Therapeutic Category: Phosphodiesterase III inhibitor

Uses: Cilostazol is indicated for the treatment of intermittent claudication to aid patients in increasing walking distance.¹ It is also used off label for the prevention of restenosis following angioplasty, either alone or in combination with other platelet inhibitors such as aspirin and ticlopidine.^2,3 Based on literature reports, cilostazol is comparable in safety and efficacy to aspirin and ticlopidine for the prevention of stent thrombosis after implantation.^2,3 Other off label uses that need more research to determine safety and efficacy include the treatment of bradyarrythmias, cerebrovascular disease, and graft-versus-host disease.⁴

Mechanism of Action: Cilostazol has high specificity for inhibition of phosphodiesterase III (PDE III).¹ Although the mechanism of action in intermittent claudication is not fully understood, it is known that cilostazol and its metabolites inhibit the isoenzyme cyclic AMP PDE III.^1,4,5 Inhibition of cAMP PDE III causes increased levels of cAMP resulting in vasodilation and inhibition of platelet aggregation.^1,4,5 The inhibition of platelet aggregation by cilostazol is reversible, unlike other platelet aggregation inhibitors such as aspirin and clopidogrel which irreversibly inhibit platelet function.¹ Cilostazol inhibits platelet aggregation induced by a variety of different stimuli including ADP, collagen, arachidonic acid, epinephrine, thromboxane A2, platelet activating factor, and shear stress.⁴ Cilostazol has also been shown in some studies to reduce triglycerides and increase HDL cholesterol. The exact mechanism of these actions has not been fully established.

Pharmacokinetics: Some basic pharmacokinetic parameters of cliostazol are as follows:

The pharmacokinetics of cilostazol are approximately dose-proportional. Cilostazol is absorbed well following oral administration, with an approximate 90% increase in C_max and a 25% increase in AUC when taken with a high fat meal.⁵ Cilostazol is metabolized extensively by liver isoenzymes, primarily CYP3A4 and, to some degree, CYP2C19, to active metabolites.^1,4,5 The most active of these compounds, 3,4-dehydro-cilostazol (DHC), is 4-7 times more active than the parent compound cilostazol and accounts for at least 50% of total activity of cilostazol.⁵ Another predominate metabolite, 4’-trans-hydroxy-cilostazol (HC), is one fifth as active as the parent compound. The parent compound of cilostazol is 95 to 98% protein bound, predominately to albumin.^1,4,5 Cilostazol’s metabolites, DHC and HC, are also predominately bound to albumin, 97.4% and 66%, respectively. Significant plasma protein binding displacement interactions have not yet been reported.⁵

Cilostazol compared to placebo for intermittent claudication⁶

A multicenter, randomized, double-blind, parallel study was performed by Beebe et al. in order to assess the efficacy and safety of cilostazol versus placebo for the treatment of intermittent claudication. Six hundred sixty-three patients were screened from 37 outpatient vascular clinics throughout the United States; 516 of these patients met the inclusion criteria of greater than 40 years of age with at least a 6-month history of stable, symptomatic intermittent claudication secondary to lower extremity arterial occlusive disease, a resting ankle brachial index of 0.90 or less, and a 10 mm Hg or more decrease in ankle artery blood pressure after the onset of maximal walking distance. Patients were excluded with ischemic pain at rest, gross obesity, childbearing potential, hypertension, metastatic malignancies, exercise-limiting cardiac disease, and history of bleeding tendencies. The 516 eligible patients were randomized to receive either 100mg cilostazol twice daily (n=175), cilostazol 50mg twice daily (n=171), or placebo (n=170). There were no significant differences between the groups’ demographic or baseline characteristics (p>0.14). Subjects were evaluated for pain-free walking distance and maximal walking distance using a treadmill test conducted at least 3 times at baseline and at weeks 4, 8, 16, 20, and 24. Other evaluations included analysis of the association between cilostazol administration and death rate and adverse events, and telephone questionnaires were used to assess the patients’ perception of improvement in physical, social, and mental health. A total of 419 were included in the intention-to-treat analysis of efficacy. Of these patients, 316 completed all treadmill visits up to 24 weeks. Improvements were seen in pain-free walking distance and maximal walking distance by week 4 in the cilostazol groups. By the end of 24 weeks, the geometric mean change from baseline in pain-free walking distance increased by 59% in the cilostazol 100mg twice daily group (P<0.001 vs placebo), 48% in the cilostazol 50mg twice daily group (P<0.001 vs placebo), and 20% in the placebo group. In maximal walking distance, the cilostazol 100mg twice daily group improved 51% (p<0.001 vs placebo), the cilostazol 50mg twice daily group improved 38% (p<0.001 vs placebo), and the placebo group improved by 15%. There was no statistical analysis performed to assess differences between cilostazol groups. Patients’ perception of their own physical health improved significantly (p<0.05). However, there was no significant improvement in mental health measures such as social function and pain/discomfort in social activities. Ninety-eight patients withdrew from the study, with 75 of these due to adverse events. The most common adverse event associated with cilostazol therapy was mild or moderate headache (34% with 100mg BID, 23% with 50mg BID). Palpitations were reported in 11% and 5% of patients taking cilostazol 100mg BID and 50mg BID, respectively, most of whom had a history of hypertension, cardiac disease, or both. They caused four patients to withdraw from the 100mg BID group and three from the 50mg BID group. The majority of cases of GI upset (total=102) were mild to moderate. One patient with a history of stomach problems did withdraw due to continuous, severe diarrhea. One strength of this study is the inclusion of all 516 patients in the safety analysis. A total of 143 patients in each arm of the study were needed for 80% power (based 5% significance). Another strength is the inclusion of the patients’ perceptions of walking improvement. While most perceived physical health improvement, it was interesting to note that most did not have improved mental or social attitudes. A perceived improvement in physical condition did not necessarily correlate with a perceived improvement in social functioning.

Compared to Pentoxifylline in Intermittent Claudication⁷

A randomized, double-blind, placebo controlled, multi-center trial was performed by Dawson et al. to assess the safety and efficacy of cilostazol versus pentoxifylline for the treatment of intermittent claudication. Of 922 patients screened, 699 met the inclusion criteria and were randomly assigned to receive cilostazol 100mg twice daily (n=227), pentoxifylline 400mg three times daily (n=232), or placebo (n=239). The dosages used for cilostazol and pentoxifylline have been shown in other clinical trials to be the dosages at which maximum efficacy will be achieved. Patient demographic and baseline characteristics were not significantly different between the groups (p>0.25). The inclusion criteria were the presence of symptoms for at least 6 months without substantial changes in the previous 3 months and confirmed peripheral artery disease. At baseline the patients had to be able to walk a minimum distance of 53.6 meters and a maximum of 537.6 meters. Of the 699 patients included, 159 withdrew before the final assessment, with similar rates of withdrawal in both the cilostazol and pentoxifylline groups (both higher than placebo). Patients were assessed every four weeks by walking on a treadmill set at a pace of 3.2 km/h with a incline that would increase 3.5% every 3 minutes. Patients were neither encouraged nor discouraged to make lifestyle changes, were allowed to use no more than 81 mg of aspirin per day or 1,200 mg ibuprofen per day for pain. All statistical analyses were done on an intention-to-treat basis that included all patients enrolled with at least one efficacy assessment. The cilostazol group showed a statistically significant improvement in pain-free walking distance and maximal walking distance from the first efficacy measures at week four of the study, with improvement continuing until the end of the study at week twenty-four. After week 24, the cilostazol group improved from baseline in pain-free walking distance by a mean 94+127 meters (p=0.0001 vs. pentoxifylline), and improved from baseline by a mean 107+158 meters (p=0.0005 vs. pentoxifylline) in maximal walking distance. There was no statistically significant difference in pain-free walking distance (p=0.07) or maximal walking distance (p=0.82) between the pentoxifylline and placebo groups. Adverse events were more common in the cilostazol and pentoxifylline groups compared to placebo (p=0.01) and occurred more often in the cilostazol group. The most common adverse events in the cilostazol group were headache (p<0.001 vs. placebo and pentoxifylline), diarrhea (p<0.001 vs. placebo and pentoxifylline), abnormal stools (p<0.001 vs. placebo and pentoxifylline), and palpitations (p<0.001 vs. placebo and pentoxifylline).A disadvantage was that the study did not assess adherence to the study regimen. The patients were given a 4-week supply of medicine at each efficacy assessment, but no mention was made of patients returning any unused medicine at each assessment. Despite this disadvantage, this study was well designed. The study had 95% power, based on 200 subjects in each arm and 5% significance, to detect treatment differences.

Compared to Aspirin in prevention of restenosis²

From November of 1995 to March of 1997, Kunishima et al. conducted a prospective study comparing cilostazol with aspirin for prevention of subacute thrombosis and restenosis in patients who had undergone successful, elective implantation of Palmaz-Schatz stents. Each patient received heparin 10,000 IU at the beginning of catherization, after which no other anticoagulant was used for the remainder of the study. The surgeon performing the procedure decided upon the type of balloon, inflation pressure, inflation time, and number of inflations. Three days prior to the procedure, patients were randomly assigned to receive either aspirin 81 mg per day (40 patients with 45 lesions) or cilostazol 200 mg per day (30 patients with 37 lesions). There were no significant differences between the two groups in clinical history (23 patients had a diagnosis of angina and 47 had a previous myocardial infarction), reference diameter and minimal lumen diameter (MLD) prior to stent implantation, and follow up coronary angiogram (CAG) time. The patients maintained their regimen and were observed in outpatient settings at least once a month for nine months. Any patient who experienced coronary symptoms underwent immediate CAG. Other patients received follow-up CAG within 3 to 9 months of initial stent implantation. Lesion variables that were analyzed on follow up were proximal and distal reference diameter in both obliques, absolute MLD, and lesion length. Any patient that could not be followed was excluded from the study. Restenosis was defined based on the International Society and Federation of Cardiology and World Health Organization definition, "an immediate post-PTCA (percutaneous transluminal coronary angioplasty) diameter stenosis of less than 50% that increases to 50% or greater at follow up". Subacute thrombosis occurred in one patient in the aspirin group. No side effects were reported with either group. Four patients were excluded in the aspirin group and 2 patients were excluded in the cilostazol group. The follow up MLD in the aspirin group was 1.89+1.08 mm and 2.34+0.74 mm in the cilostazol group (p<0.05). Restenosis occurred in 11 of 41 lesions (26.8%) in the aspirin group and in 3 of 35 lesions (8.6%) in the cilostazol group (p<0.05). This study has several limitations. The study was not blinded allowing for possible bias, a relatively small group of patients was used, and surgeons had discretion in performing the angioplasty that may have led to some interpatient variability due to differences in initial treatment. Despite these limitations, there may be potential benefit for the use of cilostazol in preventing subacute thrombsis and restenosis in stent patients. However, additional large well-designed studies are needed.

Compared to Ticlopidine in Coronary Artery Stenting³

Between May 1996 and October 1998, Yoon et al. performed a study to compare a regimen of ticlopine and aspirin (TA) with cilostazol and aspirin (CA) for the treatment of thrombosis following coronary artery stenting. Three hundred consecutive patients in whom stent implantation was necessary were enrolled. Necessary stent implantation included elective stenting, bailout procedures after failed balloon angioplasty, and in patients with a suboptimal result (residual stenosis >30%). Patients with a history of bleeding diasthesis, severe hepatic or renal dysfunction, thrombocytopenia (<150,000/mm³) or leukopenia (<3,000/mm³) were excluded. Patients were randomized 3 days prior to stent implantation to receive cilostazol 100mg twice daily for 30 days (n=147) or ticlopine 250mg twice daily for 30 days (n=149). Both groups received aspirin 100mg every day indefinitely. Both regimens were started two days prior to stenting. Differences in demographic and baseline characteristics of patients were not statistically significant. Various stent procedures were used based on the discretion of the surgeon, but there were no statistically significant differences in stent procedures. Patients were seen for follow up one month following stent implantation to assess changes in minimal luminal diameter, reference diameter, diameter stenosis, lesion length, laboratory values, and physical examination. Patients were deemed to have received optimal therapy when residual stenosis was >30% with Thrombolysis In Mycocardial Infarction III distal flow. The primary end point evaluated after 30 days were major cardiac events (death, bypass surgery, myocardial infarction, and repeat angioplasty) and angiographic stent thrombosis. Secondary endpoints assessed were local vascular complications, hematologic abnormalities (thrombocytopenia--platelet count<80,000/mm³, or neutropenia--<1,200/mm³), and other side effects causing discontinuation. Results of stenting were suboptimal in 2 patients in the CA group and 4 patients in the TA group. The primary endpoint occurred in 2 patients in the CA group and 3 patients in the TA group (p=1.0). Two patients in each group had a myocardial infarction and one patient in the TA group died. One patient in each group experienced stent thrombosis. Two patients in the CA group reached a secondary endpoint. One of these suffered diabetic retinopathy following retinal surgery and the other discontinued the drug due to severe gastritis. Five patients in the TA group reached a secondary endpoint. Of those, one patient developed local bleeding with a retroperitoneal hematoma that required a transfusion, two patients developed neutropenia, and two patients discontinued the drugs due to adverse reactions (skin rash and gastrointestinal disturbance). Randomization was not blinded, which is a study limitation. No power was given in this study. It is unclear if the study contained enough subjects in each study arm to detect a small significant difference between the two groups.

Adverse Effects: Decreased survival in patients with congestive heart failure, classes III-IV, has been documented in patients receiving phosphodiesterase inhibitors compared to placebo. Cilostazol and many of its metabolites are phosphodiesterase inhibitors. Therefore, Pletal is contraindicated in patients with congestive heart failure.^1,4,5

The above figures were compiled from eight placebo-controlled trials that totaled 2274 patients receiving either 100mg once daily oral cilostazol, 50% twice daily oral cilostazol, or placebo.⁵ The incidence of the three side effects with placebo were: headache 14%, palpitations 7%, and diarrhea 7%. Adverse effects with an incidence of >2% included: abdominal pain, back pain, infection, tachycardia, abnormal stools, dyspepsia, flatulence, nausea, peripheral edema, myalgia, dizziness, vertigo, increased cough, pharyngitis, and rhinitis.⁵

Drug Interactions: Since cilostazol is extensively metabolized by CYP3A4, any strong inhibitor of CYP3A4 could cause an increase in plasma levels of cilostazol and its active metabolites. These strong inhibitors include ketoconazole, itraconazole, fluconazole, miconazole, macrolide antibiotics, fluvoxamine, fluoxetine, nefazodone, and grapefruit juice.^1,4,5 It is recommended to use a cilostazol dosing regimen of 50mg twice daily if any of the previously mentioned strong inhibitors are used with cilostazol.^1,4,5 Omeprazole is an inhibitor of CYP219 so it will not affect plasma levels of the parent compound. However cilostazol’s most active metabolite, DHC, is metabolized primarily by CYP2C19. Omeprazole inhibition may cause a 69% increase in systemic exposure to DHC. Thus, it is recommended to initiate cilostazol at a dose of 50mg twice daily with concomitant use.^1,4,5 Diltiazem is a moderate inhibitor of CYP3A4; it will increase cilostazol parent compound plasma levels by 53%, requiring a dosage decrease to 50mg twice daily. Cilostazol has no clinically significant interactions with aspirin and warfarin, two other medicines that may interfere with the clotting of blood.

Dosing and Administration: For treatment of intermittent claudication the recommended dosage of cilostazol is 100mg twice daily.^1,4,5 It should be taken at least half an hour prior to and two hours after meals to avoid increased absorption due to fatty foods.^1-3 Cilostazol also comes in a 50mg tablet that can be given to patients twice daily if coadministration with a previously mentioned strong inhibitor of CYP3A4 cannot be avoided. Some patients may respond to the effects of cilostazol within 2 to 4 weeks after beginning therapy. For most patients, though, it takes typically up to 12 weeks of therapy to see the peak benefit from cilostazol.

Elderly ^1,4,5

There is no dosage adjustment needed in elderly patients.

Renal Dysfunction ^1,4,5

There is no dosage adjustment required with renal impairment.

Hepatic Dysfunction ^1,4,5

There is no dosage adjustment required with mild hepatic insufficiency. Cilostazol has not been studied in moderate and severe hepatic failure.

Patient Counseling Information: The brand name of cilostazol is Pletal® and it is used to help the blood flow into your legs to allow you to walk farther distances without pain. You should not take Pletal® if you have an allergic reaction to cilostazol or if you have heart failure. Take the dose as described to you by your doctor; this may require you to take two tablets a day. Try to take the tablets at the same time each day. Take your tablets one-half hour before or two hours after a meal. Do not drink grapefruit juice. Store at room temperature away from heat (i.e., stove in kitchen), moisture (i.e., in bathroom), and direct light. It may take up to 12 weeks to notice your leg pain getting better. If you miss a dose take it as soon as possible. If it is close to your next dose, skip the missed dose and DO NOT double your dose at your next dosing. Cilostazol interacts with some medicines. Be sure to tell your doctor or pharmacist about all of the medicines (prescription, non-prescription, and herbals) you are currently taking. If you are pregnant, talk to your doctor before taking this medicine. Do not take this medicine if you are breastfeeding. Potential side effects include headache, feeling dizzy, and diarrhea or other changes in your bowels. Call your doctor immediately if you experience fast or pounding heart, feel short of breath, or develop swelling in your hands or feet.⁴

Conclusion: Intermittent claudication is a disorder that can have an effect on quality of life from pain experienced in the lower legs upon any type of exertion. It is the most common manifestation of peripheral artery disease (PAD). Cilostazol helps to treat intermittent claudication by causing vasodilation and inhibiting platelet aggregation, allowing for easier blood flow to the lower legs to reduce pain. It may take up to 12 weeks of continous therapy with cilostazol to achieve maximal benefit. A patient’s walking distance free of pain may double when maximal benefit is achieved. Cilostazol has also shown the ability to reduce triglycerides and raise HDL, which can be of some benefit in patients with PAD. Cilostazol is a promising new therapy for patients with intermittent claudication and should be considered the drug of choice for those patients without evidence of CHF. One study showed some promise of cilostazol to reduce bronchoresponsiveness to a methacholine challenge in eight college age women.⁸ More studies need to be performed to assess the efficacy of cilostazol for bronchospastic conditions. Cilostazol can cause side effects such as headache, GI disturbances, and palpitations. Although headache occurs in >10% of patients, symptoms are usually mild to moderate and generally do not necessitate discontinuation. Palpitations and GI upset also tend to be mild although they could result in drug discontinuation in some patients. Cilostazol has the benefit of reversibly inhibiting the function of platelets, unlike aspirin or Plavix® which will irreversibly inhibit the platelet for the duration of its life cycle. Some clinical trials have studied the effectiveness of cilostazol for prevention of restenosis. While the results are promising, more studies should be performed to assess its efficacy and clinical usefulness in these patients.

1) Drug Facts and Comparisons. Updated Monthly.  St. Louis: Walters Kluver; 2001. p. 147-48.

3) Yoon Y, Shim WH, Lee DH, Pyun WB, Kim IJ, Jang Y, Cho SY. Usefulness of cilostazol versus ticlopine in coronary artery stenting. Am J Cardio 1999 15;84(12):1375-80.

4) DRUGDEX® editorial staff: Cilostazol drug evaluation. In: Gelman Cr, Rumack BH, Hutchinson TA (Eds): DRGDEX ® System. MICROMEDEX, Inc., Englewood, Colorado (Edition expires November 2001)

5) Otsuka America Pharmaceutical. Prescribing information for Pletal®. 2000. Available at web address: http://www.pletal.com/pro/0_7.asp

6) Beebe HG, Dawson DL, Cutler BS, Herd JA, Strandness DE Jr., Bortey EB,Forbes WP. A new pharmacological treatment for intermittent claudication:results of a randomized, multicenter trial. Arch Intern Med 1999; 159(17):2041-50.

7) Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2^nd, Martin JD, Bortey EB, Forbes WP, Strandness DE Jr. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000; 109(7):523-30.

8) Fujimura M, Kamio Y, Saito M, Hashimoto T, Matsuda T. Bronchodilator andbronchoprotective effects of cilostazol in humans in vivo. Am J Respir Crit Care Med 1995 ; 151(1):222-5.

Prepared by: 

Dan DiBacco, PharmD Candidate

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