G. BIONDI-ZOCCAI, 1 P. OMEDE’, 1 F. SCIUTO, 1 C. MORETTI, 1 P. LOMBARDI, 1 D. SILLANO, 1

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SIGNIFICANT BENEFITS OF CILOSTAZOL SIGNIFICANT BENEFITS OF CILOSTAZOL

ON RESTENOSIS AND TARGET VESSEL ON RESTENOSIS AND TARGET VESSEL

REVASCULARIZATION AFTER PERCUTANEOUS REVASCULARIZATION AFTER PERCUTANEOUS

CORONARY INTERVENTION: EVIDENCE CORONARY INTERVENTION: EVIDENCE

FROM A META-ANALYSISFROM A META-ANALYSIS

G. BIONDI-ZOCCAI,1 P. OMEDE’,1 F. SCIUTO,1

C. MORETTI,1 P. LOMBARDI,1 D. SILLANO,1

P. GARRONE,1 G. TREVI,1 AND I. SHEIBAN1

1University of Turin, Turin, Italy (gbiondizoccai@gmail.com)

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BACKGROUND

• Drug-eluting stents reduce the risk of restenosis after percutaneous coronary intervention (PCI), but may pose a risk of thrombosis

• Cilostazol is an oral phosphodiesterase inhibitor which has antiplatelet activities as well as pleiotropic effects including inhibition of neointimal hyperplasia

• Thus, cilostazol could hold the promise of preventing both restenosis and thrombosis after PCI, but data to date are inconclusive

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OBJECTIVES

• To perform a systematic review of

randomized clinical trials focusing on

cilostazol versus control therapy in

patients undergoing PCI

• To pool major angiographic and clinical

outcomes with meta-analysis

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METHODS

• Several databases (BioMedCentral, CENTRAL, clinicaltrials.gov, EMBASE, and PubMed) were systematically searched for pertinent clinical studies published up to May 2007

• Major selection criteria were:– randomized treatment allocation, – comparison of cilostazol vs control, – after PCI, – follow-up ≥1 month

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METHODS

• The co-primary efficacy end-points of the analysis were the mid-term risk of binary angiographic restenosis and the rate of repeat revascularization at the longest available follow-up

• As secondary end-points, we considered the rate of major adverse cardiac events, ie death, myocardial infarction, or repeat revascularization; stent thrombosis; and bleeding (as defined by each investigator)

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METHODS• Relative risks (RR) were computed from individual studies and

pooled according to a random-effect method (with 95% confidence intervals) using RevMan 4.2

• Small study bias and/or publication bias (ie the likelihood of small yet nominally significant studies being selectively published in the literature) was appraised by means of visual inspection of funnel plot, and analytically with Egger and Peters test

• The Egger method plots linearly the standard normal deviate as dependent variable and 1/standard error of the RR as independent variable, with test results based on the p value of the regression constant.

• The Peters method plots linearly the natural logarithm of the RR as dependent variable and 1/sample size as independent variable, with test results based on the p value of the regression coefficient

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REVIEW PROFILE

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INCLUDED STUDIES

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RESULTS

• A total of 22 RCTs were included (4928 patients), with median follow-up of 6 months.

• Pooled analysis showed that cilostazol was associated with statistically significant reductions in binary angiographic restenosis (RR=0.59 [0.48-0.73], p<0.001) and repeat revascularization (RR=0.70 [0.56-0.89], p=0.003)

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RESULTS

• Cilostazol appeared also safe, with no significant increase in the risk of stent thrombosis (RR=1.49 [0.85-2.61], p=0.16) or bleeding (RR=0.72 [0.44-1.18], p=0.19)

• However, small study bias was evident for both binary restenosis (p<0.001) and repeat revascularization (p=0.016), suggesting that most of the apparent benefits of cilostazol could be due to this type of confounding effect

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BINARY RESTENOSIS

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TARGET VESSEL REVASCULARIZATION

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FUNNEL PLOT FOR BINARY RESTENOSIS

Pre

cisi

on

(sta

ndar

d e

rror

of

log

rel

ativ

e ris

k)

Effect(relative risk)

Favours cilostazol Favours control

P<0.001 at Egger test

P<0.001 at Peters test

0.01 0.1 1 10 100

0.0

0.4

0.8

1.2

1.6

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FUNNEL PLOT FOR BINARY RESTENOSIS

Pre

cisi

on

(sta

ndar

d e

rror

of

log

rel

ativ

e ris

k)

Effect(relative risk)

Favours cilostazol Favours control

P<0.001 at Egger test

P<0.001 at Peters test

0.01 0.1 1 10 100

0.0

0.4

0.8

1.2

1.6

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FUNNEL PLOT FOR TVR

0.01 0.1 1 10 100

0.0

0.2

0.4

0.6

0.8

Pre

cisi

on

(sta

ndar

d e

rror

of

log

rel

ativ

e ris

k)

Effect(relative risk)

Favours cilostazol Favours control

P=0.016 at Egger test

P<0.001 at Peters test

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FUNNEL PLOT FOR TVR

0.01 0.1 1 10 100

0.0

0.2

0.4

0.6

0.8

Pre

cisi

on

(sta

ndar

d e

rror

of

log

rel

ativ

e ris

k)

Effect(relative risk)

Favours cilostazol Favours control

P=0.016 at Egger test

P<0.001 at Peters test

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SENSITIVITY ANALYSES

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CONCLUSIONS

• Cilostazol appears effective and safe in reducing the risk of restenosis and repeat revascularization after PCI, but available evidence is limited by small study effects

• Awaiting larger RCTs, this inexpensive treatment can be envisaged in selected patients in which DES are contraindicated, or when there is a need for further neointimal hyperplasia inhibition

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