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Cilostazol (Pletal®) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.
Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo. Additionally, a large comparative 24-week trial showed that cilostazol 100mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo).
Cilostazol was generally well tolerated. Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.
Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e. g. erythromycin or diltiazem) or CYP2C19 (e. g. omeprazole). As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, cilostazol itself does not appear to inhibit CYP3A4. Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation.
Conclusion: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication. In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline. Cilostazol is also generally well tolerated. Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication. Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment. Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.
Cilostazol has antiplatelet, antithrombotic and vasodilating properties. In vitro, ex vivo and in vivo studies have shown that cilostazol inhibits both primary and secondary platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine (adrenaline), thrombin, remnant-like lipoprotein and shear stress without affecting bleeding time. In animal models, cilostazol inhibited thrombus formation induced by various stimuli.
Cilostazol causes vasodilation by inhibiting calcium-induced contractions of smooth muscle cells (SMCs) while having no direct effect on contractile proteins. Cilostazol 100mg twice daily for 6 weeks significantly increased skin temperature, ankle blood flow and skin blood flow in the legs of patients with intermittent claudication (p < 0.05).
The drug also inhibits proliferation of vascular SMCs induced by a variety of growth factors in animal models and human cells in vitro and demonstrates beneficial effects on certain plasma lipids. High density lipoprotein-cholesterol levels increased and levels of triglycerides decreased relative to placebo or baseline after 8–12 weeks’ treatment with cilostazol 100mg twice daily in two randomized, double-blind trials.
The precise mechanism by which cilostazol improves the symptoms of intermittent claudication is not fully known, but is thought to be multifactorial. Cilostazol is a selective inhibitor of phosphodiesterase-III (PDE-III), thereby suppressing cyclic adenosine monophosphate (cAMP) degradation. Cilostazol also inhibits adenosine uptake into cells which augments the cAMP-elevating effect of PDE-III inhibition.
In patients with intermittent claudication, steady state was reached within 4 days following multiple doses of cilostazol. The peak plasma concentration (Cmax) at steady state was 1331.5 μg/L with a regimen of 100mg twice daily and occurred 2.7 hours after the final dose. The high apparent volume of distribution of cilostazol (2.76 L/kg) suggests extensive tissue binding. Cilostazol is extensively bound to plasma proteins with a free fraction of 2–5%.
Coadministration of cilostazol with food (a high fat meal) increased the rate and also the extent of cilostazol absorption.
Cilostazol is extensively metabolized (oxidative metabolism) to dehydro-cilostazol (OPC-13015) by cytochrome P450 (CYP) 3A4 and to monohydroxy-cilostazol (OPC-13213) via CYP2C19. A radiolabeled dose of cilostazol in healthy volunteers showed that urine (73.8%) and feces (21.7%) were the major routes of excretion. Cilostazol had an elimination half-life of 10.5 hours in patients with intermittent claudication.
The pharmacokinetic profiles of cilostazol and its two main metabolites (OPC-13015 and OPC-13213) after the administration of cilostazol 100mg twice daily over a 7-day period to healthy middle-aged and elderly men and women (aged 50–80 years) were not significantly affected by age or gender.
Mild to moderate renal impairment did not affect the pharmacokinetics of multiple doses of cilostazol (50mg twice daily for 6 days). However, severe renal impairment alters plasma concentrations and the protein binding of cilostazol and its metabolites, and the drug is contraindicated in these patients in Europe. Mild or moderate hepatic impairment had no appreciable effect on the pharmacokinetic properties of a single dose of cilostazol 100mg or its metabolites, while the effects of severe hepatic impairment on cilostazol pharmacokinetics have not been evaluated.
Coadministration of cilostazol with moderate inhibitors of CYP3A4 led to significantly increased cilostazol Cmax values (by 47% with erythromycin) or exposure (by 53% with diltiazem). Coadministration of cilostazol with an inhibitor of CYP2C19, omeprazole, resulted in a significant increase in the systemic exposure of cilostazol (26%).
Cilostazol does not appear to inhibit CYP3A4, as there were no changes in the pharmacokinetics of a single dose of lovastatin 80mg or its metabolites when coadministered with cilostazol at steady state (lovastatin is primarily metabolised by CYP3A4.
There were no clinically significant interactions after coadministration of cilostazol 100mg twice daily and aspirin 325 mg/day and cilostazol 100mg twice daily and a single dose of warfarin 25mg as measured by the prothrombin time, activated partial thromboplastin time and bleeding time or platelet aggregation.
Results from eight well designed 12- to 24-week clinical trials involving more than 2000 patients with intermittent claudication have shown that treatment with cilostazol 100mg twice daily is generally associated with significant improvements in maximum walking distance (MWD) and pain-free walking distance (PFWD) at study end compared with placebo (p < 0.05). The efficacy of cilostazol was seen as early as 4 weeks after initiation of therapy.
The efficacy of cilostazol 50mg twice daily has been studied in two clinical trials. One trial, found that cilostazol 50mg twice daily resulted in significantly greater improvements in MWD (p < 0.001) and PFWD (p < 0.001) compared with placebo. However, the other trial found no significant difference in the improvements in MWD seen with cilostazol 50mg twice daily and placebo.
Cilostazol 100mg twice daily (n = 205 intent-to-treat [ITT] analysis) was significantly more effective in increasing the MWD (p < 0.0002) and PFWD (p < 0.02) than pentoxifylline 400mg three times daily (n = 212 ITT analysis) after 24 weeks of treatment in a large clinical trial in patients with moderate to severe intermittent claudication. There was no significant difference between pentoxifylline and placebo with regards to changes in walking distance during the trial.
Evidence suggests that patients with intermittent claudication perceive their functional status and quality of life to be significantly improved with cilostazol compared with placebo. Patient perceptions of functional status or quality of life were similar for those receiving cilostazol 100mg twice daily or pentoxifylline 400mg three times daily. However, significantly more patients treated with cilostazol assessed their response to treatment as successful relative to baseline compared with those receiving pentoxifylline.
Treatment with cilostazol 100mg twice daily significantly increased the resting ankle brachial index (ABI) compared with placebo (p < 0.05); however, this was only a moderate improvement in terms of clinical significance. There was no significant difference for the change in ABI between the cilostazol or pentoxifylline treatment groups.
Withdrawal of treatment was studied in a subgroup of patients (n = 45) who participated in the large comparative study with pentoxifylline. The results of this small study suggest that withdrawal of cilostazol resulted in a significant loss of walking distance in patients with intermittent claudication by 2 weeks (p = 0.001). Conversely, the withdrawal of pentoxifylline did not significantly affect walking distances.
Cilostazol was generally well tolerated in clinical trials. Pooled tolerability data from placebo-controlled clinical trials indicated headache, diarrhea, abnormal stools, pain, infection, pharyngitis, rhinitis, peripheral edema and nausea were the most common adverse events, occurring in 5% or more of cilostazol recipients (n = 1301). Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.
Adverse events reported more often with cilostazol than with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. However, a similar percentage of patients receiving cilostazol and pentoxifylline withdrew from the large clinical trial because of adverse events (16% vs 19%).
The rate of serious adverse events (myocardial infarction, chest pain or angina pectoris) was low and similar between the three treatment groups (cilostazol, pentoxifylline and placebo).
Data from a single study presented as an abstract and poster suggest that although cilostazol has a higher acquisition cost than both pentoxifylline and placebo the incremental cost per quality-adjusted life-year is reasonable compared with pentoxifylline and placebo. No studies assessing the cost effectiveness of cilostazol have been reported.
Dosage and Administration
Cilostazol is indicated for the reduction of symptoms of intermittent claudication in the US and for the improvement of MWD and PFWD in patients with intermittent claudication in Europe.
The recommended dosage of cilostazol for intermittent claudication is 100mg twice daily administered orally half an hour before, or 2 hours after, meals. No dosage adjustments are recommended for the elderly. In Europe, no dosage adjustments are recommended for patients with mild hepatic impairment or those with mild to moderate renal dysfunction (creatinine clearance [CLCR] of >1.5 L/h [>25 mL/min]).
Cilostazol is contraindicated in patients with congestive heart failure of any severity due to theoretical concerns related to its mechanism of action and classification as a PDE-III inhibitor. Caution is recommended when using cilostazol in patients with coronary heart disease as the long-term effects of cilostazol in these patients are unknown. The effects of cilostazol in patients with moderate or severe hepatic impairment and in nursing or pregnant women have not been extensively studied; however, in Europe cilostazol is contraindicated in these patients. In Europe, cilostazol is also contraindicated in patients with severe renal impairment (CLCR <-1.5 L/h [<-25 mL/min]), patients with any known predisposition to bleeding, those with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopics or patients with a prolongation of the corrected QT interval. In the US, caution is recommended when cilostazol is to be coadministered with inhibitors of CYP3A4 or CYP2C19 and a lower dosage of 50mg twice daily should be considered; however, in Europe cilostazol is contraindicated in patients receiving these drugs.
KeywordsPeripheral Arterial Disease Hepatic Impairment Pentoxifylline Cilostazol Severe Renal Impairment
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