Abstract
Intermittent claudication (IC) comprises the most common presenting symptoms of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Typical symptoms of IC are aching pain, numbness, and fatigue in the lower extremities. Symptoms are induced by walking or exercise and usually resolve with rest. The cornerstone of treating IC is risk‐factor reduction and a supervised exercise regimen. Pharmacotherapy specifically indicated for the treatment of IC includes a new drug, cilostazol, and the traditional drug, pentoxifylline. Cilostazol also has antiplatelet, antithrombotic, and vasodilatory activity, as well as a positive effect on serum lipids. Eight multicenter clinical trials, seven in the U.S. and one in the U.K., used objective and subjective clinical endpoints to assess the treatment efficacy of cilostazol. Objective endpoints included maximal and pain‐free walking distance (MWD and PFWD, respectively), the ankle‐brachial index, peripheral hemodynamic measurements, and serum lipid levels. Subjective endpoints, assessed by patient questionnaires, included perceived functional status and health‐related quality of life. Cilostazol treatment showed statistically significant increases in MWD and PFWD within 4 weeks, as well as improvements in physical functional status at 24 weeks, compared with placebo and pentoxifylline. Increases in high‐density lipoprotein cholesterol and decreases in plasma triglycerides were also noted. Subjective assessments appeared to match objective parameters.
Keywords: cilostazol, intermittent claudication, peripheral arterial disease, clinical trial endpoints
Full Text
The Full Text of this article is available as a PDF (48.8 KB).
References
- 1. Kannel WB, McGee DL: Update on some epidemiologic features of intermittent claudication: The Framingham Study. J Am Geriat Soc 1985; 33: 13–18 [DOI] [PubMed] [Google Scholar]
- 2. Criqui MH: Epidemiology and prognostic significance of peripheral arterial disease. Am J Med 1999;(suppl): 1–9
- 3. TransAtlantic Inter‐Society Consensus (TASC) Working Group : Management of peripheral arterial disease (PAD). J Vasc Surg 2000; 31 (suppl 1): S1–S296 [PubMed] [Google Scholar]
- 4. Regensteiner JG, Steiner JF, Hiatt WR: Exercise training improves functional status in patients with peripheral arterial disease. J Vasc Surg 1996; 23: 104–115 [DOI] [PubMed] [Google Scholar]
- 5. Hirsch AT, Treat‐Jacobson D, Lando HA, Hatsukami DK: The role of tobacco cessation, antiplatelet and lipid‐lowering therapies in the treatment of peripheral arterial disease. Vasc Med 1997; 2: 243–251 [DOI] [PubMed] [Google Scholar]
- 6. Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP: Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Vascular Clinical Trialists. Circulation 1995; 92: 614–621 [DOI] [PubMed] [Google Scholar]
- 7. Hiatt WR, Nawaz D, Regensteiner JG, Hossack KF: The evaluation of exercise performance in patients with peripheral vascular disease. J Cardiopulm Rehab 1988; 12: 525–532 [Google Scholar]
- 8. Bruce RA, Kusumi F, Hosmer D: Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973; 85: 546–562 [DOI] [PubMed] [Google Scholar]
- 9. Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A: Comparison of methods for the scoring and statistical analysis of SF‐36 health profile and summary measures: Summary of results from the Medical Outcomes Study. Med Care 1995; 33: AS264–AS279 [PubMed] [Google Scholar]
- 10. Regensteiner JG, Steiner JF, Panzer RJ, Hiatt WR: Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vasc Med Biol 1990; 2: 142–152 [Google Scholar]
- 11. 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: 2041–2050 [DOI] [PubMed] [Google Scholar]
- 12. Jackson MR, Clagett GP: Antithrombotic therapy in peripheral arterial occlusive disease. Chest 1998; 114: 666S–682S [DOI] [PubMed] [Google Scholar]
- 13. American Pharmaceutical Association : New Drugs of 1999. J Am Pharm Assoc 2000; 40: 181–221 [DOI] [PubMed] [Google Scholar]
- 14. Nishi T, Kimura Y, Nakagawa K: Research and development of cilostazol: An antiplatelet agent. Yakugaku Zasshi 2000; 120: 1247–1260 [DOI] [PubMed] [Google Scholar]
- 15. Toyonaga S, Nakatsu T, Murakami T, Kusachi S, Mashima K, Tominaga Y, Yamane S, Uesugi T, Kanai H, Tsuji T: Effects of cilostazol on heart rate and its variation in patients with atrial fibrillation associated with bradycardia. J Cardiovasc Pharmacol Ther 2000; 5: 183–191 [DOI] [PubMed] [Google Scholar]
- 16. Bramer SL, Forbes WP, Mallikaarjun S: Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clin Pharmacokinet 1999; 37 (suppl 2): 1–11 [DOI] [PubMed] [Google Scholar]
- 17. Usuda N, Nagata T, Naka M, Hidaka H: The localization of a new antithrombotic agent, cilostazol, in CHO‐K1 cells as demonstrated by autoradiography. Arzneimittelforschung 1985; 35: 1141–1143 [PubMed] [Google Scholar]
- 18. Kimura Y, Tani T, Kanbe T, Watanabe K: Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 1985; 35: 1144–1149 [PubMed] [Google Scholar]
- 19. Kamiya T, Sakaguchi S: Hemodynamic effects of the antithrombotic drug cilostazol in chronic arterial occlusion in the extremities. Arzneimittelforschung 1985; 35: 1201–1203 [PubMed] [Google Scholar]
- 20. Matsuo T, Matsuo M, Kario K, Suzuki S: Characteristics of heparin‐induced platelet aggregates in chronic hemodialysis with long‐term heparin use. Haemostasis 2000; 30: 249–257 [DOI] [PubMed] [Google Scholar]
- 21. Tsuchikane E, Kobayashi T, Awata N: The potential of cilostazol in interventional cardiology. Curr Interv Cardiol Rep 2000; 2: 143–148 [PubMed] [Google Scholar]
- 22. Tani T, Uehara K, Sudo T, Marukawa K, Yasuda Y, Kimura Y: Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats. Atherosclerosis 2000; 152: 299–305 [DOI] [PubMed] [Google Scholar]
- 23. Nakaya Y, Minami A, Sakamoto S, Niwa Y, Ohnaka M, Harada N, Nakamura T: Cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in the Otsuka Long‐Evans Tokushima Fatty Rat, a model of spontaneous NIDDM. Diabetes Obes Metab 1999; 1: 37–41 [DOI] [PubMed] [Google Scholar]
- 24. Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr: Cilostazol has beneficial effects in treatment of intermittent claudi‐cation: Results from a multicenter, randomized, prospective, double‐blind trial. Circulation 1998; 98: 678–686 [DOI] [PubMed] [Google Scholar]
- 25. Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, Forbes WP: Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998; 27: 267–274 [DOI] [PubMed] [Google Scholar]
- 26. Dawson DL, Cutler BS, Hiatt WR, Hobson RW, Martin JD, Bortey E, Forbes WP, Strandness DE Jr: A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000; 109: 523–530 [DOI] [PubMed] [Google Scholar]
- 27. Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson M, Gordon IL, Bortey EB, Forbes WP: Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol 1998; 18: 1942–1947 [DOI] [PubMed] [Google Scholar]
- 28. Otsuka America Pharmaceutical, Inc. : Cilostazol for use in patients with intermittent claudication. Advisory Committee Meeting Dossier (Cilostazol OPC‐13013) June 3, 1998.
- 29. Strandness DE Jr, Dalman R, Panian S, Rendell M, Comp P, Bortey EB, Heckman JD, Forbes WP: Two doses of cilostazol versus placebo in the treatment of claudication: Results of a randomized, multicenter trial (abstr). Circulation 1998; 95: 1–12 [Google Scholar]
- 30. Dawson DL, DeMaioribus CA, Hagino RT, Light JT, Bradley DV Jr, Britt KE, Charles BE: The effect of withdrawal of drugs treating intermittent claudication. Am J Surg 1999; 178: 141–146 [DOI] [PubMed] [Google Scholar]
- 31. Mallikaarjun S, Forbes WP, Bramer SL: Effect of renal impairment on the pharmacokinetics of cilostazol and its metabolites. Clin Pharmacokinet 1999; 37 (suppl 2): 33–40 [DOI] [PubMed] [Google Scholar]
- 32. Bramer SL, Forbes WP: Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol. Clin Pharmacokinet 1999; 37 (suppl 2): 25–32 [DOI] [PubMed] [Google Scholar]
- 33. Mallikaarjun S, Forbes WP, Bramer SL: Interaction potential and tolerability of the coadministration of cilostazol and aspirin. Clin Pharmacokinet 1999; 37 (suppl 2): 87–93 [DOI] [PubMed] [Google Scholar]
- 34. Mallikaarjun S, Bramer SL: Effect of cilostazol on the pharmacokinetics and pharmacodynamics of warfarin. Clin Pharmacokinet 1999; 37 (suppl 2): 79–86 [DOI] [PubMed] [Google Scholar]
- 35. Bramer SL, Brisson J, Corey AE, Mallikaarjun S: Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers. Clin Pharmacokinet 1999; 37 (suppl 2): 69–77 [DOI] [PubMed] [Google Scholar]