Effect of the Novel Antiplatelet Agent Cilostazol on Plasma Lipoproteins in Patients With Intermittent Claudication

Abstract

Abstract-Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (PϽ0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (PϽ0.001 and PϽ0.01, respectively). Both HDL 3 and HDL 2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL 2 . Individuals with baseline hypertriglyceridemia (Ͼ140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, PϽ0.002) increase in the apoA1 to apoB ratio. ilostazol is a vasodilator and platelet aggregation inhibitor that has been marketed since 1988 in Japan for treatment of ischemic symptoms of peripheral vascular disease. Cilostazol {6[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)-quinolinone} is a 2-oxoquinolone derivative (molecular weight, 369.47) that has a plasma half-life of 10.5Ϯ4.4 hours after oral administration (Figure 1). Cilostazol inhibits both primary and secondary platelet aggregation in response to ADP, collagen, epinephrine, and arachidonic acid.1,2 The antiplatelet and vasodilator properties of cilostazol have been attributed to its ability to elevate intracellular levels of cAMP.3 Cilostazol is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Japanese studies performed in diabetic patients have indicated that, in addition to its vasodilator and antiplatelet properties, cilostazol may also favorably modify plasma lipoproteins by increasing HDL cholesterol (HDL-C) and reducing triglycerides. 4 The purpose of the present study was to determine whether cilostazol favorably modifies plasma lipoproteins in a general population of patients with stable IC. Methods Patient PopulationThe study included subjects with documented chronic, stable, symptomatic IC secondary to peripheral arterial disease (PAD). PAD was defined as an ankle-brachial index (ABI) Յ0.90; termination of walking on a variable-load, constant-speed treadmill due to IC (Ͼ54 and Ͻ805 m); and a Doppler-measured drop of Ն10 mm Hg in blood pressure of 1 ankle after the treadmill test. For patients without a qualifying ABI, a 20 -mm Hg drop in postexe...

Cilostazol, um inibidor da fosfodiesterase III: perspectivas futuras na aterosclerose

“…This drug promotes lower TG levels, increases HDL in patients with POAD 41 , improves postprandial lipemia in patients with DM 42 , increases NO expression, has a positive effect on apoptosis, prevents thrombosis after stenting and has demonstrated the ability to interfere in various stages of the atherosclerotic process.…”

“…In 189 individuals with POAD and without hyperlipidemia, cilostazol reduced TG by 15% and increased HDL by 9.5%, in a double blind multicenter study, controlled with placebo and twelve weeks of follow-up 41 . It also improved postprandial lipemia in 112 patients with type 2 DM or glucose intolerance, controlled with placebo during twelve weeks of follow-up 42 .…”

The Management of Peripheral Arterial Disease (PAD) in Primary Care

“…Cilostazol has been shown to significantly increase (35-109%) walking distance in people with claudication in several large double blind placebo controlled randomized trials (Money et al, 1998, Elam et al, 1998). The precise role of cilostazol remains to be defined, but a trial of the drug is probably indicated in patients who have unacceptable symptoms despite three to six months of adherence to best medical treatment.…”

Measuring treatment effects of Cilostazol on clinical trial endpoints in patients with intermittent claudication

“…In studies in which the ABI was evaluated, improvement was also noted in this parameter compared with placebo. 25,27 The beneficial effects of cilostazol on serum lipids have also been demonstrated in patients with IC. After 12 weeks of cilostazol therapy (100 mg b.i.d.)…”

“…Cilostazol treatment in these patients resulted in statistically significant increases in treadmill walking time (35%) and in the ABI (9%), thus indicating that the drug simultaneously improves physical capacity and plasma lipid profiles. 27 In studies that have looked at HQL measures in patients with IC, 11,25 the physical health concepts of the SF-36 showed improvement at 16-24 weeks in patients on cilostazol. Similarly, there were improvements in patients' perceptions of walking speed and distance on the WIQ, as well as walking pain/discomfort on the COM.…”