to implant a heparin-bonded stent graft was per the physician’s discretion. Patients who were scheduled to undergo bypass surgery or major amputation were excluded. The study was conducted in accordance with the principles under the Declaration of Helsinki and approved by the ethics committees of the participating centers. Written informed consent was obtained from all the participants or their families.
Initially, 372 patients (425 limbs with PAD) were registered. Subsequently, 1 patient who did not undergo heparin-bonded stent graft implantation, 80 cases with spot implantation, 31 patients not receiving the dual-antiplatelet therapy regimen, 37 cases receiving anticoagulation therapy, and 20 cases with missing baseline data were excluded. The first registered limb was included for the patients registered with bilateral PAD. Hence, 231 patients (231 limbs) were included in the analysis who received the dual-antiplatelet therapy regimen comprising aspirin and a thienopyridine but did not receive anticoagulation therapy and underwent full-coverage heparin-bonded stent graft implantation.
Study Endpoints and Definition
The main outcome measure was the proportion of 12-month restenosis assessed by duplex ultrasound or follow-up angiography, with a tolerance of ±2 months. Restenosis was defined based on a peak systolic velocity ratio (PSV-R) ＞2.4 by duplex ultrasound or the recurrence of stenosis ≥ 50% of the arterial diameter determined by angiography. Secondary outcomes included the 12-month cumulative incidence of major amputation, surgical reconstruction, target lesion revascularization (TLR), and acute thrombotic occlusion. TLR was clinically-driven and conducted for cases of stenosis ≥ 50% of the arterial diameter within 5 mm of the stent edges after recording recurrent clinical symptoms.
Statistical Analysis
Data on baseline characteristics are presented as means±standard deviations (SDs) for continuous variables and percentages for categorical variables, unless otherwise mentioned. Statistical significance was set at 2-sided p＜0.05, and 95% confidence intervals (CIs) are reported where appropriate. The crude differences in baseline characteristics between groups were tested by the Welch’s t-test for continuous variables, Fisher’s exact test for dichotomous variables, and Mann-Whitney U test for ordinal categorical variables.
The comparison of clinical outcomes between subgroups with and without cilostazol treatment were performed using the propensity score-matching method to minimize the intergroup differences in baseline characteristics. The propensity score was calculated using a logistic regression model. The following explanatory variables were included in the model: age, sex, ambulatory status, smoking, diabetes mellitus (DM), renal function, chronic heart failure, statin use, chronic limb-threatening ischemia, ankle-brachial index, history of revascularization, angiographically assessed reference distal vessel diameter, lesion length, chronic total occlusion, severe calcification (peripheral artery calcification scoring system grade 4), popliteal involvement, below-the-knee runoff, and IVUS-determined vessel diameter. Matching was performed on the logit of the propensity score within the caliper of 0.2 SD of the logit of propensity score. To maximize the statistical power to detect intergroup prognostic differences, we extracted as many matched samples in the cilostazol-free group to one in the cilostazol group as possible. After matching, intergroup differences were analyzed with stratification by pairs, and weighted descriptive statistics were reported. The intergroup difference in baseline characteristics was assessed according to the standardized difference. The intergroup difference in the primary outcome, i.e., the proportion of 12-month restenosis, being a binary endpoint, was analyzed using the generalized linear mixed model with a logit-link function in which the inter-pair variability was treated as the random effects. Time-to-event outcomes were analyzed using the Kaplan-Meier estimator and log-rank test. Missing data on 12-month restenosis were addressed with multiple imputations in the chained equations method. In this procedure, we generated 10 imputed datasets and combined the analytic results based on Rubin’s rule. We also calculated hazard ratios of cilostazol treatment for restenosis risk, using the Cox proportional hazards regression model in which time to the detection of restenosis was set as the outcome measure. All statistical analyses were performed using R version 3.6.0 (R Development Core Team, Vienna, Austria).
Results
Of the 231 patients, 56 (24%) received cilostazol, whereas the remaining 175 (76%) did not. Data on 1 -year restenosis were available for 200 patients (87%), of whom 52 patients were treated with cilostazol, and the remaining 148 patients were free from cilostazol. The baseline characteristics are shown in Table 1. Patients receiving cilostazol had a higher prevalence of statin use (73% vs 51%), lower prevalence of chronic limb-threatening ischemia (9% vs 26%), higher ankle-brachial index (0.60±0.19 vs 0.53±0.20), larger distal reference vessel diameter (5.5±0.7 vs 4.9±0.8 mm), lower prevalence of chronic total occlusion (57% vs 75%), and higher prevalence of a popliteal lesion (68% vs 35%) than those not receiving cilostazol. Fig.1A revealed the crude analysis. The proportion of 12-month restenosis was 11.1% [2.5 to 19.6%] in the cilostazol group versus 25.9% [18.9 to 32.9%] in the cilostazol-free group (P=0.030). The Kaplan-Meier estimates of the 12-month cumulative incidence rate were 11.3% [2.3 to 19.5%] versus 21.1% [14.3 to 27.3%] for the detection of restenosis as a time-to-event (P=0.12), 1.8% [0.0 to 5.2%] versus 1.8% [0.0 to 3.8%] for surgical reconstruction (P=0.98), 9.5% [1.2 to 17.2%] versus 17.9% [11.6 to 23.8%] for target lesion revascularization (P=0.14), and 0.0% [0.0 to 0.0%] versus 7.4% [3.2 to 11.4%] for acute thrombotic occlusion (P=0.042), respectively.
Table 1.
Baseline characteristics of study population before and after matching.
|
Before matching |
After matching |
| Patients with cilostazol (n= 56)
|
Patients without cilostazol (n= 175)
|
Standardized difference (%) |
P value
|
Patients with cilostazol (n= 39)
|
Patients without cilostazol (n= 139)
|
Standardized difference (%) |
| Male sex |
64% |
68% |
7.9 |
0.63 |
59% |
62% |
6.5 |
| Age (years) |
75±9 |
75±8 |
1.4 |
0.93 |
74±10 |
74±8 |
6.8 |
| Non-ambulatory status |
5% |
8% |
10.6 |
0.77 |
5% |
7% |
7.6 |
| Smoking |
|
|
|
0.32 |
|
|
|
| Never |
29% |
24% |
10.4 |
|
26% |
29% |
6.7 |
| Past |
55% |
50% |
10.2 |
|
54% |
53% |
2.0 |
| Current |
16% |
26% |
23.9 |
|
21% |
19% |
5.0 |
| Diabetes mellitus |
62% |
51% |
22.5 |
0.17 |
56% |
57% |
0.6 |
| Renal function |
|
|
|
0.15 |
|
|
|
| eGFR ≥ 30 ml/min/1.73 m2
|
57% |
68% |
22.6 |
|
64% |
65% |
1.7 |
| eGFR ＜30 ml/min/1.73 m2
|
16% |
17% |
1.4 |
|
15% |
18% |
8.0 |
| On dialysis |
27% |
15% |
28.1 |
|
21% |
17% |
9.8 |
| Chronic heart failure |
16% |
9% |
21.0 |
0.15 |
10% |
8% |
8.4 |
| Statin use |
73% |
51% |
47.3 |
0.003 |
69% |
66% |
6.9 |
| Chronic limb-threatening ischemia |
9% |
26% |
46.8 |
0.005 |
13% |
14% |
4.7 |
| Ankle-brachial index |
0.60±0.19 |
0.53±0.20 |
36.7 |
0.017 |
0.57±0.21 |
0.57±0.17 |
2.9 |
| Restenotic lesion |
20% |
18% |
4.9 |
0.84 |
21% |
22% |
3.1 |
| In-stent lesion |
18% |
17% |
1.9 |
1.00 |
21% |
21% |
2.3 |
| In-stent occlusion1 |
12% |
9% |
10.8 |
0.45 |
13% |
14% |
2.9 |
| Distal reference vessel diameter (mm) |
5.5±0.7 |
4.9±0.8 |
77.1 |
＜0.001 |
5.4±0.7 |
5.4±1.0 |
1.7 |
| Lesion length (cm) |
25±7 |
25±7 |
1.8 |
0.90 |
25±7 |
25±9 |
4.2 |
| Chronic total occlusion |
57% |
75% |
38.1 |
0.018 |
67% |
65% |
2.7 |
| Severe calcification |
27% |
23% |
7.7 |
0.60 |
21% |
22% |
2.4 |
| Popliteal lesion |
68% |
35% |
68.6 |
＜0.001 |
56% |
55% |
2.4 |
| The number of patent tibial vessels |
1.9±0.7 |
1.9±0.9 |
2.7 |
0.85 |
1.9±0.8 |
1.9±0.8 |
4.2 |
| IVUS-assessed vessel diameter (mm) |
5.7±1.2 |
5.4±1.2 |
22.3 |
0.15 |
5.5±1.1 |
5.5±1.1 |
8.4 |
Data are means±standard deviations for continuous variables and percentages for categorical variables.
Abbreviations: ITPW, inverse probability of treatment weighting; eGFR (mL/min/1.73 m2), estimated Glomerular Filtration Rate: 194×(SCr)-1.094×(Age)-0.287×0.739 (if female); IVUS, intravascular ultrasonography.
The propensity score matching extracted 39 pairs (39 patients in the cilostazol group and 139 patients in the cilostazol-free group). The standardized difference in baseline characteristics were below 10%, indicating that there were no significant intergroup differences (Table 1).
Fig.1B summarizes the 12-month clinical outcomes in the matched population. Cilostazol-treated patients had a lower 12-month proportion of restenosis than cilostazol-free patients (8.2% [95% CI, 0.3 to 16.2%] vs 27.3% [19.5 to 35.0%]). The odds ratio of cilostazol for the 12-month restenosis was 0.27 [95% CI, 0.08 to 0.97] (p=0.045). When restenosis was evaluated as a time-to-event instead of a binary endpoint, the Kaplan-Meier estimate of the 12-month cumulative incidence of restenosis was 7.9% [95% CI, 0.0 to 16.1%] versus 23.4% [95% CI, 11.5 to 33.7%] (P=0.11 by the log-rank test); the hazard ratio was calculated to be 0.38 [95% CI, 0.10 to 1.32] (P=0.13) by the stratified Cox proportional hazards regression model. No patient in either group underwent a major amputation. Furthermore, the cumulative incidence rates of surgical reconstruction, target lesion revascularization and acute thrombotic occlusion (p values by the log-rank test) were 2.6% [95% CI, 0.0 to 7.4%] versus 1.8% [0.0 to 3.9%] (P=0.43), 5.3% [0.0 to 12.3%] versus 20.5% [9.3 to 30.4%] (P=0.067), and 0.0% [0.0% to 0.0%] versus 11.8% [2.0 to 20.6%] (P=0.0499), respectively. Kaplan-Meier estimates are illustrated in Supplementary Fig.1.
Subsequently, we performed an interaction analysis, as shown in Fig.2. No baseline characteristics had significant interaction effect on the relationship between cilostazol administration and the 12-month restenosis risk. The interaction analysis based on the Cox proportional hazards regression model, where the restenosis was treated as a time-to-event instead of a binary endpoint, is shown in Supplementary Fig.2. The hazard ratio of cilostazol treatment was smaller in statin users than in non-users (P for interaction =0.049).
Discussion
The present study demonstrated that additional cilostazol administration with dual-antiplatelet therapy was associated with a reduced risk of 1-year restenosis and acute thrombotic occlusion following heparin-bonded stent graft implantation for complex FP lesions. DM, statin use, and IVUS-evaluated vessel diameter ≥ 5 mm significantly affected the association between cilostazol treatment and the 12-month restenosis rates.
Heparin-bonded stent graft contain polytetrafluoroethylene and theoretically block the neointimal proliferation of the stented segment14). Previous study reported that use of drug-coated balloons over the edges of heparin-boned stent graft reduced the rate of edge stenosis. Subsequently, this strategy showed improvement of the rate of patency and TLR following heparin-bonded stent graft implantation15). Based on this clinical scenario, management of edge restenosis would be important in maintaining the patency of heparin-bonded stent graft. Cilostazol administration can suppressed neointimal hyperplasia at the edge of heparin-bonded stent graft and might reduce the restenosis including occlusion following heparin-bonded stent graft implantation in this study.
Regarding secondary outcome measures, although the 12-month rate of TLR was numerically lower in the cilostazol-treated group than in the cilostazol-free group, the difference was not statistically significant due to the small sample size. We speculated that the reduction of restenosis rate was attributable to the prevention of neointimal hyperplasia at the edge of the stent graft by cilostazol therapy, which would affect the improvement of TLR rate; however, further investigation is warranted to confirm this improvement.
In terms of the relationship between cilostazol administration and the 12-month restenosis risk, primary interaction analysis shows no baseline characteristics had significant interaction effect but analysis based on the Cox proportional hazards regression model revealed that the hazard ratio of cilostazol treatment was smaller in statin users than in non-users. Several studies reported that statins inhibit proliferation of smooth muscle cell and subsequently reduce the rate of restenosis after peripheral intervention16, 17), and a combination therapy of statin plus cilostazol may have a synergistic effect against restenosis occurrence in patients undergoing heparin-bonded stent graft implantation.
This study has several limitations. First, VANQUISH was an observational study, and medication regimens was determined by physician discretion. In addition, cilostazol dose was not randomized in current study. To minimize the intergroup difference, propensity score matching analysis was conducted but substantial bias could not be completely eliminated. A large-scale, prospective randomization trial will be warranted to confirm the beneficial effect of cilostazol in the treatment of heparin-bonded stent graft. Also, whether additional cilostazol therapy under DAPT administration increase bleeding risk should be confirmed. Second, imaging assessments during the initial treatment and those of 1-year patency were not performed by a core laboratory, and data of restenosis site was not collected. However, each participating site had experience with several clinical trials on FP-specific devices. Third, the study population included only Japanese patients. Fourth, the study population was small and we must therefore caution the readers against the risk of bias caused by our small sample size, which could not be judged by p values. Furthermore, the current sample size was insufficient to detect clinically meaningful differences. For example, the current sample size had a power of only 18.2% to detect the difference between 15% of 1-year restenosis rate in cilostazol-treated group and 25% of the corresponding rate in cilostazol-free group. Fifth, the primary patency was evaluated only at 1 year, and the evaluation at no other timepoints (e.g., 6 months) were scheduled in this current study. We supplementarily presented the Kaplan-Meier estimates for patency data. However, the Kaplan-Meier method was originally for right-censored data, and not for interval-censored variables such as patency data. It should be noted that the Kaplan-Meier analysis for interval-censored data could yield artificially low event incidence rates. Lastly, the follow-up evaluations did not include the assessment of symptoms.
Conclusion
Additional cilostazol administration with DAPT was associated with a reduced risk of restenosis and acute thrombotic occlusion following heparin-bonded stent graft implantation for complex FP lesions. Whereas TLR and surgical reconstruction rates were not significantly different between the cilostazol-treated and cilostazol-free groups.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Kazuki Tobita is a consultant of Gore, has served as a proctor of the Viabahn heparin-bonded stent graft, and has received honorarium from Gore, Medtronic. Osamu Iida has received a consultant fee from NIPRO and speaker’s fees from Gore, Boston Scientific, Terumo and Medtronic Japan. Yoshimitsu Soga has received honorarium from Gore, Boston Scientific, Medtronic Japan and Terumo. Terutoshi Yamaoka has received speaker’s fees from Gore, Boston Scientific, and Medtronic Japan. Shigo Ichihashi has received clinical reach funding form Gore. Mitsuyoshi Takahara and Shigeru Saito have nothing to disclose.
Funding
The authors report receiving the following financial support for the research, authorship, and publication of this article: The VANQUISH study was supported by the Research Association for Lower Limb Artery Revascularization (LIBERAL) sponsored by the following companies (in alphabetical order): Boston Scientific Japan K.K.; HOKUSHIN MEDICAL Co., Ltd., Japan; MID, Inc.; Orbusneich Foundation; Terumo Corp.; and W.L. Gore & Associates, Co., Ltd. The funding companies played no role in the study’s design, selection of the enrolled patients, treatment strategy, revascularization procedures or equipment, or the collection, analysis, or interpretation of the data.
Acknowledgements
We thank the VANQUISH investigators for their support and advice on the experimental design.
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