Impact of cilostazol on intimal proliferation after directional coronary atherectomy

Interventional Cardiology

Impact of cilostazol on intimal proliferation after directional coronary atherectomy Etsuo Tsuchikane, MD, Osamu Katoh, MD, Satoru Sumitsuji, MD, Atsunori Fukuhara, MD, Masanobu Funamoto, MD, Satoru Otsuji, MD, Hitone Tateyama, MD, Nobuhisa Awata, MD, and Tohru Kobayashi, MD Osaka, Japan

Cilostazol, a novel platelet aggregation inhibitor, inhibits intimal proliferation in animal models. We randomly assigned 41 patients with lesions suitable for directional coronary atherectomy to the cilostazol group (200 mg/day) or the aspirin (250 mg/day) group. Medication was started before directional coronary atherectomy and was continued to a 6-month followup. Serial quantitative coronary angiography and intravascular ultrasound study were performed. Baseline characteristics were not different between the two groups. However, the minimal lumen diameter at follow-up was larger (2.33 ± 0.60 mm vs 1.81 ± 0.68 mm, p = 0.016) and the percent diameter stenosis (24.5% ± 16.6% vs 40.9% ± 21.0%, p = 0.010) was smaller in the cilostazol group. The change in vessel area was not different, but the percent plaque area at follow-up was smaller in the cilostazol group (55.7% ± 11.2% vs 64.5% ± 14.5%, p = 0.044). The restenosis rate was significantly lower in the cilostazol group (0% vs 26%, p = 0.020). We conclude that cilostazol appears to have an inhibitory effect on intimal proliferation after directional coronary atherectomy and may reduce restenosis. (Am Heart J 1998;135:495-502.)

With the recent introduction of stents and other new devices, indications for percutaneous transluminal coronary angioplasty (PTCA) are expanding. On the other hand, post-PTCA restenosis is seen in 30% to 40% of patients and is still a major drawback of the procedure.1-3 Although recent intravascular ultrasound (IVUS) data have indicated that late vascular remodeling is a mechanism of restenosis,4,5 smooth muscle cell (SMC) proliferation is a major cause of restenosis.6-8 When platelets aggregate, they are thought to release growth factors that promote SMC proliferation and migration.9,10 However, no drug has yet been found that has succeeded in significantly lowering restenosis by inhibiting platelet aggregation.11,12 Cilostazol is a recently synthesized antiplatelet medication that increases the concentration of cyclic adenosine monophosphate (AMP) within platelets by selectively blocking phosphodiesterase and as a result inhibits platelet aggregation.13,14 This drug was also found to inhibit intimal proliferation in denuded carotid arteries of rats15 and in stented arteries of dogs.16 As yet From the Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Diseases. Submitted May 21, 1997; accepted Sept. 2, 1997. Reprint requests: Etsuo Tsuchikane, MD, The Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari, Osaka-city, Osaka, 537 Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/86109

no studies have been conducted showing postangioplasty inhibition of SMC growth with the use of this drug in human beings. In this study we examined the inhibitory effect of cilostazol on intimal proliferation after directional coronary atherectomy (DCA) with quantitative coronary angiography (QCA) and IVUS.

Methods Patients The study population consisted of 41 patients who were DCA candidates (nonleft main trunk native coronary stenosis of a vessel at least 2.5 mm in diameter with no angiographic evidence of severe calcification) with de novo lesions who agreed to participate as subjects. All patients had stable angina and underwent elective procedures. Patients with acute myocardial ischemia (within 1 week of the procedure), severe left ventricular dysfunction, or cardiogenic shock were excluded. This study population was a part of 65 patients who underwent DCA and a part of 579 patients who underwent PTCA during this study period.

Randomization Randomization was carried out by means of sealed envelopes 1 week before the procedure. Twenty-one subjects were randomly assigned to the cilostazol group and 20 to the aspirin control group. There was no placebo control and thus no blinding of clinicians or patients. However, this assignment was concealed to a DCA operator.

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Table I. Baseline patient characteristics

No. Male (%) Age (yr) Previous MI (%) Previous CABG (%) Angina (%) Multivessel disease (%) Hypertension (%) Diabetes mellitus (%) Smoking (%) Hyperlipidemia (%)

Cilostazol

Aspirin

p Value

20 19 (95) 60 ± 8 7 (35) 1 (5) 15 (75) 5 (25) 5 (25) 4 (20) 12 (60) 15 (75)

19 18 (95) 61 ± 9 5 (25) 1 (5) 14 (74) 6 (32) 4 (21) 2 (11) 14 (74) 12 (63)

0.97 0.86 0.56 0.97 0.93 0.65 0.77 0.41 0.36 0.42

MI, Myocardial infarction; CABG, coronary artery bypass graft.

Medication Patients of both groups were admitted 1 week before the procedure, and internal medication was commenced immediately after randomization because we intended to stabilize the antiplatelet effect of both drugs before the procedure. The daily dose of cilostazol was 200 mg, and that of aspirin was 250 mg. A total of 100 mg cilostazol was administered twice a day, and aspirin was administered once a day in the morning. This medication was continued until follow-up. No other antiplatelets or anticoagulants were administered. However, nitroglycerin, calcium blockers, and β-blockers were allowed when indicated.

DCA procedure After a sheath introducer was inserted into the femoral artery, all patients were given 100 U/kg body weight of intravenous heparin. The atherectomy device used was 7F or 7FG introduced through a 10F guiding catheter. The goal was to debulk enough tissue to attain a residual plaque plus media area that was less than 50% of the total vessel area. No adjunctive balloon angioplasty was performed.

QCA and IVUS All preprocedure and postprocedure angiography and IVUS imaging was conducted immediately after the administration of 200 µg intracoronary nitroglycerin. Angiography was performed so that each lesion was viewed from at least two angles. Off-line QCA was conducted with the view revealing the highest degree of stenosis. Calculations were made with the Cardiovascular Measurement System (CMSMEDIS Medical Imaging Systems) by an isolated operator who was unaware of the patient’s group assignment. The lesion length, reference diameter, minimal lumen diameter (MLD), and percent diameter stenosis (%DS) were calculated. Acute gain was defined as the difference between pre-MLD and post-MLD, and late loss was defined as the difference

between post-MLD and follow-up MLD. Loss index was calculated as late loss divided by acute gain. IVUS studies were performed with CVIS Insight with a single-element, 30 MHz beveled transducer within a 3.2F short monorail imaging catheter. Imaging was performed beginning at a point distal to the lesion and ending at the aortic ostium with the motorized pull-back system at 0.5 cm/sec. The measurement was obtained at the same point as the smallest lumen of the preprocedure. Care was taken to assess the vessel at the same point during all subsequent imaging by accurately measuring distances from side branches used as landmarks. Calculations were made off-line by an experienced operator who was unaware of the patient’s group assignment. Total vessel area (VA) and lumen area were calculated, and the difference between these two values was defined as the plaque plus media area (PA). PA was then divided by VA to obtain percent PA.

Follow-up After patient discharge clinical follow-up examinations were conducted on an outpatient basis at least once a month. Patients were informed regarding bleeding and the drug’s side effects and were asked whether they had any such symptoms. Hematologic testing was conducted if granulocytopenia or liver dysfunction was suspected. Follow-up angiography was performed if positive results were obtained from exercise electrocardiography or if the patient had angina. All other patients were given follow-up angiography 6 months after the procedure. Follow-up coronary angiography was performed with guiding catheters at least 8F in diameter, and the views showing the highest degree of stenosis were used for QCA. IVUS imaging was also performed in the same manner as before. Angiographic restenosis was defined as diameter stenosis of greater than 50%

Statistical analysis Quantities were expressed as mean value ± SD. Variable categories were expressed as frequencies. Statview version 4.11 was used for data analysis. The Student’s t test or nonparametric analysis by the Mann-Whitney U test was used for numeric comparisons between groups. The chi-squared test or the Fisher exact test was used for comparison of variable categories expressed as frequencies.

Results Two enrolled patients were dropped from the study at the time of their procedures. One who belonged to the cilostazol group had a lesion with superficial calcification extending over more than 180 degrees of vessel circumference as viewed with IVUS. We determined that adequate debulking with DCA would be impossible, so balloon angioplasty and Palmaz-Schatz stent implantation were performed. The other patient, who belonged to the aspirin group, was stented with a

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Table II. Baseline lesion characteristics

No. Diseased vessel RCA (%) LAD (%) LCx (%) AHA/ACC type A (%) B1 (%) B2 (%) C (%) Calcified (%) Eccentric (%) Ostial (%) Lesion length (mm) RD (mm) Pre-MLD (mm) Pre-DS (%) Used atherocatheter size 7F (%) 7FG (%) No. of cuts Maximum inflation pressure at cutting (psi)

Cilostazol

Aspirin

20

19

7 (35) 9 (45) 4 (20)

9 (47) 9 (47) 1 (5)

2 (10) 7 (35) 11 (55) 0 (0) 5 (25) 16 (80) 1 (5) 11.3 ± 3.8 3.04 ± 0.29 0.89 ± 0.26 71 ± 9

1 (5) 9 (47) 8 (42) 1 (5) 5 (26) 16 (84) 2 (10) 11.5 ± 5.5 3.16 ± 0.42 0.83 ± 0.26 73 ± 10

12 (60) 8 (40) 19 ± 4 34 ± 12

11 (53) 9 (47) 20 ± 5 33 ± 10

p Value

0.36

0.56 0.93 0.73 0.52 0.90 0.30 0.52 0.36 0.89 0.83 0.79

RCA, Right coronary artery; LAD, left anterior descending artery; LCx, left circumflex artery; AHA, American Heart Association; ACC, American College of Cardiology; RD, Reference diameter.

Palmaz-Schatz stent because of a device-caused dissection that extended from the lesion distally. No major complications (acute myocardial infarction, emergent bypass surgery, or death) occurred among the 39 patients who received DCA alone. Creatine kinase was measured routinely approximately 12 hours after the procedure. No patients of either group displayed a creatine kinase rise of more than five times the normal value, and a threefold rise was seen in only one patient who was in the cilostazol group. One patient in the cilostazol group reported a slight headache when the drug was commenced, but the headache disappeared with continuation of the drug.

Patient characteristics Baseline characteristics of the 39 patients are shown in Table I. No significant difference was seen between the two groups with regard to age, sex, previous myocardial infarction, previous coronary bypass surgery, presence of angina, or number of diseased vessels. There was also no significant difference between the two groups with regard to the number of patients with coronary risk factors.

Lesion characteristics and DCA procedural results Lesion characteristics and DCA procedure results of the two groups are shown on Table II. No significant difference was found between the two groups as to lesion location, American Heart Association/American College of Cardiology type, lesion morphologic characteristics, or QCA data of preprocedure. With regard to DCA procedure, used atherocatheter size, number of cuts, and maximum balloon pressure at cutting were not different between the two groups.

Follow-up During the follow-up period adverse effects such as liver dysfunction or bleeding were not observed; therefore none of patients discontinued medication. No patients had unstable angina or myocardial infarction. Patients had routine stress electrocardiography. In the aspirin group two patients, although they had no angina at 3 and 4 months after the procedure, exhibited a ST segment depression under stress electrocardiography and so were examined with angiography. The thirty-seven other patients underwent follow-up angiography and IVUS at a 6-month follow-up. The mean follow-up duration was 209 ± 38 days.

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Figure 1

Reference diameter pre-DCA, post-DCA, and at follow-up. No significant difference was found among groups.

Figure 2

MLD pre-DCA, post-DCA, and at follow-up. MLD at follow-up of colstazol group was significantly larger than that of aspirin group (p = 0.016).

QCA analysis Figs. 1, 2, and 3 show time lines of QCA data for the two groups. The vessel reference diameters of the cilostazol group were slightly larger but not significantly (Fig. 1). Fig. 2 shows that no significant difference was found between the two groups in pre-DCA MLD and post-DCA MLD. However, at a 6-month follow-up the cilostazol group showed a significantly larger MLD than that of the aspirin group (2.33 ± 0.44 mm vs 1.81 ± 0.68 mm, p = 0.016). Immediate preprocedure and postprocedure %DS also was not significantly different between the two groups but was significantly lower in

the cilostazol group (24.5% ± 16.6% vs 40.9% ± 21.0%, p = 0.010). No significant difference was found between the two groups with regard to acute gain (1.93 ± 0.47 mm vs 1.94 ± 0.44 mm, NS), but late loss was smaller (0.48 ± 0.48 mm vs 0.96 ± 0.76 mm, p = 0.056) for the cilostazol group, and loss index (0.27 ± 0.29 vs 0.49 ± 0.35, p = 0.043) was significantly lower for the cilostazol group (Fig. 3).

QCU analysis QCU data were also analyzed. As seen in Fig. 4, the pre-DCA VA value was marginally greater in the

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Figure 3

Acute gain, late loss, and loss index of two groups. Loss index of cilostazol group was significantly lower than that of aspirin group (p = 0.043).

Figure 4

Total vessel area pre-DCA, post-DCA, and at follow-up. No significant difference was found between two groups.

aspirin group. No significant difference was seen as to the change in VA between the two groups. Fig. 5 gives the increase of lumen area of the two groups as measured by IVUS. No difference between the groups was found with respect to the increase of lumen area, and in both groups approximately three fourths of the lumen gain was determined to be caused by a decrease in PA. We therefore concluded that there was no difference as to the mechanism of lumen dilation. PA immediately after DCA was not different between the two groups (cilostazol group, 8.2 ± 3.1 mm2 vs aspirin group, 9.1 ± 4.7 mm2), but at follow-up it was lower for the cilostazol group (8.7 ± 3.1 mm2 vs 10.9 ± 5.9

mm2). The pre-DCA percent PA of the two groups was also a similar value (47.0% ± 9.8% vs 48.0% ± 12.2%), but the follow-up percent PA was significantly lower for the cilostazol group (55.7% ± 11.2% vs 64.5% ± 13.5%, p = 0.044, Fig. 6).

Restenosis The restenosis rate was 0% for the cilostazol group and 26% for the aspirin group, a significantly lower rate for the former group (p = 0.020, Fig. 7). PTCA was repeated for three of the five patients in the aspirin group with restenosis. The target lesion revascularization rate was 16%.

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Figure 5

Figure 7

Angiographic restenosis rate and target lesion revascularization (TLR) rate at follow-up. Restenosis rate of cilostazol group was significantly lower than that of aspirin group (p = 0.020).

Mechanism of lumen dilation of two groups. Lower part of bar describes decrease of plaque plus media area; upper part describes increase of total vessel area. No difference was found between two groups with respect to mechanism of lumen dilation.

Figure 6

vascular remodeling to be a cause of restenosis,4,5 but neointimal hyperplasia caused by SMC growth is also thought to play a major role.6-8 Because SMC migration and proliferation are instigated by growth factors that are released from activated platelets, growth factors are seen as an important factor in the process of restenosis.9,10 However, there have been no reports as yet of antiplatelet medication lowering post-PTCA restenosis rates.11,12

Clinical impact of cilostazol on restenosis

Percent plaque plus media area (%PA) at postdirectional coronary atherectomy and follow-up. %PA at follow-up of cilostazol group was significantly smaller than that of aspirin group (p = 0.044).

Discussion Restenosis after PTCA Although post-PTCA restenosis has been reduced with the development of stents17,18 and other new devices, it remains a major problem of angioplasty.1-3 IVUS studies conducted in recent years have shown

Animal studies testing the efficacy of cilostazol, a platelet aggregation inhibitor recently developed in Japan,13 have shown that this drug controls intimal hyperplasia in denuded carotid arteries of rats15 and in stented external iliac arteries of dogs.16 In this study we have demonstrated that cilostazol reduces angiographic restenosis after DCA in human. We have also shown by IVUS measurements that the mechanism of restenosis rate reduction was the drug’s effect in inhibiting neointimal growth and that vascular remodeling was not involved. Factors that have been known to affect post-PTCA restenosis rates include age, sex, coronary risk factors, lesion diameter/length/morphologic characteristics, device used, postprocedure MLD, and others. Although this study was a prospective randomized trial based on only 39 patients, no difference was found in patient background characteristics and preprocedure lesion morphologic characteristics. No difference was observed in the QCA-observed acute gain and IVUSderived remaining %PA, so we were able to debulk lesions of the two groups of patients in a similar fashion, resulting in similar postprocedure lesion morpho-

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logic characteristics. No patients had acute closure, and drug regimens were kept constant for all patients of the two groups. Therefore it is thought that differences that were found between the two groups at follow-up were caused by the effect of this antiplatelet medication. Because no difference in VA was found between the two groups at follow-up, it was thought that cilostazol had no effect on vascular remodeling. Therefore we think that differences between groups with respect to vessel diameter or restenosis are caused by differences in PA as seen on IVUS. That is, cilostazol controls the growth of SMC after DCA and thereby inhibits neointimal proliferation.

Mechanisms in which cilostazol inhibits neointimal proliferation Cilostazol acts by selectively inhibiting phosphodiesterase III, an enzyme that breaks down cyclic adenosine monophosphate (AMP) within platelets. A higher level of cyclic AMP stimulates production of cyclic AMP-dependent protein kinase, resulting in a lower level of intracellular Ca+ ions, which in turn represses platelet activity.14 In vitro studies have shown cilostazol to be a more powerful antiplatelet agent than aspirin, dipyridamole, or ticlopidine.14,19 This finding has also been demonstrated in vivo.14,20 One of the mechanisms in which cilostazol controls SMC growth is thought to be inhibition of growth factors released by platelets.15,16,21 It has also been reported that cilostazol inhibits production of platelet-derived growth factors in human umbilical vein endothelial cell cultures.22 However, it is also known that SMC growth factors are produced in microphages and T lymphocytes and from SMCs themselves,23 so it is unlikely that inhibition of platelet activity is the only mechanism of this drug’s effectiveness in suppressing SMC growth. Cilostazol is also thought to directly inhibit SMC proliferation. It has been clearly demonstrated to control rat carotid artery intimal proliferation in vivo.15 In vitro studies involving rat aortic smooth muscle cell cultures have shown that increasing the concentration of cilostazol resulted in an increase of intracellular cyclic AMP and a lowered 3H-thymidine uptake.21 This finding suggests that cilostazol inhibits SMC growth by affecting its deoxyribonucleic acid. The exact mechanism in which increase in the concentration of cyclic AMP results in inhibition of cell growth is not yet clear.24,25 One possible mechanism involves inhibition of the mitogen activated protein kinase cascade through the action of cyclic AMP-dependent protein kinase.26,27

Tsuchikane et al.

Study limitations Although this was a prospective study, the number of patients enrolled was only 39. Although it was randomized, it was not a double-blind trial because we intended to investigate the drug’s efficacy as a preliminary study. Only two-dimensional IVUS measurements were used to observe vessel cross-sections without making use of three-dimensional algorithms showing the entire lesion. Choosing DCA as the device resulted in a change in vessel diameter (a change in VA as measured by IVUS). Because our intention was to measure the effect of cilostazol on postangioplasty neointimal proliferation, a better protocol may have been 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.28 However, we chose DCA in our protocol because cilostazol’s efficacy in controlling subacute thrombosis after stenting has not yet been established. To confirm the drug’s efficacy in reducing restenosis, a carefully designed, large-scale, multicenter, double-blind randomized study is required in which conventional balloon angioplasty or other devices, especially stents, are used.

Conclusions This study demonstrates that cilostazol may be able to inhibit neointimal proliferation and thereby reduce the restenosis rate after PTCA.

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