Cilostazol for peripheral arterial disease – a position paper from the Italian Society for Angiology and Vascular Medicine

Introduction

Peripheral arterial disease (PAD) afflicts approximately 240 million people globally. PAD increasingly appears to have peculiar connotations as a vascular condition with a high risk of major cardiovascular events (MACE) and major lower limb ischemic events (MALE) although it shares the risk factors of atherosclerosis with ischemic heart disease and cerebrovascular disease. To date, PAD remains under-diagnosed and under-treated despite being a powerful marker of cardiovascular risk, which often gives it the appellation of an “orphan epidemic.” Optimal medical therapy aims to reduce MACE and MALE and improve symptoms [1].

Cilostazol is a 2-oxyquinolone derivative that specifically inhibits phosphodiesterase III and, consequently, increases cyclic adenosine monophosphate (cAMP) levels [2]. Phosphodiesterase (PDE) III is predominantly found in platelets, cardiac myocytes, vascular and visceral smooth muscle, liver, kidney, and corpus cavernosum (Figure 1). PDE III can hydrolyse both cyclic guanosine monophosphate and cAMP, although it has a greater affinity toward cAMP [2]. Cilostazol specifically inhibits PDE III, which gives cilostazol an inhibitory effect on platelet activity, a vasodilatory action, an antiproliferative activity, a lipid-lowering effect, protection against ischemia-reperfusion injury, and neuroprotection [2]. The anti-platelet activity, unlike aspirin, is carried out through an intracellular action, whereas the increased endothelial production of nitric oxide acts as a myorelaxant on the smooth muscle cells of the vascular wall [3].

Furthermore, cilostazol has been shown to have pleiotropic biochemical effects, in addition to the activities mentioned above, showing favourable clinical outcomes in other atherosclerotic vascular diseases such as coronary and cerebral artery disease [2].

Recently, data from Cilostazol Stroke Prevention Study Combination (CSPS) reported that dual antiplatelet therapy (DAPT) with either aspirin or clopidogrel and with cilostazol, in patients with noncardioembolic stroke, reduced the risk of ischemic recurrence without increasing the bleeding risk 8–180 days after stroke compared with SAPT with aspirin or clopidogrel alone [4].

Very recent data from CSPS confirmed the remarkable benefits of DAPT using cilostazol for subjects with lacunar infarction in reducing recurrent ischemic events without increased life-threatening bleeding [5].

Moreover, some studies revealed that cilostazol can reduce the incidence of restenosis after endovascular revascularization procedures. This effect would be determined by platelet-derived growth factor activity which would prevent intimal hyperplasia and reduce the proliferation of vessel wall smooth muscle cells [6]. Therefore, all these activities make cilostazol a molecule of interest for patients with vascular diseases.

Anyhow, cilostazol was approved for treating patients with PAD and intermittent claudication (IC) first in Japan in 1980, later in the United States and the United Kingdom in 1999 and 2001 respectively, and finally in Italy in 2008. Currently, cilostazol is typically administered at a dose of 50–100 mg twice daily in patients with IC in PAD [7, 8, 9].

Although supervised exercise should be made available as part of the initial treatment for all patients with peripheral arterial disease, cilostazol utilization was considered by the several guidelines on PAD for treating IC [10, 11, 12, 13]. For AHA guidelines of 2005 and of 2017, cilostazol was an effective therapy to improve symptoms and increase walking distance in patients with PAD and intermittent claudication [10, 13]. TASC guidelines recommended a 3- to 6-month course of cilostazol as first-line pharmacotherapy for the relief of claudication symptoms [11], whereas the 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Disease in collaboration with the European Society for Vascular Surgery did not suggest the use of cilostazol since the beneficial effects on walking distance, if any, was generally mild to moderate, with large variability [14]. The more recent ESVM guidelines recommend cilostazol in case of the patients’ quality of life substantially limited, and walking training restricted, unfeasible or ineffective. It must be noticed that for ESVM guidelines cilostazol had to be discontinued if symptoms failed to improve after 3 months [15]. According to ESVM guidelines, cilostazol may be prescribed only if the patients’ quality of life is substantially limited by intermittent claudication and walking training is restricted, unfeasible or ineffective.

This review aimed to focus on and emphasize the role of cilostazol in treating patients with PAD, particularly with confidence interval (CI), approved by both governmental institutions and guidelines and in restenosis after lower limb revascularization. Indications that are not currently recommended but are of interest in PAD treatment will also be mentioned.

Cilostazol in treating patients with PAD and IC

We review some of the most relevant studies on the efficacy and safety of cilostazol in patients with PAD and IC.

In 1999, Beebe et al. evaluated the efficacy and safety of cilostazol in relieving IC of patients with PAD in a multicentre, randomized, double-blind clinical study [16]. This study randomized 516 males and females with moderate, severe chronic, and stable IC to receive cilostazol at 100 mg or 50 mg, or placebo twice daily (b.i.d.) for 24 weeks. The outcome measures included pain-free (PFWD) and maximal walking distance (MWD) via treadmill testing. The long-term use of cilostazol significantly improved walking distance in patients with IC compared with a placebo.

In 2002, Strandness et al. [17] conducted a multicentre, double-blind, 24-week, randomized, placebo-controlled, parallel study to compare the safety and efficacy of cilostazol in patients with PAD and moderately severe IC. A total of 394 patients were randomized into three treatment groups: cilostazol at 100 mg (n=133), cilostazol at 50 mg (n=132), or placebo (n=129) b.i.d. Patients receiving cilostazol at 100 mg b.i.d. experienced a 22% net improvement in initial claudication distance (ICD) (p=0.0015) and 22% in MWD compared with placebo (p=0.0003). Quality-of-life and functional status assessments corroborated these objective results. The authors concluded that cilostazol, particularly 100 mg twice daily, significantly improves symptoms in patients with IC [17].

In 2000, Dawson et al. [18] performed a double-blind, placebo-controlled, multicentre clinical trial assessing the relative efficacy and safety of cilostazol vs. pentoxifylline. They randomly assigned 699 patients to one of the three blinded treatments: cilostazol (100 mg orally b.i.d.), pentoxifylline (400 mg orally three times daily), and placebo. The primary endpoint was to compare the effects of cilostazol and pentoxifylline on MWD on a standardized treadmill test at baseline and every four weeks until 24 weeks. The mean MWD in patients treated with cilostazol (n=227) was significantly greater than with pentoxifylline (n=232) or placebo (n=239). The mean MWD increased by a mean of 107 m (54% from baseline) after 24 weeks of cilostazol treatment, which was significantly more than the 64 m (30%) achieved with pentoxifylline (p<0.001). The improvement with pentoxifylline was similar (p=0.82) to the placebo group (65 m, with an average increase of 34%). Therefore, cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with IC.

The first Cochrane review conducted by Robless et al. in 1996 analysed eight randomized controlled trials (RCTs) comparing cilostazol with a placebo. Patients receiving cilostazol at 100 mg b.i.d had an increased MWD of 49.7 m than the placebo. Functional status and quality-of-life (QoL) comparisons highlighted a significant improvement in the physical health sub-scales of physical function (p=0.002) and bodily pain (p<0.05). The authors concluded that cilostazol improved walking distance in people with IC. However, the reduction of adverse cardiovascular events had no data [19].

In 2010, Pande and Hiatt et al. performed a meta-analysis of nine RCTs evaluating the duration and prediction of cilostazol in IC [20]. The analysis included 1116 subjects receiving cilostazol at 100 mg b.i.d. and 1135 subjects receiving a placebo. Cilostazol was associated with a 50.7% improvement from baseline in MWD, compared with placebo (24.3%), with an absolute significant improvement of 42.1 m compared with placebo (p<0.001), over a mean follow-up period of 20.4 weeks. Continued increases were observed over the 24 weeks of the treatment period. The benefits from cilostazol treatment were seen in all subgroups after stratifying by age, gender, smoking status, PAD duration, diabetes, hypertension, prior myocardial infarction, or prior beta-blocker use. Pande concluded that cilostazol achieved benefits within walking distance in patients with PAD and IC, irrespective of baseline clinical characteristics, and it did not increase the risk of all-cause mortality (response rate [RR]: 0.95 [0.68–1.35]) [20].

A more recent Cochrane review by Bedenis et al. in 2014 analysed [21] double-blind, RCTs comparing cilostazol with a placebo or medications currently used to increase walking distance. A total of 3718 patients with IC due to PAD have been treated with cilostazol at 50 mg, 100 mg, and 150 mg b.i.d. compared with placebo, and cilostazol at 100 mg b.i.d compared with pentoxifylline at 400 mg thrice daily [21]. The treatment duration ranged from 6 to 26 weeks. Bedenis et al. revealed that absolute claudication distance (ACD, the maximum distance walked on a treadmill) was significantly increased in participants taking cilostazol at 100 mg and 50 mg b.i.d. compared with placebo (weighted mean differences [WMD]: 43.12 meters, 95% CI: 18.28–67.96 m, p=0.0007 and WMD: 32.00 m, 95% CI: 14.17–49.83 m, p=0.0004), respectively, despite the low quality of the trials methodology, with an unclear risk of bias. This review revealed that only one study assessed cardiovascular events with unclear evidence of all-cause mortality and cardiovascular event reductions between any treatment groups. Moreover, the meta-analysis reported that cilostazol treatment was associated with higher odds of adverse events, including headaches, diarrhea, abnormal stool, dizziness, and palpitations. QoL measurement was insufficient within the studies, although the cilostazol group demonstrated some possible indications. The authors concluded that cilostazol treatment improved walking distance in patients with PAD with IC with mild adverse side effects. Insufficient data suggest all-cause mortality and cardiovascular event reduction with cilostazol treatment, as well as QoL improvement [21].

Recently, Brown et al [22] updated the previous Cochrane review to determine the effect of cilostazol on ICD, ACD, mortality, and vascular events in patients with stable IC. They considered double-blind, RCTs of cilostazol versus placebo, or other drugs used to improve claudication distance in patients with stable IC. The authors included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies compared cilostazol with pentoxifylline. Treatment duration ranged from 6 to 26 weeks. All participants had IC secondary to PAD. Cilostazol has been shown to improve walking distance in people with IC. However, participants taking cilostazol had higher odds of experiencing headaches. Meta-analysis could not be undertaken, despite the importance of QoL to patients, because of differences in measures and reporting used. Lastly, this meta-analysis revealed no significant difference between cilostazol and pentoxifylline in improving walking distance due to scarce data.

Several guidelines on PAD suggest cilostazol to improve walking distance after lifestyle modification and supervised exercise training in patients with IC [10, 11, 12, 13, 14, 15]. Cilostazol has been suggested by guidelines from 2005 to 2016 to improve walking distance in patients complaining of claudication: both the European and American guidelines for PAD suggested cilostazol (Class of recommendation: I, level of evidence: B) as it was considered to have some effectiveness in improving walking distance in patients with claudication (Table I).

Table I European and American guidelines for the use of drugs to improve the symptoms (intermittent claudication) in patients with peripheral arterial disease [10, 11, 12, 13, 14, 15]

PAD	Guideline	Country	Year	Recommendation	Class of evidence, grade of recommendation
IC	ACC/AHA [10]	United States	2005	Cilostazol (100 mg orally twice daily) is indicated as an effective therapy to improve symptoms and increase walking distance in patients with lower extremity PAD and IC	1, Grade A
IC	TASC II [11]	Trans-Atlantic Inter-Society	2007	A 3- to 6-month course of cilostazol should be the first-choice drug therapy for the relief of claudication symptoms, based on evidence shown to improve both treadmill exercise performance and quality of life	1, Grade A
IC	ESC [12]	European Union	2012	Cilostazol was considered the best-documented drug in terms of walking distance improvement	Not reported
IC	ACC/AHA [13]	United States	2016	Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication	1, Grade A
IC	ESC [14]	European Union	2017	Cilostazol is not an effective therapy for IC: the beneficial effects, if any, are generally mild to moderate, with large variability.
				Also, the incremental benefit of these treatments in addition to exercise therapy and statins is unknown.
IC	ESVM [15]	European Union	2019	Cilostazol should be considered as it may be beneficial in improving walking distance in patients with claudication	1, Grade B

Table I European and American guidelines for the use of drugs to improve the symptoms (intermittent claudication) in patients with peripheral arterial disease [10, 11, 12, 13, 14, 15]

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In 2017, the European Guidelines of The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology and of the European Society for Vascular Surgery did not suggest the use of cilostazol [14]. The use of cilostazol raised questions, primarily regarding its questionable and dubious effectiveness: the beneficial effects on walking distance was generally mild to moderate, with large variability and the incremental benefit of cilostazol in addition to exercise therapy and statins was not unknown. On the contrary, for the European Society of Vascular Medicine (ESVM) Guidelines, cilostazol should be considered as it may be beneficial in improving walking distance in patients with claudication [15]. The ESVM guideline suggested that Cilostazol should be prescribed only in patients with substantially limited QoL and restricted, unfeasible, or ineffective walking training (Class of recommendation: I, Level of Evidence: B). It must be noticed that treatment with cilostazol should be discontinued if symptoms fail to improve after 3 months [15].

In summary, cilostazol could be effective on improve walking distance for patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures. However, it should be prescribed only in patients with substantially limited QoL and restricted, unfeasible, or ineffective walking training.

Cilostazol in reducing restenosis after endovascular treatment (EVT)

Some studies revealed that cilostazol could reduce the incidence of restenosis after endovascular revascularization procedures. The action of cilostazol on platelet-derived growth factors could prevent intimal hyperplasia and reduce the proliferation of vessel wall smooth muscle cells [20].

In 2008, Iida et al. investigated the efficacy of cilostazol in reducing restenosis after EVT in an RCT [23]. Cilostazol (200 mg/day, n 63) or ticlopidine (200 mg/day, n 64) in addition to aspirin (100 mg/day) was given to 127 patients with de novo femoropopliteal (FP) lesions. Restenosis, amputation, and death were significantly lower in the cilostazol group [23].

Robertson et al. [24] evaluated whether any antithrombotic drug is more effective in preventing restenosis or re-occlusion after peripheral EVT, compared to another antithrombotic drug, with no treatment, placebo, or other vasoactive drugs.

The authors concluded limited evidence indicating reduced restenosis/re-occlusion at 6 months following peripheral EVT with antiplatelet drugs compared with placebo/control. Data on bleeding and other potential gastrointestinal side effects were not consistently reported. Interestingly, some evidence indicated variation in effect according to different drugs with cilostazol. Treatment with cilostazol resulted in statistically significantly fewer re-occlusions than ticlopidine 12 months postoperatively (odds ratio [OR]: 0.32, 95% CI: 0.13–0.76; p=0.01) [24]. However, available trials were generally small and of variable quality, and the side effects of drugs were not consistently addressed.

In 2013, Iida et al. [25] revealed that cilostazol reduced angiographic restenosis after percutaneous transluminal angioplasty in 200 patients with provisional nitinol stent and FP lesions. Patients were randomly assigned 1:1 to receive oral aspirin with or without cilostazol. The angiographic restenosis rate was 20% (15/75) in the cilostazol group compared to 49% (38/77) in the non-cilostazol group after 12 months (p=0.0001). The cilostazol group had a significantly higher 12-month event-free survival (83% vs. 71%, p=0.02), although cardiovascular event rates were similar in both groups. The study results indicated the use of cilostazol as first-line antiplatelet therapy for reducing the incidence of restenosis in patients undergoing EVT with stenting for FP disease. Moreover, cilostazol has additional beneficial effects on arterial compliance, symptomatology, and QoL. A change in Rutherford classification, which was significantly lower in the cilostazol group than in the non-cilostazol group (p=0.03), was observed at 12 months pre-procedure between the groups [25].

In 2014, Warner et al. reviewed six studies in which almost 1500 patients received cilostazol plus antiplatelet treatment versus standard antiplatelet therapy alone after EVT of the FP segment. The results revealed that the addition of cilostazol decreased the restenosis after a follow-up from 18 to 37 months (RR: 0.71; 95% CI: 0.60–0.84; p<0.001), improving the amputation-free survival (AFS) (hazard ratio [HR]: 0.63; 95% CI: 0.47–0.85; p=0.002), limb salvage (HR: 0.42; 95% CI: 0.27–0.66; P<0.001), and freedom from target lesion revascularization (RR: 1.36; 95% CI: 1.14–1.61; p<0.001). Mortality among patients receiving cilostazol revealed no significant reduction (RR: 0.73; 95% CI: 0.45–1.19; p=0.21) [26].

A retrospective study by Neel et al. conducted in the United States in 2015 identified 22,954 patients who underwent lower extremities revascularization (LER). The amputation rates up to 1 year in 1999 patients treated with cilostazol was 14.8% versus 24% in the control group (P<0.0001). Further, results were confirmed in patients with comorbidities, and cilostazol treatment significantly improved 1-year AFS for patients with diabetes (HR: 1.61; 95% CI: 1.36–1.92; P<0.001) and renal failure (HR: 1.61; 95% CI: 1.28–2.02; P<0.001) [27].

Cilostazol continues to attract the interest of researchers in vascular settings although it remains unapproved for this indication in some European countries.

A more recent meta-analysis conducted by Iftikhar et al. reviewed 24 studies with 2434 patients. The primary efficacy outcome was the patency rate after stenting. The cilostazol group had better results (OR: 0.55; 95% CI: 0.43–0.71) than those without cilostazol [28].

A subsequent meta-analysis conducted by Megaly et al. in 2019 included 8 studies, with 3 RCTs and 5 observational, including 3846 patients (4713 lesions) and with a mean follow-up of 12.5 ± 5 months. The study revealed that cilostazol was associated with higher primary patency (OR: 2.28, 95% CI: 1.77–2.94, p<0.001, I²=24%), lower risk of target lesion revascularization (OR: 0.37, 95% CI: 0.26–0.52), p<0.001, I²=0%), and lower risk of major amputation (OR: 0.15, 95% CI: 0.04–0.62, p=0.008, I²=0%). The use of cilostazol was associated with significantly higher odds of primary patency in RCTs compared with observational studies (OR: 3.37 vs. 2.28, p=0.03) [29].

Lately, the ZERO study investigated the efficacy of cilostazol in improving drug-eluting stet (DES) patency by determining the effectiveness of DES or nitinol bare metal stent (BNS) with or without cilostazol in improving patency, 12 months after EVT for FP injuries. DES techniques play an essential role in EVT for FP lesions. Furthermore, cilostazol improved patency after BNS implantation for FP lesions. A prospective, open-label, multicentre study treated 85 patients with symptomatic claudication or rest pain with FP lesions with DES and cilostazol. Their results were compared with 255 patients from the DEBATE SFA study, in which patients were randomly assigned to the BNS, BNS with cilostazol, or DES hospital groups. The 12-month patency rates for the BNS, BNS and cilostazol, DES, and DES and cilostazol groups were 77.6%, 93.1%, 82.8%, and 94.2%, respectively (p=0.007). The patency rates in the two cilostazol groups (BNS and DES) were higher than the cilostazol groups, respectively. Therefore, cilostazol improved patency after EVT with DES in FP lesions and small vessels [30].

The role of cilostazol therapy in patients with advanced PAD, such as critical limb ischemia (CLI), has been investigated. In 2021, Desai et al. conducted a meta-analysis of RCTs and cohort studies evaluating the effect of cilostazol versus standard antiplatelet therapy on limb-related outcomes (AFS and limb salvage) and arterial patency-related outcomes (restenosis, freedom from target lesion revascularization (TLR), and repeat revascularization) [31]. This meta-analysis included 4 RCTS and 6 retrospective cohort studies including 3136 patients with advanced PAD and CLI. Patients were treated with revascularization procedures and had cilostazol added to DAPT. The authors observed a reduction of restenosis and all other limb-related events and arterial patency-related outcomes. Cilostazol increased the AFS (HR: 0.79; 95% CI: 0.69–0.91) and limb salvage rate (HR: 0.42; 95% CI: 0.27–0.66) and decreased repeat revascularization (RR: 0.44; 95% CI: 0.37–0.52) and restenosis (RR, 0.68; 95% CI, 0.61–0.76), thereby confirming the results of previous studies. Cilostazol also increased freedom from TLR (RR: 1.35; 95% CI: 1.21–1.53) with no difference in all-cause mortality in the mean follow-up time average of 24 months. However, the addition of cilostazol to DAPT is not suggested neither approved by guidelines in patients with CLI.

Recently, the outcomes of revascularization in patients with treated CLI were evaluated in real-world settings. The RIVALUTANDO Study [32], which is a prospective 12-month follow-up multicentre cohort study, enrolled patients (n=287) with CLI undergoing open, endovascular, or hybrid lower extremity revascularization. The primary endpoint was AFS at 12 months. MACE and MALE were evaluated at 30 days, demonstrating rates of 3.1% and 2.1%, respectively. The overall survival rate was 88.8%, the AFS was 86.6%, the primary patency was 70.5%, and freedom from MALE was 62.5% at 1 year. Multivariate analysis revealed smoking (HR=2.2, P=0.04), renal failure (HR=2.3, P=0.03), Rutherford class (≥5) (HR=3.2, P=0.01), and below-the-knee disease (HR=2.0, P=0.05) as significant predictors of amputation. The administration of cilostazol (HR=0.77, p=0.05) resulted a significant protective factor for restenosis. Medical treatment, including statins, cilostazol, and iloprost, were associated with improved 1-year freedom from restenosis and amputation [32].

Further studies over the years have revealed the role of cilostazol in reducing restenosis (Table II) [23, 33, 34, 35, 36, 37, 38, 39, 40].

Table II The efficacy of cilostazol in reducing restenosis after endovascular revascularization in patients with PAD

Study	Population involved	Primary outcome	Efficacy results
Soga Y, 2009 [33]	Randomly assigned 80 patients with IC due to a FP lesion to receive or not receive cilostazol in addition to aspirin.	The primary endpoint was the binary restenosis rate, and the secondary endpoint was re-occlusion.	Freedom from target vessel revascularization at 2 years after EVT was significantly higher compared with the control group (84.6% vs. 62.2%, p=0.04). The restenosis rate was lower in the cilostazol group (43.6% vs. 70.3%, p=0.02).
Ikushima I, 2011 [34]	Of the 28 patients with PAD, who had successfully undergone stent implantation, 15 received cilostazol, 13 received ticlopidine	The primary endpoint was the comparison between cilostazol and ticlopidine regarding the occurrence of in-stent stenosis in patients who had undergone stent implantation for SFA.	Patients receiving cilostazol had a significantly reduced risk of restenosis (hazard ratio: 5.4; p=0.042).
Soga Y, 2012a [35]	Of the 63 patients with CLI: – 32 received cilostazol, – 31 received aspirin or thienopyridines alone.	The primary endpoint measure was binary restenosis on an angiogram at 3 months.	Binary restenosis was significantly lower in the cilostazol group than in the non-cilostazol group in a lesion-based analysis (56.8% vs. 86.0%; p=0.015). Cilostazol was associated with reduced angiographic restenosis after adjustment for co-variables.
		Secondary endpoint measures were re-occlusion and clinically driven TLR.
Iida O, 2008 [23]	Of the 127 patients who were successfully treated with EVT for de novo FP lesions: – 63 received cilostazol+aspirin, – 64 received ticlopidine+aspirin.	The primary endpoint was patency in treated segments.	The patency rate was significantly higher in the cilostazol group than in the ticlopidine group (p=0.013).
		The secondary endpoints were TLR and all events, including restenosis, amputation, and death from any causes.	Restenosis was significantly lower in patients treated with cilostazol than in those treated with ticlopidine (p=0.031).
Soga Y, 2012b [36]	Of the 861 consecutive patients who underwent successful stenting for de novo lesions: – 492 received aspirin+clopidogrel+cilostazol, – 369 received aspirin+clopidogrel.	The primary endpoint was the binary restenosis rate.	Binary restenosis rates were significantly lower in the cilostazol group (31.2% vs. 42.9% at 5 years, p=0.02).
		Secondary endpoints were re-occlusion, all-cause mortality, and limb salvage in patients with CLI.	In-stent re-occlusion rate was lower in patients who received cilostazol (10.8% vs. 18.2% at 5 years, p=0.09) compared with the control.
Nanto K, 2015 [37]	A total of 2737 patients (mean age: 72 ± 9 years; 61% diabetic; and 26% on regular dialysis) underwent EVT for FP lesions from 2004 to December 2011.	The primary endpoint was to evaluate the role of cilostazol in reducing angiographic restenosis rate in patients undergoing EVT for FP.	Cilostazol treatment was inversely associated with restenosis for the first 2 years following EVT (p<0.05).
Tomoi Y, 2017 [38]	Of the 338 patients who underwent endovascular therapy for FP ISR: – 24 treated with cilostazol, – 217 were not treated with cilostazol, – 97 patients who received cilostazol after the initial stent implantation were excluded.	The primary endpoint was a 2-year Re-ISR after treatment.	At 2 years, freedom from recurrent ISR (Re-ISR) was significantly higher in the cilostazol group than in the group of patients not receiving cilostazol (48.6% vs. 32.4%, p=0.047).
		The secondary end points were recurrent TLR and re-occlusion at 2 years.
Zen K, 2017 [39]	A total of 399 patients-maintained therapy with aspirin and thienopyridine, with or without cilostazol, during the 1-year follow-up period.	The primary endpoint was a 12-month restenosis rate. Restenosis was defined as the recurrence of 50% diameter stenosis or peak systolic velocity ratio of >2.4 determined by angiography or DUS, respectively	The 1-year restenosis rate was 33% (95% CI: 23%–43%) in the cilostazol-treated group and 51% (95% CI: 41%–62%) in the cilostazol-free group (p=0.008). The odds ratio was 0.5 (95% CI: 0.3–0.8)
Soga Y, 2018 [40]	A total of 200 patients (mean age 73 years; 131 males) were treated for FP disease from March 2009 to April 2011 at 13 cardiovascular centers in Japan.	The primary endpoint was the primary patency.	Primary patency was significantly higher in the cilostazol group than in the no-cilostazol group (69% vs. 54%, p=0.026) at 3 years. The cilostazol group had better 3-year freedom from CD-TLR (78% vs. 63%, p=0.014), although overall survival estimates did not significantly differ (p=0.95).
		The secondary endpoints were freedom from clinically driven TLR (CD-TLR) and overall survival.

Table II The efficacy of cilostazol in reducing restenosis after endovascular revascularization in patients with PAD

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Discussion

Cilostazol is approved and suggested in treating PAD with IC. Cilostazol has been implicated in several basic pathways, including adenosine reuptake inhibition, and the inhibition of multidrug resistance protein 4, among others. It has demonstrated antiplatelet, antiproliferative, vasodilatory, and recently, ischemic-reperfusion protective properties. The pleiotropic effect of cilostazol has been investigated for clinical use in various settings: after percutaneous coronary intervention, peripheral EVT, and secondary stroke prevention. This review highlighted the effects of cilostazol on IC in PAD and on restenosis reduction after EVT and the evidence for its clinical use.

Several large-scale, placebo-controlled, and meta-analysis have revealed a significantly increased pain-free and maximum walking distance in addition to superiority over other drugs, i.e., pentoxifylline, in IC with exertional leg pain resolving with rest, which is a typical symptom in patients with PAD, although a proportion of patients with PAD presents with atypical claudication or no exertional leg symptoms [16, 17, 18, 19, 20, 21]. The hemodynamic discrepancy between the metabolic muscle tissue demand and the blood flow during walking in IC determines transient muscle ischemia with cramping pain, for which the patient is forced to stop to restore the microcirculatory homeostasis of the muscle tissue with pain relief [41]. IC is a marker of atherosclerosis and cardiovascular risk in addition to being a PAD symptom. Guidelines recommended the so-called best medical treatment (BMT), which lowers MACE and MALE and improves function and symptoms. The cornerstones of BMT, as shown in Figure 2, include lifestyle therapeutic modifications, especially smoking cessation, and exercise, targeting blood pressure goals, low-density lipoprotein, and glucose-lowering, and antithrombotic therapies.

Although Bonaca, in his “Peripheral Vascular Disease Compendium”, recommended cilostazol as first-line therapy for symptomatic patients with IC [42], exercise therapy is the first line therapy given to its effectiveness in improving quality of life, symptoms, and maximal walking distance. Supervised exercise training should be made available as part of the initial treatment for all patients with peripheral arterial disease and is recommended by all guidelines (Class of recommendation: I, Level of Evidence: B). Cilostazol should be used to improve walking distance in patients with disabling IC who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures.

The data by Warner [26] in 2014 and Desai [31] in 2021 demonstrated increased AFS and limb salvage rate and decreased restenosis without affecting the risk of bleeding in the addition of cilostazol to DAPT. Based on this evidence, cilostazol should be considered for MALE reduction in patients with high bleeding risk (shown in Figure 2).

The physical activity of patients affected by PAD and IC is limited, and the consequences embrace the psychophysical sphere with poor QoL and depression. Therefore, IC treatment and walking performance improvement become fundamental points in the patient’s overall therapy. Structured walking training at least three times a week for 30 to 60 minutes have demonstrated increasing walking distances amounting to 200% after 12 weeks. Hence, the guidelines recommend that supervised training programs under regular instruction be offered as first line therapy for IC. It must be noticed that they are more effective than unstructured vascular training. When supervised exercise is not possible or unsuccessful, cilostazol is suggested for its beneficial effects in patients with IC and substantially limited QoL, walking training restricted unfeasible or ineffective. Importantly, cilostazol use is associated with QoL and function improvements. The benefits of cilostazol concerning claudication symptoms and walking distance have been confirmed, specifically among patients with diabetes [2]. However, it should be discontinued if symptoms fail to improve after 3 months.

The patient’s walking performance improvement is probably due to its vasodilator and antiplatelet aggregation effects. The inhibition of phosphodiesterase’s with an increase in intracellular cAMP determines the endothelial release of nitric oxide, with a consequent smooth muscle cell relaxation of the arteriolar wall, and vasodilatation. This effect could enhance the existing arterial collateral circulation, improving the patient’s walking distance. However, the exact mechanism through which cilostazol improves walking capacity is unknown [3].

Moreover, cilostazol has significant effects on atherogenic dyslipidaemia beyond its antiplatelet and vasodilator properties. Cilostazol can significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B, and postprandial lipemia. Cilostazol improves the pro-atherogenic lipid profile in patients with PAD or type 2 diabetes. The benefits of lipid lowering with statins and other lipid reducing agents in PAD is without doubt and some evidence support the use of statin in improving claudication. Several small studies applying various doses of atorvastatin or simvastatin to treat patients with claudication showed an increase of absolute walking distances compared to placebo [43, 44].

The more recently reviewed data from Brown et al. in 2021 [22] emphasized the benefit of cilostazol in improving walking distance in people with IC secondary to PAD: patients taking cilostazol for 3–6 months could walk approximately 26 m further before the onset of calf pain and 40 m in terms of total distance on a treadmill compared to participants taking placebo. The authors affirm that the value of these increases in walking distance would be patient specific. However, the same author emphasized that Cochrane shows some limitations: many included studies were quite “old” and were conducted before BMT was recommended or applied in patients with stable IC; therefore, it might not be an accurate representation of current practice. A further limitation to this evidence is that the Cochrane of Brown, published in 2021, has included and analysed the same 15 studies of the previous Cochrane published in 2014 by Bedenis, adding just one outdated study, published in 2001. Moreover, studies have low to moderate qualities. The cilostazol group had nearly three times the odds of experiencing headaches compared to the placebo group. However, these events are generally mild and treatable [21]. Insufficient data about the effectiveness of cilostazol for events, such as amputation, revascularization, cardiovascular events, and QoL improvement, have been evaluated because the primary outcome of included studies in both Cochranes was the ICD.

In the last decade, numerous pieces of evidence have been produced on the use of cilostazol in restenosis. Restenosis is a major complication of revascularization procedures with a significant clinical impact due to revascularized vascular lumen re-occlusion. The incidence rate of restenosis varies from 5% to 70% after peripheral revascularization, with considerable variability due to the characteristics of the procedure and the type of patients [6].

Recently, in 2019, a consensus from the European Society of Cardiology and the European Society of Vascular and Endovascular Surgery revealed a significant impact of restenosis and occlusion on patients’ lives. Restenosis and occlusion range from 5% in the inguinal area to >50% in the infrapopliteal area, recording an almost uniform failure rate over 5 years after revascularization with an increased risk of limb loss [45]. Mechanical injury to the arterial wall of the treated vessel causes a complex inflammatory response resulting in platelet activation, fibrin deposition, leukocyte migration, and smooth muscle cell hyperproliferation, but the pathogenetic mechanisms underlying the development of restenosis remain unclear [6].

Currently, cilostazol is not suggested or recommended by guidelines for restenosis prevention. However, no drugs have been authorized for restenosis prevention after peripheral revascularization procedures, and the only useful strategy is now represented by medical devices: drug-eluting stents releasing antiproliferative drugs. Oral antiplatelet aggregation drugs (e.g., aspirin, clopidogrel, prasugrel, ticlopidine, ticagrelor) should be administered after a cardiac revascularization procedure to prevent stent or by-pass re-occlusion essentially due to thrombotic events, but they have no relevant effects on re-occlusion phenomena caused by target vessel restenosis (hyperproliferative events). Additionally, statins have been proposed as anti-restenosis agents but with no adequate clinical findings, and their impact on stent restenosis remains controversial [16].

The dual antiplatelets (aspirin and clopidogrel) may be reasonable for at least one month in patients with PAD after percutaneous transluminal angioplasty or stenting, but the data for the use of dual antiplatelet therapy in this population are lacking. Recently, the VOYAGER trial showed that low-dose rivaroxaban (2.5 mg) taken twice a day plus aspirin (100 mg) once a day reduced reduced the incidence of the composite outcome of acute limb ischemia, amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular death when compared with aspirin alone [46]. Although rivaroxaban increased bleeding, there was no increase in post-procedural take-back bleeding, intracranial bleeding, or fatal bleeding, and the overall rates of bleeding were low. Prediction scores can help evaluate the risk of bleeding for more appropriate medical treatment in patients undergoing both endovascular and open surgical revascularizations.

Cilostazol, besides the vasodilatory and antiplatelet properties, has also an antiproliferative action on the smooth muscle cells of the vessels. Recent studies have demonstrated a marked reduction in restenosis rates following coronary and peripheral interventions with cilostazol administration, in addition to standard therapy (DAPT with ASA and clopidogrel) compared to placebo. A favourable effect on re-endothelization mediated by hepatocyte growth factor [47] and endothelial precursor cells [48] as well as on inhibiting smooth muscle cell proliferation [49] and leukocyte adhesion to the endothelium due to an anti-inflammatory effect [6] has been reported. These effects may suggest some efficacy of cilostazol in preventing restenosis and improving the long-term outcome of revascularization interventions. Preliminary report indicated no increase in bleeding when cilostazol is used with DAPT compared to dual antiplatelet therapy alone although the currently approved label of cilostazol in Europe indicates the increased risk of bleeding with concomitant cilostazol administration and dual antiplatelet therapy [50]. An RCT with patients with acute coronary syndrome undergoing stenting revealed that triple therapy had similar bleeding events compared with DAPT [51]. However, randomized clinical studies are needed to ascertain if the combination treatment with ASA and cilostazol can improve patency and reduce amputation rates following infrainguinal EVT. Only the addition of rivaroxaban to aspirin as a secondary prevention strategy for PAD surgical revascularization is a major advancement over previous studies from an efficacy standpoint (number needed to treat, 24) to reduce adverse cardiovascular and limb events [52].

As far as it concerns safety, the use of cilostazol is contraindicated in patients clinically manifesting heart failure, unstable angina, and MI, or undergoing coronary intervention within 6 months, as well as severe tachyarrhythmia. However, cilostazol has been studied in patients undergoing coronary intervention after discharge and in addition to DAPT with favourable results in MACE reduction without increasing bleeding or mortality [50]. The main side effects, headache, and diarrhoea are attributed to the vasodilating properties of cilostazol. The incidence of side effects reported varied between the studies, but the most reported potentially drug-related events were headache, diarrhoea, abnormal stools, dizziness, pain, and palpitations, which were mild or moderate and occurred mainly during the first 2 weeks of therapy [16]. Many patients may not tolerate this medication for this reason. Notably, the collaborative European study published in 2017 by Castellsague et al. revealed that cilostazol users are elderly patients with cardiovascular disease and other comorbidity and concurrent use of interacting drugs [53]. These results indicate that cilostazol is usually prescribed to a vulnerable population at high risk of complications, especially cardiovascular events.

Conclusions

In conclusion, cilostazol is an agent with a pleiotropic mechanism of action and multiple beneficial effects through a combination of platelet inhibition, vasodilation, antiproliferative, and lipid-lowering properties. These properties indicate promising effects of cilostazol in managing atherosclerotic vascular disease, especially in peripheral arteries. Cilostazol may improve the walking performance of IC in PAD and may reduce the incidence of restenosis after peripheral revascularization procedures. Cilostazol could stabilize PAD progression in different moments of the patient’s history, namely stable claudication, and after revascularization with an increased risk of restenosis and re-occlusion in patients with PAD. However, robust clinical trials confirming its efficacy are lacking. Cilostazol may be used to improve walking distance in patients with disabling IC who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures, and it should be discontinued if symptoms fail to improve after 3 months.