Comparison of On-Treatment Platelet Reactivity Between Triple Antiplatelet Therapy With Cilostazol and Standard Dual Antiplatelet Therapy in Patients Undergoing Coronary Interventions

Abstract

Background:

The recent literature has shown that triple antiplatelet therapy with cilostazol in addition to the standard dual antiplatelet therapy with aspirin and clopidogrel may reduce platelet reactivity and improve clinical outcomes following percutaneous coronary intervention. The purpose of this meta-analysis is to compare the efficacy of triple antiplatelet therapy and dual antiplatelet therapy in regard to on-treatment platelet reactivity.

Methods:

Nine studies (n = 2179) comparing on-treatment platelet reactivity between dual antiplatelet therapy (n = 1193) and triple antiplatelet therapy (n = 986) in patients undergoing percutaneous coronary intervention were included. Primary end points were P2Y12 reaction unit (PRU) and platelet reactivity index (PRI). Secondary end points were platelet aggregation with adenosine diphosphate (ADP) 5 and 20 µmol/L and P2Y12% inhibition. Mean difference (MD) and 95% confidence intervals (CI) were computed and 2-sided α error <.05 was considered as a level of significance.

Results:

Compared to dual antiplatelet therapy, triple antiplatelet therapy had significantly lower maximum platelet aggregation with ADP 5 µmol/L (MD: −14.4, CI: −21.6 to −7.2, P < .001) and 20 µmol/L (MD: −14.9, CI: −22.9 to −6.8, P < .001), significantly lower PRUs (MD: −45, CI: −59.4 to −30.6, P < .001) and PRI (MD: −26, CI: −36.8 to −15.2, P < .001), and significantly higher P2Y12% inhibition (MD: 18.5, CI: 2.3 to 34.6, P = .025).

Conclusion:

Addition of cilostazol to conventional dual antiplatelet therapy significantly lowers platelet reactivity and may explain a decrease in thromboembolic events following coronary intervention; however, additional studies evaluating clinical outcomes will be helpful to determine the benefit of triple antiplatelet therapy.

Keywords

cilostazol antiplatelet therapy platelet reactivity percutaneous coronary intervention

Introduction

Dual antiplatelet therapy with aspirin and clopidogrel is currently the standard of care for patients undergoing percutaneous coronary intervention (PCI) with or without stent placement. Despite appropriate treatment, nearly 15% to 30% of the patients still experience major adverse cardiovascular events (MACE).^1–6 The failure of this treatment is explained by a phenomenon called high residual platelet reactivity. High residual platelet reactivity is not an uncommon occurrence in patients that are treated with dual antiplatelet therapy.^7,8 Several modifiable and nonmodifiable factors are associated with diminished clopidogrel response. Some of these factors include pharmacogenetic polymorphisms (CYP2C19*2 and *3, ABCB1 and ITGB3), noncompliance, smoker’s paradox, drug–drug interactions (proton pump inhibitors, lipophilic statins, and calcium channel blockers), gender and racial differences, diabetes, obesity, and acute coronary syndrome.^9–12

Recent studies demonstrate that a significant benefit is achieved by adding cilostazol to the standard dual antiplatelet therapy.^13,14 This change is most pronounced in the subpopulation of patients with diabetes mellitus. However, it has not been established that the benefit of triple antiplatelet therapy is due to increased platelet inhibition.^15–23 The purpose of this study is to compare the effect of triple antiplatelet therapy and dual antiplatelet therapy in regard to on-treatment platelet reactivity and function via meta-analysis of the existing studies. To the best of our knowledge, this comparison has not been previously illustrated.

Methods

The meta-analysis was performed in accordance with the guidelines from both Meta-analysis of Observational Studies in Epidemiology (MOOSE [A]) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements for reporting systematic reviews.²⁴ We conducted the meta-analysis in adherence with the general guidelines of the Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2, and the specific recommendations of genetic meta-analysis of the HuGE Review Handbook, version 1.0.

Literature Search

We searched the National Library of Medicine, PubMed, National Institutes of Health clinical trials registry, and the Cochrane Central Register of Controlled Trials to recruit clinical studies that compared on-treatment platelet reactivity between dual antiplatelet therapy and triple antiplatelet therapy with addition of cilostazol in patients undergoing percutaneous coronary intervention. We also searched Internet-based sources of information to include clinical trials in cardiology (www.cardiosource.com/clinicaltrials, www.theheart.org, www.clinicaltrialresults.com., and www.tctmd.com) as well as conference proceedings from meetings of the American College of Cardiology, the American Heart Association, and the European Society of Cardiology. Searches were restricted to the period from January 2000 through October 2012. The keywords used for search were “dual antiplatelet,” “triple antiplatelet,” “percutaneous coronary intervention,” “cilostazol,” “platelet reactivity,” and “platelet aggregation.”

Study Selection

Two independent authors (HP and TS) reviewed all titles and abstracts from the results of our computerized search. The related article links were also reviewed as possible studies to be included in the analysis. In addition to our computerized search, reference list of all retrieved articles was manually reviewed to complete our search. Study selection process is outlined in Figure 1.

Figure 1.

Study selection process.

Inclusion and Exclusion Criteria

In our analysis, we included the results of studies that compared on-treatment platelet reactivity in patients treated with standard dual antiplatelet therapy (aspirin and clopidogrel) and triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) following PCI. Studies had to meet the following criteria to be included in our analysis: (1) studies must compare on-treatment platelet reactivity in patients with coronary artery disease (CAD) undergoing PCI. (2) On-treatment platelet reactivity must be measured with at least one of the following methods: platelet aggregation induced with 5 and 20 µmol/L of adenosine diphosphate (ADP) measured by light transmittance aggregometry (LTA),^25–27 P2Y12% inhibition and P2Y12 reaction unit (PRU) measured by VerifyNow assay,²⁸ and platelet reactivity index (PRI) measured by Vasodilator Stimulated Phosphoprotein Phosphorylation (VASP-P).^27,29 Studies that did not meet any of the above-mentioned criteria were excluded.

End Points

The primary end points of the study were PRU and PRI. The secondary end points were platelet aggregation, induced by 5 and 20 µmol/L of ADP and P2Y12% inhibition.

Data Abstraction

After identifying all relevant articles, we extracted characteristics of each study (author, year, design of the study, baseline patient characteristics, type of stent placed, baseline clinical characteristics of patients, follow-up time) and outcomes of on-treatment platelet reactivity as described in inclusion criteria 2. Two reviewers (HP and TS) independently extracted data and assessed the outcomes. Interrater agreement was 90%, and disagreements were resolved by consensus.

Statistical Analysis

Combined mean difference (MD) and 95% confidence intervals (CIs) were computed for each end point using the Comprehensive Meta-Analysis software package (version CM 2.2, Biostat, Englewood, New Jersey). Heterogeneity among the studies was assessed for each end point by employing the Cochran Q statistic and the I² statistics (Table 1). The I² indicates the percentage of the total variability that is due to the heterogeneity of the studies. Values of I² <25%, ≥25% to <50%, and ≥50% were considered to represent low, modest, and large heterogeneity, respectively. Those studies that were homogeneous for an end point were analyzed by the fixed effect model, while those studies that were heterogeneous for an end point were analyzed by the random effect model. Given the mixed study designs, sensitivity analyses of the results were performed by conducting a second set of meta-analyses limited only to randomized trials. A 2-sided α error of <.05 was considered to be statistically significant.

Table 1.

Test of Heterogeneity Among Studies for Each Outcome and Test for Publication Bias.

Outcome	Q Value	df (Q)	P Value	I-Squared	Results	Publication Bias
PRU	22.9	4	.000	83	Heterogenic	Probable
PRI	0.2	1	.684	0	Homogenic	NA—at least 3 studies required
P2Y12% inhibition	3.5	1	.060	72	Heterogenic	NA—at least 3 studies required
Maximum platelet aggregation with 5 µmol/L of ADP	12.0	4	.018	67	Heterogenic	No
Maximum platelet aggregation with 20 µmol/L of ADP	19.0	5	.002	74	Heterogenic	Possible
Late platelet aggregation with 20 µmol/L of ADP	2.4	1	.118	59	Homogenic	NA—at least 3 studies required

Abbreviations: PRU, platelet reactivity unit; PRI, platelet reactivity index; ADP, adenosine diphosphate; df, degrees of freedom; NA, not applicable.

Table 2.

Study Characteristics.

Study	Design	Study Population		Type of Stent Placed		Total Patients		Follow-up (Days)	End Points Studied
Study	Design	TAT	DAT	TAT	DAT	TAT	DAT	Follow-up (Days)	End Points Studied
Park¹⁹	Retrospective analysis of RCT	Age (Y): 64 ±9, male: 65%, HTN: 68.1%, DM: 37.8%, smoker: 18.5%, CKD: 2.5%, stable angina: 48.3%, unstable angina: 44.5% and AMI: 7.3	Age (Y): 63 ± 8.3, male: 74.2%, HTN: 67.8%, DM: 29.2%, smoker: 22.8%, CKD: 0.8%, stable angina: 47%, unstable angina: 48.7%, and AMI: 4.2%	Drug eluting stent but not specified further	Drug eluting stent but not specified further	238	236	180	PRU
Woo²¹	RCT	Age (Y): 53.9 ± 6.6, male: 60%, HTN: 72%, DM: 28%, smoker: 24%, CKD: 100%, and stable CAD: 100%	Age (Y): 53.5 ± 12.8, male: 54%, HTN: 67%, DM: 29%, smoker: 25%, CKD: 100%, and stable CAD: 100%	Not specified	Not specified	25	24	14	PRU, P2Y12% inhibition, and maximum platelet aggregation induced with 5 and 20 µmol/L of ADP
Suh²⁰	Retrospective analysis of RCT	Age (Y): 64.8±13, male: 68.6%, HTN: 64.5%, DM: 35.5%, smoker: 23.7%, stable angina: 41.3%, unstable angina: 42.8%, AMI: 10.3%, and silent ischemia: 1.9%	Age (Y): 64.8± 13, male: 68.3%, HTN: 66.9%, DM: 32.2%, smoker: 26.8%, stable angina: 37.1%, AMI: 47.6%, 10.2%, and silent ischemia: 1.2%	Paclitaxel-eluting stent (TAXUS): 49.1% and Zotarolimus-eluting stent (Endeavor): 46.7%	Paclitaxel-eluting stent (TAXUS): 51.4% and Zotarolimus-eluting stent (Endeavor): 43.3%	457	458	180	PRU
Yang²²	Prospective cohort study	Not specified	Not specified	DES in at least 87%	DES in at least 87%	188	356	2	PRU
Jeong¹⁷	RCT	Age (Y): 61.3 ±12.1, male: 70%, DM: 30%, HTN: 56.7%, smoker: 53.3%, STEMI: 46.7%, NSTEMI: 53.3%, CKD: 23.3%, and HLP: 30%	Age (Y): 64 ±13.3, male: 73.3%, DM: 13.3%, HTN: 36.7%, smoker: 70%, STEMI: 56.7%, NSTEMI: 43.3%, CKD: 13.3%, and HLP: 43.3%	Sirolimus: 23.3%, Paclitaxel: 66.7%, and Zotarolimus: 10%	Sirolimus: 33.3%, Paclitaxel: 56.7%, and Zotarolimus: 10%	30	30	30	PRU, P2Y12% inhibition, and maximum and late platelet aggregation with 20 and 5 µmol/L of ADP
Fu¹⁶	Retrospective	Age (Y): 70 ± 11, male: 63%, HTN: 75%, DM: 100%, and smoker: 50%	Age (Y): 69 ± 8, male: 76%, HTN: 76%, DM: 53%, and smoker: 27%	BMS: 13%, Sirolimus: 63%, and Paclitaxel: 25%	BMS: 18%, Sirolimus: 56%, Paclitaxel: 21%, Zotarolimus: 3%, and Everolimus: 3%	8	34	60	PRI and maximum platelet aggregation induced with 5 and 20 µmol/L of ADP
Yang²³	Retrospective	Age (Y): 63.4 ± 7.6, male: 40%, smoker: 14.3%, and HTN: 61.9%	Age (Y): 63.8 ± 8.2, male: 60%, smoker: 20.6%, and HTN: 57.1%	Sirolimus: 85.7% and Paclitaxel: 14.3%	Sirolimus: 88.2% and Paclitaxel: 11.8%	21	34	>30	Maximum platelet aggregation induced with 20 µmol/L of ADP
Angiolillo¹⁵	Randomized-controlled cross-over trial	Age (Y): 64 ±10, Male: 60%, HTN: 96%, DM:100%, and smoker: 24% (population baseline characteristics were not differentiated between 2 groups)		Not Specified	Not Specified	9	11	28	PRI and maximum and late platelet aggregation induced with 5 and 20 µmol/L of ADP
Lee¹⁸	RCT	Age (Y): 56.6 + 9.4, men: 60%, HTN: 50%, DM: 20%, and smoker: 50%	Age (Y): 56.0 ± 10.2, men: 50%, HTN: 50%, DM: 30%, smoker: 50%	Not Specified	Not Specified	10	10	30	Maximum platelet aggregation induced with 5 and 20 µmol/L of ADP

Abbreviations: RCT, randomized controlled trial; Y, years; HTN, hypertension; DM, diabetes mellitus; STEMI, ST elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; CKD, chronic kidney disease; HLP, hyperlipidemia; DES, drug eluting stent; PRU, platelet reactivity unit; PRI, platelet reactivity index; ADP, adenosine diphosphate; DAT, dual antiplatelet therapy with aspirin and clopidogrel; TAT, triple antiplatelet therapy with aspirin, clopidogrel, and cilostazol; BMS, bare metal stent; AMI, acute myocardial infarction.

Heterogeneity Testing

The test of heterogeneity addresses the question of whether the observed differences among the trials in an outcome exceed the amount of difference that would be expected by chance. If the differences between studies in an effect size exceed that amount, the trials are heterogeneous for that particular outcome, otherwise they are homogeneous. The results of heterogeneity testing are shown in Table 1. The studies were heterogeneous for on-treatment platelet reactivity by PRU, P2Y12% inhibition, and maximum platelet aggregation with 5 and 20 µmol/L ADP. The studies were homogeneous for on-treatment platelet reactivity measured by PRI and late platelet aggregation by 20 µmol/L ADP.

Results

Literature Search

A total of 467 articles were identified, 83 were potentially relevant studies and screened for retrieval. After title and abstract evaluation, 65 studies were excluded and 18 studies were retrieved for a more detailed screening. Of the 18 studies, 9 studies were excluded, because they did not meet the inclusion criteria. The remaining 9 studies^15–23 that compared triple antiplatelet therapy to dual antiplatelet therapy for on-treatment platelet reactivity in patients following PCI were included in the final analysis (Figure 1).

Overview of Study and Patient Characteristics

Seven studies^15,17–22 were prospective cohort studies. Of the 7 studies,^15,17–21 6 were either randomized controlled trials or retrospective analyses of randomized controlled trials. One study²² was a nonrandomized prospective cohort study. Two studies^16,23 were retrospective analyses (Table 2). The study population of Woo et al²¹ was comprised of patients with chronic kidney disease, whereas Angiolillo et al¹⁵ studied all the outcomes in a diabetic patient population who had documented CAD, who had previously undergone PCI, and were in the maintenance phase of clopidogrel treatment with 75 mg daily. Jeong et al¹⁷ studied desired outcomes in patients who had percutaneous coronary intervention for acute myocardial infarction. Park et al¹⁹ had a study population that consisted of patients with CYP2C19 loss of function alleles. Yang et al²² excluded patients with ST segment myocardial infarction from their study. Lee et al¹⁸ included only the patients who underwent elective PCI. Indications for PCIs are not provided by some of the studies.^16,18,23,30 The detailed characteristic of each study is described in Table 2.

Clinical Outcomes

The studies included in this meta-analysis consist of a total of 2179 patients; on-treatment platelet reactivity was compared in patients on triple antiplatelet therapy (n = 986) and dual antiplatelet therapy (n = 1193) following PCI. Mean follow-up for each outcome is shown in Table 3.

Table 3.

Follow-Up Duration for Each Outcome.

Outcome	Studies	Total Population	Follow-Up Days	Mean Per Patient Follow-Up (Days)
PRU	Park¹⁹	474	180	124
	Woo²¹	49	14
	Suh²⁰	915	180
	Yang²²	544	2
	Jeong¹⁷	60	30
PRI	Fu¹⁶	42	60	50
PRI	Angiolillo¹⁵	20	28	50
P2Y12% inhibition	Woo²¹	49	14	23
P2Y12% inhibition	Jeong¹⁷	60	30	23
Max platelet aggregation with 5 µmol/L of ADP	Woo²¹	49	14	32
	Jeong¹⁷	60	30
	Fu¹⁶	42	60
	Angiolillo¹⁵	20	28
	Lee¹⁸	20	30
Max platelet aggregation with 20 µmol/L of ADP	Woo²¹	49	14	32
	Jeong¹⁷	60	30
	Fu¹⁵	42	60
	Yang²³	55	30
	Angiolillo¹⁵	20	28
	Lee¹⁸	20	30

Late platelet aggregation with 20 µmol/L of ADP	Jeong¹⁷	60	30	30
Late platelet aggregation with 20 µmol/L of ADP	Angiolillo¹⁵	20	28	30

Abbreviations: PRU, platelet reactivity unit; PRI, platelet reactivity index; ADP, adenosine diphosphate; Max, maximum.

VerifyNow Assay

The PRUs were significantly lower in triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −44.99 PRU, CI: −59.4 to −30.57 PRU, P < .001; Figure 2A). The P2Y12% inhibition was significantly higher in triple antiplatelet therapy compared to dual antiplatelet therapy (MD: 18.45%, CI: 2.31- 34.6%, P = .025) (Figure 2B).

Figure 2.

Meta-analysis of on-treatment platelet reactivity assessed with (A) P2Y12 reaction unit and (B) P2Y12% inhibition determined by VerifyNow assay between triple antiplatelet and dual antiplatelet therapies. TAT indicates triple antiplatelet therapy; DAT, dual antiplatelet therapy; CI, confidence interval.

Vasodilator-Stimulated Phosphoprotein Phosphorylation Assay

The PRI was significantly lower with triple antiplatelet therapy compared to the dual antiplatelet therapy (MD: −25.99 PRI, CI: −36.79 to −15.19 PRI, P < .001; Figure 3).

Figure 3.

Meta-analysis of on-treatment platelet reactivity measured with P2Y12 reactivity index determined through assessment of VASP-P between triple antiplatelet and dual antiplatelet therapies. TAT indicates triple antiplatelet therapy; DAT, dual antiplatelet therapy; CI, confidence interval; VASP-P, vasodilator-stimulated phosphoprotein, phosphorylation.

Light Transmittance Aggregometry

The maximum platelet aggregation induced with 5 µmol/L ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −14.4%, CI: −21.55 to −7.25%, P < .001; Figure 4A). The maximum platelet aggregation induced with 20 µmol/L of ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −14.87%, CI: −22.9 to −6.83%, P < .001; Figure 4B). The late platelet aggregation induced by 20 µmol/L of ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −22.67%, CI: −31.56 to −13.78%, P < .001; Figure 4C).

Figure 4.

Meta-analysis of (A) maximum platelet aggregation (%) induced with 5 µmol/L ADP, (B) 20 µmol/L ADP, and (C) late platelet aggregation (%) induced with 20 µmol/L ADP determined using LTA between triple antiplatelet and dual antiplatelet therapies. TAT indicates triple antiplatelet therapy; DAT, dual antiplatelet therapy; CI, confidence interval; LTA, light transmittance aggregometry.

Sensitivity Analysis

There were significant differences in study designs between the published articles. Therefore, a sensitivity analysis was performed by conducting a second meta-analysis limited only to randomized controlled trials. The results obtained from the randomized trials were similar to that seen when all the studies were included in the analysis in terms of both magnitude and level of significance.

VerifyNow Assay

The PRUs were significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −46.79 PRU, CI: −64.9 to −28.68 PRU, P < .001). P2Y12% inhibition was significantly higher with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: 18.44%, CI: 2.30 to 34.58%, P = .025).

Vasodilator-Stimulated Phosphoprotein Phosphorylation Assay

The PRI was significantly lower with triple antiplatelet therapy compared to the dual antiplatelet therapy (MD: −23.60 PRI, CI: −39.36 to −7.84 PRI, P = .003).

Light Transmittance Aggregometry

The maximum platelet aggregation induced with 5 µmol/L ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −18.1%, CI: −22.9 to −13.3%, P < .001). The maximum platelet aggregation induced by 20 µmol/L ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −19.5%, CI: −25.5 to −13.5%, P < .001). The late platelet aggregation induced with 20 µmol/L ADP was significantly lower with triple antiplatelet therapy compared to dual antiplatelet therapy (MD: −22.74%, CI: −31.73 to −13.75%, P<.001).

Discussion

The results of our meta-analysis show a significant decrease in on-treatment platelet reactivity with triple antiplatelet therapy with adjunctive cilostazol compared to standard dual antiplatelet therapy in patients undergoing coronary artery stenting irrespective of the type of platelet function assay used. Most cases of acute myocardial infarction are caused by formation of platelet-rich thrombus at the site of atherosclerotic plaque rupture or erosion. The PCI with or without stenting increases the burden of developing large thrombus within the coronary arteries and predispose to thrombotic events because of enhanced platelet reactivity.^31,32 Clopidogrel is a prodrug that is metabolized by the hepatic cytochrome P450 (CYP) enzyme into an active form. This activity is influenced by a variety of factors, such as age, sex, and ethnicity.^33,34 The CYP2C19 isozyme is a major contributor in the conversion of the prodrug clopidogrel to its active form.^9–11 Mutations to this enzyme can significantly alter the efficacy of the medication by interfering with its metabolism to an active form. Even single-nucleotide polymorphisms in genes encoding for the enzyme can result in profound changes in the antiplatelet effect of clopidogrel.^35–37 The CYP2C19*2 or *3 polymorphism and mutation have been associated with suboptimal clopidogrel function, especially in Asian–Japanese patients.^9–11 Cilostazol is a selective phosphodiesterase-3 inhibitor commonly used in patients with peripheral arterial disease. Cilostazol is currently approved by the Food and Drug Administration for symptomatic relief of claudication pain in peripheral artery disease. The medication is not currently approved for use in patients with CAD who have demonstrated inadequate response with clopidogrel. Cilostazol acts by increasing the levels of intraplatelet cyclic adenosine monophosphate³⁵ and consequently VASP-P, which inhibits glycoprotein IIb/IIIa receptor activation, leading to inhibition of platelet aggregation.^38,39 Cilostazol has also been reported to have anti-inflammatory and antiapoptotic effects in some Asian studies. Cilostazol has been widely used in combination with aspirin for the prevention of stent thrombosis in patients undergoing PCI. Data suggest that the efficacy of cilostazol is similar to thienopyridines.^35,40

Studies indicate that increased potency of the antiplatelet medications may be associated with a further decrease in the risk of cardiovascular death and myocardial infarction.^37,41–44 Prasugrel has a greater inhibitory effect on ADP-induced platelet aggregation than high maintenance dose of clopidogrel.⁴³ Studies have shown that prasugrel significantly reduced the ischemic events by 19% compared to the standard dose of clopidogrel (hazard ratio: 0.81, CI: 0.73- 0.90, P < .001) in patients with acute coronary syndrome.^14,41,42 Similarly, ticagrelor, another drug recently approved for use in acute coronary syndrome, has shown to achieve more rapid and greater platelet inhibition than high loading dose clopidogrel.⁴⁵ Ticagrelor has also demonstrated fewer cardiovascular deaths and myocardial infarctions when compared to the standard dose of clopidogrel.⁴⁶ Bonello et al demonstrated benefit from tailored therapy consisting of a loading dose of clopidogrel that is adjusted according to platelet reactivity monitoring in patients with the CYP2C19*2 polymorphism who undergo emergent PCI mostly for stable CAD.⁴⁷ However, recent studies show that tailored therapy consisting of adjusted dose of thienopyridines based on monitoring of platelet reactivity is not beneficial for elective PCI in patients with stable CAD and non-ST segment elevation myocardial infarction.^48,49 These studies demonstrate that adjusting antiplatelet therapy with high dose of clopidogrel based on platelet reactivity monitoring after successful elective PCI with drug-eluting stent placement, in the setting of stable CAD, does not reduce cardiovascular mortality, nonfatal myocardial infarction, or stent thrombosis in short-term follow-up at 6 to 12 months despite significantly greater reduction in high on-treatment platelet reactivity.^48,49 These data suggest that high on-treatment platelet reactivity is not the only factor responsible for adverse cardiovascular events following elective PCI. Although lowering platelet reactivity is an important element in improving MACE and major adverse cerebrovascular events, there are evidences that other elements such as elevated plasma fibrinogen >345 mg/dL in the absence of systemic inflammation and C-reactive protein level <0.5 mg/dL are independent risk factors for adverse cardiovascular events following elective PCI in stable CAD.⁵⁰ Neutrophil-mediated inflammatory response may also be associated with increasing cardiovascular events in patients with stable coronary disease.⁵¹ The neutrophil-mediated inflammatory response accelerates plaque instability and increases the risk of plaque enlargement and rupture.⁵² Since platelet reactivity is not the sole cause of adverse cardiovascular events in patients with CAD following PCI, monitoring of platelet reactivity and tailored therapy may not add additional benefit. Dual antiplatelet therapy with clopidogrel may not be adequate to prevent ischemic heart events. The current literature shows that the addition of cilostazol significantly decreases the on-treatment platelet reactivity and further decreases the risk of MACE.^{14,37,53–57}

The major concern with using triple antiplatelet therapy is an increased risk of bleeding. In reality, triple antiplatelet therapy with cilostazol has been shown to reduce MACE and stent thrombosis compared with standard dual antiplatelet therapy without increasing the risk of bleeding.^14,53–56 Treatment with cilostazol, however, has been shown to be associated with reduced bleeding events compared to other antiplatelet drugs.^35,40 Triple antiplatelet therapy with cilostazol may be as safe as standard dual antiplatelet therapy and may result in significant reductions in cardiovascular outcomes.^14,53–57 A recently published randomized-controlled trial by Yang et al found that dual antiplatelet therapy with aspirin and prasugrel may lead to greater reductions in on-treatment platelet reactivity compared to triple antiplatelet therapy with aspirin, clopidogrel, and cilostazol in patients undergoing PCI for ST segment elevation myocardial infarction.⁵⁷ However, there are currently no data comparing improvements in clinical cardiovascular outcomes and bleeding events between the newer dual antiplatelet therapy and the triple antiplatelet therapy. Randomized clinical trials are needed for further evaluation of long-term MACE and risk of bleeding comparing between patients on newer dual antiplatelet therapy with prasugrel or ticagrelor and patients on triple antiplatelet therapy with cilostazol.

Limitations

Our meta-analysis has several limitations. The baseline characteristics between the 2 groups cannot be compared completely as in most meta-analyses because of differences in the study protocols across the component trials. The sensitivity analysis limited only to the randomized controlled trials resulted in very similar results to those seen when all studies were included in the analysis. It is true for the magnitude of effect size and the level of significance in each analysis suggesting generalizability of the results. The results of this study may not be applicable to a more general population, because most studies were performed in East Asian populations. In addition, there is a potential for publication bias. Many of these trials were small trials with limited ability to assess outcomes. The overall follow-up period was short. The timing of on-treatment platelet reactivity measurement after initiation of antiplatelet therapy was not consistent in all the studies. Many of these studies were underpowered with limited ability to assess the desired outcomes. The study did not correlate change in platelet reactivity with change in cardiovascular events. Due to the meta-analysis nature of the study, we were unable to evaluate the effects of various factors such as gender, race, and ethnic backgrounds on the measured outcomes. The analysis was also limited in comparing on-treatment platelet reactivity in patients following PCI for each indication of stable CAD, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction, and unstable angina.

Conclusion

Addition of cilostazol to conventional dual antiplatelet therapy significantly lowers on-treatment platelet reactivity and aggregation following PCI. Although not measured in our study, the decrease in on-treatment platelet reactivity with triple antiplatelet therapy might be associated with a decrease in thrombotic events in these patients. If so, in high-risk patients with predicted or known inadequate responses to clopidogrel, the addition of cilostazol might be beneficial. However, platelet reactivity is not the only factor in preventing adverse cardiovascular events following PCI. Hence, further studies are needed to analyze the effect of higher potency of triple antiplatelet therapy to lower platelet reactivity on long-term clinical cardiovascular outcomes.

Footnotes

Authors’ Note

The study work was done at East Tennessee State University jointly with Chicago Medical School/RFUMS.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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