Skip to main content
Erschienen in: BMC Cardiovascular Disorders 1/2017

Open Access 01.12.2017 | Research article

Individualized dual antiplatelet therapy based on platelet function testing in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials

verfasst von: Yijiang Zhou, Yanwei Wang, Yutao Wu, Chaoyang Huang, Hui Yan, Weiguo Zhu, Weiwei Xu, Li Zhang, Jianhua Zhu

Erschienen in: BMC Cardiovascular Disorders | Ausgabe 1/2017

Abstract

Background

High on-treatment platelet reactivity (HPR) represents a strong risk factor for thrombotic events after PCI. We aim to evaluate the efficacy and safety of individualizing intensified dual antiplatelet therapy (DAPT) in PCI-treated patients with HPR based on platelet function testing (PFT).

Methods

Electronic databases were searched for randomized control trials that reported the clinical outcomes of using an intensified antiplatelet protocol with P2Y12 receptor inhibitor comparing with standard maintenance dose of clopidogrel on the basis of platelet function testing. Clinical endpoints were assessed.

Results

From 2005 to 2016, thirteen clinical studies comprising 7290 patients were included for analysis. Compared with standard antiplatelet therapy with clopidogrel, the intensified protocol based on platelet function testing was associated with a significant reduction in major adverse cardiovascular events (RR:0.55, 95% CI: 0.36–0.84, p = 0.005), cardiovascular death (RR:0.60, 95% CI: 0.38–0.96, p = 0.03), stent thrombosis (RR:0.58, 95% CI: 0.36–0.93, p = 0.02) and target vessel revascularization (RR:0.33, 95% CI: 0.14–0.76, p = 0.009). No significant difference was found in the rate of bleeding events between intensified and standard protocol.

Conclusions

Compared with standard clopidogrel therapy, individualized intensified antiplatelet therapy on the basis of platelet reactivity testing reduces the incidence of cardiovascular events in patient undergoing PCI, without increasing the risk of bleeding.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12872-017-0582-6) contains supplementary material, which is available to authorized users.
Abkürzungen
ACS
Acute coronary syndrome
CI
Confidence interval
HPR
High on-treatment platelet reactivity
MACE
Major adverse cardiovascular event
LD
Loading dose
MD
Maintenance dose
MI
Myocardial infarction
NSTEMI
Non-ST segment elevation myocardial infarction
RR
Risk ratio
PCI
Percutaneous coronary intervention
RCT
Randomized, controlled trial
ST
Stent thrombosis
STEMI
ST-segment elevation myocardial infarction
TVR
Target vessel revascularization
TIMI
Thrombolysis in Myocardial Infarction

Background

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 antagonist represents the standard of care in patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary interventions (PCI) [1]. However, a concerning issue is that wide inter-individual variability exists among P2Y12 antagonist, especially clopidogrel [24]. The incidence of high on-treatment platelet reactivity (HPR) can be as high as in one-third of patients treated with clopidogrel, and HPR is present even in those receiving the more potent P2Y12 antagonists ticagrelor and prasugrel [5]. Numerous studies have demonstrated that HPR is associated with increased cardiovascular death and thrombotic events [6, 7]. Several small clinical studies have shown that increasing the dose of clopidogrel or switching to a more potent P2Y12 receptor inhibitor in patients with HPR can significantly reduce the incidence of major adverse cardiac events (MACE) [810]. However, large randomized trials failed to demonstrate similar improvements in clinical outcomes with a tailored antiplatelet therapy based on platelet function monitoring [1114]. Therefore, though some studies found platelet reactivity-guided antiplatelet therapy to be beneficial in certain clinical endpoints like bleeding and stent thrombosis [15], the usefulness of tailored antiplatelet therapy during PCI is still controversial. In the present study, we performed meta-analysis on previous studies to evaluate the clinical efficacy and safety of individualized intensification of antiplatelet therapy with P2Y12 inhibitors versus standard dose clopidogrel on the basis of platelet function testing(PFT) in patients undergoing PCI.

Methods

PubMed, MEDLINE and ClinicalTrials were searched for clinical studies published between January 2005 and September 2016. The key words we used included the following terms: ‘platelet function’, ‘platelet reactivity’, ‘platelet aggregation’, ‘platelet aggregometry’, ‘antiplatelet resistance’,‘high on treatment platelet reactivity’,‘P2Y12-ADP receptor inhibitor’, ‘clopidogrel’, ‘prasugrel’, ‘ticagrelor’ and ‘percutaneous coronary intervention’. In addition, references of relevant studies and reviews, editorials, and letters, together with related conference abstracts were also searched.
The main criteria for inclusion in this analysis were trials that compared clinical efficacy and/or safety of an intensified antiplatelet therapy with that of standard-dose clopidogrel therapy on the basis of platelet reactivity testing in patients undergoing PCI. Studies without platelet function testing were excluded. Similarly, studies that compared only the pharmacological efficacy of a platelet function-guided anti-platelet therapy were also excluded. Moreover, studies in which platelet inhibitor other than P2Y12 inhibitors were used were excluded.
According to international consensus and previous studies [16, 17],the accepted ADP-specific platelet function devices were: (a) VerifyNow P2Y12 assay, (b) Multiplate analyzer with ADP test, (c) Flow cytometric assessment of vasodilator stimulated phosphoprotein (VASP) phosphorylation index, and (d) Conventional light transmission aggregometry (LTA).
The efficacy endpoints of the analysis included: (a) Major adverse cardiovascular events (MACE), (b) Cardiovascular death, (c) Definite/probable ST, (d) Myocardial infarction (MI), (e) Stroke and (f) Target vessel revascularization (TVR). All of them were defined according to the study definition. In particular, MACE was primarily defined as a composite of cardiovascular death, myocardial infarction and definite/probable stent thrombosis, though a few studies also included endpoint of stroke or transient ischemic attack (TIA). The main safety endpoint was major bleeding and major or minor bleeding events, which were defined according to the study definition,including BARC, TIMI, GUSTO and STEEPLE [1821]. The net clinical end point was defined as a composite of MACE and major bleeding.
Two investigators independently assessed reports for eligibility on the title and/or at abstract level, with divergences resolved with a third reviewer; studies that met inclusion criteria were selected for further analysis. The risk of bias was evaluated by the same two reviewer authors, in accordance with The Cochrane Collaboration methods [22].
Meta-analysis was performed using the Review Manager 5.3 and STATA 14 statistical software. Reported event frequencies were used to calculate risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity of the trial results was quantified with the Chi2 heterogeneity statistic, with inconsistency assessed by means of I2. Results were reported as the p value of the Chi2 test (p < 0.05 for heterogeneous results) and percentage of the I2. Interpretation of the latter was made by assigning attributes of low, moderate, and high in case of 0–25%, 50–75% and more than 75%, respectively. We used a random-effects or a fixed-effect model based on degree of heterogeneity. The random-effects model results in wider confidence intervals and provides more conservative and robust results, and it was used when I2 > 50%. Subgroup analyses were performed according to strategies to overcome HPR, intervention duration, follow-up duration and method of platelet function testing. Analysis of variance(ANOVA) were further carried out between different subgroups. To determine the impact of baseline risks and study characteristics on the MACE and net clinical benefit, meta-regression analyses were performed with STATA 14 software. To study the relevance of publication bias, funnel plots were constructed plotting the trial results against their precision. Begg’s regression intercept was used to assess asymmetry of these funnel plots. Only composite clinical endpoints were used from the meta-analysis. The Duval and Tweedie’s “Trim and Fill” method was used to impute ‘hypothetical’ missing studies and to calculate adjusted versus observed RRs.

Results

Through searching with aforementioned key words, 3466 reports were retrieved, of which 2239 relevant publications were identified at the abstract and title level. Full text assessment was performed in 32 trials. By applying the inclusion and exclusion criteria, thirteen studies involving 7290 (range: 60–2440) patients were qualified for the analysis (Fig. 1). A summary table of review authors’ judgements for each risk of bias item for each study was shown in Fig. 2. The detailed characteristics of the included studies are shown in Table 1. Studies vary according to publication year, risk profiles of the recruited patients, platelet function assay used, definition of HPR, intensified antiplatelet strategy applied and clinical endpoints. All studies used P2Y12 antagonist for intensified antiplatelet regime: two studies administered repeated loading dose of 600 mg clopidogrel [8, 9]; seven studies increased maintenance dose of clopidogrel [11, 2328]; two studies used repeated loading dose of 600 mg clopidogrel combined with increased maintenance dose of clopidogrel or prasugrel [29, 30]; another two studies used prasugrel for loading and maintenance [13, 14].
Table 1
Study characteristics
Author
Acronym
Date
Blinding
Patient no. (tailored/control)
Platelet function assay
HPR cut-off
Aleil
 
2008
No
31/62
VASP
VASP-PRI > 69%
Bonello
 
2008
No
78/84
VASP
VASP-PRI > 50%
Bonello
 
2009
No
215/214
VASP
VASP-PRI > 50%
Aradi
DOSER
2010
Yes
36/38
LTA, 5 μM ADP
>34%AGGmax
Price
GRAVITAS
2010
No
1109/1105
VerifyNow,P2Y12
>230PRU
Ari
EFFICIENT
2011
Yes
47/47
VerifyNow P2Y12
<40%inhibition
Hazarbasanov
 
2011
No
97/95
VerifyNow P2Y12
>208PRU
Tousek
 
2011
No
30/30
VerifyNow P2Y12
>240PRU
Trenk
TRIGGER-PCI
2011
Yes
212/211
VerifyNow P2Y12
>208PRU
Wang
 
2011
No
150/156
VASP
VASP-PRI > 50%
Collet
ARCTIC
2012
No
1213/1227
VerifyNow,P2Y12
>235PRU
Samardzic
 
2014
No
43/44
MEA
>46 U
Cayla
ANTARCTIC
2016
No
435/442
VerifyNow,P2Y12
>208PRU
Author
Clinical setting
Modified treatment
Intervention duration
Follow-up
Aleil
Scheduled for elective coronary stenting
150 mg MD clopidogrel
2 weeks
1 month
Bonello
Stable angina:52% NSTEMI:48% STEMI: 0%
Repeated 600 mg clopidogrel LD
One week
30 days
Bonello
Stable angina:48% NSTEMI:52% STEMI: 0%
Repeated 600 mg clopidogrel LD
One week
30 days
Aradi
Stable angina:100%
600 mg LD +150 mg MD clopidogrel
1 month
12 months
Price
Stable angina:60% NSTEMI:10.1% STEMI: 0.4%
600 mg LD +150 mg MD clopidogrel
6 months
6 months
Ari
Stable angina:100%
150 mg MD clopidogrel
1 month
6 months
Hazarbasanov
Stable angina:43% NSTEMI:33% STEMI: 24%
600 mg LD +150 mg clopidogrel
1 month
6 months
Tousek
Stable angina:23% NSTEMI:34% STEMI: 43%
clopidogrel starting at 150 mg/day with further dose increase
1 month
6 months
Trenk
Stable angina:100%
60 mg LD +10 mg MD Prasugrel
6 months
6 months
Wang
Stable angina:80% NSTEMI:20% STEMI: 0%
increase in clopidogrel MD up to 375 mg
11 months
1 year
Collet
Scheduled for elective coronary stenting
Repeated 600 mg clopidogrel LD + 150 mg MD clopidogrel/10 mg MD Prasugrel
12 months
12 months
Samardzic
Stable angina:16% NSTEMI:23%STEMI:60%
up to clopidogrel 600 mg × 2 + (75-300 mg MD)
12 months
12 months
Cayla
Stable angina:18% NSTEMI:48%STEMI:34%
5–10 mg MD Prasugrel
12 months
12 months
Abbreviations ACS acute coronary syndrome, CV cardiovascular, HTPR high on-treatment platelet reactivity, LD loading dose, MD maintenance dose, MI myocardial infarction, STEMI ST-segment elevation myocardial infarction, NSTEMI non-ST segment elevation myocardial infarction, ST stent thrombosis, TVR target vessel revascularization, MACE major adverse cardiovascular events RCT randomized, controlled trial
Based on the pooled results, the intensified therapy was associated with a significant reduction in major adverse cardiovascular events (MACE) (RR: 0.55, 95% CI: 0.36–0.84, p = 0.005; Fig. 3). Moreover, intensified antiplatelet strategy guided by platelet function testing reduced rate of cardiovascular death (RR: 0.60, 95% CI: 0.38–0.96, p = 0.03), definite/probable stent thrombosis (RR: 0.58, 95% CI: 0.36–0.93, p = 0.02) and target vessel revascularization (TVR) (RR: 0.33, 95% CI: 0.14–0.76, p = 0.009) (Figs. 4a-c). On the other hand, there was no difference in incidence of death from any cause (RR: 0.95, 95% CI: 0.65–1.39, p = 0.81) or myocardial infarction (RR: 1.02, 95% CI: 0.91–1.15, p = 0.74) between platelet function-guided intensified antiplatelet strategy with standard maintenance dose of clopidogrel therapy (Fig. 4d-e).
No difference in the rate of major bleeding events (RR: 0.75, 95% CI: 0.54–1.03, p = 0.08) or major or minor bleeding events (RR: 1.04, 95% CI: 0.88–1.23, p = 0.67) was observed between the two therapeutic groups (Fig. 5).
The net clinical benefit, consisting of both thrombotic and bleeding events, was also superior in intensified therapy (RR: 0.67, 95% CI: 0.49–0.93, p = 0.02) (Fig. 6).
Subgroup analyses were performed. According to strategies to overcome HPR (repeated clopidogrel loading, increased clopidogrel maintenance dose or switching to prasugrel), pooled results showed that repeated loading or increased maintenance dose of clopidogrel significantly reduced the incidence of MACE without increasing major bleeding events, favoring a net clinical benefit. However, switching to prasugrel was similar with standard therapy in MACE, major bleeding and net clinical benefit. Pooled results from trials with intervention duration of 1 month or less and follow-up time of 1 month showed that intensified antiplatelet strategy significantly decreased the MACE, cardiovascular death and net clinical events. Results from studies using VASP showed that intensified therapy was associated with less incidence of MACE, cardiovascular death and net clinical events (Table 2). ANOVA analyses were also performed between subgroups according to strategies to overcome HPR, intervention duration, follow-up duration and platelet function testing, showing that differences across subgroups in MACE and net clinical events are significant (Table 2). What’s more, pooled result from studies only included patients with stable coronary artery disease showed that intensified therapy decreased the incidence of MACE (RR: 0.23, 95%CI: 0.09–0.60, p = 0.002 (Additional file 1).
Table 2
Subgroup analysis
 
MACE
Cardiovascular death
Major bleeding
Net clinical events
 
RR(95% CI)
I2 (%)
p
RR(95% CI)
I2 (%)
p
RR(95% CI)
I2 (%)
p
RR(95% CI)
I2 (%)
p
Strategies to overcome HPR
 
0.02
  
0.26
  
0.60
  
<0.001
Repeated LD
0.06(0.01–0.29)
0
<0.001
0.15(0.02–1.18)
0
0.07
1.02(0.21–5.02)
0
0.98
0.14(0.05–0.38)
0
<0.001
Increased MD
0.56(0.39–0.96)
66
0.003
0.41(0.20–0.84)
0
0.01
0.69(0.38–1.25)
0
0.22
0.59(0.44–0.81)
10
0.001
Switch to prasugrel
0.77(0.28–2.15)
49
0.62
   
1.01(0.49–2.11)
5
0.97
1.00(0.81–1.24)
0
1.00
Intervention duration
 
<0.001
  
0.06
  
0.26
  
<0.001
≤1 month
0.16(0.07–0.37)
0
<0.001
0.17(0.04–0.75)
0
0.02
1.51(0.43–5.34)
0
0.52
0.21(0.11–0.42)
0
<0.001
>1 month
0.81(0.58–1.14)
65
0.23
0.75(0.45–1.25)
6
0.27
0.71(0.51–0.99)
0
0.05
0.93(0.75–1.14)
54
0.47
Follow up duration
 
0.03
  
0.11
  
0.91
  
<0.001
1 month
0.09(0.02–0.40)
0
0.001
0.15(0.02–1.18)
0
0.07
1.02(0.21–5.02)
0
0.98
0.15(0.06–0.38)
0
<0.001
6 months
0.48(0.21–1.11)
38
0.09
0.30(0.09–1.00)
0
0.05
0.77(0.44–1.36)
11
0.38
0.72(0.49–1.08)
2
0.11
12 months
0.73(0.46–1.14)
75
0.16
0.84(0.49–1.15)
0
0.53
0.72(0.49–1.08)
0
0.11
0.93(0.72–1.21)
71
0.60
Platelet function device
 
0.05
  
0.27
  
0.72
  
<0.001
VerifyNow
0.94(0.70–1.27)
37
0.69
0.69(0.37–1.32)
39
0.26
0.76(0.54–1.05)
0
0.10
0.98(0.82–1.16)
26
0.79
VASP
0.20(0.05–0.91)
58
0.04
0.38(0.16–0.89)
0
0.03
1.02(0.21–5.02)
0
0.98
0.27(0.12–0.59)
38
0.001
To evaluate the impact of baseline clinical risks and study characteristics on the MACE and net clinical benefit of the individualized therapy, we performed meta-regression for different variables, including percentage of ACS patients, study size, patient age, cut-off value for HPR, follow-up time (≤1 months or >1 months) and intervention duration (1 month, 6 months or 12 months) (Table 3). Our analysis showed that study size and intervention duration were significantly associated MACE, and the above two factors as well as follow-up time were associated with net clinical benefit, suggesting the heterogeneity in clinical efficacy were partially explained by these factors .
Table 3
Meta-regression analyses for MACE and net clinical benefit
 
MACE
Net clinical benefit
 
p
Adj-R2 (%)
I2 (%)
Tau2
p
Adj-R2 (%)
I2 (%)
Tau2
Percentage of ACS
0.028
7.59
54.65
0.3979
0.211
0
54.62
0.4356
Age
0.229
0
70.27
0.456
0.195
8.99
50.75
0.2937
Verifynow cutoff value
0.566
0
22.14
0
0.864
0
20.59
0.1935
Study size
0.005
44.13
46.13
0.2406
0.032
4.91
66.22
0.3069
Follow up
0.077
22.45
60.23
0.3181
0.022
61.72
40.97
0.1219
Intervention duration
0.005
76.06
36.87
0.09818
0.006
86.69
18.98
0.04239
To check for the possibility of a publication bias, we used Begg’s test and found no publication bias in cardiovascular death (p = 0.536), definite/probable ST (p = 0.108), myocardial infarction (p = 0.386), MACE (p = 0.583), major bleeding (p = 0.175) and net clinical benefits (p = 0.350). Furthermore, sensitivity analysis by Trim and Fill method showed that the pooled results of MACE and net clinical benefits were reliable.

Discussion

The results our meta-analysis showed that in patients undergoing PCI with HPR, a strategy of individualized intensification of dual antiplatelet therapy reduces adverse cardiovascular events, including cardiovascular death, stent thrombosis and target vessel revascularization, without increasing hemorrhagic complications.
Dual antiplatelet therapy with aspirin and P2Y12 antagonists has become the standard therapy for preventing adverse cardiovascular events after PCI. However, considerable inter-individual variability exists among patients receiving clopidogrel. Many observational studies have established HPR as the risk factor for ischemic events after PCI, but whether modifying HPR with intensified antiplatelet regime can improve cardiovascular outcome is still controversial. AHA/ACC guidelines of PCI recommend that in patients at high risk of stent thrombosis, platelet aggregation test may be applied, and that if platelet inhibition is inadequate, clopidogrel dose may be increased [31, 32]. Since the prognostic value of bleeding complications is equally important as ischemic events, a personalized approach to tailor the antiplatelet therapy for patients with variable on-treatment platelet reactivity is an attractive strategy. Though small clinical trials have demonstrated that increasing the dose of clopidogrel in patients with HPR can reduce the incidence of major adverse cardiac events, some large randomized trials failed to demonstrate an improvements in clinical outcomes with a tailored anti-platelet therapy based on platelet-function monitoring [11, 13, 29]. The small number of events in low risk patients included in these trials might be accountable for negative results. Moreover, poor responsiveness is likely due to multifactorial reasons, including clinical, cellular and genetic factors, with gene polymorphisms emerging as one of the major determinants of clopidogrel response [3335]. Different mutations may lead to discrepant gene function, therefore resulting in poor to no clopidogrel response. Intensified anti-platelet regime used in these trials might overcome certain types of mutations, but could not achieve sufficient platelet inhibition in patients with specific genotype. What’s more, recent studies demonstrated that the magnitude of the association between HPR on clopidogrel treatment and incidence of MACE is strongly dependent on the level of patients’ cardiovascular risk [36].
Previously published meta-analysis on intensified antiplatelet therapy on the basis of platelet reactivity testing suggested that in patients undergoing PCI who have HPR, more potent antiplatelet regime reduced the rate of thrombotic events without increasing the risk for bleeding events [37, 38]. But these studies synthesized different classes of antiplatelet agents, including peri-procedural use of glycoprotein IIb/IIIa receptor inhibitors (GPIs). Our study focused on dual antiplatelet therapy with aspirin and P2Y12 antagonists only, since we believe with broader application of newer P2Y12 inhibitors, procedural use of GPI would be gradually decreasing. Our results clearly showed that individualized intensification of dual anti-platelet therapy reduced adverse cardiovascular events,which might mainly derive from the decreasing of cardiovascular death, stent thrombosis and target vessel revascularization, leading to net clinical benefit.
From our subgroup analysis, we found strategy of overcoming HPR had a major impact on clinical efficacy. While repeated loading or increased maintenance dose of clopidogrel significantly reduced incidence of MACE and favored net clinical benefit, it is intriguing to find the newer P2Y12 inhibitors prasugrel did not. Though the reason remained unknown, possible explanations are: 1) number of studies that used prasugrel (only TRIGGER-PCI and ANTARCTIC study) is far less than those used higher doses of clopidogrel, potentially biasing the result; 2) TRIGGER-PCI study included patients at low ischemic rate, possibly masking the benefit of prasugrel; 3) ANTARCTIC study only enrolled patients of 75 years or older, its failure to demonstrate the benefit of prasugrel is limited to this sub-population. Whether PFT-based prasugrel dosing could reduce ischemic event in a broader patient population with higher risks needs further investigation. It would also be interesting test another new P2Y12 inhibitor, ticagrelor. Our analysis and meta-regression analysis also showed studies with short intervention duration (≤1 month) and follow-up time (1 month) were more beneficial than those with longer intervention or follow-up duration in the endpoints of MACE, cardiovascular death and net clinical events. It seems reasonable that the PFT-guided anti-platelet therapy is prone to reduce shorter-term cardiovascular events, since platelet function testing are mostly performed peri-procedurally and reflects peri-procedural thrombotic burden. It is also interesting from our analysis that considering studies using only Verifynow, such strategy did not reduce any cardiovascular outcomes, as opposed to VASP. One reason is that studies using Verifynow adopted different thresholds for HPR, ranging from >208 PRU to >240 PRU. Also possible is that VerifyNow-P2Y12 cartridge might be influenced by many factors such as time between process, platelet count, hematocrit and etc. However, whether VASP is indeed better than VerifyNow in guiding individualized DAPT needs further study.
Previous studies reported inconsistent results in the relationship between HPR and bleeding. Sibbing et al. showed that patients with and without HPR had similar incidence of major and minor bleeding [4]. However, ADAPT-DES trial found that HPR was inversely related to bleeding events [39]. Evidence is still lacking in applying PFT to estimate bleeding risk. In our study, we found no difference in bleeding events between two groups, indicating only the safety of PFT-based intensified antiplatelet therapy.
Newly developed P2Y12 inhibitors prasugrel and ticagrelor are more potent and have a faster onset of action than clopidogrel, making them particularly attractive for patients undergoing PCI. In ACS patients exhibiting HPR on clopidogrel after PCI, both ticagrelor and prasugrel provide effective and sufficient platelet inhibition [40]. Studies have demonstrated that in patients with HPR, switching to prasugrel achieved adequate platelet inhibition and reduced thrombotic events [41, 42]. With increasing usage of newer P2Y12 inhibitors for coronary intervention, it may seem less necessary to concern about platelet resistance. However, there are still several issues unsettled. A proportion of patients treated with new P2Y12 inhibitors still display HPR, particularly during acute phase of myocardial infarction, putting forward an issue of how to deal with these non-responders. More importantly, new P2Y12 inhibitors carry an increased bleeding risk, so it would be challenging to tailor these agents with a balance between ischemic events and hemorrhagic complications. Platelet function testing may help sort out patients with benefit/risk ratio favorable for more potent anti-platelet therapy. As indicated in our analysis, the individualized approach based on PFT can improve net clinical benefit and should be considered to guide anti-platelet regime in future practice. Still, an appropriate defining of therapeutic window based on different methods of PFT needs further investigation to optimize intensified anti-platelet therapy.
It is noteworthy that our study included target vessel revascularization in the endpoint. The rationale of incorporating TVR in our analysis was that several studies have demonstrated a significant increase in revascularization rate in patients with HPR [43, 44]. More importantly, though still controversial, the notion that intensified antiplatelet therapy may have an inhibitory effect upon in-stent restenosis has been supported by some studies. For example, the DECLARE study series showed that cilostazol-based triple antiplatelet therapy could reduce angiographic restenosis and target lesion revascularization [45, 46]. Experimental research also indicated that the more potent ticagrelor could effectively inhibit neointima formation and potentially reduce restenosis [47]. Furthermore, the recent TRANSLATE-ACS study showed that switching clopidogrel to prasugrel led a significant decrease in unplanned revascularization rate [44]. In agreement with above findings, our pooled result also revealed association between intensified P2Y12 inhibition and reduction of TVR. However, since current level of evidence is still low, further study is needed to confirm whether more potent anti-platelet regime would decrease in-stent restenosis and incidence of TVR.
Our study has several limitations that should be taken into account. First, since there is no general agreement on standard definition of platelet resistance, studies included in our analysis used different definitions of platelet resistance or non-responsiveness. Defining HPR also varies according to the method of PFT, though there is an adequate correlation between different tests [48]. Since HPR cutoff values reported in many studies are associated with high negative predictive values and low positive predictive values, it may have an impact on the pooled results. Second, while most studies defined MACE as composite of cardiovascular death, myocardial infarction and definite/probable stent thrombosis, three studies included stroke/TIA in MACE as well. However, due to low incidence of stroke/TIA in these studies, the difference in the definition of MACE across studies is unlikely to affect our pooled results. Third, trials included in our study used different strategies to overcome HPR, so the extent of platelet inhibition is not same. Tailored therapy like doubling the dose of clopidogrel may still be insufficient to repress platelet activity. Forth, risk profile of patients included in our study was different. Patients in high risk group tend to have higher cardiovascular events, which may also affect the pooled results. What’s more, a small part of patients with low on-treatment reactivity were mixed in platelet function monitoring group in some studies, such as ARCTIC and ANTARCTIC trials. Such design may partly neutralize the benefit of tailored therapy, and have some affect in the pooled results.

Conclusion

In conclusion, the present meta-analysis from RCTs suggests that in patients undergoing PCI who have HPR based on platelet function testing, intensified dual anti-platelet therapy reduces the incidence of thrombotic events without increasing the risk of major bleeding compared with standard clopidogrel therapy.

Acknowledgments

The authors would like to thank Jessica M. Lee for her assistance in polishing the manuscript. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Availability of data and materials

All data and material are allowed for the publication.

Funding

This work was supported by the National Natural Science Foundation of China (81,400,224, 81,300,203) and the Zhejiang Medical Science & Technology Project (2015KYA071).

Authors’ contributions

YZ and YW are the primary authors who were responsible for study design. YW and WX collected data. CH, HY and WZ analyzed the data and drafted the manuscript. All authors revised and approved the final version for publication.

Competing interests

The authors declare that they have no competing interests.
Ethical approval was not applicable for this systematic review and meta-analysis.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
Literatur
1.
Zurück zum Zitat O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2013;82(1):E1–27.PubMedCrossRef O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2013;82(1):E1–27.PubMedCrossRef
2.
Zurück zum Zitat Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107(23):2908–13.PubMedCrossRef Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107(23):2908–13.PubMedCrossRef
3.
Zurück zum Zitat Kereiakes DJ, Gurbel PA. Peri-procedural platelet function and platelet inhibition in percutaneous coronary intervention. JACC Cardiovasc Interv. 2008;1(2):111–21.PubMedCrossRef Kereiakes DJ, Gurbel PA. Peri-procedural platelet function and platelet inhibition in percutaneous coronary intervention. JACC Cardiovasc Interv. 2008;1(2):111–21.PubMedCrossRef
4.
Zurück zum Zitat Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schomig A, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. 2009;53(10):849–56.PubMedCrossRef Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schomig A, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. 2009;53(10):849–56.PubMedCrossRef
5.
Zurück zum Zitat Siller-Matula JM, Trenk D, Schror K, Gawaz M, Kristensen SD, Storey RF, et al. Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv. 2013;6(11):1111–28.PubMedCrossRef Siller-Matula JM, Trenk D, Schror K, Gawaz M, Kristensen SD, Storey RF, et al. Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv. 2013;6(11):1111–28.PubMedCrossRef
6.
Zurück zum Zitat Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010;56(12):919–33.PubMedCrossRef Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010;56(12):919–33.PubMedCrossRef
7.
Zurück zum Zitat Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306(11):1215–23.PubMedCrossRef Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306(11):1215–23.PubMedCrossRef
8.
Zurück zum Zitat Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51(14):1404–11.PubMedCrossRef Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51(14):1404–11.PubMedCrossRef
9.
Zurück zum Zitat Bonello L, Camoin-Jau L, Armero S, Com O, Arques S, Burignat-Bonello C, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009;103(1):5–10.PubMedCrossRef Bonello L, Camoin-Jau L, Armero S, Com O, Arques S, Burignat-Bonello C, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009;103(1):5–10.PubMedCrossRef
10.
Zurück zum Zitat Mayer K, Schulz S, Bernlochner I, Morath T, Braun S, Hausleiter J, et al. A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost. 2014;112(2):342–51.PubMedCrossRef Mayer K, Schulz S, Bernlochner I, Morath T, Braun S, Hausleiter J, et al. A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost. 2014;112(2):342–51.PubMedCrossRef
11.
Zurück zum Zitat Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305(11):1097–105.PubMedCrossRef Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305(11):1097–105.PubMedCrossRef
12.
Zurück zum Zitat Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367(22):2100–9.PubMedCrossRef Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367(22):2100–9.PubMedCrossRef
13.
Zurück zum Zitat Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol. 2012;59(24):2159–64.PubMedCrossRef Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol. 2012;59(24):2159–64.PubMedCrossRef
14.
Zurück zum Zitat Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet. 2016;388(10055):2015-22. Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet. 2016;388(10055):2015-22.
15.
Zurück zum Zitat Steiner S, Moertl D. Platelet reactivity tests for assessing antiplatelet drug response: what the clinician needs to know. Expert Rev Cardiovasc Ther. 2013;11(8):975–84.PubMedCrossRef Steiner S, Moertl D. Platelet reactivity tests for assessing antiplatelet drug response: what the clinician needs to know. Expert Rev Cardiovasc Ther. 2013;11(8):975–84.PubMedCrossRef
16.
Zurück zum Zitat Gorog DA, Fuster V. Platelet function tests in clinical cardiology: unfulfilled expectations. J Am Coll Cardiol. 2013;61(21):2115–29.PubMedCrossRef Gorog DA, Fuster V. Platelet function tests in clinical cardiology: unfulfilled expectations. J Am Coll Cardiol. 2013;61(21):2115–29.PubMedCrossRef
17.
Zurück zum Zitat Aradi D, Storey RF, Komocsi A, Trenk D, Gulba D, Kiss RG, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014;35(4):209–15.PubMedCrossRef Aradi D, Storey RF, Komocsi A, Trenk D, Gulba D, Kiss RG, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014;35(4):209–15.PubMedCrossRef
18.
Zurück zum Zitat Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial--phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11(1):1–11.PubMedCrossRef Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial--phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11(1):1–11.PubMedCrossRef
19.
Zurück zum Zitat The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673–82.CrossRef The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673–82.CrossRef
20.
Zurück zum Zitat Montalescot G, White HD, Gallo R, Cohen M, Steg PG, Aylward PE, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med. 2006;355(10):1006–17.PubMedCrossRef Montalescot G, White HD, Gallo R, Cohen M, Steg PG, Aylward PE, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med. 2006;355(10):1006–17.PubMedCrossRef
21.
Zurück zum Zitat Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47.PubMedCrossRef Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47.PubMedCrossRef
22.
Zurück zum Zitat Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.PubMedPubMedCentralCrossRef Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.PubMedPubMedCentralCrossRef
23.
Zurück zum Zitat Aleil B, Jacquemin L, De Poli F, Zaehringer M, Collet JP, Montalescot G, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv. 2008;1(6):631–8.PubMedCrossRef Aleil B, Jacquemin L, De Poli F, Zaehringer M, Collet JP, Montalescot G, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv. 2008;1(6):631–8.PubMedCrossRef
24.
Zurück zum Zitat Tousek P, Osmancik P, Paulu P, Kocka V, Widimsky P. Clopidogrel up-titration versus standard dose in patients with high residual platelet reactivity after percutaneous coronary intervention: a single-center pilot randomised study. Int J Cardiol. 2011;150(2):231–2.PubMedCrossRef Tousek P, Osmancik P, Paulu P, Kocka V, Widimsky P. Clopidogrel up-titration versus standard dose in patients with high residual platelet reactivity after percutaneous coronary intervention: a single-center pilot randomised study. Int J Cardiol. 2011;150(2):231–2.PubMedCrossRef
25.
Zurück zum Zitat Wang XD, Zhang DF, Zhuang SW, Lai Y. Modifying clopidogrel maintenance doses according to vasodilator-stimulated phosphoprotein phosphorylation index improves clinical outcome in patients with clopidogrel resistance. Clin Cardiol. 2011;34(5):332–8.PubMedCrossRef Wang XD, Zhang DF, Zhuang SW, Lai Y. Modifying clopidogrel maintenance doses according to vasodilator-stimulated phosphoprotein phosphorylation index improves clinical outcome in patients with clopidogrel resistance. Clin Cardiol. 2011;34(5):332–8.PubMedCrossRef
26.
Zurück zum Zitat Aradi D, Rideg O, Vorobcsuk A, Magyarlaki T, Magyari B, Konyi A, et al. Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity. Eur J Clin Investig. 2012;42(4):384–92.CrossRef Aradi D, Rideg O, Vorobcsuk A, Magyarlaki T, Magyari B, Konyi A, et al. Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity. Eur J Clin Investig. 2012;42(4):384–92.CrossRef
27.
Zurück zum Zitat Ari H, Ozkan H, Karacinar A, Ari S, Koca V, Bozat T. The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (the EFFICIENT trial). Int J Cardiol. 2012;157(3):374–80.PubMedCrossRef Ari H, Ozkan H, Karacinar A, Ari S, Koca V, Bozat T. The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (the EFFICIENT trial). Int J Cardiol. 2012;157(3):374–80.PubMedCrossRef
28.
Zurück zum Zitat Hazarbasanov D, Velchev V, Finkov B, Postadjian A, Kostov E, Rifai N, et al. Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. J Thromb Thrombolysis. 2012;34(1):85–90.PubMedCrossRef Hazarbasanov D, Velchev V, Finkov B, Postadjian A, Kostov E, Rifai N, et al. Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. J Thromb Thrombolysis. 2012;34(1):85–90.PubMedCrossRef
29.
Zurück zum Zitat Collet JP, Cayla G, Cuisset T, Elhadad S, Range G, Vicaut E, et al. Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J. 2011;161(1):5–12.e15. Collet JP, Cayla G, Cuisset T, Elhadad S, Range G, Vicaut E, et al. Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J. 2011;161(1):5–12.e15.
30.
Zurück zum Zitat Samardzic J, Krpan M, Skoric B, Pasalic M, Petricevic M, Milicic D. Serial clopidogrel dose adjustment after platelet function testing improves outcome of acute coronary syndrome patients undergoing percutaneous coronary intervention with high on-treatment platelet reactivity. J Thromb Thrombolysis. 2014;38(4):459–69.PubMedCrossRef Samardzic J, Krpan M, Skoric B, Pasalic M, Petricevic M, Milicic D. Serial clopidogrel dose adjustment after platelet function testing improves outcome of acute coronary syndrome patients undergoing percutaneous coronary intervention with high on-treatment platelet reactivity. J Thromb Thrombolysis. 2014;38(4):459–69.PubMedCrossRef
31.
Zurück zum Zitat Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 2006;113(7):e166–286.PubMedCrossRef Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 2006;113(7):e166–286.PubMedCrossRef
32.
Zurück zum Zitat Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol. 2009;53(13):1101–9.PubMedCrossRef Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol. 2009;53(13):1101–9.PubMedCrossRef
33.
Zurück zum Zitat Campo G, Fileti L, Valgimigli M, Tebaldi M, Cangiano E, Cavazza C, et al. Poor response to clopidogrel: current and future options for its management. J Thromb Thrombolysis. 2010;30(3):319–31.PubMedCrossRef Campo G, Fileti L, Valgimigli M, Tebaldi M, Cangiano E, Cavazza C, et al. Poor response to clopidogrel: current and future options for its management. J Thromb Thrombolysis. 2010;30(3):319–31.PubMedCrossRef
34.
Zurück zum Zitat Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, et al. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22(6):399–407.PubMedCrossRef Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, et al. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22(6):399–407.PubMedCrossRef
35.
Zurück zum Zitat Fileti L, Campo G, Valgimigli M. Latest clinical data on testing for high on-treatment platelet reactivity. Rev Cardiovasc Med. 2011;12(Suppl 1):S14–22.PubMed Fileti L, Campo G, Valgimigli M. Latest clinical data on testing for high on-treatment platelet reactivity. Rev Cardiovasc Med. 2011;12(Suppl 1):S14–22.PubMed
36.
Zurück zum Zitat Reny JL, Fontana P, Hochholzer W, Neumann FJ, Ten Berg J, Janssen PW, et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost. 2016;115(4):844–55.PubMedCrossRef Reny JL, Fontana P, Hochholzer W, Neumann FJ, Ten Berg J, Janssen PW, et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost. 2016;115(4):844–55.PubMedCrossRef
37.
Zurück zum Zitat Aradi D, Komocsi A, Price MJ, Cuisset T, Ari H, Hazarbasanov D, et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol. 2013;167(5):2140–8.PubMedCrossRef Aradi D, Komocsi A, Price MJ, Cuisset T, Ari H, Hazarbasanov D, et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol. 2013;167(5):2140–8.PubMedCrossRef
38.
Zurück zum Zitat Xu L, Hu XW, Zhang SH, Li JM, Zhu H, Xu K, et al. Intensified Antiplatelet Treatment Reduces Major Cardiac Events in Patients with Clopidogrel Low Response: A Meta-analysis of Randomized Controlled Trials. Chin Med J. 2016;(8):129, 984–991. Xu L, Hu XW, Zhang SH, Li JM, Zhu H, Xu K, et al. Intensified Antiplatelet Treatment Reduces Major Cardiac Events in Patients with Clopidogrel Low Response: A Meta-analysis of Randomized Controlled Trials. Chin Med J. 2016;(8):129, 984–991.
39.
Zurück zum Zitat Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382(9892):614–23.PubMedCrossRef Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382(9892):614–23.PubMedCrossRef
40.
Zurück zum Zitat Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, Theodoropoulos KC, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol. 2012;60(3):193–9.PubMedCrossRef Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, Theodoropoulos KC, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol. 2012;60(3):193–9.PubMedCrossRef
41.
Zurück zum Zitat Aradi D, Tornyos A, Pinter T, Vorobcsuk A, Konyi A, Falukozy J, et al. Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;63(11):1061–70.PubMedCrossRef Aradi D, Tornyos A, Pinter T, Vorobcsuk A, Konyi A, Falukozy J, et al. Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;63(11):1061–70.PubMedCrossRef
42.
Zurück zum Zitat Dridi NP, Johansson PI, Clemmensen P, Stissing T, Radu MD, Qayyum A, et al. Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response--the TAILOR (Thrombocytes And IndividuaLization of ORal antiplatelet therapy in percutaneous coronary intervention) randomized trial. Platelets. 2014;25(7):506–12.PubMedCrossRef Dridi NP, Johansson PI, Clemmensen P, Stissing T, Radu MD, Qayyum A, et al. Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response--the TAILOR (Thrombocytes And IndividuaLization of ORal antiplatelet therapy in percutaneous coronary intervention) randomized trial. Platelets. 2014;25(7):506–12.PubMedCrossRef
43.
Zurück zum Zitat Motoda C, Ueda H, Hayashi Y, Toyofuku M, Okimoto T, Otsuka M, et al. Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina. Circ J. 2012;76(3):641–9.PubMedCrossRef Motoda C, Ueda H, Hayashi Y, Toyofuku M, Okimoto T, Otsuka M, et al. Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina. Circ J. 2012;76(3):641–9.PubMedCrossRef
44.
Zurück zum Zitat Bagai A, Peterson ED, McCoy LA, Effron MB, Zettler ME, Stone GW, et al. Association of measured platelet reactivity with changes in P2Y12 receptor inhibitor therapy and outcomes after myocardial infarction: Insights into routine clinical practice from the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study. Am Heart J. 2017;187:19–28.PubMedCrossRef Bagai A, Peterson ED, McCoy LA, Effron MB, Zettler ME, Stone GW, et al. Association of measured platelet reactivity with changes in P2Y12 receptor inhibitor therapy and outcomes after myocardial infarction: Insights into routine clinical practice from the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study. Am Heart J. 2017;187:19–28.PubMedCrossRef
45.
Zurück zum Zitat Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, et al. Drug-eluting 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. 2008;51(12):1181–7.PubMedCrossRef Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, et al. Drug-eluting 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. 2008;51(12):1181–7.PubMedCrossRef
46.
Zurück zum Zitat Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, et al. A randomized, double-blind, multicenter comparison study of triple antiplatelet therapy with dual antiplatelet therapy to reduce restenosis after drug-eluting stent implantation in long coronary lesions: results from the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) trial. J Am Coll Cardiol. 2011;57(11):1264–70.PubMedCrossRef Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, et al. A randomized, double-blind, multicenter comparison study of triple antiplatelet therapy with dual antiplatelet therapy to reduce restenosis after drug-eluting stent implantation in long coronary lesions: results from the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) trial. J Am Coll Cardiol. 2011;57(11):1264–70.PubMedCrossRef
47.
Zurück zum Zitat Patil SB, Jackman LE, Francis SE, Judge HM, Nylander S, Storey RF. Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima. Arterioscler Thromb Vasc Biol. 2010;30(12):2385–91.PubMedCrossRef Patil SB, Jackman LE, Francis SE, Judge HM, Nylander S, Storey RF. Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima. Arterioscler Thromb Vasc Biol. 2010;30(12):2385–91.PubMedCrossRef
48.
Zurück zum Zitat Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754–62.PubMedCrossRef Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754–62.PubMedCrossRef
Metadaten
Titel
Individualized dual antiplatelet therapy based on platelet function testing in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials
verfasst von
Yijiang Zhou
Yanwei Wang
Yutao Wu
Chaoyang Huang
Hui Yan
Weiguo Zhu
Weiwei Xu
Li Zhang
Jianhua Zhu
Publikationsdatum
01.12.2017
Verlag
BioMed Central
Erschienen in
BMC Cardiovascular Disorders / Ausgabe 1/2017
Elektronische ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-017-0582-6

Weitere Artikel der Ausgabe 1/2017

BMC Cardiovascular Disorders 1/2017 Zur Ausgabe

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.