Peripheral artery disease (PAD) is linked with increased cardiovascular (CV) risk, limb morbidity and all-cause death . Age, smoking and type 2 diabetes mellitus (T2DM) are strong predictors of PAD development [2,3,4,5]. In all PAD patients, best medical therapy (BMT) should be implemented, including best pharmacological therapy (antihypertensive, lipid-lowering and antithrombotic drugs), as well as smoking cessation, healthy diet, weight loss and regular physical exercise . Unfortunately, PAD frequently remains undiagnosed, and thus untreated, due to the absence of typical clinical symptoms (i.e., intermittent claudication, IC), as well as the lack of disease awareness for both patients and physicians . In the presence of IC, the risk of CV and limb morbidity, as well as all-cause mortality, are further increased . Hence, PAD treatment should be immediately initiated, targeting at controlling CV risk factors and improving IC.
Cilostazol is a unique antiplatelet drug that selectively targets phosphodiesterase III (PDE-III), and thus, apart from inhibiting platelet aggregation (induced by epinephrine, collagen, arachidonic acid and 5′-adenosine diphosphate), it can also improve endothelial cell function . Cilostazol-induced PDE-III inhibition primarily increases cAMP levels, subsequently leading to upregulation of protein kinase A (PKA) activity, which phosphorylates key molecules in the process of platelet aggregation . Cilostazol-mediated increase in cAMP levels also involves the inhibition of adenosine re-uptake, resulting in raised circulating and interstitial adenosine levels, which, in turn, bind to adenosine receptors . Thus, adenylate cyclase activity is upregulated via Gs proteins . In addition to PDE-III, cilostazol inhibits the activity of the multidrug resistance protein 4 (MRP4), which is implicated in platelet aggregation  and residual platelet reactivity following aspirin therapy .
Potential mechanisms for the vasodilatory effect of cilostazol include PKA phosphorylation of myosin light chain kinase, transient receptor potassium canonical channels, endothelial nitric oxide synthase (eNOS) and G protein coupled receptor kinase 2, as well as hyperpolarisation of smooth muscle cell membranes and inactivation of Galpha-q-mediated signalling . In relation to its antiproliferative actions, cilostazol downregulates (via cAMP elevation and PKA activation) several endothelial adhesion molecules, such as the vascular cell adhesion molecule (VCAM), the intercellular adhesion molecule (ICAM) and E-selectin, as well as modulates growth factors [e.g. platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and nitric oxide]  Of note, cilostazol upregulates eNOS activity (thus, improving endothelial dysfunction) through multiple pathways, including activation of PKA and kinase Akt .
Cilostazol has been reported to increase pain-free walking distance in PAD patients with IC, as supported by previous Cochrane reviews, dated in 2008 and 2014 [8, 11,12,13] and an updated one, published in 2021 . Indeed, cilostazol is mainly indicated for improving IC in PAD patients, although it may also exert other “pleiotropic” CV effects (e.g. antithrombotic, vasodilation, inhibition of vascular smooth muscle cell proliferation, protection from restenosis) . Such cilostazol-induced CV benefits may lead to better limb and CV outcomes, but strong evidence is lacking in this field [14, 16,17,18,19]. Real-world data are important in addressing major public health problems, such as PAD . Furthermore, such data provides a “realistic” view of how (and if) a disease is managed in daily practice, as well as the level of clinical guidelines implementation. Therefore, we aimed to examine the effects of cilostazol on pain-free walking distance in PAD patients with IC, as well as to record how PAD is treated in primary care in a real world, prospective, observational study.