1. P. Omedé,1 A. Abbate,4 G. P. Trevi,1 and I. Sheiban1
Oral Cilostazol Prevents Restenosis And Repeat Revascularization After Percutaneous Coronary Stenting: A Meta-Analysis Of 15 Randomized Trials And 4897 Patients
G. Biondi-Zoccai,1 C. Moretti,1 M. Lotrionte,2 P. Agostoni,3 F. Sciuto,1
P. Omedé,1 A. Abbate,4 G. P. Trevi,1 and I. Sheiban1
1University of Turin, Turin, Italy 2Catholic University, Rome, Italy; 3AZ Middelheim, Antwerp, Belgium; Virginia Commonwealth University, Virginia, USA

2. BACKGROUND
Drug-eluting stents (DES) reduce the risk of restenosis after percutaneous coronary intervention (PCI) in comparison to bare-metal stents (BMS), but may pose a risk of thrombosis.
Furthermore, DES are not uniformly powerful in reducing restenosis, especially in patients with abundant neointimal hyperplasia (eg diabetics).

3. BACKGROUND
Cilostazol is an oral antiplatelet agent with pleiotropic effects, including inhibition of neointimal hyperplasia.
It is a safe agent, already approved in several countries for the symptomatic treatment of intermittent claudication and peripheral artery disease
Cilostazol could hold the promise of preventing both restenosis and thrombosis after PCI with stenting.

4. OBJECTIVES
We aimed to systematically review randomized clinical trials on the angiographic and clinical impact of cilostazol after percutaneous coronary stenting.
Our goal was specifically to pool major outcomes from included studies with meta-analytic techniques.

5. METHODS
We searched Bio-MedCentral, CENTRAL, clinicaltrials.gov, EMBASE, and PubMed for randomized trials comparing cilostazol vs control after PCI (keywords: cilostazol, coronary, and restenosis; updated March 2008).
Inclusion criteria were: (a) randomized allocation, (b) comparison of cilostazol vs control, (c) after PCI with stenting, and (d) follow-up ≥1 month.
Exclusion criteria were: (a) duplicate reports, (b) lack of outcome data beyond hospitalization, and (c) equivocal or nonrandom treatment allocation.

6. METHODS
Co-primary end-points were binary angiographic restenosis and repeat revascularization, abstracted and pooled by means of random-effect relative risks (RR) with RevMan 4.2 (Cochrane Collaboration).
Stent thrombosis and small study/ publication bias (ie the likelihood of small yet nominally significant studies being selectively published in the literature) were also appraised.

7. REVIEW PROFILE

8. INCLUDED STUDIES Study Year Pts on cilostazol Pts on control Rx
Stent type
Abe
2002 37 41
BMS
Chen
2006 52 54
CIDES
2008
113
124
DES
CREST
2005
259
267
DECLARE-Diabetes
200
DECLARE-Long
2007
250
Han 34
Inoue
2004 32
Kamishirado 57
Kozuma
2001 61 58
Kunishima
1997 35
Lee
344
345
Mizoguchi
2003 65
Ochiai
1999 23 21
Park
254
240
RACTS
202
194
Sekiguchi 89 86
Sekiya
1998 82 83
Takeyasu
427
436
Yamasaki 18 17
Yoon
147
149

9. RESULTS
A total of 21 randomized clinical trials were included (5577 patients, 2780 randomized to oral cilostazol for 1-6 months, and 2797 randomized to control therapy or placebo), with median follow-up of 6 months.
Pooled analysis showed that cilostazol was associated with statistically significant reductions in binary angiographic restenosis (relative risk=0.61 [95% confidence interval ], p<0.001) and repeat revascularization (relative risk=0.73 [ ], p=0.001).

10. RESULTS
Cilostazol appeared also safe, with no significant increase in the risk of stent thrombosis (relative risk=1.27 [ ], p=0.45) or bleeding (relative risk=0.73 [ ], p=0.19).
Sub-analysis restricted to trials using only DES, including a total of 1137 patients, confirmed that cilostazol lead to significant reductions in binary angiographic restenosis (relative risk=0.54 [ ], p=0.002).

11. RESULTS
Similarly, among patients treated solely with DES, cilostazol lead to a statistically significant reduction in repeat revascularizations (relative risk=0.47 [ ], p=0.002).
Conversely, risk of stent thrombosis or bleeding in DES-treated patients was not significantly influenced by cilostazol (respectively relative risk= 0.77 [ ], p=0.76, and relative risk=0.72 [ ], P=0.58), .
Funnel plots suggested however the presence of small study bias, but limited to the BMS group.

12. RISK OF BINARY RESTENOSIS
Study
Cilostazol
Control
RR (random)
RR (random)
or sub-category
n/N
n/N
95% CI
95% CI
01 BMS
Kunishima
3/ /41
0.32 [0.10, 1.05]
Sekiya
9/ /83
0.46 [0.22, 0.94]
Yamasaki
0/ /17
0.14 [0.01, 2.44]
Ochiai
0/ /21
0.08 [0.00, 1.42]
Park
58/ /240
0.84 [0.62, 1.15]
Kozuma
10/ /58
0.50 [0.25, 0.98]
Abe
0/ /41
0.04 [0.00, 0.58]
Kamishirado
7/ /57
0.43 [0.20, 0.97]
Mizoguchi
4/ /65
0.31 [0.11, 0.89]
Inoue
4/ /32
0.38 [0.13, 1.08]
Sekiguchi
24/ /86
1.16 [0.69, 1.94]
CREST
57/ /267
0.64 [0.48, 0.85]
Han
5/ /37
0.54 [0.21, 1.43]
RACTS
47/ /194
0.75 [0.54, 1.04]
Takeyasu
119/ /436
0.95 [0.77, 1.17]
Chen
7/ /54
0.43 [0.19, 0.95]
Subtotal (95% CI)
0.62 [0.50, 0.78]
Total events: 354 (Cilostazol), 505 (Control)
Test for heterogeneity: Chi² = 32.08, df = 15 (P = 0.006), I² = 53.2%
Test for overall effect: Z = 4.14 (P < )
02 DES
DECLARE-Long
14/ /250
0.61 [0.32, 1.16]
CIDES
9/ /124
0.49 [0.23, 1.04]
DECLARE-DIABETES
13/ /200
0.50 [0.26, 0.94]
Subtotal (95% CI)
0.54 [0.36, 0.79]
Total events: 36 (Cilostazol), 69 (Control)
Test for heterogeneity: Chi² = 0.24, df = 2 (P = 0.89), I² = 0%
Test for overall effect: Z = 3.17 (P = 0.002)
Total (95% CI)
0.61 [0.51, 0.75]
Total events: 390 (Cilostazol), 574 (Control)
Test for heterogeneity: Chi² = 34.95, df = 18 (P = 0.010), I² = 48.5%
Test for overall effect: Z = 4.86 (P < )
0.01
0.1 1 10
100
Favours cilostazol
Favours control

13. RISK OF REPEAT REVASCULARIZATION
Study
Cilostazol
Control
RR (random)
RR (random)
or sub-category
n/N
n/N
95% CI
95% CI
01 BMS
Ochiai
0/ /25
0.11 [0.01, 1.96]
Park
11/ /201
0.82 [0.38, 1.78]
Yoon
1/ /149
1.01 [0.06, 16.05]
Kozuma
15/ /65
0.56 [0.33, 0.94]
Kamishirado
4/ /57
0.35 [0.12, 1.02]
Sekiguchi
14/ /138
1.22 [0.57, 2.59]
CREST
54/ /351
0.96 [0.68, 1.35]
Han
7/ /50
0.64 [0.27, 1.51]
Lee
5/ /345
1.25 [0.34, 4.63]
RACTS
46/ /196
0.70 [0.51, 0.97]
Takeyasu
96/ /436
0.95 [0.75, 1.21]
Chen
3/ /60
0.30 [0.09, 1.04]
Subtotal (95% CI)
0.79 [0.65, 0.96]
Total events: 256 (Cilostazol), 316 (Control)
Test for heterogeneity: Chi² = 13.82, df = 11 (P = 0.24), I² = 20.4%
Test for overall effect: Z = 2.42 (P = 0.02)
02 DES
DECLARE-Long
9/ /250
0.50 [0.23, 1.09]
CIDES
7/ /139
0.46 [0.19, 1.09]
DECLARE-DIABETES
7/ /200
0.44 [0.18, 1.04]
Subtotal (95% CI)
0.47 [0.29, 0.76]
Total events: 23 (Cilostazol), 49 (Control)
Test for heterogeneity: Chi² = 0.05, df = 2 (P = 0.97), I² = 0%
Test for overall effect: Z = 3.09 (P = 0.002)
Total (95% CI)
0.73 [0.60, 0.88]
Total events: 279 (Cilostazol), 365 (Control)
Test for heterogeneity: Chi² = 18.67, df = 14 (P = 0.18), I² = 25.0%
Test for overall effect: Z = 3.24 (P = 0.001)
0.01
0.1 1 10
100
Favours cilostazol
Favours control

14. RISK OF STENT THROMBOSIS
Study
Cilostazol
Control
RR (random)
RR (random)
or sub-category
n/N
n/N
95% CI
95% CI
01 BMS
Kunishima
0/ /40
0.44 [0.02, 10.46]
Sekiya
0/ /63
0.14 [0.01, 2.71]
Park
2/ /243
1.97 [0.18, 21.56]
Yoon
1/ /149
1.01 [0.06, 16.05]
Kozuma
0/ /62
0.33 [0.01, 8.03]
Kamishirado
0/ /65
0.20 [0.01, 4.09]
Inoue
0/ /32
Not estimable
Sekiguchi
8/ /138
7.67 [0.97, 60.50]
CREST
1/ /351
0.99 [0.06, 15.79]
Han
1/ /50
3.00 [0.13, 71.92]
Lee
5/ /345
1.25 [0.34, 4.63]
RACTS
2/ /196
0.98 [0.14, 6.85]
Takeyasu
8/ /321
8.00 [1.01, 63.59]
Subtotal (95% CI)
1.37 [0.70, 2.68]
Total events: 28 (Cilostazol), 18 (Control)
Test for heterogeneity: Chi² = 11.15, df = 11 (P = 0.43), I² = 1.3%
Test for overall effect: Z = 0.92 (P = 0.36)
02 DES
DECLARE-Long
1/ /250
1.00 [0.06, 15.90]
CIDES
1/ /124
1.10 [0.07, 17.34]
DECLARE-DIABETES
0/ /200
0.33 [0.01, 8.13]
Subtotal (95% CI)
0.77 [0.14, 4.06]
Total events: 2 (Cilostazol), 3 (Control)
Test for heterogeneity: Chi² = 0.36, df = 2 (P = 0.83), I² = 0%
Test for overall effect: Z = 0.31 (P = 0.76)
Total (95% CI)
1.27 [0.69, 2.35]
Total events: 30 (Cilostazol), 21 (Control)
Test for heterogeneity: Chi² = 11.93, df = 14 (P = 0.61), I² = 0%
Test for overall effect: Z = 0.76 (P = 0.45)
0.001
0.01
0.1 1 10
100
1000
Favours cilostazol
Favours control

15. RISK OF BLEEDING Study Cilostazol Control RR (random) RR (random)
or sub-category
n/N
n/N
95% CI
95% CI
01 BMS
Kunishima
0/ /40
Not estimable
Sekiya
0/ /63
Not estimable
Ochiai
0/ /25
Not estimable
Park
2/ /243
0.66 [0.11, 3.89]
Yoon
2/ /149
0.68 [0.11, 3.99]
Kamishirado
0/ /65
0.33 [0.01, 8.03]
Inoue
0/ /32
Not estimable
Sekiguchi
3/ /138
2.88 [0.30, 27.31]
CREST
13/ /351
0.81 [0.39, 1.65]
Han
1/ /50
0.50 [0.05, 5.34]
Lee
3/ /345
0.60 [0.14, 2.50]
RACTS
0/ /196
0.14 [0.01, 2.68]
Takeyasu
1/ /321
1.00 [0.06, 15.92]
Subtotal (95% CI)
0.73 [0.44, 1.22]
Total events: 25 (Cilostazol), 35 (Control)
Test for heterogeneity: Chi² = 3.18, df = 8 (P = 0.92), I² = 0%
Test for overall effect: Z = 1.19 (P = 0.24)
02 DES
DECLARE-Long
2/ /250
0.50 [0.09, 2.71]
DECLARE-DIABETES
3/ /200
1.00 [0.20, 4.90]
Subtotal (95% CI)
0.72 [0.23, 2.30]
Total events: 5 (Cilostazol), 7 (Control)
Test for heterogeneity: Chi² = 0.34, df = 1 (P = 0.56), I² = 0%
Test for overall effect: Z = 0.55 (P = 0.58)
Total (95% CI)
0.73 [0.46, 1.17]
Total events: 30 (Cilostazol), 42 (Control)
Test for heterogeneity: Chi² = 3.53, df = 10 (P = 0.97), I² = 0%
Test for overall effect: Z = 1.31 (P = 0.19)
0.001
0.01
0.1 1 10
100
1000
Favours cilostazol
Favours control

16. FUNNEL PLOT FOR BINARY RESTENOSIS
0.0
DES
BMS
0.4
0.8
Standard error (log relative risk
1.2
1.6
0.01
0.1 1 10
100
Relative risk (fixed effect)

17. CONCLUSIONS
Cilostazol appears effective and safe in reducing the risk of restenosis and repeat revascularization after stenting implantation, in both the bare metal and DES era.
This inexpensive treatment can be envisaged in most patients treated with BMS, and in those treated with DES who remain at higher risk of restenosis and thus can benefit from further inhibition of neointimal hyperplasia.

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