Impact of Cilostazol on Restenosis After Percutaneous Coronary Balloon Angioplasty
Background—Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA.
Methods and Results—Two hundred eleven patients with 273 lesions who underwent successful PTCA were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up. Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger (1.65±0.55 vs 1.37±0.58 mm; P<0.0001) and DS was significantly lower (34.1±17.8% vs 45.6±19.3%; P<0.0001) in the cilostazol group. Restenosis and target lesion revascularization rates were also significantly lower in the cilostazol group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%; P<0.001).
Conclusions—Cilostazol significantly reduces restenosis and target lesion revascularization rates after successful PTCA.
Although there is an increasing number of indications for percutaneous transluminal coronary (balloon) angioplasty (PTCA) for revascularization in cases of coronary artery disease, restenosis after PTCA remains a serious problem associated with this procedure.1 A recent intravascular ultrasound study indicated that constrictive remodeling is one mechanism of restenosis.2 However, neointimal proliferation caused primarily by smooth muscle cell (SMC) growth is a major mechanism of restenosis.2 3 4 SMC proliferation and migration is thought to be promoted by several growth factors. Platelets play an important role in restenosis by releasing one of these growth factors.5 Although some platelet aggregation inhibitors reportedly reduce restenosis, attempts to replicate these findings have failed in clinical studies.6 7
Cilostazol (Otsuka Pharmaceutical Co, Ltd) is a new antiplatelet medication that increases the concentration of cAMP within platelets by selectively blocking phosphodiesterase type III, thereby inhibiting platelet aggregation.8 9 Cilostazol also exhibits vasodilator action.10 11 Several animal studies have shown that this drug also inhibits intimal proliferation in injured arteries.12 13 In our previous study with directional coronary atherectomy (DCA) and intravascular ultrasound, we demonstrated that cilostazol has the potential to decrease restenosis by controlling intimal proliferation after PTCA in humans.14 On the basis of these encouraging results, the present study aimed to confirm the inhibitory effect of cilostazol on restenosis after PTCA.
This study was a prospective, randomized trial comparing the effect of cilostazol on restenosis with conventional antiplatelet therapy of aspirin. However, this was not a double-blind trial. Inclusion criteria included a patient who underwent elective PTCA successfully by balloon angioplasty alone without the use of stents or atherectomy devices for stable angina or significant lesions. Procedural success was defined as immediate percent diameter stenosis (DS) <50% without complications. Patients who had a left main trunk lesion or a saphenous vein graft lesion and patients with acute myocardial ischemia (within 1 week of the procedure), severe left ventricular dysfunction, or cardiogenic shock were excluded. Patients already being administered cilostazol or antiplatelet drugs other than aspirin were also excluded.
Eligible patients were invited to participate in the trial, and informed consent was obtained under a protocol approved by our institutional review board. Randomization was performed after the procedure (with equal probability of diabetes mellitus). All enrolled patients were medicated with aspirin as an antiplatelet agent for at least 1 week before the procedure at a dosage of 250 mg once per day. The patients who were assigned to the cilostazol group started receiving oral cilostazol immediately after the procedure and discontinued the use of aspirin. The dosage of cilostazol was 200 mg, which was divided into twice-per-day doses. When any drug side effects including headache, skin rash, liver dysfunction, granulocytopenia, and bleeding were observed, cilostazol was discontinued immediately. In all other patients, medication was continued through the follow-up period. No other antiplatelet or anticoagulant agents were administered. However, nitroglycerin, calcium channel blockers, and β-blockers were used when indicated.
After patient discharge, clinical follow-up examinations were conducted on an outpatient basis at least once per month. Patients were informed of drug side effects and were asked whether they had any symptoms. Hematological testing was conducted if granulocytopenia or liver dysfunction was suspected. Follow-up angiography was performed if positive results were obtained from exercise ECG or if the patient had angina. All other patients were given follow-up angiography 3 months after the procedure.
Quantitative Coronary Angiography Analysis
All preprocedure, postprocedure, and follow-up angiography was conducted immediately after the administration of 200 μg of intracoronary nitroglycerin. Follow-up angiography was performed with guiding catheters at least 6F in diameter. Angiography was performed such that each lesion could be viewed from at least 2 angles. Off-line quantitative coronary angiography (QCA) was conducted with the view revealing the highest degree of stenosis. Calculations were performed with the use of the Cardiovascular Measurement System (CMS-MEDIS Medical Imaging Systems) by an operator who was blinded to the patient’s group assignment. Lesion length, reference diameter (RD), minimal lumen diameter (MLD), and DS were calculated. Acute gain was defined as the difference between pre-MLD and post-MLD measurements, and late loss was defined as the difference between post-MLD and follow-up MLD measurements. Loss index was calculated as late loss divided by acute gain. Angiographic restenosis was defined as DS of >50%.
This study was designed to detect a 50% relative reduction in angiographic restenosis (from 40% in the aspirin group to 20% in the cilostazol group). To achieve a power of 80% with a 2-sided level of significance of 5%, 82 patients would need to be randomly assigned to each group; hence, the planned sample size was 200 patients. Continuous variables were examined by use of the t test or nonparametric analysis by the Mann-Whitney U test. Binary and polychotomous variables were examined by use of the χ2 test. To determine the independent predictive factors for angiographic restenosis within the entire study population, multivariate logistic regression models were used by stepwise selection. Covariates examined included clinical characteristics (patient age, sex, prior myocardial infarction, prior coronary artery bypass, coronary risk factors, and the administration or nonadministration of cilostazol), lesion morphological features (target vessel, American Heart Association/American College of Cardiology [AHA/ACC] type, de novo or restenotic, moderate to severe calcification, eccentricity, ostial site), and QCA factors (preprocedural lesion length as well as RD, MLD, and DS before and after the procedure). Statview version 4.11 and SPSS version 6.1 were used for data analysis.
Study enrollment began in February 1996 and ended in September 1997. The study population consisted of 211 patients with 273 lesions. One hundred three patients with 134 lesions were randomly assigned to the cilostazol group and 108 patients with 139 lesions to the control (aspirin) group. This study population of 211 was a part of 1000 patients who underwent PTCA for 1276 lesions during this study period.
A flow chart showing the exclusion and breakdown of patients from the time of enrollment to follow-up angiography is shown in Figure 1⇓. No major adverse cardiac events (acute myocardial infarction, coronary artery bypass surgery, or death) were observed in the enrolled patients during their hospital stay. No patients of either group showed a rise in CPK >5 times the normal value, and a 3-fold rise was observed in only 5 patients in the cilostazol group and 4 patients in the control group. Three patients in the cilostazol group complained of a headache when administration of the drug was commenced. In 2 patients this symptom disappeared with continuation of the drug. However, in another patient the headache was so severe that cilostazol administration was discontinued and the patient was excluded from the study.
Nine other enrolled patients were excluded before follow-up angiography. Two patients in the cilostazol group were excluded because of a skin rash; however, no other side effects such as liver dysfunction, granulocytopenia, or bleeding were observed. Three patients in the cilostazol group and 4 patients in the control group were excluded because of inadequate medication, which was found retrospectively. These patients were switched to another drug or were simultaneously administered other antiplatelet medication such as ticlopidine on an outpatient basis.
No cases of myocardial infarction were observed during the follow-up period. However, 3 patients in the control group underwent angiography before the scheduled day because of recurrent angina. In 3 patients in the cilostazol group and 5 patients in the control group without recurrent angina or the observation of an ST-segment depression under stress ECG, the planned follow-up angiography could not be performed because of patient refusal or physician decision based on patient characteristics such as renal disorder or age. Consequently, a follow-up angiogram was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group 108±41 days after the procedure.
Baseline characteristics of the eligible patients are shown in Table 1⇓. There were no significant differences between the 2 groups with regard to age, sex, prior myocardial infarction, prior coronary bypass surgery, presence of angina, or number of diseased vessels. In addition, no significant differences were observed between the 2 groups with regard to the number of patients with coronary risk factors.
Lesion characteristics and PTCA procedural results of the 2 groups are shown in Table 2⇓. There were no significant differences between the 2 groups as to lesion location, AHA/ACC type, lesion morphology, or preprocedure QCA data. The mean RD of ≈2.5 mm in each group shows that the lesions in this study were located in relatively small vessels. The balloon-to-artery ratio and maximum balloon inflation pressure were almost identical.
Change in MLD in the 2 groups is shown in Figure 2⇓ and Table 3⇓. There were no significant differences between the 2 groups in pre-PTCA or post-PTCA MLD. However, at follow-up, the cilostazol group showed a significantly larger MLD than did the control group (1.65±0.55 vs 1.38±0.58 mm; P<0.0001). Figure 3⇓ shows cumulative distribution of DS before and after PTCA and at follow-up. Percent diameter stenosis before and after PTCA also showed no significant difference between the 2 groups but was significantly lower in the cilostazol group at follow-up (34.1±17.8% vs 45.6±19.3%; P<0.0001). No significant difference between the 2 groups was observed in acute gain (1.02±0.42 vs 1.06±0.47 mm; P=0.51), but late loss was significantly smaller (0.15±0.45 vs 0.45±0.52 mm; P<0.0001) in the cilostazol group. Consequently, the loss index was significantly lower in the cilostazol group (0.13±0.48 vs 0.46±0.53; P<0.0001) (Table 3⇓).
To examine the effect of cilostazol as a vasodilator, change in RD from the time of the procedure until follow-up was analyzed (Figure 4⇓). The RD measured by QCA significantly enlarged after the procedure compared with before the procedure in both groups (2.49±0.42 to 2.54±0.42 mm in the cilostazol group; P<0.0001, 2.48±0.51 to 2.55±0.51 mm in the control group; P<0.0001) because of the ballooning procedure. In the control group, follow-up RD was 2.52±0.53 mm; there was no significant change in RD compared with postprocedure values. However, in the cilostazol group, follow-up RD, which was measured after 3 months of continuous administration of the drug, was significantly larger than postprocedure values measured before drug administration (2.54±0.42 to 2.58±0.46 mm; P<0.0001).
Angiographic Restenosis and Target Lesion Revascularization
Angiographic restenosis and target lesion revascularization (TLR) rates are shown in Table 4⇓. The restenosis rate of 17.9% in the cilostazol group was significantly lower than the 39.5% in the control group (P<0.001). Similarly, the TLR rate was significantly lower in the cilostazol group (11.4% vs 28.7%; P<0.001). In addition, TLR rate per patient, defined as the percentage of patients who underwent TLR for at least 1 lesion in each group, was also significantly lower in the cilostazol group (12.8% vs 35.4%; P<0.001).
Predictors of Restenosis
To clarify the ability of cilostazol to reduce restenosis, potential predictors of angiographic restenosis in this cohort were input into multivariate models. Logistic regression analysis revealed that the independent predictors of restenosis were administration of cilostazol, increasing age, and increasing post-DS measurements (Table 5⇓). Among these 3 factors, cilostazol administration was found to be the most reliable predictor of restenosis (odds ratio=0.29, P=0.0001). This result could be interpreted to mean that given 2 patients of the same age and same post-DS measurements, the risk of restenosis would be reduced by ≈70% in the patient receiving cilostazol.
Cilostazol is a new antiplatelet medication recently developed in Japan.8 Animal studies have shown that cilostazol controls intimal hyperplasia in denuded carotid arteries of rats12 and in stented external iliac arteries of dogs.13 Furthermore, several prospective, randomized studies on small populations have indicated that cilostazol has the potential to reduce restenosis after DCA or stent implantation in humans.14 15 16 17 The present prospective, randomized study was conducted to confirm the efficacy of the drug in reducing restenosis after coronary balloon angioplasty. Cilostazol administration showed a significantly larger MLD (1.65 vs 1.37 mm; P<0.0001) and a lower DS (34.1% vs 45.6%; P<0.0001) at follow-up as well as a significantly reduced restenosis rate (11.4% vs 28.7%; P<0.001) and TLR rate (12.8% vs 35.4%; P<0.001) compared with aspirin administration. Multivariate analysis also revealed that cilostazol administration reduced the risk of restenosis by ≈70% (P=0.0001, odds ratio=0.29). These results clearly suggest that cilostazol reduces the risk of restenosis after balloon angioplasty.
Pharmacology of Cilostazol
Cilostazol acts by selectively inhibiting phosphodiesterase type III, an enzyme that breaks down cAMP. A higher level of cAMP stimulates production of cAMP-dependent protein kinase, resulting in a lower level of intracellular Ca+ ions within platelets, which in turn represses platelet activity.9 Studies both in vitro and in vivo have shown cilostazol to be a more powerful antiplatelet agent than aspirin, dipyridamole, or ticlopidine.9 18 The antiplatelet effect of cilostazol takes effect in vivo within 6 hours of oral ingestion, and platelet aggregation ability is recovered within 48 hours after drug withdrawal.19
In addition to its antiplatelet effects, cilostazol acts as an arterial vasodilator. Cilostazol has been reported to relax the contraction of vascular smooth muscle by raising the cAMP level in vitro.10 Intracellular cAMP blocks the release of Ca+ ions from intracellular storage granules within the SMC, thus inhibiting the function of contractile proteins. In patients with peripheral artery disease, cilostazol also improves skin blood flow and clinical signs through its vasodilating and/or antiplatelet effects.11 20
Unlike aspirin, cilostazol does not inhibit prostaglandin I2 (prostacyclin) synthesis, a compound that is known to have antithrombotic activity, inhibit platelet aggregation, and relax vascular smooth muscle. The antiplatelet effect of cilostazol is potentiated by endothelium-derived prostacyclin.21 These pharmacological characteristics may enhance the clinical efficacy of the drug.
Mechanism of Restenosis Reduction by Cilostazol
One of the mechanisms by which cilostazol reduces restenosis after PTCA is thought to be inhibition of neointimal proliferation, considered a major mechanism of restenosis after PTCA caused by SMC migration, proliferation, and matrix synthesis.3 4 22 SMC migration and proliferation are induced by growth factors released from activated platelets. As an antiplatelet medication, cilostazol controls the induction by platelet-derived growth factors.12 13 23 More importantly, cilostazol is thought to directly inhibit SMC growth. In vitro studies involving rat aortic smooth muscle cell cultures have shown that increasing the concentration of cilostazol resulted in an increase of intracellular cAMP and a decrease of 3H-thymidine uptake,23 suggesting that phosphodiesterase III inhibitors inhibit SMC growth by affecting its deoxyribonucleic acid, thereby controlling its cell proliferation.24 This direct inhibition of SMC proliferation is considered to be the main contributor to the significant reduction of late loss after PTCA seen after cilostazol administration in the present study. The precise mechanism by which an increase in the concentration of cAMP results in the inhibition of cell growth is not yet clear.24 25 One possible mechanism involves the inhibition of the mitogen-activated protein kinase cascade through the action of cAMP-dependent protein kinase.26 27
On the basis of the present results, another mechanism of restenosis reduction by cilostazol may be its action as a potent vasodilator. The cilostazol group in the present study showed an enlarged RD measured by QCA after cilostazol administration (2.54 mm after the procedure to 2.58 mm at follow-up; P<0.0001). This finding appears to reflect the vasodilator action of cilostazol on coronary arteries, because this change was not observed in the control group even after the injection of intracoronary nitroglycerin. Although the magnitude of this effect may be small, it also partially contributes to the reduction of late lumen loss at PTCA sites in the cilostazol group. This vasodilator effect is thought to result from the continuous relaxation of vascular smooth muscle caused by cilostazol administration. However, it remains unclear whether cilostazol decreases late vascular constrictive remodeling at PTCA sites.
Several recent reports have suggested that cilostazol may also affect endothelial cell growth. In vitro studies have shown that cilostazol increases the concentration of hepatocyte growth factor, which is a novel and potent member of endothelial cell specific growth factors, and consequently may attenuate endothelial cell death and stimulate its growth.28 29 30 Further investigation is required. However, cilostazol may also control neointimal proliferation by accelerating the regrowth of endothelial cells after balloon angioplasty.
Although this was a prospective, randomized study, the major limitation of the present study is that it was not a double-blind trial. To compensate for this serious limitation, we conducted the serial QCA measurement in a blinded manner. However, this technique cannot completely remove the possible bias associated with the measurement because cilostazol has an apparent vasodilator effect that would lead to a larger reference diameter at follow-up examination, even if the physician performing QCA was blinded to the treatment assignment. Similarly, there might be another bias associated with the clinical decision related to TLR assumed to be related to the potent vasodilator action of cilostazol. This is a serious limitation to the present study design and must be considered in the interpretation of these results. Furthermore, while an adequate number of lesions were examined to confirm the efficacy of the drug, these results were obtained exclusively in a single center. Given this limitation, a carefully designed, large-scale multicenter, double-blind, randomized study is needed to validate the present results. The safety and efficacy of cilostazol after stenting has already been reported.16 17 31 To measure the effect of cilostazol on neointimal proliferation, an appropriate protocol may be to analyze follow-up data after stenting, a procedure in which restenosis is thought to result largely from neointimal proliferation and not from vascular remodeling.32
Despite the apparent limitations of the present study, our results clearly suggest that cilostazol can reduce the risk of restenosis after successful balloon angioplasty.
- Received December 22, 1998.
- Revision received April 1, 1999.
- Accepted April 9, 1999.
- Copyright © 1999 by American Heart Association
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