J Thromb Thrombolysis DOI 10.1007/s11239-014-1090-5
Efficacy and safety of cilostazol based triple antiplatelet treatment versus dual antiplatelet treatment in patients undergoing coronary stent implantation: an updated meta-analysis of the randomized controlled trials Jun Chen • Haoyu Meng • Lei Xu • Jie Liu • Deyu Kong • Pengsheng Chen • Xiaoxuan Gong • Jianling Bai • Fengwei Zou • Zhijian Yang • Chunjian Li • John W. Eikelboom
Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to obtain best estimates of the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAPT: aspirin, clopidogrel and cilostazol) compared with dual antiplatelet therapy (DAPT: aspirin and clopidogrel) in patients undergoing coronary stent implantation. We searched the literature to identify all randomized clinical trials examining efficacy and safety of TAPT versus DAPT in patients undergoing coronary stent implantation. Major efficacy outcomes were death, non-fatal myocardial infarction (MI), ischemic stroke and stent thrombosis (ST) and the safety outcome was bleeding. Data were analyzed using the Review Manager 5.0.0 software. A total of 19 trials involving 7,464 patients were included. TAPT and DAPT were associated with similar rates of
death, non-fatal MI, ischemic stroke and ST, but compared with DAPT, TAPT had lower rates of target lesion revascularization (TLR) (RR 0.67, 95 % CI 0.56–0.82, P \ 0.0001) and target vessel revascularization (TVR) (RR 0.65, 95 % CI 0.55–0.77, P \ 0.00001), as well as less late loss of minimal lumen diameter (mean difference -0.14, 95 % CI -0.17–-0.11, P \ 0.00001), and less binary angiographic restenosis (RR 0.54, 95 % CI 0.45–0.65, P \ 0.00001). TAPT and DAPT had similar rates of bleeding, but TAPT had significantly higher rates of headache, palpitation, rash and gastrointestinal side-effects. Cilostazol-based TAPT compared with DAPT is associated with improved angiographic outcomes and decreased risk of TLR and TVR but does not reduce major cardiovascular events and is associated with an increase in minor adverse events.
Dr. Jun Chen, Dr. Haoyu Meng, Dr. Lei Xu and Dr. Jie Liu contributed equally to this work.
Keywords Triple antiplatelet therapy Dual antiplatelet therapy Cilostazol Stent implantation
J. Chen H. Meng L. Xu J. Liu D. Kong P. Chen X. Gong Z. Yang C. Li (&) Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China e-mail: [email protected]
Introduction
J. Liu Department of Cardiology, The Second People’s Hospital of Changzhou City, Changzhou, China J. Bai Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China F. Zou Department of Chemistry, Northwestern University, Evanston, IL, USA J. W. Eikelboom Department of Medicine, McMaster University, Hamilton, ON, Canada
Percutaneous coronary intervention (PCI) with stent implantation is widely used in the management of patients with coronary artery disease, but is associated with a risk of stent thrombosis (ST) and restenosis [1]. The introduction of drug eluting stents has substantially reduced the risk of restenosis but at the cost of an increase in ST which is associated with mortality rate as high as 40 % [2–5]. Dual antiplatelet treatment (DAPT) with the combination of aspirin and a P2Y12 receptor antagonist is effective for the prevention of ST and major cardiovascular events [6, 7], but *10 % of patients on DAPT still develop thrombotic events including recurrent myocardial infarction (MI) and ST [2–5]. Alternative antiplatelet strategies may help to further reduce the risk of thrombotic events and associated complications.
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Cilostazol is a selective inhibitor of phosphodiesterase type 3 that appears to have both antiplatelet and anti-proliferative effects [8, 9]. Cilostazol inhibits platelet aggregation in response to ADP, epinephrine, collagen and arachidonic acid, and suppresses the production of plateletderived endothelial cell growth factor [9]. Thus, cilostazol appears to be an attractive option for patients undergoing PCI and stent implantation [8, 9]. Several randomized controlled trials (RCTs) have suggested a benefit of cilostazol-based triple antiplatelet treatment (TAPT) for the prevention of thrombotic events and restenosis in patients undergoing intracoronary stent implantation, but they involved small numbers of patients and the data are inconsistent [10–13]. Although previous meta-analyses in this field identified some results associated with TAPT compared with DTPA, some recent randomized clinical trials (RCTs) have added new evidence to the comparison [14, 15]. In order to obtain best estimates of the efficacy and safety of cilostazol-based TAPT compared with DAPT, we performed a meta-analysis of the RCTs evaluating these treatments in patients undergoing intracoronary stent implantation.
Methods Eligibility and search strategy We searched electronic databases (Pubmed, Embase, Cochrane library, and Chinese Medical Journal Network databases) from establishment to Aug 2013 to identify trials that compare the efficacy and safety of TAPT with DAPT in patients undergoing coronary stent implantation using the following terms: ((triple antiplatelet therapy) OR ((cilostazol) AND (clopidogrel) AND (aspirin)) OR (cilostazol)) AND ((dual antiplatelet therapy) OR (double antiplatelet therapy) OR ((clopidogrel) AND (aspirin))) AND ((percutaneous coronary intervention) OR (PCI) OR (percutaneous transluminal coronary angioplasty) OR (ptca) OR (stent implantation) OR (stent)). We also hand searched the reference lists of relevant original and review articles. No language restrictions were enforced. Study selection and data extraction Trials were eligible for inclusion if they met the following criteria: (1) conducted in patients undergoing coronary stent implantation; (2) RCTs where patients were randomly allocated to TAPT or DAPT; (3) at least one of the following outcomes was reported: death, non-fatal MI, ischemic stroke, ST, target lesion revascularization (TLR), target vessel revascularization (TVR), and angiographic outcomes including late loss of minimal lumen diameter
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(MLD) or binary angiographic restenosis, or adverse effects including bleeding, thrombocytopenia, neutropenia, hepatic dysfunction, headache, palpitation, rash or gastrointestinal side-effects. Two authors (Dr. Haoyu Meng and Dr. Jun Chen) independently assessed trial eligibility and disagreements were resolved by discussion or involvement of a third reviewer (Dr. Li). The following data were extracted from eligible trials: author and publishing year, number of patients, type of patients, age, sex, type of stent, dose and duration of TAPT/DAPT and outcomes. In cases of incomplete or unclear data, we contacted the authors. We assessed study quality based on methods of randomization, allocation concealment, blinding and loss to follow up. Outcome definitions We accepted original trial definitions for all outcomes. Major efficacy outcomes were death, non-fatal MI, ischemic stroke and ST. Minor efficacy outcomes were TLR, TVR, as well as angiographic variables including late loss of MLD (the difference in MLD immediately after intervention and at follow-up) and binary angiographic restenosis (diameter stenosis [50 %) both in-stent and in-segment (stented segment and margins 5 mm proximal and distal to stent) [11]. Adverse effects were bleeding, thrombocytopenia (platelet \100 9 109/L), neutropenia (neutropenia \1.5 9 109/L), hepatic dysfunction, headache, palpitation, rash and gastrointestinal side-effects [12, 13]. Statistical analysis Statistical analysis was performed using Review Manager 5.0.0 (The Cochrane Collaboration, Oxford, England). The relative risk (RR) and 95 % confidence interval (CI) for categorical variables were calculated using a fixed-effect model with the Mantel–Haenszel method. The DerSimonian and Laird random effect model was also used in case of significant heterogeneity across studies. The mean difference (MD) and 95 % CI was used for continuous variables with inverse variance method. Statistical heterogeneity was evaluated using the Q statistic and I2 statistic. A 2-sided P \ 0.05 was considered statistically significant. Publication bias was examined by funnel plots and confirmed by Egger’s test.
Results Eligible studies We identified 123 potentially relevant articles and included nineteen studies in the meta-analysis (Fig. 1) [14–32].
Cilostazol based triple antiplatelet treatment Fig. 1 Trial selection flow chart. Flow chart indicates the process taken for selecting relevant randomized clinical trials included in this metaanalysis
Study characteristics A total of 7,464 patients were included in the nineteen studies [14–32]; 3,738 were allocated DAPT (aspirin 100–200 mg/ day plus clopidogrel 75 mg/day for 1–12 months) and 3,726 patients were allocated TAPT (aspirin 100–200 mg/day plus clopidogrel 75 mg/day for 1–12 months and cilostazol 100 mg bid for 1–6 months) (Table 1). The studies included between 20 and 1,212 patients, with a mean or median age of 56–71 years. The follow-up duration ranged from 1 to 60 months. Four RCTs only involved the use of bare metal stents, eight only drug-eluting stents, one only biolimuseluting stent and the remaining both types or did not specify stent type (Table 1). The assessment of the methodological quality suggested that all twelve studies had adequate randomized sequence generation. Treatment allocation in ten studies was blinded. All the articles described loss to follow up (Table 2). There was no evidence of publication bias as evidenced by symmetrical funnel plots and a negative Egger’s test (data not shown). Major efficacy outcomes Death Nineteen studies reported the data on all-cause death, including 3,726 patients allocated TAPT and 3,738 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity among these studies (P = 0.70 for all-cause death and P = 0.27 for cardiac death). Pooled
analysis showed no differences between TAPT and DAPT in either all-cause death (1.45 vs. 1.90 %, RR 0.77, CI 0.55–1.09, P = 0.15) (Fig. 2) or cardiac death (0.79 vs. 1.02 %, RR 0.79, CI 0.46–1.37, P = 0.41). Non-fatal MI Eighteen studies reported the data on non-fatal MI, including 3,666 patients allocated TAPT and 3,678 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.94). Pooled analysis showed no difference of non-fatal MI incidence between TAPT and DAPT groups (1.36 vs. 1.50 %, RR 0.92, CI 0.63–1.34, P = 0.68) (Fig. 2). Ischemic stroke Nine articles reported the data on ischemic stroke, including 1,945 patients allocated TAPT and 1,952 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.44). Pooled analysis showed that there were no difference between TAPT and DAPT in ischemic stroke (0.98 vs. 1.38 %, RR 0.71, CI 0.40–1.26, P = 0.24) (Fig. 2). ST Fourteen articles reported the data on ST, including 3,464 patients allocated TAPT and 3,466 allocated DAPT. Heterogeneity testing showed no statistical evidence of
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J. Chen et al. Table 1 Characteristics of the trials included in the meta-analysis Study
TAPT (n)
DAPT (n)
Age
Male (%)
Design
Type of stent
Dosing of aspirin
Dosing of clopidogrel
Dosing of cilostazol
Followup duration (month)
Gao et al. [14]
213
215
56
80
RCT
DES
100 mg daily
75 mg daily
100 mg twice daily
12
Youn et al. [15]
308
307
64
63
RCT
DES
12
Douglas et al. [16]
354
Chen et al. [17]
60
60
58
62
RCT
Lee et al. [18]
10
10
56
55
RCT
Kim et al. [19]
30
Lu et al. [20]
201
Kum et al. [21]
302
301
62
75
Han et al. [22]
604
608
60
73
Jeong et al. [23]
30
Lee et al. [24]
450
Ahn et al. [25]
64
Lee et al. [26]
250
Suh et al. [27]
457
458
64
71
RCT
DES
LD 300 mg, 100 mg daily
75 mg daily
100 mg twice daily
Lu et al. [28]
100
100
62
62
RCT
BMS or DES
100 mg daily
75 mg daily
LD 200 mg,
Han et al. [29]
60
BMS or DES
300 mg daily
Wang et al. [30]
95
Wang et al. [31]
78
86
69
83
RCT
Lu et al. [32]
60
58
71
56
RCT
351
30 201
30 450
66 249
60 98
60
63 61
63 61
64 62
61 62
74
70 61
72 36
62 71
72 69
RCT
RCT RCT
BMS
LD 300 mg,
LD 300-600 mg,
LD 200 mg,
100 mg daily
75 mg daily
100 mg twice daily (3 month) 100 mg twice daily
6
LD 300 mg,
LD 300–600 mg,
100 mg daily
75 mg daily (1 month)
BMS
100 mg daily
75 mg daily (6 month)
100 mg twice daily (6 month)
9
Not mentioned
200 mg daily
1
DES
LD 300 mg,
LD 200 mg,
75 mg daily
200 mg daily
LD 300 mg,
LD 600 mg,
LD 400 mg,
100 mg daily
75 mg daily
100 mg twice daily
LD 300 mg,
100 mg twice daily
6
1
BMS or DES
100 mg daily
RCT
DES
LD 300 mg, 100 mg daily
LD 300 mg, 75 mg daily
100 mg twice daily (1 month)
6
RCT
BMS or DES
MD 300 mg (1 month),
LD 300–600 mg,
100 mg twice daily (6 month)
12
200 mg daily
1
RCT RCT
RCT RCT
RCT RCT
DES DES
DES DES
BMS
75 mg daily
100 mg daily
75 mg daily (3–12 month)
LD 300 mg,
LD 600 mg,
200 mg daily
75 mg daily
200 mg daily
LD 300 mg,
LD 200 mg,
24
LD 200 mg,
75 mg daily ([6 month) LD 300 mg,
100 mg twice daily (6 month) LD 200 mg,
24
100 mg daily
75 mg daily
100 mg twice daily
200 mg daily
LD 300 mg,
LD 200 mg,
75 mg daily
100 mg twice daily (8 month)
LD 300-600 mg,
LD 200 mg,
12
6 60
100 mg twice daily (6 month) LD 300 mg, 75 mg daily LD 300 mg,
LD 300-600 mg,
100 mg daily
75 mg daily
BMS or DES
LD 300 mg,
LD 300 mg,
100 mg daily
75 mg daily
BMS
100 mg daily
75 mg daily
100 mg twice daily (3 month)
3
100 mg twice daily (6 month)
12
100 mg twice daily (6 month)
12
100 mg twice daily (6 month)
6
LD loading dose, mg milligram, RCT randomized controlled trial, BMS bare metal stent, DES drug-eluting stent, ACS acute coronary syndrome, STEMI ST-segment elevation myocardial infarction, AMI acute myocardial infarction, PCI percutaneous coronary intervention
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Cilostazol based triple antiplatelet treatment Table 2 Publication bias graph Study
Adequate sequence generation
Allocation concealment
Blinding
Incomplete outcome data addressed
Gao et al. [14]
Yes
Unclear
Yes
Yes
Young et al. [15]
Yes
Yes
Yes
Yes
Douglas et al. [16]
Yes
Yes
Yes
Yes
Chen et al. [17]
Yes
Yes
Yes
Yes
Lee et al. [18]
Yes
Unclear
No
Yes
Kim et al. [19]
Yes
Unclear
No
Yes
Lu et al. [20] Kum et al. [21]
Yes Yes
Unclear Yes
No No
Yes Yes
Han et al. [22]
Yes
Unclear
No
Yes
Jeong et al. [23]
Yes
Unclear
No
Yes
Lee et al. [24]
Yes
Yes
No
Yes
Ahn et al. [25]
Yes
Unclear
No
Yes
Lee et al. [26]
Yes
Yes
Yes
Yes
Suh et al. [27]
Yes
Yes
No
Yes
Lu et al. [28]
Yes
Unclear
Yes
Yes
Han et al. [29]
Yes
Yes
Yes
Yes
Wang et al. [30]
Yes
Unclear
Yes
Yes
Wang et al. [31]
Yes
Unclear
Yes
Yes
Lu et al. [32]
Yes
Unclear
Yes
Yes
Unclear insufficient information from one article about the process to permit judgment of ‘Yes’ or ‘No’
heterogeneity (P = 0.80). Pooled analysis showed that there was no difference between TAPT and DAPT in the incidence of ST (0.69 vs. 1.13 %, RR 0.62, CI 0.38–1.03, P = 0.06) (Fig. 2). Minor efficacy outcomes TLR Ten articles reported the data on TLR, including 2,625 patients allocated TAPT and 2,622 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.21). Pooled analysis showed that TAPT significantly reduced the incidence of TLR compared with DAPT (5.94 vs. 8.81 %, RR 0.67, 95 % CI 0.56–0.82, P \ 0.0001) (Fig. 3). TVR Thirteen articles reported the data on TVR, including 2,789 patients allocated TAPT and 2,793 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.20). Pooled analysis showed that TAPT significantly reduced the incidence of TVR compared with DAPT (6.99 vs. 10.7 %, RR 0.65, 95 % CI 0.55–0.77, P \ 0.00001) (Fig. 3).
Late loss Six articles reported the data on late loss of MLD, including 1,870 patients allocated TAPT and 1,894 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.45). Pooled analysis showed that the late loss in MLD of TAPT group was significantly lower than that of DAPT group (MD -0.14; 95 % CI -0.17–-0.11, P \ 0.00001). Subgroup analysis of the in-segment and in-stent late loss of MLD favored TAPT for both in-segment (MD -0.15; 95 % CI -0.20– -0.10, P \ 0.00001) (Fig. 4) and in-stent (MD -0.12; 95 % CI -0.17–-0.07, P \ 0.00001) (Fig. 4) late loss. Binary angiographic restenosis Six articles reported the data on binary angiographic restenosis, including 1,870 patients allocated TAPT and 1,894 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 1.00). Pooled analysis showed that binary angiographic restenosis was significantly lower in TAPT group compared to that in DAPT group (12.0 vs. 19.7 %, RR 0.54, 95 % CI 0.45–0.65, P \ 0.00001). Subgroup analysis showed the results favored the TAPT group for both in-segment (12.4 vs. 20.5 %, RR 0.61, 95 % CI 0.49–0.75, P \ 0.00001)
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Fig. 2 TAPT versus DAPT in the incidence of death, non-fatal MI, ischemic stroke and ST. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple
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antiplatelet therapy, DAPT dual antiplatelet therapy, MI myocardial infarction, ST stent thrombosis, CI confidence intervals
Cilostazol based triple antiplatelet treatment
Fig. 2 continued
(Fig. 4) and in-stent (11.6 vs. 18.3 %, RR 0.63, 95 % CI 0.51–0.79, P \ 0.0001) (Fig. 4) restenosis.
minor and minimal bleeding between TAPT and DAPT (data not shown).
Adverse effects
Other adverse effects
Bleeding
TAPT and DAPT were associated with similar rates of thrombocytopenia (0.44 vs. 0.55 %, RR 0.82, 95 % CI 0.24–2.84), neutropenia (0.22 vs. 0.16 %, RR 1.29, 95 % CI 0.32–5.20) and hepatic dysfunction (0.70 vs. 1.27 %, RR 0.58, 95 % CI 0.29–1.16) (P [ 0.05), but TAPT was associated with an increased incidence of headache (4.71 vs. 1.48 %, RR 3.08, 95 % CI 1.98–4.80), palpitation (5.42 vs. 1.62 %, RR 3.32, 95 % CI 2.13–5.20), rash (3.62 vs. 1.76 %, RR 2.06, 95 % CI 1.39–3.07) and gastrointestinal
Sixteen articles reported the data on bleeding, including 3,354 patients allocated TAPT and 3,367 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.97). Pooled analysis showed no difference between TAPT and DAPT in the risk of bleeding (3.37 vs. 2.79 %, RR 1.20, 95 % CI 0.92–1.57, P = 0.17) (Fig. 5). Pooled analysis revealed no differences in major,
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Fig. 3 TAPT versus DAPT in the incidence of TLR and TVR. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy, DAPT dual
antiplatelet therapy, TLR target lesion revascularization, TVR target vessel revascularization, CI confidence intervals
disorder (2.41 vs. 1.29 %, RR 1.88, 95 % CI 1.14–3.10) compared with DAPT (P \ 0.05).
different from that of aspirin and clopidogrel. Thus, TAPT would be expected to inhibit platelet aggregation synergistically. It does appear to be effective for the prevention of restenosis which is caused by progressive endothelial hyperplasia [33, 34], and is usually manifest by angina or repeat revascularization (TLR and TVR) rather than acute ischemic cardiovascular events such as MI and ST [24–26]. The exact mechanisms of beneficial effects of TAPT remains uncertain, but the possible ones would be as follows. First, it appears to be explained by cilostazol’s ability to block the growth of the vascular smooth muscle cells and stimulate the production of the hepatocyte growth factor leading to accelerated regeneration of endothelial cells [35]. Second, cilostazol suppresses P-selectin-mediated platelet activation, platelet-leukocyte interaction, and subsequent Mac-1-mediated leukocyte activation, each of which may contribute to reduction of restenosis after coronary stent implantation [36]. Third, cilostazol was
Discussion The major findings of this meta-analysis are as follows: (1) TAPT reduces the risk of late loss of MLD and binary angiographic restenosis as well as TLR and TVR compared to DAPT in patients undergoing coronary stent implantation; (2) TAPT does not reduce death, non-fatal MI, ischemic stroke or ST or increase bleeding compared to DAPT; (3) TAPT increases the incidence of minor side effects of headache, palpitation, rash and gastrointestinal disorder compared to DAPT. Cilostazol is a phosphodiesterase III inhibitor that plays the role of hydrolyzing cyclic adenosine monophosphate (cAMP) within platelets. The mechanism of cilostazol is
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Cilostazol based triple antiplatelet treatment
Fig. 4 TAPT versus DAPT in late loss of MLD and restenosis. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy,
DAPT dual antiplatelet therapy, MLD minimal lumen diameter, CI confidence intervals
associated with up-regulation of antioncogenes p53 and p21, as well as hepatocyte growth factor released from vascular smooth muscle cells after vessel injury, providing further explanation for its anti-proliferation effects [37]. Laboratory studies using conventional platelet aggregation and point of care testing have demonstrated that
cilostazol based TAPT produces greater platelet inhibition than DAPT [18, 19, 23, 27]. However, these effects did not translate into a reduction in major cardiovascular events or ST [27, 37]. There may be several possible explanations for this discrepancy. First, several trials conducted with combinations of proven effective antiplatelet drugs, including
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Fig. 5 TAPT versus DAPT in the incidence of bleeding. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy, DAPT dual antiplatelet therapy, CI confidence intervals
aspirin, P2Y12 inhibitors and glycoprotein IIb/IIIa inhibitors, have not demonstrated a benefit of more intensive antiplatelet regimens compared with standard dual antiplatelet therapy despite producing more effective platelet inhibition [38–40]. In each of these trials the likely explanation is lack of statistical power because the numbers of patients randomized are modest. We cannot determine whether the lack of effect of cilostazol on clinical outcomes is explained by inadequate statistical power or lack of effectiveness of cilostazol as an antiplatelet drug. Second, despite the greater reduction of platelet reactivity by addition of cilostazol to convention DAPT, a significant number of patients in the TAPT group still belonged to the hyporesponders to TAPT. It may be an explanation of the finding that enhanced platelet inhibition with TAPT did not decrease the actual number of clinical events [27]. Third, as reported in the DECREASE registry study, the longer duration of triple therapy after drug-eluting stent implantation was associated with the lower risk of ST and MI [41]. However, the TAPT duration and the follow-up period in some RCTs were only 1 month. Thus, the short triple therapy duration and follow-up period may in part contribute to the negative results of the major cardiovascular events [18, 19, 23]. The clinical benefit of intensified antiplatelet therapy may be offset by an associated increase in bleeding complications. However, there were similar episodes of bleeding complications between TAPT and DAPT, which was also demonstrated in previous meta-analyses [42, 43]. The adverse drug effects of TAPT were headache, palpitation,
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rash and gastrointestinal disorder accompanied by the vasodilatory effects of cilostazol. Most of the adverse effects were mild and tolerable to patients and may be resolved after cilostazol discontinuation and supportive care. Our results confirm and extend the findings of previous meta-analysis of cilostazol-based triple therapy following PCI [10, 42–46]. Unlike some or all of the previous analyses, our meta-analysis has several aspects that are specific or innovative. First, our inclusion criteria is more strict, we exclude the RCTs of non-routine cilostazol dosage (50 mg, bid), as well as the inappropriate control groups (ticlopidine or doubling clopidogrel), and the comparison between TAPT and DAPT can be standardized; Second, the major adverse cardiovascular events (MACEs) were differently defined in the recruited studies, and we believe that merging these differently identified MACEs as a composite endpoint as previous meta-analyses is inappropriate. So we analyzed each adverse event (death, non-fatal MI, ischemic stroke and ST) separately rather than pooled the composite events together while performing the meta-analysis. Finally, this study included the latest RCTs which made the sample size maximized and the results more accurate and realistic. Limitations Our study has potential limitations. First, the studies were of modest size and the pooled data cannot exclude significant benefits of cilostazol based TAPT on major cardiovascular events. Second, the studies varied substantially in their design, treatment durations and follow-up and this
Cilostazol based triple antiplatelet treatment
heterogeneity may have limited power to demonstrate significant treatment effects. Third, most of the RCTs in our study were performed in South Korea and China, and their results may not be generalizable to other populations.
Conclusions Cilostazol based TAPT can reduce late loss of MLD, stent restenosis, TLR, and TVR but does not impact ST or major cardiovascular events. Further evaluation of Cilostazol based TAPT in an adequately powered RCT appears warranted to determine whether these benefits can translate into a reduction in major vascular events with an acceptable safety profile. Acknowledgments This work was supported by a grant from the National Natural Science Funding of China (81170181), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD). Conflict of interests manuscript.
No conflicts of interest are involved in this
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9. Cone J, Wang S, Tandon N, Fong M, Sun B et al (1999) Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells. J Cardiovasc Pharmacol 34:497–504 10. Singh I, Shafiq N, Pandhi P, Reddy S, Pattanaik S et al (2009) Triple antiplatelet therapy vs. dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: an evidencebased approach to answering a clinical query. Br J Clin Pharmacol 68:4–13 11. Min PK, Jung JH, Ko YG, Choi D, Jang Y et al (2007) Effect of cilostazol on in-stent neointimal hyperplasia after coronary artery stenting: a quantitative coronary angiography and volumetric intravascular ultrasound study. Circ J 71:1685–1690 12. Lee SW, Park SW, Kim YH, Yun SC, Park DW et al (2007) Comparison of triple versus dual antiplatelet therapy after drugeluting stent implantation (from the DECLARE-Long trial). Am J Cardiol 100:1103–1108 13. Lee SW, Park SW, Kim YH, Yun SC, Park DW et al (2008) Drugeluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES trial (a randomized comparison of triple antiplatelet therapy with dual antiplatelet therapy after drug-eluting stent implantation in diabetic patients). J Am Coll Cardiol 51:1181–1187 14. Gao W, Zhang Q, Ge H, Guo Y, Zhou Z (2013) Efficacy and safety of triple antiplatelet therapy in obese patients undergoing stent implantation. Angiology 64:554–558 15. Youn YJ, Lee JW, Ahn SG, Lee SH, Choi H et al (2014) Multicenter randomized trial of 3-month cilostazol use in addition to dual antiplatelet therapy after biolimus-eluting stent implantation for long or multivessel coronary artery disease. Am Heart J 167:241–248 16. Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, Grines CL, Block E et al (2005) Coronary stent restenosis in patients treated with cilostazol. Circulation 112:2826–2832 17. Chen YD, Lu YL, Jin ZN, Yuan F, Lu SZ (2006) A prospective randomized antiplatelet trial of cilostazol versus clopidogrel in patients with bare metal stent. Chin Med J (Engl) 119:360–366 18. Lee BK, Lee SW, Park SW, Lee SW, Park DW et al (2007) Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation. Am J Cardiol 100:610–614 19. Kim JY, Lee K, Shin M, Ahn M, Choe H et al (2007) Cilostazol could ameliorate platelet responsiveness to clopidogrel in patients undergoing primary percutaneous coronary intervention. Circ J 71:1867–1872 20. Lu YL, Chen YD, Lu SZ (2007) Effects of intensive antiplatelet therapy in patients with high platelet aggregability after percutaneous coronary intervention. Zhonghua Xin Xue Guan Bing Za Zhi 35:793–796 [in Chinese] 21. Kum DS, Kim MH, Paik JH, Yu LH, Han J et al (2009) Clinical effects of additional cilostazol administration after drug-eluting stent insertion. Korean Circ J 39:21–25 22. Han Y, Li Y, Wang S, Jing Q, Wang Z et al (2009) Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: a randomized, controlled study. Am Heart J 157:733–739 23. Jeong YH, Hwang JY, Kim IS, Park Y, Hwang SJ et al (2010) Adding cilostazol to dual antiplatelet therapy achieves greater platelet inhibition than high maintenance dose clopidogrel in patients with acute myocardial infarction results of the adjunctive cilostazol versus high maintenance dose clopidogrel in patients with AMI (ACCEL-AMI) study. Circ Cardiovasc Interv 3:17–26 24. Lee SW, Chun KJ, Park SW, Kim HS, Kim YH et al (2010) Comparison of triple antiplatelet therapy and dual antiplatelet
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Efficacy and safety of cilostazol based triple antiplatelet treatment versus dual antiplatelet treatment in patients undergoing coronary stent implantation: an updated meta-analysis of the randomized controlled trials Jun Chen • Haoyu Meng • Lei Xu • Jie Liu • Deyu Kong • Pengsheng Chen • Xiaoxuan Gong • Jianling Bai • Fengwei Zou • Zhijian Yang • Chunjian Li • John W. Eikelboom
Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to obtain best estimates of the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAPT: aspirin, clopidogrel and cilostazol) compared with dual antiplatelet therapy (DAPT: aspirin and clopidogrel) in patients undergoing coronary stent implantation. We searched the literature to identify all randomized clinical trials examining efficacy and safety of TAPT versus DAPT in patients undergoing coronary stent implantation. Major efficacy outcomes were death, non-fatal myocardial infarction (MI), ischemic stroke and stent thrombosis (ST) and the safety outcome was bleeding. Data were analyzed using the Review Manager 5.0.0 software. A total of 19 trials involving 7,464 patients were included. TAPT and DAPT were associated with similar rates of
death, non-fatal MI, ischemic stroke and ST, but compared with DAPT, TAPT had lower rates of target lesion revascularization (TLR) (RR 0.67, 95 % CI 0.56–0.82, P \ 0.0001) and target vessel revascularization (TVR) (RR 0.65, 95 % CI 0.55–0.77, P \ 0.00001), as well as less late loss of minimal lumen diameter (mean difference -0.14, 95 % CI -0.17–-0.11, P \ 0.00001), and less binary angiographic restenosis (RR 0.54, 95 % CI 0.45–0.65, P \ 0.00001). TAPT and DAPT had similar rates of bleeding, but TAPT had significantly higher rates of headache, palpitation, rash and gastrointestinal side-effects. Cilostazol-based TAPT compared with DAPT is associated with improved angiographic outcomes and decreased risk of TLR and TVR but does not reduce major cardiovascular events and is associated with an increase in minor adverse events.
Dr. Jun Chen, Dr. Haoyu Meng, Dr. Lei Xu and Dr. Jie Liu contributed equally to this work.
Keywords Triple antiplatelet therapy Dual antiplatelet therapy Cilostazol Stent implantation
J. Chen H. Meng L. Xu J. Liu D. Kong P. Chen X. Gong Z. Yang C. Li (&) Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China e-mail: [email protected]
Introduction
J. Liu Department of Cardiology, The Second People’s Hospital of Changzhou City, Changzhou, China J. Bai Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China F. Zou Department of Chemistry, Northwestern University, Evanston, IL, USA J. W. Eikelboom Department of Medicine, McMaster University, Hamilton, ON, Canada
Percutaneous coronary intervention (PCI) with stent implantation is widely used in the management of patients with coronary artery disease, but is associated with a risk of stent thrombosis (ST) and restenosis [1]. The introduction of drug eluting stents has substantially reduced the risk of restenosis but at the cost of an increase in ST which is associated with mortality rate as high as 40 % [2–5]. Dual antiplatelet treatment (DAPT) with the combination of aspirin and a P2Y12 receptor antagonist is effective for the prevention of ST and major cardiovascular events [6, 7], but *10 % of patients on DAPT still develop thrombotic events including recurrent myocardial infarction (MI) and ST [2–5]. Alternative antiplatelet strategies may help to further reduce the risk of thrombotic events and associated complications.
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Cilostazol is a selective inhibitor of phosphodiesterase type 3 that appears to have both antiplatelet and anti-proliferative effects [8, 9]. Cilostazol inhibits platelet aggregation in response to ADP, epinephrine, collagen and arachidonic acid, and suppresses the production of plateletderived endothelial cell growth factor [9]. Thus, cilostazol appears to be an attractive option for patients undergoing PCI and stent implantation [8, 9]. Several randomized controlled trials (RCTs) have suggested a benefit of cilostazol-based triple antiplatelet treatment (TAPT) for the prevention of thrombotic events and restenosis in patients undergoing intracoronary stent implantation, but they involved small numbers of patients and the data are inconsistent [10–13]. Although previous meta-analyses in this field identified some results associated with TAPT compared with DTPA, some recent randomized clinical trials (RCTs) have added new evidence to the comparison [14, 15]. In order to obtain best estimates of the efficacy and safety of cilostazol-based TAPT compared with DAPT, we performed a meta-analysis of the RCTs evaluating these treatments in patients undergoing intracoronary stent implantation.
Methods Eligibility and search strategy We searched electronic databases (Pubmed, Embase, Cochrane library, and Chinese Medical Journal Network databases) from establishment to Aug 2013 to identify trials that compare the efficacy and safety of TAPT with DAPT in patients undergoing coronary stent implantation using the following terms: ((triple antiplatelet therapy) OR ((cilostazol) AND (clopidogrel) AND (aspirin)) OR (cilostazol)) AND ((dual antiplatelet therapy) OR (double antiplatelet therapy) OR ((clopidogrel) AND (aspirin))) AND ((percutaneous coronary intervention) OR (PCI) OR (percutaneous transluminal coronary angioplasty) OR (ptca) OR (stent implantation) OR (stent)). We also hand searched the reference lists of relevant original and review articles. No language restrictions were enforced. Study selection and data extraction Trials were eligible for inclusion if they met the following criteria: (1) conducted in patients undergoing coronary stent implantation; (2) RCTs where patients were randomly allocated to TAPT or DAPT; (3) at least one of the following outcomes was reported: death, non-fatal MI, ischemic stroke, ST, target lesion revascularization (TLR), target vessel revascularization (TVR), and angiographic outcomes including late loss of minimal lumen diameter
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(MLD) or binary angiographic restenosis, or adverse effects including bleeding, thrombocytopenia, neutropenia, hepatic dysfunction, headache, palpitation, rash or gastrointestinal side-effects. Two authors (Dr. Haoyu Meng and Dr. Jun Chen) independently assessed trial eligibility and disagreements were resolved by discussion or involvement of a third reviewer (Dr. Li). The following data were extracted from eligible trials: author and publishing year, number of patients, type of patients, age, sex, type of stent, dose and duration of TAPT/DAPT and outcomes. In cases of incomplete or unclear data, we contacted the authors. We assessed study quality based on methods of randomization, allocation concealment, blinding and loss to follow up. Outcome definitions We accepted original trial definitions for all outcomes. Major efficacy outcomes were death, non-fatal MI, ischemic stroke and ST. Minor efficacy outcomes were TLR, TVR, as well as angiographic variables including late loss of MLD (the difference in MLD immediately after intervention and at follow-up) and binary angiographic restenosis (diameter stenosis [50 %) both in-stent and in-segment (stented segment and margins 5 mm proximal and distal to stent) [11]. Adverse effects were bleeding, thrombocytopenia (platelet \100 9 109/L), neutropenia (neutropenia \1.5 9 109/L), hepatic dysfunction, headache, palpitation, rash and gastrointestinal side-effects [12, 13]. Statistical analysis Statistical analysis was performed using Review Manager 5.0.0 (The Cochrane Collaboration, Oxford, England). The relative risk (RR) and 95 % confidence interval (CI) for categorical variables were calculated using a fixed-effect model with the Mantel–Haenszel method. The DerSimonian and Laird random effect model was also used in case of significant heterogeneity across studies. The mean difference (MD) and 95 % CI was used for continuous variables with inverse variance method. Statistical heterogeneity was evaluated using the Q statistic and I2 statistic. A 2-sided P \ 0.05 was considered statistically significant. Publication bias was examined by funnel plots and confirmed by Egger’s test.
Results Eligible studies We identified 123 potentially relevant articles and included nineteen studies in the meta-analysis (Fig. 1) [14–32].
Cilostazol based triple antiplatelet treatment Fig. 1 Trial selection flow chart. Flow chart indicates the process taken for selecting relevant randomized clinical trials included in this metaanalysis
Study characteristics A total of 7,464 patients were included in the nineteen studies [14–32]; 3,738 were allocated DAPT (aspirin 100–200 mg/ day plus clopidogrel 75 mg/day for 1–12 months) and 3,726 patients were allocated TAPT (aspirin 100–200 mg/day plus clopidogrel 75 mg/day for 1–12 months and cilostazol 100 mg bid for 1–6 months) (Table 1). The studies included between 20 and 1,212 patients, with a mean or median age of 56–71 years. The follow-up duration ranged from 1 to 60 months. Four RCTs only involved the use of bare metal stents, eight only drug-eluting stents, one only biolimuseluting stent and the remaining both types or did not specify stent type (Table 1). The assessment of the methodological quality suggested that all twelve studies had adequate randomized sequence generation. Treatment allocation in ten studies was blinded. All the articles described loss to follow up (Table 2). There was no evidence of publication bias as evidenced by symmetrical funnel plots and a negative Egger’s test (data not shown). Major efficacy outcomes Death Nineteen studies reported the data on all-cause death, including 3,726 patients allocated TAPT and 3,738 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity among these studies (P = 0.70 for all-cause death and P = 0.27 for cardiac death). Pooled
analysis showed no differences between TAPT and DAPT in either all-cause death (1.45 vs. 1.90 %, RR 0.77, CI 0.55–1.09, P = 0.15) (Fig. 2) or cardiac death (0.79 vs. 1.02 %, RR 0.79, CI 0.46–1.37, P = 0.41). Non-fatal MI Eighteen studies reported the data on non-fatal MI, including 3,666 patients allocated TAPT and 3,678 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.94). Pooled analysis showed no difference of non-fatal MI incidence between TAPT and DAPT groups (1.36 vs. 1.50 %, RR 0.92, CI 0.63–1.34, P = 0.68) (Fig. 2). Ischemic stroke Nine articles reported the data on ischemic stroke, including 1,945 patients allocated TAPT and 1,952 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.44). Pooled analysis showed that there were no difference between TAPT and DAPT in ischemic stroke (0.98 vs. 1.38 %, RR 0.71, CI 0.40–1.26, P = 0.24) (Fig. 2). ST Fourteen articles reported the data on ST, including 3,464 patients allocated TAPT and 3,466 allocated DAPT. Heterogeneity testing showed no statistical evidence of
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J. Chen et al. Table 1 Characteristics of the trials included in the meta-analysis Study
TAPT (n)
DAPT (n)
Age
Male (%)
Design
Type of stent
Dosing of aspirin
Dosing of clopidogrel
Dosing of cilostazol
Followup duration (month)
Gao et al. [14]
213
215
56
80
RCT
DES
100 mg daily
75 mg daily
100 mg twice daily
12
Youn et al. [15]
308
307
64
63
RCT
DES
12
Douglas et al. [16]
354
Chen et al. [17]
60
60
58
62
RCT
Lee et al. [18]
10
10
56
55
RCT
Kim et al. [19]
30
Lu et al. [20]
201
Kum et al. [21]
302
301
62
75
Han et al. [22]
604
608
60
73
Jeong et al. [23]
30
Lee et al. [24]
450
Ahn et al. [25]
64
Lee et al. [26]
250
Suh et al. [27]
457
458
64
71
RCT
DES
LD 300 mg, 100 mg daily
75 mg daily
100 mg twice daily
Lu et al. [28]
100
100
62
62
RCT
BMS or DES
100 mg daily
75 mg daily
LD 200 mg,
Han et al. [29]
60
BMS or DES
300 mg daily
Wang et al. [30]
95
Wang et al. [31]
78
86
69
83
RCT
Lu et al. [32]
60
58
71
56
RCT
351
30 201
30 450
66 249
60 98
60
63 61
63 61
64 62
61 62
74
70 61
72 36
62 71
72 69
RCT
RCT RCT
BMS
LD 300 mg,
LD 300-600 mg,
LD 200 mg,
100 mg daily
75 mg daily
100 mg twice daily (3 month) 100 mg twice daily
6
LD 300 mg,
LD 300–600 mg,
100 mg daily
75 mg daily (1 month)
BMS
100 mg daily
75 mg daily (6 month)
100 mg twice daily (6 month)
9
Not mentioned
200 mg daily
1
DES
LD 300 mg,
LD 200 mg,
75 mg daily
200 mg daily
LD 300 mg,
LD 600 mg,
LD 400 mg,
100 mg daily
75 mg daily
100 mg twice daily
LD 300 mg,
100 mg twice daily
6
1
BMS or DES
100 mg daily
RCT
DES
LD 300 mg, 100 mg daily
LD 300 mg, 75 mg daily
100 mg twice daily (1 month)
6
RCT
BMS or DES
MD 300 mg (1 month),
LD 300–600 mg,
100 mg twice daily (6 month)
12
200 mg daily
1
RCT RCT
RCT RCT
RCT RCT
DES DES
DES DES
BMS
75 mg daily
100 mg daily
75 mg daily (3–12 month)
LD 300 mg,
LD 600 mg,
200 mg daily
75 mg daily
200 mg daily
LD 300 mg,
LD 200 mg,
24
LD 200 mg,
75 mg daily ([6 month) LD 300 mg,
100 mg twice daily (6 month) LD 200 mg,
24
100 mg daily
75 mg daily
100 mg twice daily
200 mg daily
LD 300 mg,
LD 200 mg,
75 mg daily
100 mg twice daily (8 month)
LD 300-600 mg,
LD 200 mg,
12
6 60
100 mg twice daily (6 month) LD 300 mg, 75 mg daily LD 300 mg,
LD 300-600 mg,
100 mg daily
75 mg daily
BMS or DES
LD 300 mg,
LD 300 mg,
100 mg daily
75 mg daily
BMS
100 mg daily
75 mg daily
100 mg twice daily (3 month)
3
100 mg twice daily (6 month)
12
100 mg twice daily (6 month)
12
100 mg twice daily (6 month)
6
LD loading dose, mg milligram, RCT randomized controlled trial, BMS bare metal stent, DES drug-eluting stent, ACS acute coronary syndrome, STEMI ST-segment elevation myocardial infarction, AMI acute myocardial infarction, PCI percutaneous coronary intervention
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Cilostazol based triple antiplatelet treatment Table 2 Publication bias graph Study
Adequate sequence generation
Allocation concealment
Blinding
Incomplete outcome data addressed
Gao et al. [14]
Yes
Unclear
Yes
Yes
Young et al. [15]
Yes
Yes
Yes
Yes
Douglas et al. [16]
Yes
Yes
Yes
Yes
Chen et al. [17]
Yes
Yes
Yes
Yes
Lee et al. [18]
Yes
Unclear
No
Yes
Kim et al. [19]
Yes
Unclear
No
Yes
Lu et al. [20] Kum et al. [21]
Yes Yes
Unclear Yes
No No
Yes Yes
Han et al. [22]
Yes
Unclear
No
Yes
Jeong et al. [23]
Yes
Unclear
No
Yes
Lee et al. [24]
Yes
Yes
No
Yes
Ahn et al. [25]
Yes
Unclear
No
Yes
Lee et al. [26]
Yes
Yes
Yes
Yes
Suh et al. [27]
Yes
Yes
No
Yes
Lu et al. [28]
Yes
Unclear
Yes
Yes
Han et al. [29]
Yes
Yes
Yes
Yes
Wang et al. [30]
Yes
Unclear
Yes
Yes
Wang et al. [31]
Yes
Unclear
Yes
Yes
Lu et al. [32]
Yes
Unclear
Yes
Yes
Unclear insufficient information from one article about the process to permit judgment of ‘Yes’ or ‘No’
heterogeneity (P = 0.80). Pooled analysis showed that there was no difference between TAPT and DAPT in the incidence of ST (0.69 vs. 1.13 %, RR 0.62, CI 0.38–1.03, P = 0.06) (Fig. 2). Minor efficacy outcomes TLR Ten articles reported the data on TLR, including 2,625 patients allocated TAPT and 2,622 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.21). Pooled analysis showed that TAPT significantly reduced the incidence of TLR compared with DAPT (5.94 vs. 8.81 %, RR 0.67, 95 % CI 0.56–0.82, P \ 0.0001) (Fig. 3). TVR Thirteen articles reported the data on TVR, including 2,789 patients allocated TAPT and 2,793 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.20). Pooled analysis showed that TAPT significantly reduced the incidence of TVR compared with DAPT (6.99 vs. 10.7 %, RR 0.65, 95 % CI 0.55–0.77, P \ 0.00001) (Fig. 3).
Late loss Six articles reported the data on late loss of MLD, including 1,870 patients allocated TAPT and 1,894 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.45). Pooled analysis showed that the late loss in MLD of TAPT group was significantly lower than that of DAPT group (MD -0.14; 95 % CI -0.17–-0.11, P \ 0.00001). Subgroup analysis of the in-segment and in-stent late loss of MLD favored TAPT for both in-segment (MD -0.15; 95 % CI -0.20– -0.10, P \ 0.00001) (Fig. 4) and in-stent (MD -0.12; 95 % CI -0.17–-0.07, P \ 0.00001) (Fig. 4) late loss. Binary angiographic restenosis Six articles reported the data on binary angiographic restenosis, including 1,870 patients allocated TAPT and 1,894 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 1.00). Pooled analysis showed that binary angiographic restenosis was significantly lower in TAPT group compared to that in DAPT group (12.0 vs. 19.7 %, RR 0.54, 95 % CI 0.45–0.65, P \ 0.00001). Subgroup analysis showed the results favored the TAPT group for both in-segment (12.4 vs. 20.5 %, RR 0.61, 95 % CI 0.49–0.75, P \ 0.00001)
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Fig. 2 TAPT versus DAPT in the incidence of death, non-fatal MI, ischemic stroke and ST. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple
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antiplatelet therapy, DAPT dual antiplatelet therapy, MI myocardial infarction, ST stent thrombosis, CI confidence intervals
Cilostazol based triple antiplatelet treatment
Fig. 2 continued
(Fig. 4) and in-stent (11.6 vs. 18.3 %, RR 0.63, 95 % CI 0.51–0.79, P \ 0.0001) (Fig. 4) restenosis.
minor and minimal bleeding between TAPT and DAPT (data not shown).
Adverse effects
Other adverse effects
Bleeding
TAPT and DAPT were associated with similar rates of thrombocytopenia (0.44 vs. 0.55 %, RR 0.82, 95 % CI 0.24–2.84), neutropenia (0.22 vs. 0.16 %, RR 1.29, 95 % CI 0.32–5.20) and hepatic dysfunction (0.70 vs. 1.27 %, RR 0.58, 95 % CI 0.29–1.16) (P [ 0.05), but TAPT was associated with an increased incidence of headache (4.71 vs. 1.48 %, RR 3.08, 95 % CI 1.98–4.80), palpitation (5.42 vs. 1.62 %, RR 3.32, 95 % CI 2.13–5.20), rash (3.62 vs. 1.76 %, RR 2.06, 95 % CI 1.39–3.07) and gastrointestinal
Sixteen articles reported the data on bleeding, including 3,354 patients allocated TAPT and 3,367 allocated DAPT. Heterogeneity testing showed no statistical evidence of heterogeneity (P = 0.97). Pooled analysis showed no difference between TAPT and DAPT in the risk of bleeding (3.37 vs. 2.79 %, RR 1.20, 95 % CI 0.92–1.57, P = 0.17) (Fig. 5). Pooled analysis revealed no differences in major,
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Fig. 3 TAPT versus DAPT in the incidence of TLR and TVR. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy, DAPT dual
antiplatelet therapy, TLR target lesion revascularization, TVR target vessel revascularization, CI confidence intervals
disorder (2.41 vs. 1.29 %, RR 1.88, 95 % CI 1.14–3.10) compared with DAPT (P \ 0.05).
different from that of aspirin and clopidogrel. Thus, TAPT would be expected to inhibit platelet aggregation synergistically. It does appear to be effective for the prevention of restenosis which is caused by progressive endothelial hyperplasia [33, 34], and is usually manifest by angina or repeat revascularization (TLR and TVR) rather than acute ischemic cardiovascular events such as MI and ST [24–26]. The exact mechanisms of beneficial effects of TAPT remains uncertain, but the possible ones would be as follows. First, it appears to be explained by cilostazol’s ability to block the growth of the vascular smooth muscle cells and stimulate the production of the hepatocyte growth factor leading to accelerated regeneration of endothelial cells [35]. Second, cilostazol suppresses P-selectin-mediated platelet activation, platelet-leukocyte interaction, and subsequent Mac-1-mediated leukocyte activation, each of which may contribute to reduction of restenosis after coronary stent implantation [36]. Third, cilostazol was
Discussion The major findings of this meta-analysis are as follows: (1) TAPT reduces the risk of late loss of MLD and binary angiographic restenosis as well as TLR and TVR compared to DAPT in patients undergoing coronary stent implantation; (2) TAPT does not reduce death, non-fatal MI, ischemic stroke or ST or increase bleeding compared to DAPT; (3) TAPT increases the incidence of minor side effects of headache, palpitation, rash and gastrointestinal disorder compared to DAPT. Cilostazol is a phosphodiesterase III inhibitor that plays the role of hydrolyzing cyclic adenosine monophosphate (cAMP) within platelets. The mechanism of cilostazol is
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Fig. 4 TAPT versus DAPT in late loss of MLD and restenosis. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy,
DAPT dual antiplatelet therapy, MLD minimal lumen diameter, CI confidence intervals
associated with up-regulation of antioncogenes p53 and p21, as well as hepatocyte growth factor released from vascular smooth muscle cells after vessel injury, providing further explanation for its anti-proliferation effects [37]. Laboratory studies using conventional platelet aggregation and point of care testing have demonstrated that
cilostazol based TAPT produces greater platelet inhibition than DAPT [18, 19, 23, 27]. However, these effects did not translate into a reduction in major cardiovascular events or ST [27, 37]. There may be several possible explanations for this discrepancy. First, several trials conducted with combinations of proven effective antiplatelet drugs, including
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Fig. 5 TAPT versus DAPT in the incidence of bleeding. The size of the data markers (squares) is proportional to the statistical weight of each trial. TAPT triple antiplatelet therapy, DAPT dual antiplatelet therapy, CI confidence intervals
aspirin, P2Y12 inhibitors and glycoprotein IIb/IIIa inhibitors, have not demonstrated a benefit of more intensive antiplatelet regimens compared with standard dual antiplatelet therapy despite producing more effective platelet inhibition [38–40]. In each of these trials the likely explanation is lack of statistical power because the numbers of patients randomized are modest. We cannot determine whether the lack of effect of cilostazol on clinical outcomes is explained by inadequate statistical power or lack of effectiveness of cilostazol as an antiplatelet drug. Second, despite the greater reduction of platelet reactivity by addition of cilostazol to convention DAPT, a significant number of patients in the TAPT group still belonged to the hyporesponders to TAPT. It may be an explanation of the finding that enhanced platelet inhibition with TAPT did not decrease the actual number of clinical events [27]. Third, as reported in the DECREASE registry study, the longer duration of triple therapy after drug-eluting stent implantation was associated with the lower risk of ST and MI [41]. However, the TAPT duration and the follow-up period in some RCTs were only 1 month. Thus, the short triple therapy duration and follow-up period may in part contribute to the negative results of the major cardiovascular events [18, 19, 23]. The clinical benefit of intensified antiplatelet therapy may be offset by an associated increase in bleeding complications. However, there were similar episodes of bleeding complications between TAPT and DAPT, which was also demonstrated in previous meta-analyses [42, 43]. The adverse drug effects of TAPT were headache, palpitation,
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rash and gastrointestinal disorder accompanied by the vasodilatory effects of cilostazol. Most of the adverse effects were mild and tolerable to patients and may be resolved after cilostazol discontinuation and supportive care. Our results confirm and extend the findings of previous meta-analysis of cilostazol-based triple therapy following PCI [10, 42–46]. Unlike some or all of the previous analyses, our meta-analysis has several aspects that are specific or innovative. First, our inclusion criteria is more strict, we exclude the RCTs of non-routine cilostazol dosage (50 mg, bid), as well as the inappropriate control groups (ticlopidine or doubling clopidogrel), and the comparison between TAPT and DAPT can be standardized; Second, the major adverse cardiovascular events (MACEs) were differently defined in the recruited studies, and we believe that merging these differently identified MACEs as a composite endpoint as previous meta-analyses is inappropriate. So we analyzed each adverse event (death, non-fatal MI, ischemic stroke and ST) separately rather than pooled the composite events together while performing the meta-analysis. Finally, this study included the latest RCTs which made the sample size maximized and the results more accurate and realistic. Limitations Our study has potential limitations. First, the studies were of modest size and the pooled data cannot exclude significant benefits of cilostazol based TAPT on major cardiovascular events. Second, the studies varied substantially in their design, treatment durations and follow-up and this
Cilostazol based triple antiplatelet treatment
heterogeneity may have limited power to demonstrate significant treatment effects. Third, most of the RCTs in our study were performed in South Korea and China, and their results may not be generalizable to other populations.
Conclusions Cilostazol based TAPT can reduce late loss of MLD, stent restenosis, TLR, and TVR but does not impact ST or major cardiovascular events. Further evaluation of Cilostazol based TAPT in an adequately powered RCT appears warranted to determine whether these benefits can translate into a reduction in major vascular events with an acceptable safety profile. Acknowledgments This work was supported by a grant from the National Natural Science Funding of China (81170181), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD). Conflict of interests manuscript.
No conflicts of interest are involved in this
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