Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary
Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual
Platelet Reactivity to ADP Detected by a Point-of-Care Assay: A 12-Month
Follow-Up
Rossella Marcucci, Anna Maria Gori, Rita Paniccia, Betti Giusti, Serafina Valente,
Cristina Giglioli, Piergiovanni Buonamici, David Antoniucci, Rosanna Abbate and
Gian Franco Gensini
Circulation 2009;119;237-242; originally published online Dec 31, 2008;
DOI: 10.1161/CIRCULATIONAHA.108.812636
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Coronary Heart Disease
Cardiovascular Death and Nonfatal Myocardial Infarction
in Acute Coronary Syndrome Patients Receiving Coronary
Stenting Are Predicted by Residual Platelet Reactivity to
ADP Detected by a Point-of-Care Assay
A 12-Month Follow-Up
Rossella Marcucci, MD; Anna Maria Gori, BS; Rita Paniccia, BS; Betti Giusti, BS;
Serafina Valente, MD; Cristina Giglioli, MD; Piergiovanni Buonamici, MD; David Antoniucci, MD;
Rosanna Abbate, MD; Gian Franco Gensini, MD
Background—The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to
evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care
assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary
intervention.
Methods and Results—We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to
ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous
coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg
clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points
of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel
revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal
MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis,
the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values
ⱖ240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and
independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors,
renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number
of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95%
CI 1.08 to 6.07, P⫽0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P⫽0.004). No significant association
was found between high RPR and the risk of target-vessel revascularization.
Conclusions—RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to
detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff
value was identified as being 240 P2Y12 reaction units. (Circulation. 2009;119:237-242.)
Key Words: aspirin 䡲 clopidogrel 䡲 platelets 䡲 bedside testing 䡲 acute coronary syndrome
D
ual-antiplatelet treatment with aspirin and clopidogrel in
patients undergoing percutaneous coronary intervention
(PCI) has dramatically reduced the rate of major adverse
cardiac events.1,2 A growing body of evidence demonstrates
that an in vitro high residual platelet reactivity (RPR) in
patients undergoing dual-antiplatelet treatment is associated
with an increased risk of adverse cardiovascular events such
as stent thrombosis and cardiovascular death.3– 8
Clinical Perspective p 242
Clopidogrel nonresponsiveness as assessed by light transmittance aggregometry induced by ADP 10 ␮mol/L is an
independent predictor of drug-eluting stent–implantation
thrombosis.7 Light transmittance aggregometry is considered
to be the standard method for assessment of platelet function,
but logistic problems make its routine use difficult. In recent
Received August 6, 2008; accepted October 23, 2008.
From the Department of Medical and Surgical Critical Care and the Center for the Study at the Molecular and Clinical Level of Chronic, Degenerative
and Neoplastic Diseases to Develop Novel Therapies (R.M., A.M.G., R.P., B.G., R.A., G.F.G.), University of Florence, Florence, Italy; Department of
Heart and Vessels (R.M., A.M.G., R.P., B.G., S.V., C.G., P.B., D.A., R.A., G.F.G.), Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; and
Centro S. Maria agli Ulivi (G.F.G.), Fondazione Don Carlo Gnocchi Onlus IRCCS, Impruneta, Florence, Italy.
Correspondence to Rossella Marcucci, Department of Medical and Surgical Critical Care, University of Florence, University of Florence, Viale
Morgagni 85, 50134 Florence Italy. E-mail rossella.marcucci@unifi.it
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.812636
237
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by on January 26, 2009
238
Circulation
January 20, 2009
years, point-of-care assays of platelet function have become
available, including the VerifyNow system, which provides
values of RPR after ADP stimulus correlated with those
found by ADP light transmittance aggregometry.9 One study
based on 380 patients undergoing PCI and clopidogrel treatment has demonstrated that high ADP RPR, as measured by
VerifyNow, is associated with postdischarge (6-month
follow-up) adverse events after PCI with drug-eluting stents.8
The aim of the present study was to evaluate whether the
VerifyNow assay is able to predict 12-month clinical recurrences in a large sample of patients with acute coronary
syndrome (ACS) treated by PCI.
Methods
Study Population
Patients with ACS who underwent PCI and who had an anticipated
compliance to dual-antiplatelet treatment for 12 months were considered eligible for the study. Informed written consent was obtained
from all patients, and the study was approved by the local ethics
review board.
PCI and Antiplatelet Management
All interventions were performed according to current standard
guidelines, and the type of stent implanted and the use of glycoprotein IIb/IIIa inhibitors were at the discretion of the operator. All
patients received 1 clopidogrel loading dose of 600 mg followed by
a daily dose of 75 mg. All patients received unfractionated heparin
70 IU/kg during the procedure and acetylsalicylic acid 500 mg IV
followed by a daily dose of 100 to 325 mg PO.
RPR Assessment
Venous blood samples anticoagulated with sodium citrate 0.109
mol/L (ratio 9:1) were taken from each patient within 24 hours after
600-mg clopidogrel loading. For patients who received both the
loading dose of clopidogrel and a glycoprotein IIb/IIIa inhibitor in
the catheterization laboratory, blood samples were obtained 6 days
afterward, while the patient was taking the 75-mg maintenance dose
of clopidogrel.
The VerifyNow system (Accumetrics, San Diego, Calif) is a
turbidimetry-based optical detection device that measures plateletinduced aggregation in a system containing fibrinogen-coated beads.
The instrument measures changes in light transmission and thus the
rate of aggregation in whole blood. In the cartridge of the VerifyNow
P2Y12 assay, there is a channel in which inhibition of the ADP
P2Y12 receptor is measured. This channel contains ADP as platelet
agonist and prostaglandin E1 as a suppressor of intracellular free
calcium levels, to reduce the nonspecific contribution of ADP
binding to P2Y1 receptors. Results are expressed as P2Y12 reaction
units (PRU).
The reference interval in a sample of 98 healthy volunteers
obtained in our laboratory is 244 to 382 PRU (5th to 95th percentile
of control distribution, n⫽98). Samples from 5 control subjects and
5 coronary artery disease patients taking dual-antiplatelet therapy
and the VerifyNow assay wet quality control (level 1⫽normal and
level 2⫽abnormal) were assessed 4 times to determine our laboratory coefficient of variation for the assay. The mean coefficients of
variation were 3.5% in control subjects, 3.2% in coronary artery
disease patients, and 2.5% and 3.4% for level 1 and 2 quality
controls, respectively.9
Data Collection and Follow-Up
All data were collected prospectively and entered into a central
database. Clinical follow-up information was obtained by contacting
all patients at 12 months, and source documents of potential events
were obtained.
The end points of the study were as follows: (1) Cardiovascular
death, defined as death in the presence of ACS, significant cardiac
arrhythmia, or refractory congestive heart failure; 2) nonfatal myocardial infarction (MI; a rise in serum troponin I or an increase in
creatine kinase-MB isoenzyme at least twice the upper normal limits
with at least 1 of the following: acute onset of prolonged [ⱖ20
minutes] typical ischemic chest pain; ST-segment elevation of at
least 1 mm in 2 or more contiguous ECG leads, or ST-segment
depression ⱖ0.5 mm in ⱖ2 contiguous leads; or T-wave inversion
⬎1 mm in leads with predominant R waves); and (3) target-vessel
revascularization by repeat PCI or CABG.
Statistical Analysis
Continuous variables are presented as median (range). Categorical
data are reported as frequencies. Differences in continuous variables
were compared by the Student t test or Mann–Whitney U test, as
appropriate. Dichotomous variables were compared by ␹2 test or
Fisher’s exact test, as appropriate.
A receiver operating characteristic curve analysis was used to
determine the ability of the VerifyNow P2Y12 assay to distinguish
between patients with and without postdischarge events after PCI.
The optimal cutoff point was calculated by determining the posttreatment PRU that provided the greatest sum of sensitivity and
specificity. Cumulative survival curves for patients with and without
high RPR (RPR as defined by PRU ⱖ240) were constructed by the
Kaplan–Meier method, and the log-rank test was used to assess
statistical differences between these 2 survival curves. After assessment of the proportional hazard assumption, univariate and multivariate hazard regression models of Cox were used, respectively, to
identify risk factors for clinical end points and to adjust for potential
confounders that were associated with clinical end points on univariate analysis (cardiovascular risk factors, renal failure, left ventricular ejection fraction ⬍40%, multivessel disease, total stent length,
bifurcation lesions, number of lesions treated, type of stent used, and
use of glycoprotein IIb/IIIa inhibitors).
A significance level was defined as P⬍0.05. All analysis was
performed with SPSS 14.0 (SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
From January 2005 to March 2006, 683 patients were
enrolled in the present study. Baseline characteristics including RPR are shown in Table 1. PRU values were normally
distributed. The mean platelet reactivity was 193.6⫾86.9
PRU. Table 2 shows clinical outcomes at 12 months. The
1-year follow-up rate was 100%. There were 51 adverse
events: 24 cardiovascular deaths (3.5%), 27 nonfatal MIs
(3.9%), and 40 target-vessel revascularizations (5.8%).
Receiver operating characteristic curve analysis demonstrated that PRU was able to distinguish between patients
with and without subsequent ischemic events (namely, cardiovascular deaths and nonfatal MI) at 12-month follow-up
(area under the curve 0.66, 95% CI 0.57 to 0.78, P⬍0.001;
Figure 1). Table 3 shows that the addition of RPR to a model
that included classic and procedural risk factors moderately
but significantly improved the area under the curve for the
detection of 12-month follow-up cardiovascular deaths and
nonfatal MIs. A PRU ⱖ240 was identified as the optimal
cutoff to predict cardiovascular death and nonfatal MI at
12-month follow-up, providing a sensitivity of 61% (95% CI
47.0% to 75.8%), a specificity of 70% (95% CI 66.4% to
73.5%), a negative predictive value of 96% (95% CI 94.6% to
98.0%), and a positive predictive value of 12% (95% CI 0.7%
to 1.6%). Patients with RPR PRU above the optimal cutoff
value were significantly older, more likely to be female, more
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Marcucci et al
Table 1.
Platelet Reactivity and Ischemic Events
239
Clinical Characteristics of Patients Investigated
Age, y
Male gender, n (%)
Overall Group (n⫽683)
RPR* (n⫽219)
No RPR* (n⫽464)
P†
69 (29–94)
73 (46–93)
68 (29–94)
⬍0.005
517 (75.6)
141 (64.3)
376 (81.0)
⬍0.005
⬍0.005
Diabetes, n (%)
178 (26.0)
75 (34.2)
103 (22.2)
Smoking, n (%)
210 (30.8)
68 (31.1)
142 (30.6)
NS
Hypertension, n (%)
460 (67.3)
154 (70.3)
306 (65.9)
NS
Dyslipidemia, n (%)
357 (52.3)
124 (56.6)
233 (50.2)
NS
NS
BMI ⬎25 kg/m , n (%)
250 (36.6)
87 (39.7)
163 (35.1)
Family history of CAD, n (%)
132 (19.3)
48 (21.9)
84 (18.1)
NS
LVEF ⬍40%, n (%)
174 (25.5)
67 (30.6)
107 (23.1)
⬍0.005
Renal failure,* n (%)
69 (10.1)
15 (6.8)
54 (11.6)
NS
2
STEMI, n (%)
191 (28)
63 (28.7)
128 (27.5)
NS
ACE inhibitors, n (%)
444 (65)
142 (64.8)
302 (65.1)
NS
␤-Blockers, n (%)
271 (39.6)
88 (40.2)
183 (39.4)
NS
Statins, n (%)
410 (60)
131 (59.9)
279 (60.1)
NS
Pump inhibitors, n (%)
635 (92.9)
201 (91.7)
434 (93.5)
NS
Glycoprotein IIb/IIIa, n (%)
205 (30)
72 (32.9)
133 (28.6)
NS
No. of lesions treated
1314
437
877
䡠䡠䡠
No. of vessels treated
1154
391
763
䡠䡠䡠
NS
Drug-eluting stent, n (%)
121 (17.7)
52 (23.7)
69 (14.8)
Bifurcation lesion, n (%)
248 (36.3)
83 (37.9)
165 (35.5)
NS
37⫾26
39⫾31
37⫾29
NS
Total stent length, mm
BMI indicates body mass index; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; and STEMI, ST-elevation MI.
*RPR as defined by PRU above the optimal cutoff point by receiver operating characteristic curve analysis (PRU ⱖ240); renal
insufficiency was defined by creatinine levels ⬎2.0 mg/dL.
†RPR vs no RPR.
likely to be diabetic, and more likely to have reduced left
ventricular ejection fraction than patients without RPR (Table 1).
The event-free survival curves for cardiovascular death and
nonfatal MI according to the presence of RPR are shown in
Figures 2 and 3. On univariate Cox regression analysis, RPR
measured by VerifyNow (cutoff ⱖ240 PRU) was associated
with a significantly higher risk of both cardiovascular death
(hazard ratio [HR] 2.38, 95% CI 1.15 to 5.20, P⫽0.031) and
nonfatal MI (HR 2.73, 95% CI 1.54 to 5.01, P⫽0.006),
whereas no significant association was detected with targetvessel revascularization (HR 1.48, 95% CI 0.78 to 2.78,
P⫽0.225). These results were confirmed after adjustment for
cardiovascular risk factors, renal failure, reduced ejection
fraction, multivessel disease, total stent length, bifurcation
lesions, number of lesions treated, type of stent used, and use
of glycoprotein IIb/IIIa inhibitors (cardiovascular death: HR
2.55, 95% CI 1.08 to 6.07, P⫽0.034; nonfatal MI: HR 3.36,
95% CI 1.49 to 7.58, P⫽0.004).
Table 2.
The HR for cardiovascular death and nonfatal MI was also
analyzed with respect to PRU quartiles (Figure 4). The
highest quartile, which corresponded to PRU values ⱖ258,
was associated with a significantly increased risk for ischemic recurrences (HR 3.6, 95% CI 1.5 to 9.09, P for trend
0.005).
We also tested the association between RPR and 12-month
follow-up cardiovascular events using the cutoff previously
calculated in the study by Price et al8 (PRU values ⱖ235).
Two hundred thirty-one patients (33.8%) had PRU values
ⱖ235; on univariate Cox regression analysis, PRU ⱖ235 was
associated with an increased risk of both cardiovascular death
(HR 2.37, 95% CI 1.06 to 5.30, P⫽0.035) and nonfatal MI
(HR 2.94, 95% CI 1.37 to 6.34, P⫽0.006). These results were
confirmed after adjustment for classic and procedural cardiovascular risk factors (HR 2.41, 95% CI 1.01 to 5.72, P⫽0.046
and HR 3.12, 95% CI 1.38 to 7.02, P⫽0.006, respectively, for
cardiovascular death and nonfatal MI).
Clinical Outcome at 12-Month Follow-Up
Overall Group (n⫽683)
RPR* (n⫽219)
No RPR (n⫽464)
HR (95% CI)
P
Cardiovascular death and nonfatal MI, n (%)
44 (6.4%)
27 (12.3)
17 (3.6)
2.52 (1.30–5.13)
0.011
Cardiovascular death, n (%)
24 (3.5)
13 (5.9)
11 (2.4)
2.38 (1.15–5.20)
0.031
Nonfatal MI, n (%)
27 (3.9)
16 (7.3)
11 (2.4)
2.73 (1.54–5.01)
0.006
Target-lesion revascularization, n (%)
40 (5.8)
16 (7.3)
24 (5.2)
1.48 (0.78–2.78)
0.225
*RPR as defined by PRU ⱖ240.
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240
Circulation
January 20, 2009
1.0
No RPR (PRU <240)
CV death-free Survival
1.00
SENSITIVITY
0.8
0.5
RPR (PRU ≥240)
0.98
0.96
0.94
0.3
log-rank test p=0.02
0.92
0
0.0
0.3
0.5
0.8
4
6
8
10
12
Time (months)
1.0
Figure 2. Survival free from cardiovascular (CV) death in
patients with and without PRU ⱖ240.
1-SPECIFICITY
Figure 1. Receiver-operating characteristic curve for the VerifyNow P2Y12 assay.
Discussion
In this prospective study of a large number of patients
undergoing dual-antiplatelet therapy, we found that RPR to
ADP measured by a point-of-care assay was an independent
predictor of cardiovascular death and nonfatal MI at 12month follow-up in patients with ACS who underwent PCI.
The cutoff value for the identification of patients at higher
risk for ischemic events was 240 PRU. This value is consistent with that revealed by the study of Price et al, based on
380 patients,8 and by the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during
Angioplasty-Platelet Reactivity Predicts Outcome) study,10
published during the revision of this report and based on 160
patients. The high negative predictive value (96%) suggests
that patients with PRU values ⬍240 can be labeled as being
at low risk of recurrences, whereas because of the low
positive predictive value (12%), PRU values ⱖ240 include
patients who will not experience an ischemic event.
In the present study, as well as in the study by Price et al,8
the predictive accuracy of the VerifyNow assay in the
identification of high-risk patients was moderate (69%).
Table 3. Area Under the Receiver Operating Characteristic
Curve of Different Regression Models for the Detection of
Cardiovascular Death and Nonfatal MI at 12-Month Follow-Up
AUC (95% CI)
Model 1: Classic cardiovascular risk factors*
0.67 (0.58–0.77)
Model 2: Model 1⫹procedural risk factors†
0.71 (0.62–0.80)
Model 3: Model 2⫹residual platelet reactivity
0.79 (0.72–0.86)
AUC indicates area under the curve.
P⫽0.004, model 3 vs model 1; P⫽0.021, model 3 vs model 2.
*Age, sex, hypertension, diabetes, dyslipidemia, smoking habit, and renal
failure.
†Type of stent, bifurcation lesion, total length of stent, No. of vessels treated,
No. of stents implanted, use of glycoprotein IIb/IIIa inhibitors.
The addition of RPR according to VerifyNow P2Y12 to the
classic and procedural cardiovascular risk factors moderately
but significantly enhanced the predictive ability to define the
risk of recurrences. In a recent study,11 a higher (95%)
predictive accuracy of a platelet aggregation test for ischemic
events was obtained when platelet function was assessed by
arachidonic acid and collagen in addition to ADP stimulation,
which emphasizes that a single pathway assessment does not
encompass the complexity of the platelet role in thrombotic
events. Currently, a number of assays for platelet reactivity
by different methods and agonists are under laboratory and
clinical evaluation.12,13 Among these, a flow-cytometric
vasodilator-stimulated phosphoprotein phosphorylation assay
was able to detect a reduced response to clopidogrel14,15 and
to successfully drive the antiplatelet therapy in 162 patients
undergoing PCI.16
We are aware that platelet reactivity at the time of ACS
may be influenced by a number of clinical and laboratory
No RPR (PRU <240)
1.00
Non-fatal MI-free Survival
0.0
2
RPR (PRU ≥240)
0.98
0.96
0.94
log-rank test p=0.01
0.92
0
2
4
6
8
10
12
Time (months)
Figure 3. Survival free from nonfatal MI in patients with and
without PRU ⱖ240.
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Marcucci et al
3.
4.
5.
6.
7.
Figure 4. HRs for cardiovascular (CV) death and nonfatal MI by
quartiles of PRU values. Q indicates quartile.
parameters, including the high level of the inflammatory
state17–19 and the increased platelet turnover.20 –23 Consequently, a percentage of patients with RPR in the acute phase
of disease might subsequently return to an adequate platelet
inhibition level after a standard dose of clopidogrel. Therefore, the present results strengthen the evidence that an
impaired and reduced inhibition of platelet function by
clopidogrel in the acute phase of the disease is associated
with subsequent worse clinical follow-up, which underscores
the importance of optimal platelet inhibition in the acute
phase of the disease. This paradigm mirrors the clinical
relevance of the optimization of anticoagulation therapy in
the acute phase of deep venous thrombosis to the risk of
clinical recurrence, ie, the better the anticoagulation therapy
in the acute phase, the lower the risk of clinical recurrence.
However, the availability of a simple test for the assessment
of this biological entity (persistent in vitro platelet hyperreactivity with therapy) in the panel of clinical, laboratory, and
procedural risk factors may allow better risk stratification and
identification of patients in whom an “aggressive” blood is
likely to play a key role in making the patient a “vulnerable”
patient.
In conclusion, the results of the present study indicate that
platelet hyperreactivity, measured by the point-of-care assay
VerifyNow P2Y12, is able to identify ACS patients at higher
risk of 12-month adverse clinical events and that the cutoff
value of 240 PRU can be used for clinical and intervention
trials.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Sources of Funding
This study was supported in part by a grant to the FiorGen
Foundation by Ente Cassa di Risparmio Florence, Italy.
Disclosures
17.
None.
18.
References
1. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study
of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin
after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation. 2000;102:624 – 629.
2. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK,
Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA.
Effects of pretreatment with clopidogrel and aspirin followed by
19.
Platelet Reactivity and Ischemic Events
241
long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533.
Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin
“resistance” and risk of cardiovascular morbidity: systematic review and
meta-analysis. BMJ. 2008;336:195–198.
Sofi F, Marcucci R, Gori AM, Abbate R, Gensini GF. Residual platelet
reactivity on aspirin therapy and recurrent cardiovascular events: a metaanalysis. Int J Cardiol. 2008;128:166 –171.
Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV.
Association of laboratory-defined aspirin resistance with a higher risk of
recurrent cardiovascular events: a systematic review and meta-analysis.
Arch Intern Med. 2007;167:1593–1599.
Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW,
Huisman MV. Clopidogrel nonresponsiveness in patients undergoing
percutaneous coronary intervention with stenting: a systematic review
and meta-analysis. Am Heart J. 2007;154:221–231.
Buonamici PG, Marcucci R, Migliorini A, Gensini GF, Santini A,
Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of
platelet reactivity after clopidogrel administration on drug-eluting stent
thrombosis. J Am Coll Cardiol. 2007;24:2312–2317.
Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP,
Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance
of post-clopidogrel platelet reactivity assessed by a point-of-care assay on
thrombotic events after drug-eluting stent implantation. Eur Heart J.
2008;29:992–1000.
Paniccia R, Antonucci E, Gori AM, Marcucci R, Giglioli C, Antoniucci
D, Gensini GF, Abbate R, Prisco D. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary
artery disease patients. J Thromb Haemost. 2007;5:1839 –1847.
Patti G, Nusca A, Mangiacapra F, Gatto L, D’Ambrosio A, Di Sciascio G.
Point-of-care measurement of clopidogrel responsiveness predicts clinical
outcome in patients undergoing percutaneous coronary intervention. J Am
Coll Cardiol. 2008;52:1128 –1133.
Gori AM, Marcucci R, Migliorini A, Valenti R, Moschi G, Paniccia R,
Buonamici P, Gensini GF, Vergara R, Abbate R, Antoniucci D. Incidence
and clinical Impact of dual nonresponsiveness to aspirin and clopidogrel
in patients with drug eluting stents. J Am Coll Cardiol. 2008;52:734 –739.
Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet
function monitoring in patients with coronary artery disease. J Am Coll
Cardiol. 2007;50:1822–1834.
Sibbing D, Braun S, Jawansky S, Vogt W, Mehilli J, Schömig A, Kastrati
A, von Beckerath N. Assessment of ADP-induced platelet aggregation
with light transmission aggregometry and multiple electrode platelet
aggregometry before and after clopidogrel treatment. Thromb Haemost.
2008;99:121–126.
Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow
cytometric analysis of intraplatelet VASP phosphorylation for the
detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost. 2005;3:85–92.
Frere C, Cuisset T, Quilici J, Camoin L, Carvajal J, Morange PE, Lambert
M, Juhan-Vague I, Bonnet JL, Alessi MC. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for
clinical outcomes in non-ST elevation acute coronary syndrome. Thromb
Haemost. 2007;98:838 – 843.
Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg
O, Simeoni MC, Barragan P, Dignat-George F, Paganelli F. 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;51:1404 –1411.
Fuchs I, Frossard M, Spiel A, Riedmüller E, Laggner AN, Jilma B.
Platelet function in patients with acute coronary syndrome (ACS) predicts
recurrent ACS. J Thromb Haemost. 2006;4:2547–2552.
Marcucci R, Gori AM, Paniccia R, Giglioli C, Buonamici P, Antoniucci
D, Gensini GF, Abbate R. Residual platelet reactivity is associated with
clinical and laboratory characteristics in patients with ischemic heart
disease undergoing PCI on dual antiplatelet therapy. Atherosclerosis.
2007;195:217–223.
Gori AM, Cesari F, Marcucci R, Giusti B, Paniccia R, Antonucci E,
Gensini GF, Abbate R. The balance between pro- and anti-inflammatory
cytokines is associated with platelet aggregability in acute coronary
syndrome patients. Atherosclerosis. April 11, 2008. doi:10.1016/j.
atherosclerosis.2008.04.001.
Downloaded from circ.ahajournals.org by on January 26, 2009
242
Circulation
January 20, 2009
20. Jakubowski JA, Thompson CB, Vaillancourt R, Valeri CR, Deykin D.
Arachidonic acid metabolism by platelets of differing size. Br J
Haematol. 1983;53:503–511.
21. Martin JF, Trowbridge EA, Salmon GL, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet
thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res. 1983;32:443– 460.
22. Tschoepe D, Roesen P, Kauffmann L, Schauseil S, Kehrel B, Ostermann
H, Gries FA. Evidence for abnormal platelet glycoprotein expression in
diabetes mellitus. Eur J Clin Invest. 1990;20:166 –170.
23. Cesari F, Marcucci R, Caporale R, Paniccia R, Romano E, Gensini GF,
Abbate R, Gori AM. Relationship between high platelet turnover and
platelet function in high-risk patients with coronary artery disease on dual
antiplatelet therapy. Thromb Haemost. 2008;99:930 –935.
CLINICAL PERSPECTIVE
A growing body of evidence shows that an in vitro residual platelet reactivity (RPR) in patients undergoing
dual-antiplatelet (aspirin plus clopidogrel) treatment is associated with an increased risk of adverse cardiovascular events
in high-risk vascular patients. Light transmittance aggregometry is considered the standard method for assessment of
platelet function, but logistic problems make its routine use difficult. In recent years, point-of-care assays of platelet
function have become available, including the VerifyNow P2Y12 system, which provides values of RPR after ADP
stimulus correlated with those found by light transmittance aggregometry induced by ADP. In 683 patients with acute
coronary syndrome treated by percutaneous coronary intervention, we sought to verify whether the VerifyNow P2Y12
assay is able to predict clinical recurrences, and we found that RPR to ADP measured by a point-of-care assay is an
independent predictor of cardiovascular death and nonfatal myocardial infarction at 12-month follow-up. The availability
of a simple test for assessment of this biological entity (persistent in vitro platelet hyperreactivity with therapy) in the panel
of clinical, laboratory, and procedural risk factors may allow for better risk stratification and identification of patients in
whom an aggressive blood is likely to play a key role in making the patient a vulnerable patient.
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