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(Circulation. 2005;112:2826-2832.)
© 2005 American Heart Association, Inc.

Interventional Cardiology

Coronary Stent Restenosis in Patients Treated With Cilostazol

John S. Douglas, Jr, MD; David R. Holmes, Jr, MD; Dean J. Kereiakes, MD; Cindy L. Grines, MD; Elizabeth Block, BS; Ziyad M.B. Ghazzal, MD; Douglas C. Morris, MD; Henry Liberman, MD; Karen Parker, BS; Claudine Jurkovitz, MD; Nancy Murrah, BSN; Jovonne Foster, MS; Pamela Hyde, BSN; G.B. John Mancini, MD; William S. Weintraub, MD, for the Cilostazol for Restenosis Trial (CREST) Investigators^*

From the Emory University School of Medicine (J.S.D., E.B., Z.M.B.G., D.C.M., H.L., K.P., C.J., N.M., J.F., P.H., W.S.W.), Atlanta, Ga; the Mayo Clinic (D.R.H.), Rochester, Minn; the Lindner Clinical Trial Center and Ohio Heart Health Center (D.J.K.), Cincinnati, Ohio; the William Beaumont Hospital (C.L.G.), Royal Oak, Mich; and the University of British Columbia (G.B.J.M.), Vancouver, Canada.

Correspondence to John S. Douglas, Jr, MD, Andreas Gruentzig Cardiovascular Center, Emory University Hospital, Ste F606, 1364 Clifton Rd, Atlanta, GA 30322. E-mail john_douglas{at}emoryhealthcare.org

Received January 5, 2005; revision received August 3, 2005; accepted August 8, 2005.

	Abstract

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Background— Restenosis after implantation of coronary artery stents remains a significant clinical problem. We undertook a randomized, double-blind, placebo-controlled trial to determine whether cilostazol, a drug that suppresses intimal proliferation, would reduce renarrowing in patients after stent implantation in native coronary arteries.

Methods and Results— We assigned 705 patients who had successful coronary stent implantation to receive, in addition to aspirin, cilostazol 100 mg BID or placebo for 6 months; clopidogrel 75 mg daily was administered to all patients for 30 days. Restenosis was determined by quantitative coronary angiography at 6 months. The minimal luminal diameter at 6 months for cilostazol-treated patients was 1.77 mm for the analysis segment (stent plus 5-mm borders) compared with 1.62 mm in the placebo group (P=0.01). Restenosis, defined as 50% narrowing, occurred in 22.0% of patients in the cilostazol group and in 34.5% of the placebo group (P=0.002), a 36% relative risk reduction. Restenosis was significantly lower in cilostazol-treated diabetics (17.7% versus 37.7%, P=0.01) and in those with small vessels (23.6% versus 35.2%, P=0.02), long lesions (29.9% versus 46.6%, P=0.04), and left anterior descending coronary artery site (19.3% versus 39.8%, P=0.001). There was no difference in bleeding, rehospitalization, target-vessel revascularization, myocardial infarction, or death.

Conclusions— Treatment with the drug cilostazol resulted in a significantly larger minimal luminal diameter and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were apparent in patients at high risk for restenosis.

Key Words: stents • restenosis • coronary disease • angioplasty

	Introduction

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Use of metallic stents has significantly improved outcomes after percutaneous coronary intervention (PCI) leading to stent implantation in a majority of the &1 million patients who undergo this procedure annually in the United States and worldwide.^1–3 Restenosis due to intimal hyperplasia within or adjacent to the stent has been the major limitation of percutaneous revascularization, affecting a quarter or more of stent-treated patients overall and up to one half of patients with long lesions or multiple stented sites.⁴ Restenosis results in reduced quality of life and increased costs. Stents coated with sirolimus or paclitaxel have been shown to significantly reduce restenosis in selected coronary lesions with no effect on mortality or rates of myocardial infarction (MI).^5–7 However, their cost (&$3000 per drug-eluting stent) has hampered global utilization, and some questions remain regarding increased thrombogenicity and long-term outcomes.^8,9 Although contemporary utilization rates of drug-eluting stents are increasing, their use is less frequent in some regions outside the United States.^10,11 Thus, there remain an appreciable number of patients at risk for restenosis. Furthermore, angiographic and clinical restenosis in the more complex patient subsets undergoing drug-eluting stent deployment in "real-world" practice will likely exceed that observed in premarket, randomized, controlled trials.

Editorial p 2759

Use of systemic pharmacological therapy to inhibit coronary stent restenosis has been largely unsuccessful.^12–14 Animal studies and small, unblinded, clinical trials have suggested, however, that cilostazol, a phosphodiesterase III inhibitor approved by the US Food and Drug Administration (FDA) for treatment of intermittent claudication,¹⁵ reduces smooth muscle proliferation¹⁶ and intimal hyperplasia after endothelial injury¹⁷ and lowers restenosis after balloon angioplasty¹⁸ and stent implantation when compared with aspirin or ticlopidine.^19,20 We therefore conducted a multicenter study to determine the efficacy of cilostazol compared with placebo in preventing restenosis after successful coronary stent implantation on a background of usual antiplatelet therapy with aspirin and clopidogrel.

	Methods

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Study Design
This prospective, randomized, double-blind, placebo-controlled trial compared the ability of cilostazol and placebo to prevent renarrowing after PCI with bare-metal stent implantation in a native coronary artery, as evaluated by quantitative coronary angiography at 6 months. The design and rationale of the study have been reported previously.²¹

Patients with stable or unstable angina or silent myocardial ischemia undergoing coronary stent implantation at 19 clinical sites (see Appendix: http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.104.530097/DC1) were recruited to the trial before intervention. Local investigational review board approval and written, informed consent were obtained. Patients eligible for the study were >18 years old; women of child-bearing potential required a negative pregnancy test and commitment to use of contraceptives during the study. Other inclusion criteria were the presence of a de novo target-lesion stenosis of >50% but <100% in a native coronary artery that was successfully treated by placement of a bare-metal intracoronary stent with residual stenosis <10% by visual estimate, with grade 3 flow by the Thrombolysis in Myocardial Infarction trial classification, and without residual dissection. Patients were ineligible if the stented segment was 40 mm long by visual estimate, if the patient had undergone a prior percutaneous coronary revascularization within 6 months, or if the patient had experienced an acute MI within the past 24 hours. Target lesions with moderate to severe calcification, intraluminal thrombus, or encompassing side branches >2 mm in diameter were excluded. Other exclusion criteria were a platelet count <150 000/mL; a known bleeding diathesis; active peptic ulcer disease or gastrointestinal bleeding; intolerance to cilostazol, aspirin, or clopidogrel; use of cilostazol in the prior 6 months; renal insufficiency with a serum creatinine value >2.5 mg/dL; congestive heart failure or left ventricular ejection fraction <30%; requirement for warfarin anticoagulation; known hepatic dysfunction; or major life-threatening illness. Follow-up quantitative coronary angiography was performed at 6 months or sooner if symptoms recurred; documentation of angiographic restenosis at any time was a study end point. Patients who underwent coronary angiography at 4 months or less and were free of restenosis were asked to return for the 6-month angiographic follow-up.

Study Procedures
Before stent implantation, all patients received aspirin, and patients who were not taking clopidogrel received a loading dose of at least 300 mg. Stenting was performed at the discretion of the operator using commercially available bare, stainless steel stents. The coordinating center developed a randomization scheme, and matching unmarked bottles of 50 mg cilostazol and placebo were prepared with a patient allocation number. Each site received a list of sequential allocation numbers. After successful stent implantation, patients were given the next number that randomly assigned them in a 1:1 ratio to placebo or cilostazol. The study drug was begun within 6 hours of stent implantation. Patients received 2 study tablets BID for 6 months unless concomitant medications that could inhibit hepatic cytochrome P-450 isoenzymes were required; in that case, only 1 tablet was prescribed twice daily. These medications were listed in the published FDA-approved directions for use. Patients were advised to avoid consumption of grapefruit, which contains an inhibitor of P-450 isoenzymes. Patients received clopidogrel 75 mg daily for 30 days and were asked to take 1 aspirin daily for the duration of the study.

Follow-Up
Patients were contacted at 1 month, returned for a clinic visit at 3 months, and were asked to return for follow-up angiography at 6 months. Patients were monitored at these times for occurrence of bleeding, rehospitalization, MI, stroke, and repeated revascularization. ECGs obtained at baseline, in the hospital after stent implantation, and at 6 months were evaluated at the ECG core laboratory.

Quantitative Coronary Angiography
Baseline coronary angiograms were performed in multiple views after intracoronary nitroglycerin administration, and the same views were repeated after stent implantation and at late follow-up. Quantitative analysis of the stented sites was performed with automatic edge-detection equipment at the angiographic core laboratory. Measurements included minimal luminal diameter, reference-vessel diameter, lesion length, and percent diameter stenosis. Restenosis was defined as stenosis of 50% or more of the reference lumen diameter. The analysis segment included the stented segment plus 5 mm proximal and distal to the stent. In-stent restenosis indicated restenosis within the margins of the stent. In patients with restenosis, the length of the restenosis lesion was the length of any compromised lumen 50% within the analysis segment.

End Points of the Study and Definitions
The primary end point was minimal luminal diameter of the first lesion stented per patient as assessed by quantitative coronary angiography at the angiographic core laboratory. Secondary angiographic end points included the percent stenosis at the target site and the rate of restenosis (luminal narrowing of 50% or more). Events monitored at the clinical site were the occurrence of death, MI, stroke, bleeding, repeated revascularization of the target vessel, and rehospitalization. Subacute stent thrombosis was defined as angiographically confirmed occlusion of the stented segment or, in the absence of angiography, the occurrence of MI or cardiac death within 30 days after the index hospitalization. MI was defined by a significant elevation of serum biomarkers (troponin above the local MI level or creatine kinase-MB levels twice normal) and/or new Q waves on the ECG; stroke indicated the occurrence of a neurological deficit that persisted for at least 24 hours; major bleeding was defined as a need for transfusion, a reduction in hemoglobin of >5 mg/dL, need for surgical intervention, or resulting in hypotension requiring inotropic support.

Statistical Analysis
On the basis of an expected minimal luminal diameter of &1.40 mm in the placebo group and 1.65 mm in the treated group, we calculated that to achieve 90% power, 123 patients per treatment arm were required. A second power calculation was performed based on an expected restenosis rate of 30% in the placebo group and of 20% in the treated group; to achieve 80% power, 294 patients per arm were required. Enrollment of 700 patients was planned. All analyses were based on an intention-to-treat principle. Continuous variables were compared by unpaired t test or ANOVA and categorical variables by ². Correlates of binary categorical variables were determined by multivariable logistic regression and correlates of continuous variables, by multiple linear regression. Missing data were accounted for by multiple imputation. Data storage and statistical analysis were performed at the coordinating center (Emory Center for Outcomes Research, Atlanta, Ga).

	Results

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Baseline Clinical Characteristics
A total of 705 patients were randomly assigned to either cilostazol (354 patients) or placebo (351 patients) after successful stent implantation between November 2001 and April 2003. The 2 treatment groups were similar with respect to important baseline characteristics (Table 1). There was, however, more disease of the left anterior descending (LAD) coronary artery in the cilostazol-treated patients and more right and circumflex artery disease in the placebo group.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Clinical and Angiographic Characteristics of the Patients*

Procedural Results
The 2 patient groups were treated comparably with respect to the stent procedure (Table 2). The number of stents, deployment pressures, short-term gain, final percent stenosis, and final minimal luminal diameter were similar. Stents used were made of bare, stainless steel. The distribution of the various commercially available stents in the control and treatment groups was similar (P=0.62). All patients received unfractionated heparin. Approximately one half of patients also received glycoprotein IIb/IIIa platelet receptor inhibitors, and the use of the 3 available inhibitors was similar in the 2 treatment groups (P=0.71).

View this table: [in this window] [in a new window]   TABLE 2. Procedural Results

Compliance
At 3 months, 90% of patients were taking the study drug as directed (88% in the cilostazol group and 91% in the placebo group), and at 6 months, 72% of patients reported taking the study drug as directed (71% in the cilostazol group and 72% in the placebo group). The most common reasons for discontinuing the study drug were chest pain, headache, and bleeding. More patients in the cilostazol group stopped treatment because of headache (14 versus 3 placebo patients). In contrast, more patients in the placebo group stopped treatment because of chest pain (26 versus 16 cilostazol patients).

Primary and Secondary Outcomes
Five hundred twenty-six of the randomized 705 patients (74.6%) underwent quantitative coronary angiography at 6 months after stent implantation. As shown in Table 3, the primary end point, minimal luminal diameter of the analysis segment (stent plus 5-mm borders) as determined by the angiographic core laboratory, was significantly larger in the cilostazol-treated group compared with the placebo group because of significantly less late loss in cilostazol-treated patients (0.57 mm, P<0.01). Multivariable linear regression analysis showed that cilostazol treatment was an independent predictor of a larger minimum luminal diameter (P=0.02) after controlling for age, ejection fraction, lesion length, LAD site, Canadian angina class, unstable angina, diabetes, sex, hypertension, peripheral vascular disease, cerebrovascular disease, prior PCI, prior MI, and coronary bypass surgery. The restenosis rate was significantly lower in the cilostazol group compared with the placebo group, and the degree of stenosis at 6 months was significantly less (Figure 1). Importantly, there were no significant differences with respect to baseline characteristics between those with and without angiographic follow-up or between cilostazol-treated and placebo patients in the angiographic cohort.

View this table: [in this window] [in a new window]   TABLE 3. Angiographic and Clinical Outcomes at 6 Months

View larger version (17K): [in this window] [in a new window]   Figure 1. Cumulative distribution curves for percent stenosis of the analysis segment in patients who were treated with cilostazol and patients who received placebo before, immediately after stent implantation, and at 6 months. The mean diameter stenosis in the cilostazol-treated patients was significantly less than in placebo patients (37.8% vs 42.0%, P=0.01).

As shown in Table 3, outcomes at 6 months were similar for cilostazol-treated and placebo groups with respect to a number of important clinical events. The occurrence rates of death, MI, stroke, bleeding, target-vessel revascularization, and rehospitalization were not shown to be different in the 2 groups. There was also no difference in the type of bleeding (major or minor) experienced by the 2 treatment groups (P=0.80 and 0.55, respectively). Bleeding was more common in patients receiving glycoprotein IIb/IIIa platelet receptor inhibitors, but the occurrence was similar in cilostazol and placebo groups (10 and 11 patients, respectively). There were 5 deaths during the study, 3 in the cilostazol group (lung cancer, sudden death at 22 days, and repeated PCI–related death at 147 days) and 2 in the placebo group (automobile accident and sudden death at 69 days).

When the outcomes of patients who were study drug–compliant at 3 months were analyzed, cilostazol treatment was associated with a significantly larger minimum luminal diameter (1.75 versus 1.64 mm, P=0.04), and restenosis was significantly lower (21% versus 31%, P=0.01; n=200 cilostazol, n=204 placebo). Similar results were noted for compliant patients at 6 months (minimum luminal diameter of 1.81 mm versus 1.68 mm, P=0.04 and restenosis in 20% and 30%, P=0.03; n=159 cilostazol, n=163 placebo).

Multivariable logistic regression analysis showed that treatment with the drug cilostazol was an independent predictor of freedom from restenosis (risk ratio, 0.52; 95% confidence interval, 0.33 to 0.89; P=0.004) after controlling for age, ejection fraction, lesion length, LAD site, Canadian angina class, unstable angina, diabetes, sex, hypertension, peripheral vascular disease, cerebrovascular disease, prior PCI, prior MI, and coronary bypass surgery. Reduction in the risk of restenosis with cilostazol treatment occurred in patients normally judged to be at high risk for restenosis, including those with lesions in the LAD coronary artery, patients receiving treatment for diabetes mellitus, and those with long lesions and small coronary artery diameters (Figure 2). Cilostazol-treated patients with diabetes who were treated with oral medications experienced a highly significant 63% reduction in the risk of restenosis (P=0.006). However, among the 136 female patients who underwent angiographic follow-up, a significant reduction in restenosis was not observed in cilostazol-treated patients. At 6 months, the minimum luminal diameter for female patients in the cilostazol group was 1.46±0.67 mm compared with 1.54±0.64 mm in the control group (P=0.41). Women were generally older (63 versus 59 years, P<0.01) and had significantly more insulin-dependent diabetes (8% versus 3%, P=0.02), cigarette smoking (50% versus 33%, P<0.01), vascular disease, and smaller vessels (2.56 versus 2.79 mm, P<0.01) but were equally compliant as male patients with the study medications. One-hundred forty-nine patients were found to have in-segment restenosis at follow-up angiography (57 cilostazol-treated patients and 92 placebo patients), 10 of whom had total occlusions (6 cilostazol-treated and 5 placebo patients). Among the 126 patients with nonocclusive restenosis whose follow-up angiograms were adequate for quantitative measurement of the length of the restenosis lesion, 35 patients had restenosis lesion lengths >5 mm, representing a more diffuse pattern (12 cilostazol-treated and 23 placebo patients). The mean restenosis lesion lengths in cilostazol and placebo groups, however, were not significantly different.

View larger version (21K): [in this window] [in a new window]   Figure 2. Univariate subgroup analysis for the 6-month rate of angiographic restenosis (50% of the reference lumen diameter) in the analysis segment of patients treated with cilostazol compared with patients receiving placebo. RR indicates relative risk; CI, confidence interval.

	Discussion

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This randomized, double-blind, placebo-controlled trial that tested the effect of cilostazol after coronary stent implantation showed that a larger minimal luminal diameter was achieved at 6 months in the cilostazol group because of significantly less late lumen loss (0.57 mm compared with 0.75 mm, P<0.01), as determined by quantitative coronary angiography at an independent core laboratory. This resulted in significantly lower binary restenosis in cilostazol-treated patients, a 36% relative risk reduction. The reduction in restenosis observed in cilostazol-treated patients in this trial was greater than that observed in the pivotal STRESS and BENESTENT trials, which compared stents with balloon angioplasty; in those trials, binary restenosis was reduced by 27% and 31%, respectively.^1,2 Although the suppression of late lumen loss by cilostazol was not as potent as that observed with the use of drug-eluting stents, it was highly statistically significant and of a magnitude to be clinically relevant. Late lumen loss in the analysis segment was 0.24 mm with sirolimus-eluting stents and 0.23 mm for paclitaxel-eluting stents.^5,6 Although the angiographic follow-up rate of 74.6% is a limitation of this study, it is similar to the 76.4% rate of follow-up angiography in prespecified patients in TAXUS-IV⁶. The choice of bare, stainless steel stents was at the discretion of the operator; however, the distribution of commercially available stents in the control and treatment groups was similar. The in-segment restenosis rate of 34.5% in this study compares with 36.3% in SIRIUS⁵ and 26.6% in TAXUS IV.⁶

After coronary stent implantation, recognized predictors of increased restenosis include diabetes mellitus, small vessel diameter, lesion length, and LAD coronary artery site. Although cilostazol proved to be effective in reducing the rate of restenosis in nondiabetics, its use in oral agent–treated diabetics was associated with a highly significant 63% reduction in restenosis (Figure 2). Target-vessel revascularization occurred in 11% of cilostazol patients in this subgroup and in 16% of placebo patients. Whether this drug is especially beneficial in the oral agent–treated diabetic population, as suggested by these outcomes, must be determined by further study. The insulin-treated angiographic subgroup was too small to provide meaningful data. As shown in Figure 2, a significant reduction in restenosis was observed independent of lesion length or vessel diameter. Notably, cilostazol-treated patients with stent implantation in the LAD coronary artery experienced a 52% reduction in the risk of restenosis, which compares favorably with the 74% reduction in restenosis of this vessel in the SIRIUS trial, wherein restenosis was reduced from 41.6% to 10.2%.²² Among the 136 women in the angiographic cohort, there was not a significant reduction in restenosis. Whether this was due to a lack of treatment effect or inadequate sample size is uncertain. Women had more adverse characteristics, as reflected by more insulin-dependent diabetes and current smoking, smaller vessels, and more class 3 and 4 angina, and they were generally older by &4 years.

Patients randomly assigned to treatment with cilostazol did not experience increased bleeding compared with placebo despite the use of glycoprotein IIb/IIIa platelet receptor inhibitors in approximately one half of patients and the concomitant use of clopidogrel for 30 days and aspirin for the duration of the study. Similarly, there was no difference in serious adverse cardiac events, stroke, or rehospitalization during the 6-month follow-up. Although the reduction in restenosis experienced with cilostazol treatment was not associated with lowered target-vessel revascularization, this trial was underpowered to examine clinical events. In addition, a decision to repeat intervention at the time of follow-up angiography was made independently by the physician performing the catheterization. Ischemia testing was not required before follow-up angiography. Cutlip et al²³ reported that in multicenter trials, follow-up angiography led to 44% more repeated interventions than studies without mandated angiography. This suggests that non–ischemia-producing lesions were treated at the time of follow-up angiography. Repeated intervention in clinically "silent" lesions is also suggested in this study by a target-vessel revascularization rate of 16%, approximating the restenosis rate observed in some subgroups. In previous studies, ischemia-driven target-vessel revascularization was reported in only &50% of patients with angiographic restenosis.^1,2

The mechanism by which cilostazol treatment resulted in reduced restenosis cannot be discerned from the present study. Experimental animal and human studies have shown cilostazol-associated suppression of intimal hyperplasia.^16,17 In a study of 70 patients, cilostazol inhibited stent-induced P-selection expression on platelets and upregulation of leukocyte Mac-1, and both of these actions were correlated with the degree of late lumen loss after coronary stent implantation.²⁴ The significant reduction in angiographically determined late loss observed in this study suggests that a reduction in intimal hyperplasia occurred in the cilostazol-treated patients.

Despite the effectiveness of drug-eluting stents in many patient subgroups, restenosis remains a significant clinical problem. Drug-eluting stents are not uniformly affordable, and this issue becomes especially problematic when multiple stents are required.^25,26 The British National Institute for Clinical Excellence, which provides guidance for National Health Service Physicians, recommended that drug-eluting stents be utilized only for vessels <3 mm diameter or for lesions >15 mm in length and estimated that the use of drug-eluting stents could be as high as one third of all stents.²⁷ A recently published Italian regional registry reported use of drug-eluting stents in only 16.5% of cases.¹¹ Supporting some degree of restraint in the use of this costly new technology is the apparent lack of any effect on mortality or rates of MI and the paucity of outcome data in many lesion types.^5–7 Drug-eluting stents constituted 70% of total stent usage in a registry of centers in the National Heart, Lung, and Blood Institute Dynamic Registry recently presented.¹⁰ Many patients therefore in the United States and even more abroad remain at risk for restenosis, even in the era of drug-eluting stents, and may benefit from adjunctive systemic therapy to prevent restenosis.

Further studies are indicated to determine the place of cilostazol treatment in the broad spectrum of patients undergoing coronary stent implantation. Although statistically significant restenosis reduction was evident in nondiabetics, in oral-treatment diabetics, and in patients with small vessels, long lesions, and LAD site, these were not prespecified subgroups. Insufficient numbers of insulin-treated diabetics were enrolled to assess efficacy in this very difficult subgroup of patients. This study was also underpowered to assess treatment effects in female patients. No information is available regarding the use of cilostazol in patients receiving drug-eluting stents. Patients included in the present trial were at low risk for bleeding and had previously untreated native coronary stenoses without severe lesion complexity, acute MI presentation, or total coronary occlusion. Whether these excluded patients, especially those likely to have thrombus-associated lesions, would benefit from the combined antiplatelet, antithrombotic, and antiproliferative effects of a drug such as cilostazol is worthy of investigation.

In conclusion, cilostazol significantly reduced renarrowing after coronary stent implantation with bare metal stents. This effect was noted in most major subgroups and was accomplished with no increase in adverse events.

	Acknowledgments

 
This study was supported by a grant from Otsuka America Pharmaceutical, Inc. The authors thank Tila Millen for expert technical assistance and Grant Anderson for data management.

Disclosure

Dr Weintraub reports having served as a consultant to Otsuka America Pharmaceutical. Drs Weintraub, Douglas, and Jurkovitz report having received research grant support and/or lecture fees from Otsuka.

	Footnotes

 
*The centers, investigators, and research coordinators participating in CREST appear in the Appendix, which is available in the online-only Data Supplement at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.104.530097/DC1.

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