Cilostazol added to aspirin and clopidogrel reduces revascularization without increases in major adverse events in patients with drug-eluting stents: A meta-analysis of randomized controlled trials

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Abstract

Background

The effects of cilostazol added to aspirin and clopidogrel (triple antiplatelet therapy: TAT) on clinical outcomes after drug-eluting stent (DES) implantation are unknown.

Methods

We conducted a meta-analysis of randomized controlled trials (RCTs) comparing TAT with aspirin and clopidogrel (dual antiplatelet therapy: DAT) in DES patients. Clinical end points were target lesion (TLR) and/or vessel (TVR) revascularization, death, myocardial infarction (MI), stent thrombosis (ST), bleeding, rash, gastrointestinal (GI) side effects, and drug discontinuation. We calculated the pooled estimate based on a fixed-effects model using Peto odds ratio (OR) for rare events. If heterogeneity was observed across an individual RCT, an analysis based on a random-effects model was performed.

Results

Eight RCTs were included in this meta-analysis, involving 3590 patients (TAT:DAT = 1800:1790). Up to 24 months, TAT showed a significant reduction in TLR (OR: 0.58, 95% confidence interval (CI): 0.43 to 0.78, p < 0.001) and TVR (OR: 0.58, 95% CI: 0.40 to 0.83, p = 0.003) compared with DAT. The incidence of death, MI, ST, or overall or major bleeding was comparable between the 2 groups, whereas the proportion of rash (OR: 2.50, 95% CI: 1.52 to 4.10, p < 0.001), GI side effects (OR: 3.14, 95% CI: 1.79 to 5.50, p < 0.001), or drug discontinuation (OR: 6.81, 95% CI: 2.12 to 21.86, p < 0.001) was higher in TAT than DAT.

Conclusions

In this meta-analysis, TAT was associated with significantly effective outcomes for TLR and TVR without any increase in major adverse events but was associated with tolerance issues compared with DAT after DES implantation.

Introduction

Although restenosis after percutaneous coronary intervention (PCI) has been drastically reduced by drug-eluting stents (DESs) compared to bare metal stents (BMSs) [1], [2], [3], it still remains at approximately 10% [4], thus, efforts to further reduce restenosis continue.

Cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, has been shown to inhibit neointimal hyperplasia after balloon injury or stenting [5], [6], which is the primary cause of in-stent restenosis [7], [8]. On the other hand, while cilostazol has an antiplatelet activity, it does not increase the risk of bleeding when administered in addition to aspirin and clopidogrel [9]. Currently, dual antiplatelet therapy (DAT) with aspirin and clopidogrel is recommended for at least 12 months after DES deployment [10]. Based on the favorable attributes of cilostazol, perhaps triple antiplatelet therapy (TAT), that is cilostazol administration adding to DAT, may further reduce angiographic or clinically driven restenosis without an increase in bleeding.

Recently, several meta-analyses of randomized controlled trials (RCTs) have reported a reduction in angiographic restenosis, target lesion (TLR), or vessel (TVR) revascularization without an increase in adverse events in administration of cilostazol [11], [12], [13], [14], [15]. However, most of them included RCTs that had not compared TAT with DAT [12], [14], [15], and all of them included RCTs of BMSs as well as those of DESs. To investigate the effects of TAT as compared to DAT on clinical outcomes in patients undergoing DES deployment, we conducted a meta-analysis of RCTs.

Section snippets

Materials and methods

An electronic search was performed for articles in any language using MEDLINE, EMBASE, the Cochrane Library, and Web of Knowledge. Search terms included “aspirin”, “clopidogrel”, “cilostazol”, “drug”, “eluting”, “stent”, and “randomized”. The same terms or relevant trials were also searched on the website including the U.S. National Institute of Health (including clinicaltrials.gov), TCTMD.com, crtonline.org, escardio.org, and pcronline.com. The final search was run in March, 2012. The clinical

Results

Fig. 1 shows a flow diagram of study selection in this meta-analysis. Two studies were excluded because of BMS patients in the sample [24], [25], and 3 studies (including abstracts of scientific sessions) due to the existence of other reports at longer-term follow up in the same studies, respectively. During additional web searches of the U.S. National Institute of Health, TCTMD.com, crtonline.org, escardio.org, and pcronline.com, we excluded 1 RCT using BMS [26], 3 studies that were already

Discussion

The main findings of this meta-analysis of RCTs using DESs were: (1) TAT was associated with a significantly lower incidence of TLR and TVR compared with DAT; (2) the incidence of major adverse events such as all-cause death, MI, ST, or bleeding, was similar between TAT and DAT; and (3) the incidence of minor side effects such as rash, GI side effects, or drug discontinuation was much higher in TAT than in DAT.

A reduction in TVR in TAT as compared to DAT in DES patients was reported separately

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      However, some of these trials had small sample sizes and their results may be not conclusive. A previous meta-analysis [19] demonstrated that cilostazol was associated with significant reductions in restenosis and repeat revascularization, with no significant increase in the risk of ST or bleeding after DES implantation. However, TAT duration and follow-up period in some randomized controlled trials (RCTs) analyzed were as short as only 1 month.

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    There was no grant support for this study.

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