Clinical trial NCT02374957
Conditions: Peripheral Arterial Disease Claudication (Finding)
Keywords: leg pain claudication
Sponsor: Wake Forest University Health Sciences
Start date: 2015-02-01; Completion date: 2017-06-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Twenty patients will be recruited to CLEAR. Ten will be randomized to the treatment arm (Cilostazol) and tenwill be randomized to the control group. Patients randomized to the treatment arm will receive Cilostazol for 90 days. The primary purpose of this study is to collect quality of life data on patients undergoing peripheral revascularization in order to determine the sample size required to adequately power a trial of Cilostazol versus usual care without Cilostazol and its effect on quality of life.

Detailed description:
Cilostazol is the only medication approved for use in peripheral arterial disease (PAD) patients to reduce claudication symptoms. Contemporary data has demonstrated that Cilostazol improves patency after endovascular interventions in multiple randomized trials and retrospective studies done in Japan in both critical limb ischemia and claudication patients. However, Cilostazol use after peripheral revascularization has been sporadic and there has been no research to estimate patient quality of life with use of Cilostazol after open or endovascular lower extremity revascularization.

This is a prospective investigator initiated single-center open-label, non-placebo controlled pilot study. Eligible patients would be randomized to either the Cilostazol treatment or the non-Cilostazol treatment groups using a closed envelope randomization technique. Twenty patients will be recruited and randomized; Ten to the treatment group and tento the control group.

The primary purpose of this pilot study is to collect quality of life data on patients undergoing peripheral revascularization in order to determine the sample size required for adequate powered trial of Cilostazol versus usual care without Cilostazol and its effect on Quality of Life.

Arms: arm 1: Administer Cilostazol100 mg twice daily for 90 days. arm 2: No Cilostazol
Interventions: intervention 1: Cilostazol
Intervention descriptions: intervention 1: 100 mg twice daily for 90 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
A pilot study of cilostazol to improve quality-of-life and long term patency after open or endovascular 
revascularization for peripheral artery disease 
 
October 24, 2018 
 
NCT #02374957 
 
 


 
 
A pilot study of cilostazol to improve quality-of-life and long term patency after open or endovascular 
revascularization for peripheral artery disease 
Principle Investigator 
Matthew Edwards 
Background 
Cilostazol is considered a cAMP (phosphodiasterase) inhibitor and is the only medication 
approved for use in peripheral arterial disease (PAD) patients to reduce claudication symptoms.  
Contemporary data has demonstrated Cilostazol to improve patency after endovascular interventions in 
multiple randomized trials and retrospective studies in both critical ischemia and claudication patients.1-
5 Recent meta-analysis showed decreased restenosis, target vessel revascularization and major 
amputation in patients receiving Cilostazol.6 Cilostazol has also been shown to improve adverse 
outcomes after coronary stent implantations.7Cilostazol was also shown to be equivalent to warfarin 
anticoagulation in a small, randomized trial for femoral-popliteal bypass for graft patency.8  
 
 
Peripheral vascular graft or angioplasty/stent failure, especially early, is caused by intimal 
hyperplasia and smooth muscle activation and proliferation. No human studies have shown a role of 
Cilostazol in curtailing these, but animal research provides insight into potential therapeutic strategies 
to reduce early graft or angioplasty/stent failure.  In one animal model, Cilostazol was associated with 
decreased intimal hyperplasia in a vein graft.9 Cilostazol reduces smooth muscle constriction and 
proliferation in animal models and also promotes angiogenesis in non-primate models.10-12  
 
Cilostazol has been shown to be safe for long term use in patients with vascular disease.7, 13  
Cilostazol is contraindicated for use in patients with congestive heart failure due to decreased survival 
associated with use of other cAMP inhibitors in patients with Class III/IV CHF. No direct studies for 
Cilostazol have been undertaken in this regard. Cilostazol is also contraindicated in patients with allergic 
response to the drug, bleeding diathesis, intracranial bleeding or active bleeding peptic ulcer disease. It 
is not approved for use in pregnancy due to fetal defects and also shown to be excreted in milk. 
 
Cilostazol use after peripheral revascularization has been sporadic and there has been no 
research to estimate patient quality of life with use of Cilostazol after open or endovascular lower 


extremity revascularization. Moreover, prior randomized trials, as mentioned above, have all been 
performed in Japan, therefore results may not be generalizable to North American population.   
Methods 
We propose to study the effect of Cilostazol on patient quality of life (measured using standard 
QOL assessment tools in PAD patients (EQ-5D and EACH Qc) and relation of these to patency after lower 
extremity infra-inguinal bypass and endovascular interventions (angioplasty with or without stent 
placement) in a stratified randomized trial. Secondary endpoints would be limb salvage, minor (distal to 
calcaneus) and major amputation, claudication symptoms and distance and ischemic rest pain, stroke or 
other cardiovascular events, and overall survival. Adverse outcomes would also be collected, including - 
bleeding, need for blood transfusion, medication reaction (allergic or bleeding episodes), and 
cardiopulmonary failure.  
This is a prospective investigator initiated single-center open-label, non-placebo controlled pilot 
study.  All patients meeting the inclusion criteria would be screened for eligibility and after informed 
consent, randomization would be performed to either the Cilostazol treatment (drug group) or the non-
Cilostazol treatment (control group) groups, stratified for endovascular or open interventions, using a 
closed envelope randomization technique. Eligible patients would be consented prior to surgery or 
within 48 hours of index procedure. Patients on Cilostazol prior to surgery would still be eligible and 
medication discontinued if randomized to control group.  Cilostazol will be provided to patients 
randomized to the treatment arm free of charge for three months. . If you are randomized to the 
treatment arm (receiving Cilostazol) we will provide you with Cilostazol 100 mg, twice a day, free of 
charge for a period of three months. Patients who have renal impairment (problems with their kidneys) 
will be given 50 mg, twice a day instead of 100 mg, twice a day.  Cilostazol has a half- life of 13 hours, 
therefore a washout period will not be necessary. Concurrent medication use based on comorbidities 
including diabetic, anti-hypertensive medications, lipid lowering agents would be prescribed based on 
standard practice and not dependent on study group or enrollment in the study. 
Also concurrent use of single or dual antiplatelet therapy (aspirin with or without ADP receptor blocker 
or similar medication) would be used at discretion of treating physician.  Patients who need to be on 
anticoagulation, with warfarin or other oral anticoagulants, for high risk revascularization or other 
comorbidities, would have single antiplatelet agent (as above) only for secondary prevention of 
thrombotic events. Cilostazol use in either group would not lead to a change in their 
antiplatelet/anticoagulation regimen.  
 


Pre-operative demographic, medication use and co-morbidity data and operative data would be 
retrieved from EMR. Patient follow up would be based on our current standard protocol which includes 
duplex of the graft or intervened artery at 4-6 weeks and 3-6 months.  Cilostazol will be provided to 
patients free of charge for three months. Restenosis is defined as stenosis>50% based on our current 
vascular laboratory criteria or based on arteriogram imaging if performed at discretion of treating 
physician. Clinical examination and medication use and other secondary and adverse outcomes would 
be evaluated and QOL questionnaires administered at above time points. Quality-of-life (QOL) 
questionnaires (EQ-5D and EACH Qc) will be administered at enrollment and each follow up visit. 
 
Purpose 
The primary purpose of this pilot study is to collect QOL data on patients undergoing peripheral 
revascularization in order to determine the sample size required for adequate powered trial of Cilostazol 
versus usual care without Cilostazol and its effect on QOL. Thirty patients, fifteen in each arm, will be 
recruited into the pilot study in order to obtain sufficient data needed to estimate the variance and 
within-subject correlation of the outcome measures.  
 
Benefits/Risks 
Benefits include: possible improvement in quality of life for patients suffering from claudication 
after revascularization, improvement in graft patency and decreased restenosis and potential 
amputation. Risks include possible allergic reaction to the drug. 
Inclusion 
1.  Patents should be older than 35 years of age 
2.  Patients treated for atherosclerotic PAD  
3.  Able to provide informed consent 
4.  Lower extremity open or endovascular revascularization, including bypass (autogenous or 
prosthetic), angioplasty and/or stenting, with or without concomitant aorto-iliac intervention. 
Exclusion 
1. Known congestive heart failure Class III/IV, systolic, acute or chronic 
2. Allergic reaction to phosphodiasterase inhibitors 
3. Intracranial bleeding within 3 months or active bleeding peptic ulcer disease 
4. Traumatic vascular injuries requiring revascularization 


5. Pregnant or breast feeding women, or plan to get pregnant over the study period (for five years 
after enrollment) 
6. Planned ipsilateral major amputation within 30 days of index procedure 
7. Moderate to severe hepatic impairment 
Analysis  
 Data will be collected and stored on a password protected secure server which only study team 
members can access. QOL instruments (EQ-5D and EACH Qc) will be scored from the baseline, 4-6 week 
and 3 month visits. Cross-sectional and change scores will be calculated to estimate effect size and 
variance of QOL outcomes measures. These data will be used to assess potential efficacy and to project 
sample size requirements for a future trial. Treatment arm differences in early (4-6 week) and late (3 
month) month changes in QOL scores will be tested using two-group t-tests.  
Follow-up graft patency will be assessed as a secondary outcome and will be measured early 
(within 14 day of intervention) and late (six weeks and three months) using duplex ultrasound. 
Treatment arm differences time to patency failure will be compared using Kaplan-Meier survival curves 
and log-rank tests. Information on the following tertiary outcomes will also be ascertained at six weeks 
and three months follow-up: (1) amputation, (2) death due to any cause, (3) clinical symptoms of 
claudication or rest pain (critical limb ischemia), and (4) stroke. Statistical comparison for differences 
between groups will not be performed for tertiary outcomes due to small sample size and power. 
 
Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
separate master log.  The master log will be kept secure, with access limited to designated study 
personnel.  Following data collection subject identifying information will be destroyed at the earliest 
opportunity, consistent with data validation and study design, producing an anonymous analytical data 
set.  Data access will be limited to study staff.  Data and records will be kept locked and secured, with 
any computer data password protected.  No reference to any individual participant will appear in 
reports, presentations, or publications that may arise from the study. 
 


Data and Safety Monitoring 
 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be reported to the principle investigator and the Institutional Review Board by the study 
coordinator within seven business days of the event. 
 
Financial reimbursement 
No reimbursement will be provided to the patients or investigators for this study. All follow up is 
consistent with our current protocol in the care of these patients.  Cilostazol will be provided to those 
patients randomized to the treatment arm free of charge for three months. At the end of the three 
month period, providers may choose to prescribe Cilostazol for patients if they want to continue the 
drug.  
 
 
 


 
Reference List 
 
 
(1)  Iida O, Nanto S, Uematsu M, Morozumi T, Kitakaze M, Nagata S. Cilostazol reduces restenosis 
after endovascular therapy in patients with femoropopliteal lesions. J Vasc Surg 2008 
Jul;48(1):144-9. 
 
(2)  Ikushima I, Yonenaga K, Iwakiri H, Nagoshi H, Kumagai H, Yamashita Y. A better effect of 
cilostazol for reducing in-stent restenosis after femoropopliteal artery stent placement in 
comparison with ticlopidine. Med Devices (Auckl ) 2011;4:83-9. 
 
(3)  Soga Y, Yokoi H, Kawasaki T, Nakashima H, Tsurugida M, Hikichi Y, et al. Efficacy of cilostazol 
after endovascular therapy for femoropopliteal artery disease in patients with intermittent 
claudication. J Am Coll Cardiol 2009 Jan 6;53(1):48-53. 
 
(4)  Soga Y, Iida O, Hirano K, Suzuki K, Kawasaki D, Miyashita Y, et al. Impact of cilostazol after 
endovascular treatment for infrainguinal disease in patients with critical limb ischemia. J Vasc 
Surg 2011 Dec;54(6):1659-67. 
 
(5)  Soga Y, Iida O, Hirano K, Suzuki K, Yokoi H, Nobuyoshi M. Restenosis after stent implantation for 
superficial femoral artery disease in patients treated with cilostazol. Catheter Cardiovasc Interv 
2012 Mar 1;79(4):541-8. 
 
(6)  Warner CJ, Greaves SW, Larson RJ, Stone DH, Powell RJ, Walsh DB, et al. Cilostazol is associated 
with improved outcomes after peripheral endovascular interventions. J Vasc Surg 2014 
Jun;59(6):1607-14. 
 
(7)  Geng DF, Liu M, Jin DM, Wu W, Deng J, Wang JF. Cilostazol-based triple antiplatelet therapy 
compared to dual antiplatelet therapy in patients with coronary stent implantation: a meta-
analysis of 5,821 patients. Cardiology 2012;122(3):148-57. 
 
(8)  Ohtake H, Urayama H, Kimura K, Yokoi K, Tsunezuka Y, Kawakami T, et al. Comparison of 
cilostazol with warfarin as antithrombotic therapy after femoro-popliteal bypass surgery using 
an ePTFE graft. Minerva Cardioangiol 1997 Nov;45(11):527-30. 


 
(9)  Yamamoto K, Onoda K, Sawada Y, Fujinaga K, Imanaka-Yoshida K, Yoshida T, et al. Locally 
applied cilostazol suppresses neointimal hyperplasia and medial thickening in a vein graft model. 
Ann Thorac Cardiovasc Surg 2007 Oct;13(5):322-30. 
 (10)  Biscetti F, Pecorini G, Straface G, Arena V, Stigliano E, Rutella S, et al. Cilostazol promotes 
angiogenesis after peripheral ischemia through a VEGF-dependent mechanism. Int J Cardiol 
2013 Aug 10;167(3):910-6. 
 (11)  Kawanabe Y, Takahashi M, Jin X, Abdul-Majeed S, Nauli AM, Sari Y, et al. Cilostazol prevents 
endothelin-induced smooth muscle constriction and proliferation. PLoS One 2012;7(9):e44476. 
 (12)  Takahashi S, Oida K, Fujiwara R, Maeda H, Hayashi S, Takai H, et al. Effect of cilostazol, a cyclic 
AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in 
culture. J Cardiovasc Pharmacol 1992 Dec;20(6):900-6. 
 (13)  Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery 
disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg 2008 
Feb;47(2):330-6.