Modifying clopidogrel maintenance doses according to vasodilatorstimulated phosphoprotein phosphorylation index improves clinical outcome in patients with clopidogrel resistance

Address for correspondence:
Yan Lai, MM
Clinical Investigation
Department of CardiologyShanghai East HospitalTongji University School of Medicine Phosphoprotein Phosphorylation IndexImproves Clinical Outcome in PatientsWith Clopidogrel Resistance Xiao-dong Wang, MD; Dai-fu Zhang, MM; Shao-wei Zhuang, MD; Yan Lai, MM Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Background: Despite dual antiplatelet therapy, the rate of major adverse cardiovascular events (MACE) afterpercutaneous coronary intervention (PCI) remains high. Ex vivo tests of clopidogrel resistance can predict MACE after PCI. The purpose of this study is to evaluate the clinical impact of adjusting phosphorylationanalysis in patients with clopidogrel resistance undergoing PCI.
Hypothesis: We hypothesized that VASP-guided clopidogrel maintenance doses, compared to fixed doses,improved clinical outcome.
Methods: This monocentric, prospective, randomized study was performed on 306 patients undergoingPCI. Patients were randomized to a control group (n = 156) and to a vasodilator-stimulated phosphoprotein(VASP)-guided group (n = 150). In the VASP-guided group, patients received adjusted maintenance doses ofclopidogrel to obtain platelet reactivity index (PRI) of <50% during 1 year after PCI. The primary endpoint wasthe rate of MACE. The secondary endpoints were major and minor bleeding.
Results: All patients completed the PCI procedure and 298 patients completed follow-up. The control andVASP-guided groups had similar demographic, clinical, and angiographic characteristics. In the VASP-guided group, PRI was significantly decreased (from 72.1% ± 11.4% to 27.7% ± 8.4%; P = 0.001) in 128 patients(87.1% of all participants). During the 1-year follow-up, 14 MACEs were recorded in the VASP-guided group and 30 MACEs were recorded in the control group (9.3% vs 20.4%, respectively; P = 0.008). There was nodifference in the rate of major and minor bleeding in the VASP-guided group compared with the control group(12.9% vs 16.6%; P = 0.06).
Conclusions: Modifying clopidogrel maintenance doses according to platelet reactivity monitoring decreasesthe rate of MACE after PCI without increasing bleeding in patients with clopidogrel resistance during 1-year Introduction
implemented, recurrent thrombotic events and in-stent During the last decade, angioplasty has become the most thrombosis still occur, which are associated with significant popular method of coronary revascularization. Since the mortality and morbidity.6-9 These clinical findings have mid-1990s, stent implantation has been the dominant put forward concern about antiplatelet-therapy resistance.
procedure to reduce the rate of acute occlusion1 and in- Aspirin resistance is recognized, and several strategies are stent restenosis.2,3 In addition, dual antiplatelet therapy recommended.10 More recently, the concept of biological with aspirin and clopidogrel has greatly decreased the resistance to clopidogrel has caused much attention.
risk of major adverse cardiovascular events (MACE) Interindividual variability in platelet response to clopidogrel after percutaneous coronary intervention (PCI).4,5 Although is known to be large. Poor responders represent between the addition of thienopyridines to aspirin is widely 10% and 40% of patients receiving therapy, depending on thetests and thresholds used.11-13 Several methods have been developed to deal with This project was sponsored by Science and Technology clopidogrel resistance,14 of which the most popular strategy Commission of Shanghai Municipality (No. SK08-6). The is increasing the loading dose (LD) utilized in patients authors have no other funding, financial relationships, or undergoing PCI to 600 mg15-18 and 900 mg.19,20 Although clopidogrel response is dose-dependent, there is a threshold Clin. Cardiol. (in press) 1
Published online in Wiley Online Library ( DOI:10.1002/clc.20884  2011 Wiley Periodicals, Inc.
to its platelet-inhibitory effect when certain doses are heparin was initiated in the intensive care unit before PCI.
administrated.19,20 In order to find a better method to Glycoprotein IIb/IIIa inhibitors were not used.
tackle clopidogrel resistance, Bonello et al21 adjusted theclopidogrel LD according to platelet monitoring using the Clopidogrel Modification
vasodilator-stimulated phosphoprotein (VASP) index in a One month after PCI, clopidogrel administration was multicenter randomized prospective study, and observed adjusted according to VASP index to keep PRI <50%. The that it was safe and significantly improved the clinical timing of VASP monitoring was 3, 6, 9, and 12 months after outcomes after PCI in patients with clopidogrel resistance.
first PRI analysis. Clopidogrel doses were increased in a In another study, Bonello et al22 also demonstrated that stepwise manner: After the first PRI monitoring (1 month tailoring the clopidogrel LD according to platelet reactivity after PCI), 150 mg clopidogrel was administered if PRI was monitoring decreased the rate of early stent thrombosis >50%. At the second PRI monitoring, 3 months later, a dose (ST) after PCI without increasing bleeding. These 2 of 225 mg clopidogrel was given to patients if PRI remained studies prove the significance of VASP-guided antiplatelet at >50%. Another 75 mg of clopidogrel would be added every therapy in clopidogrel-resistant patients. However, the 3 months if PRI >50%. At the end of 1 year, the maximum relationship between a clopidogrel maintenance dose (MD) MD of clopidogrel would be 375 mg. If PRI was <25% at and the rate of MACE after initiation of dual antiplatelet that time point, the clopidogrel dose would be decreased therapy >1 month is still uncertain. In the present study, to 75 mg daily. If PRI fluctuated between 25% and 50%, the we investigate the impact of a tailored clopidogrel MD determined dose would be maintained.
according to platelet reactivity monitoring on the rate ofMACE in patients after primary PCI during a 1-year period.
Blood Samples
Blood samples for PRI analysis were drawn by venipuncture of the antecubital vein. The initial blood drawn was discarded Patients
to avoid measuring platelet activation induced by the needle A monocentric, prospective study was undertaken in the puncture. Blood was collected into a tube containing 3.8% cardiology department of the university hospital. The trisodium citrate. The tube was inverted 3 to 5 times for study protocol was in accordance with the Declaration of gentle mixing and sent immediately to the hemostasis Helsinki and approved by the local ethics committee of our institution. All patients gave written informed consentbefore inclusion. Patients were enrolled in the study 1 month VASP Phosphorylation Analysis
after undergoing PCI for one of 3 indications: refractory The VASP phosphorylation analysis was performed within angina pectoris in addition to optimal medical therapy, silent 1 hour of blood collection by an experienced investigator ischemia on thallium scintigraphy, or non-ST-elevation using a platelet VASP kit (Becton Dickinson, Franklin Lakes, acute coronary syndrome. Other inclusion criteria were NJ) according to the manufacturer's instructions.24 Briefly, patient age >18 years and <80 years, and platelet reactivity blood samples were incubated in vitro with adenosine index (PRI) <50%. The exclusion criteria were a history diphosphate (ADP) and/or prostaglandin E1 (PGE1) before of bleeding diathesis, persistent ST-segment elevation fixation. Each sample was indirectly immunolabeled by
acute coronary syndrome (ACS), elevated levels of cardiac incubation with 16C2 fluorescein isothiocyanate (FITC) markers, New York Heart Association functional class III or followed by staining with a goat antimouse FITC polyclonal IV, contraindications to antiplatelet therapy, platelet count reagent (Becton Dickinson, Franklin Lakes, NJ). Flow <100× 109/L, creatinine clearance <25 mL/minute, use cytometric analysis was performed using a Coulter EPICS of a glycoprotein IIb/IIIa inhibitor, sudden death, and XL cytometer (FACSCalibur, BD, Franklin Lakes, NJ).
concurrent severe illness with expected survival <1 year.
Platelet population was identified on its forward andside scatter distributions, and 3000 platelet events were Angioplasty Procedure
gated and analyzed for mean fluorescence intensity (MFI)using EPICS XL software. The MFI corresponding to Percutaneous coronary intervention was carried out each experimental condition (ADP, ADP + PGE1) was according to international guidelines, using a standard determined to establish a ratio directly correlated with technique, through the radial route.23 A drug-eluting the VASP phosphorylation state. The ratio, [(MFI stent could be used according to American College of Cardiology/American Heart Association (ACC/AHA) ADP + PGE1)/MFIPGE1] × 100, is expressed in this study as a platelet reactivity index (PRI) corresponding to a guidelines. An intravenous bolus of unfractionated heparin ratio of the VASP phosphorylation of activated platelets vs (100 IU/kg) was administered at the beginning of the resting platelets and is expressed as a percentage of platelet procedure. The sheath was removed immediately at reactivity. The intra-assay coefficient of variation was <5% the end of the procedure in all cases. Combination and the interassay coefficient of variation was <8%.
usage of 100 mg aspirin and 300 mg clopidogrel LD wasadministered before PCI. After PCI, the combinationadministration of 100 mg aspirin and clopidogrel was The Early PCI Procedural Outcome
continued and the MD of clopidogrel fluctuated between 75 Stent thrombosis was classified as subacute when it and 375 mg for ≥ 1 year. For patients with non-ST-segment occurred from the end of the PCI procedure up to 30 days elevation ACS, anticoagulation with low-molecular-weight later and was classified as late when it occurred after 2 Clin. Cardiol. (in press)
X. Wang et al: VASP-guided clopidogrel maintenance dosesPublished online in Wiley Online Library (  2011 Wiley Periodicals, Inc.
30 days. Subacute and late ST were defined according to Baseline characteristics are summarized in Table 1.
Demographic data and clinical characteristics were similarin the 2 groups. The prevalence of cardiovascular riskfactors was similar, including diabetes and current smoking Clinical Endpoints
(P = 0.5 and P = 0.6, respectively). The PCI indications Clinical follow-up was initiated 1 month after PCI. Endpoints were balanced among the 3 inclusion criteria and were were recorded by an investigator who was not aware of the similar between the 2 randomized groups. The rates of treatment status and clinical characteristics of patients. The patients undergoing PCI for non-ST-elevation ACS were primary endpoint was the rate of MACE, which included similar (20% vs 20%, P = 0.7). The 2 groups did not differ cardiovascular death, angiographically confirmed ST, in left ventricular ejection fraction (P = 0.6). The PCI recurrent ACS defined by the ACC/AHA guidelines,23 and data was also similar including the number and length recurrent revascularization by either coronary angioplasty of drug-eluting stents per patient (P = 0.4 and P = 0.2, or bypass surgery. Secondary endpoints, recorded to assess safety, were major and minor bleeding. Major bleedingwas defined as intracranial bleeding or clinically overtbleeding associated with a decrease in hemoglobin of Platelet Reactivity Index
50 g/L, according to the Thrombolysis in Myocardial We analyzed post-treatment platelet function using the flow Infarction (TIMI) criteria.26 Minor bleeding was also defined cytometric assessment of VASP phosphorylation at a mean according to TIMI criteria.26 Drug-therapy compliance was time of 1, 3, 6, 9, and 12 months after the patients were randomized to the 2 groups (Table 2). The baseline PRI The treating physician and the investigators who after PCI showed no significant difference between the evaluated the clinical endpoints were blind to the results 2 groups (69.3% ± 18% for the control group vs 72.1% of platelet testing and to group assignment. Prespecified ± 11.4% for the VASP-guided group, P = 0.4). In the clinical and laboratory data during hospitalization periods follow-up at 12 months, PRI in the VASP-guided group had were obtained from hospital charts reviewed by independent decreased significantly from the baseline (27.7% ± 8.4% research personnel who were unaware of the objectives of vs 72.1% ± 11.4%, P = 0.001). The 12-month PRI in the the study. Clinical follow-up was conducted by telephone control group also declined, but did not change significantly contact or office visits. All clinical events were adjudicated (66.4% ± 18.6% vs 69.3% ± 18%, P > 0.05). The intervening by independent physicians unaware of treatment status of PCIs for the 3-month, 6-month, and 9-month follow-ups are the patients and not involved in the study.
also included in Table 2. Compared with the control group,the PRI in the VASP-guided group decreased significantlyat each follow-up period (P = 0.03, P < 0.001, P = 0.04, Statistical Analysis
Statistical analysis was performed using SPSS version 16.0 In the VASP-guided group, the numbers of patients software (SPSS Inc., Chicago, IL). Continuous variables receiving clopidogrel dose modification were 101 (66.9%, are expressed as mean ± SD. Categorical variablesare expressed as frequency and percentage. Comparisonbetween categorical variables was performed using the χ2 test or Fisher exact test when frequencies were <5.
Analysis of variance was used to compare characteristicsof quantitative variables. Kaplan-Meier curves were used to assess MACE-free survival. Differences between the curves were tested with a log-rank statistic.
Patients' Demographic, Biological, and Angiographic
From August 2008 to October 2009, 538 continuous patientsadmitted to the university hospital cardiology center wereprospectively screened for inclusion (Figure 1). In total, 232patients were not included: 20 met the exclusion criteria, and 212 had a PRI <50% after 1 month MD of clopidogrel; therefore, they were considered good responders and werenot included in the study. A total of 306 patients had a PRI>50% and were included and randomized to the controlgroup (n = 156) or the VASP-guided group (n =1 50). Five patients in the control group and 3 patients in the VASP-guided group were lost to follow-up. Ultimately, 151 patientsin the control group and 147 patients in the VASP-guided Figure 1. Study design and flow chart. Abbreviations: VASP, vasodilator-stimulated phosphoprotein.
Clin. Cardiol. (in press) 3
X. Wang et al: VASP-guided clopidogrel maintenance doses Published online in Wiley Online Library ( DOI:10.1002/clc.20884  2011 Wiley Periodicals, Inc.
Abbreviations: ACE, angiotensin-converting enzyme; BMI, body massindex; Ca, calcium; CABG, coronary artery bypass grafting; CAD, coronary artery disease; Cr, creatinine; DM, diabetes mellitus; HT,hypertension; LVEF, left ventricular ejection fraction; MD, maintenance dose; MI, myocardial infarction; NST ACS, non-ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; VASP,vasodilator-stimulated phosphoprotein.
The Early PCI Procedural Outcome
The rate of early ST was not significantly different betweenthe control group and the VASP-guided group (4.7% vs 3.9%, P = 0.3; Table 3). All ST were recorded within 30 days after PCI. There were 2 cases of acute ST (0.9%) and 6 of subacuteST (3.7%) in the control group. In the VASP-guided group, the rate of acute ST was 0.8% and the rate of subacute ST was3.2%. During 1 month after PCI, 7 patients (2.3%) underwent PCI again because of recurrent myocardial infarction, 3 in the control group and 4 in the VASP-guided group.
Primary Endpoints During Follow-Up
In the follow-up at 12 months, 3 patients in the VASP-guided group and 5 patients in the control group were lost to follow-up. The loss rate was 7.5%. During follow-up, 30 (19.2%) MACE in the control group and 14 (9.3%) MACE in the VASP-guided group occurred, resulting in a statistically difference between the 2 groups (P = 0.008).
The distribution of cardiovascular events is summarized in Kaplan-Meier Analysis
Cumulative survival in the 2 groups (Figure 2) was distinguished by the Kaplan-Meier curve. In the first 6 months, survival was significantly different. But after that, the difference stabilized and did not increase. Fewer patientsdied in the VASP-guided group.
Secondary Endpoints and Side Effects of Clopidogrel
There were no major hemorrhagic complications in either group (Table 4). Both the major and minor bleeding events between the 2 groups were not significantly different.
The present study suggests that modifying clopidogrel MDs
3 months), 119 (78.8%, 6 months), 121 (80.1%, 9 months), according to VASP index improves the clinical outcome in and 131 (87.1%, 12 months), respectively. At the end of the clopidogrel-resistant patients undergoing PCI. This strategy study, 20 of 151 patients (13.9%) in the VASP-guided group of clopidogrel MD adjustment is safe and is not associated still had the high PRI profile, at >50%.
4 Clin. Cardiol. (in press)
X. Wang et al: VASP-guided clopidogrel maintenance dosesPublished online in Wiley Online Library (  2011 Wiley Periodicals, Inc.
Table 2. PRI in the 2 Groups During 1-Year Follow-Up Abbreviations: PRI, platelet reactivity index; VASP, vasodilator-stimulated phosphoprotein.
Table 3. Early Definite ST During 1-Month Follow-Up After Primary PCI Abbreviations: DST, definite stent thrombosis; PCI, percutaneouscoronary intervention; ST, stent thrombosis; VASP, vasodilator-stimulated phosphoprotein.
The rates of diabetes mellitus and current smoking are higher in the control group, but the difference is notsignificant. These 2 demographic characteristics do not Figure 2. Kaplan-Meier analysis for 1-year follow-up. Log-rank P < 0.01.
Group 1 refers to the control group; group 2 refers to the VASP-guided In cases of clopidogrel resistance, authors have recom- group; time is given in days. Abbreviations: Cum, cumulative.
mended new antiplatelet agents ticlopidine, prasugrel,27ticagrelor,28 clopidogrel15-20 is also recommended. However, ticlopidine substrate of both cAMP-dependent and cGMP-dependent increases risk of bleeding27-29 or dyspnea.30 In addition, protein kinases. Analysis of the VASP phosphorylation ratio increasing LDs of clopidogrel does not confer more clini- can be used for measuring various signal transduction pro- cal benefit.19,20 In recent years, several studies have been cesses, including dephosphorylation following P2Y12 ADP launched focusing on VASP-guided clopidogrel modification receptor activation and its reversal by P2Y12 antagonists.31,32 in patients on clopidogrel. Vasodilator-stimulated phospho- In vitro tests of VASP phosphorylation analysis accurately protein is an intracellular actin-regulatory protein that is a detect biological clopidogrel resistance that is associatedwith worse outcome after PCI.33-35 Bonello et al21 demon-strated that PRI using VASP monitoring is safe and sig- Table 4. Major and Minor Clinical Endpoints During 1-Year Follow-Up nificantly improves clinical outcome after a 600-mg LD.
Furthermore, a tailored 600-mg clopidogrel LD according to PRI also prevents acute and subacute ST in the samepatients.22 However, these 2 studies were conducted within 1 month after stent implantation. In the present study, we report that the benefit of VASP-guided clopidogrel therapy lasts for 12 months. It confirms that VASP-guided clopido-grel dose modification relieves clopidogrel resistance and In a retrospective study, Barragan et al33 observed a strong correlation between subacute ST and a PRI >50%. The result was later confirmed in a prospective study, and the 50% threshold demonstrated a very highnegative predictive value for MACE after PCI.36 In a recent experimental study, Schumacher et al37 demonstrated thata 50% PRI corresponded to a nearly 90% P2Y blockage. So we used 50% PRI as the cutoff point.
Abbreviations: ACS, acute coronary syndrome; MACE, major adverse Our study shows that the MACE occurred during the first cardiac events; ST, stent thrombosis.
6 months in the follow-up period. In the latter 6 months of Clin. Cardiol. (in press) 5
X. Wang et al: VASP-guided clopidogrel maintenance doses Published online in Wiley Online Library ( DOI:10.1002/clc.20884  2011 Wiley Periodicals, Inc.
follow-up, the difference in the incidence of MACE between Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary the 2 groups remained stable. The results indicate that the stenting response variability, drug resistance, and the effect ofpretreatment platelet reactivity. Circulation. 2003;107:2908-2913.
effect of clopidogrel in preventing thrombosis occurs pri- Angiolillo DJ, Fern`andez-Ortiz A, Bernardo E. Variability in indi- marily within 6 months, which is in accordance with Airoldi's vidual responsiveness to clopidogrel clinical implications, man- findings in a prospective observational cohort study.38 agement, and future perspectives. J Am Coll Cardiol. 2007;49: We observed no increase in bleeding in the VASP-guided group, despite the use of the clopidogrel MD. This may be Angiolillo DJ, Fern`andez-Ortiz A, Bernardo E, et al. High clopi-dogrel loading dose during coronary stenting: effects on drug because platelet monitoring stratifies the dose of clopidogrel response and interindividual variability. Eur Heart J. 2004;25: according to the individual response, preventing high-dose usage in patients with good response.
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