Cilostazol induces cAMP elevation in vascular smooth muscle cells via inhibition of PDE III-dependent degradation and adenosine (A2)-induced stimulation of cAMP formation (Fig. 1).4) In turn, cAMP inhibits calcium entry and migration, proliferation, and matrix synthesis in smooth muscle cells. Many downstream pathways have been suggested based on in vitro studies, including inhibition of [3H] thymidine incorporation into deoxyribonucleic acid (DNA), inhibition of interleukin-6 production, activation of cAMP-dependent protein kinase-A (PKA), induction of the p53 and p21 antioncogenes and apoptosis, downregulation of p27Kip1, and inhibition of expression of the E2F1, E2F2, and E2F4 proteins.5)6) After stent placement, cilostazol inhibits stent-induced P-selectin expression on platelets and upregulates leukocyte Mac-1, thereby inhibiting neointimal growth.7)

Cilostazol induces elevation of endothelial cAMP via inhibition of PDE III degradation and A2-induced stimulation of cAMP formation in endothelial cells. Elevated cAMP stimulates endothelial cell proliferation, reduces expression of adhesion molecules (i.e., vascular cell adhesion molecule-1), inhibits cytokine release and action (monocyte chemoattractant protein-1, platelet derived growth factor, tumor necrosis factor-α), and inhibits apoptosis.8)9) Cilostazol induces nitric oxide (NO) production through endothelial nitric activation via a cAMP/PKA- and PI3K/Akt-dependent mechanism, and this effect is involved in capillary-like tube formation in human aortic endothelial cells.10) Moreover, cilostazol has a potential anti-inflammatory effect on monocyte-endothelial interactions via upregulation of intracellular cAMP.

Platelets exhibit predominant PDE III reaction, with subordinate PDE II and V reaction. Cilostazol elevates cAMP in human platelets via inhibition of PDE III-dependent degradation at high concentrations. It also potentiates the cAMP-elevating and antiplatelet effects of adenylate cyclase-activating agents (prostaglandin E1 and I2) at a low concentration.5) Increased cAMP levels facilitate the influx of free calcium ions back into storage granules in the platelets. The free calcium ions are needed for the formation of the glycoprotein IIb/IIIa complex, degranulation of the storage granules containing aggretating substances, and production of thromboxane A2 (Fig. 2).

In animal models, the antiplatelet effect of cilostazol is much stronger than that of aspirin.5) Furthermore, platelet aggregation induced by adenosine 5' diphosphase (ADP) or collagen is inhibited in dogs after oral admins-tration of cilostazol.11)

The anti-platelet and vasodilating effects of cilostazol are believed to underlie its preventive effect on recurrent stroke. It is also considered to be effective in promoting recovery from functional damage of the endothelium in cerebral penetrating arterioles. Cilostazol also promotes brain cell survival ascribed to maxi-K channel opening-coupled upregulation of creatinine kinase 2 phosphorylation and downregulation of PTEN phosphorylation, with a resultant increase in phosphorylation of Akt and CREB.12)

Cilostazol inhibits smooth muscle cell migration and proliferation and promotes endothelial cell growth. It has been viewed as a novel antiproliferative drug acting on smooth muscle cells. After its anti-restenosis mechanisms were first acertained, cilostazol was suggested as an effective agent for the prevention of restenosis after vascular interventions. Cilostazol has been proven in multiple randomized clinical trials to reduce restenosis in the setting of coronary interventions. In the balloon angioplasty era, some clinical trials suggested cilostazol as a potential agent for reducing restenosis. Balloon angioplasty plus cilostazol administration showed favorable outcomes compared to bare-metal stenting in the setting of small-vessel disease.13) After bare-metal stenting, cilostazol was comparable or superior to ticlopidine in reducing restenosis.14) On a cost-effect analysis, treatment with cilostazol proved to be a cost-saving or dominant strategy in patients with coronary bare metal stent (BMS) implantation.15)

Although the introduction of DES has dramatically reduced neointimal hyperplasia and restenosis compared with BMS, several conditions still place patients at high risk for restenosis: diabetes mellitus, long lesions, and small vessel disease.16) Combination aspirin and cilostazol therapy have been shown to reduce in-segment restenosis by 50% compared to combination aspirin and clopidogrel therapy in diabetic patients after DES implantation.17)

A similar result was demonstrated in another study documenting that triple therapy (aspirin, clopidogrel, and cilostazol) reduced in-segment restenosis by 50% compared to dual therapy (aspirin plus clopidogrel) in diabetic patients.18) In long lesions, cilostazol reduced late in-stent and in-segment loss and reduced the occurrence of target-vessel revascularization at 6 months after DES implantation.19) Furthermore, cilostazol treatment changed in-stent restenosis morphology to a more focal pattern compared to that seen in clopidogrel-treated patients.20)

During and after elective BMS implantation, aspirin plus cilostazol showed an antithrombotic effect comparable to that seen with aspirin plus ticlopidine.21) Cilostazol also demonstrated effectiveness comparable to clopidogrel in preventing thrombosis after bare-metal stenting.22) In the BMS era, there is no evidence to suggest that any one combination therapy-aspirin plus ticlopidine, aspirin plus clopidogrel, or aspirin plus cilostazol is superior to the others for use after cardiac events.

DESs appear to prolong the duration of re-endothelialization, and stent thrombosis has emerged as a major concern. Late stent thrombosis has been shown to be substantially higher among real-world patients compared to those included in clinical trials.23) Current American College of Cardiology/American Heart Association (ACC/AHA)/Society for Cardiac Angiography and Interventions (SCAI) guidelines recommend dual antiplatelet therapy for at least 12 months in patients at low risk for bleeding, especially off-label patients. Cilostazol is considered the third antiplatelet agent in patients at high risk for thrombosis. Diabetic patients who underwent DES implantation and who were treated with a combination of aspirin and cilostazol showed a late stent thrombosis rate comparable to that seen in patients treated with aspirin and clopidogrel during 7.1 months of follow-up.17) A randomized multicenter study comparing triple therapy (aspirin, clopidogrel, and cilostazol) and dual therapy (aspirin and clopidogrel) in patients with long lesions requiring a long DES showed similar rates of stent thrombosis at 9 months.19) Until now, there is no concrete evidence to suggest that triple therapy is superior to dual therapy in preventing stent thrombosis in the short-term. We need to gather data concerning the effect of cilostazol on very late stent throbosis (i.e, that presenting beyond 1 year after stent implantation). Another recommendation is substitutive or additive use of clopidogrel in nonresponders.

About 20% of patients undergoing percutaneous coronary intervention are resistant to clopidogrel. Despite clopidogrel therapy, these patients are at high risk for recurrent thrombotic events.24) Triple therapy attenuates the prevalance of clopidogrel resistance in patients undergoing coronary intervention.25)

Cilostazol seems to be an effective alternative or additive antiplatelet agent in patients who need to discontinue clopidogrel because of drug-related side effects, those at high risk for stent thrombosis, and those with clopidogrel resistance; however, available evidence remains limited due to small study effects, and large randomized clinical trials are needed.

In Korea, two agents are available for the treatment of intermittent claudication: pentoxifylline and cilostazol. Cilostazol has a vasodilating effect because it inhibits PDE III in the blood vessel by increasing cAMP levels in vascular smooth muscle cells. Cilostazol also increases nitric oxide synthesis in vascular endothelium without interfering with prostacyclin synthesis.10) The vasodilatory effect is not uniform or dose-dependent. It shows high selectivity for the vertebral and femoral arteries.26) Cilostazol therapy (200 mg/day for 6 weeks) has been shown to improve skin temperature and blood flow in the legs and feet of patients with peripheral occlusive disease.27) The clinical efficacy of cilostazol has been demonstrated in many clinical trials. It has been shown to be beneficial in improving maximal and pain-free walking distances in patients with intermittent claudication who do not have rest pain or peripheral tissue necrosis. Randomized trials have shown that the mean change in maximal walking distance is superior to that achieved with pentoxifylline; the effect is dose-responsive.28) Cilostazol also has a role in the prevention of restenosis after percutaneous transluminal angioplasty in the setting of peripheral vascular occlusion. After peripheral endovascular therapy, freedom from target-lesion revascularization and all adverse events (restenosis, amputation, and death) has been shown to be significantly higher in cilostazol-treated patients than in ticlopidine-treated ones. The American College of Chest Physicians evidence-based clinical practice guidelines (8th edition) for antithrombotic therapy for peripheral artery occlusive disease recommends cilostazol in patients with moderate-to-severe intermittent claudication who do not respond to exercise therapy and who are not candidates for surgical catheter-based intervention (Grade 1A).29)