Cilostazol Tablets (Pletal-Otsuka)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

In january, the FDA approved the first new drug for intermittent claudication in more than 15 years. Cilostazol (Pletal-Otsuka) will be co-marketed by Otsuka and Pharmacia Upjohn. While the mechanism of action of cilostazol in improving intermittent claudication is not precisely known, it is reported to have antiplatelet and vasodilation actions and also demonstrates greater dilation of the femoral arteries than other arteries.1 The drug was approved among some controversy since it is a phosphodiesterase inhibitor, a class known to be dangerous to patients with congestive heart failure.

Indications

Cilostazol is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increase in walking distance.

Dosage

The recommended dose of cilostazol is 100 mg twice daily taken one-half hour before meals or two hours after meals. Patients taking inhibitors of cytochrome P450 3A4, such as ketoconazole, itraconazole, erythromycin, or diltiazem, should undergo initial therapy with 50 mg twice of cilostazol. Grapefruit juice should be avoided as it can also inhibit 3A4.1

Cilostazol is supplied as 50 mg and 100 mg tablets.

Potential Advantages

In addition to its antiplatelet and vasodilation effect, cilostazol has been reported to have beneficial effects on lipoproteins.2 After 12 weeks of therapy (100 mg bid), plasma triglycerides decreased by 15%, high-density lipoprotein cholesterol increased by 10%, with the HDL-2 subfraction showing the greatest increase. Subjects with a baseline triglyceride of more than 140 mg/dL showed the greatest increase in HDL-C and decrease in TG.

Potential Disadvantages

Cilostazol is contraindicated in patients with congestive heart failure. The drug is a phosphodiesterase III inhibitor and drugs of this class have been shown to decrease survival in patients with class III-IV heart failure.1

Most common side effects associated with cilostazol compared to placebo are headache (34% vs 14%), diarrhea (19% vs 7%), palpitations (10% vs 1%), and tachycardia (4% vs 1%).1 Sixteen percent of patients dropped out of clinical trials, with 73% of those taking the recommended dose of 100 mg twice daily, citing side effects as the reason.5

Comments

Claudication is a common symptom of atherosclerotic occlusive disease of the lower extremities.

Intermittent claudication is generally characterized as severe pain or cramping in the legs that occurs with walking and is relieved by rest. This tends to progress as the patient is able to walk shorter and shorter distances before experiencing pain. Results from several clinical trials involving about 2000 patients showed that cilostazol improved maximal walking distance compared to placebo in patients with stable intermittent claudication.1,3,4 In general, patients on cilostazol were able to walk about 1.3 city blocks further than those on placebo. This represents a mean improvement of about 40%.1,3 Benefits may be experienced in 2-4 weeks but may take up to 12 weeks. Cilostazol has not been studied in patients with rapidly progressing claudication or other more serious conditions such as leg pain at rest.1

Cilostazol costs about $2.45 per day for either 50 mg or 100 mg twice daily. This compares to about $1.70 per day for generic pentoxifylline (400 mg three times a day).

Clinical Implications

Approximately 10% of elderly patients older than the age of 70 have symptoms of atherosclerotic occlusive disease of the lower extremities. Generally, this population has cardiovascular risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and cigarette smoking.7 Intermittant claudication is one of the most difficult clinical entities to treat. Treatment involves an exercise program, management of risk factors, and drug treatment. Cilostazol offers only moderate relief for patients with moderately severe disease.

About 50% of patients indicate that the drug improves their ability to work as assessed by the patients themselves or by physicians compared to 19-22% for patients on placebo.3

Pentoxifylline is the only other drug approved for treating intermittent claudication, and few comparisons of the two drugs are available. Two unpublished trials have been conducted to compare cilostazol and pentoxifylline with inconclusive results. One study indicated that cilostazol improved walking distance at week 24 by a mean of 113 meters compared to 68 meters for pentoxifylline. The other study showed no significant difference.5 Some of the difficulties in claudication studies in general are large placebo effects and inherent variability of this test method.3 A meta-analysis of pentoxifylline trials indicate an improvement of 48.4 m over placebo while cilostazol studies suggest a numerically better improvement of 65 m.4,6

Cilostazol offers an alternative to pentoxifylline and may prove superior in some patients, but it carries the risk of use in patients with heart failure, a condition that commonly accompanies peripheral vascular disease.

References

1. Pletal Product Information. Otsuka America. December 1998.

2. Elam MB, et al. Arterioscler Thromb Vasc Biol 1998;18(12):1942-1947.

3. Dawson DL, et al. Circulation 1998;98:678-686.

4. Money SR, et al. J Vasc Surg 1998;27(2):267-274.

5. FDC Report. The Pink Sheet. July 20, 1998.

6. Hood SC, et al. CMAJ 1996;155(8):1053-1059.

7. Santilli JD, et al. In: Rakel RE, ed. Conn’s Current Therapy. WB Saunders Company; 1996:323-324.