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(Circulation. 2001;104:181.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Platelet Reactivity Characterized Prospectively

A Determinant of Outcome 90 Days After Percutaneous Coronary Intervention

Samer S. Kabbani, MD; Matthew W. Watkins, MD; Taka Ashikaga, PhD; Edward F. Terrien, MD; Peter A. Holoch, BS; Burton E. Sobel, MD; David J. Schneider, MD

From the Department of Medicine, The University of Vermont College of Medicine, Burlington, Vt.

Correspondence to Samer S. Kabbani, MD, Cardiology Unit, Fletcher Allen Health Care, McClure 1, Burlington, VT 05401. E-mail samerk{at}pol.net

	Abstract

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Background—— Platelet activation is pivotal in the pathogenesis of complications after percutaneous coronary interventions (PCI). We previously reported substantial interindividual variability in activation of glycoprotein (GP) IIb/IIIa in response to a low concentration of ADP. We assessed GP IIb/IIIa activation prospectively to determine whether this could differentiate patients at low risk from those at high risk for complications early and late after PCI.

Methods and Results—— A total of 112 patients undergoing PCI were studied. Platelet reactivity was determined with the use of flow cytometry. Patients were classified into high and low platelet reactivity groups on the basis of extent of activation of GP IIb/IIIa in response to 0.2 µmol/L ADP. The median value was used for differentiation. The incidence during 90-day follow-up interval of a composite end point (myocardial infarction, urgent revascularization, or repeat revascularization) was determined in each group. Follow up was completed in all 112 patients. The 2 groups were similar with respect to diverse clinical characteristics. Nevertheless, the incidence of the composite end point occurred in 26.8% of the high and 7.1% in the low platelet reactivity group (P=0.01). The difference in the composite end point was most striking during the 30- to 90-day interval after PCI (16.7% versus 1.9%; P=0.02). Repeat revascularization was more frequent in those with increased platelet reactivity (17.9% versus with 3.6%, P=0.029).

Conclusions—— Prospective assessment of platelet GP IIb/IIIa activation permits stratification of patients into low- and high-risk groups with respect to adverse events after PCI.

Key Words: platelets • angioplasty • complications • restenosis

	Introduction

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Platelet reactivity is pivotal in the pathogenesis of acute coronary syndromes and complications after percutaneous coronary interventions (PCI).¹ Vascular injury, iatrogenic and spontaneous, stimulates platelet adhesion, a process mediated by platelet-membrane glycoproteins (GPs).^2,3 Platelet activation follows and is initiated by mechanical and chemical mediators involving thrombin, thromboxane-A₂, ADP, norepinephrine, and collagen. Activation results in a conformational change in GP IIb/IIIa and release of granular products.⁴ Subsequently, platelet aggregation mediated by the cross-linking of platelets by fibrinogen and, to a lesser extent, von Willebrand factor, which binds to the activated conformer of GP IIb/IIIa.

Increased platelet reactivity has been implicated in the pathogenesis of coronary events, including mortality.⁵ Intravenously administered inhibitors of GP IIb/IIIa decrease incidence of adverse events after PCI and after acute coronary syndromes.^6–9 However, conventional assessment of platelet reactivity has not provided powerful descriptors pertinent to prognosis after PCI.

We and others have shown that flow-cytometric analysis of platelets with the use of epitope-dependent monoclonal antibodies or fluorochrome-labeled ligands provides sensitive and specific assessment of platelet activation.^10–14 We have reported substantial interindividual variability in platelet reactivity, assessed in this fashion, particularly with respect to activation of GP IIb/IIIa in response to a low concentration of ADP (0.2 µmol/L).¹⁴ Accordingly, we undertook the present study to determine whether prospective assessment of platelet reactivity shortly before PCI with the use of flow cytometry could differentiate during a 90-day interval patients at low from those at high risk for adverse events after PCI.

	Methods

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Patients Studied
A total of 112 patients with symptomatic coronary artery disease who required PCI were studied, including those with stable angina, unstable angina, and non–ST elevation or ST-elevation myocardial infarction of 48 hours earlier. Coronary artery bypass surgery, elevation of plasma concentration of creatine kinase (CK) or its MB fraction (CK-MB) at the time of PCI, angina with ST-T wave changes suggestive of ischemia within 8 hours of PCI, and intravenous administration of a GP IIb/IIIa inhibitor before PCI were exclusion criteria. Administration of ADP receptor blocker before cardiac catheterization was not an exclusion criterion. The institutional review board at the University of Vermont approved the protocol. All patients provided written informed consent.

Study Design
After diagnostic angiography and before PCI, all patients were given weight-adjusted heparin. Subsequently, blood was obtained from the coronary guide catheter in the ascending aorta for assay of platelet reactivity as described below. Patients were classified into 1 of 2 groups, the high- or low-reactivity group, on the basis of GP IIb/IIIa activation in response to 0.2 µmol/L ADP. Median response for all patients was used to divide subjects into 2 groups. PCI was performed as clinically mandated. All personnel, including physicians involved in the care of each patient, were blinded to results of platelet assay.

Serial assessments of plasma CK and CK-MB were obtained at baseline, 8 hours, and 18 to 24 hours after coronary intervention. Adverse outcomes were recorded during index hospitalization and during 90 days of follow up. All patients were treated with 325 mg of aspirin daily and 75 mg of clopidogrel for 4 weeks when stents were implanted.

Assessment of Platelet Reactivity
Blood was obtained from the coronary guide catheter that was used for PCI (either Wise Guide produced by Boston Scientific Scimed or Vistabrite Tip produced by Johnson & Johnson Cordis). The first 5 mL of blood was discarded, and the following 1 mL was used to assess platelet reactivity. Blood was anticoagulated with corn trypsin inhibitor (Enzyme Research laboratories; 32 µg/mL, 1:10 vol/vol), a specific inhibitor of factor XIIa that prevents initiation of the contact pathway of coagulation and has no effect on other coagulation factors.¹⁵ Platelet reactivity was determined with respect to activation of GP IIb/IIIa and -granule degranulation (surface expression of P-selectin) as previously described.^13,14 Blood in 5-µL aliquots was placed in microcentrifuge tubes that contained 60 µL of HEPES-Tyrode’s buffer (HEPES 5 mmol/L, NaCl 137 mmol/L, NaHCO₃ 2.7 mmol/L, NaH₂PO₄ 0.36 mmol/L, CaCl₂ 2 mmol/L, and dextrose 5 mmol/L; pH 7.4), fluorochrome-labeled ligands, and platelet agonists (ADP 0, 0.2, and 1.0 µmol/L, and thrombin receptor agonist peptide[TRAP] 25 µmol/L). A peridinin chlorophyll protein–conjugated antibody to GP IIIa (CD61, 0.46 µg/mL, Becton Dickinson) was used as an activation-independent marker of platelets. This antibody does not inhibit binding of fibrinogen to the activated conformer of GP IIb/IIIa.

Fluorescein isothiocyanate (FITC)–conjugated fibrinogen (0.1 mg/mL) was used to assess activation of GP IIb/IIIa. A phycoerythrin-conjugated antibody to P-selectin (CD62 1.15 µg/mL; Becton Dickinson) was used to assess -granule degranulation. Fibrinogen (Enzyme Research) was conjugated with FITC with the use of Celite-FITC (Calbiochem). Labeling of fibrinogen with Celite-FITC does not alter binding of fibrinogen to the activated conformer of GP IIb/IIIa.¹⁶

Reaction mixture was incubated at room temperature for 15 minutes. Subsequently, platelets were fixed and red blood cells lysed with OptiLyse C 100 µL (Immunotech). Assays were performed in duplicate. To assess extent of nonspecific association of protein with platelets, FITC-labeled albumin and phycoerythrin-labeled IgG were used. Association of ligands with platelets was determined with a fluorescence-activated cell sorter (Epics Elite ESP, Coulter). Platelets were identified on the basis of size and association with CD61 antibody. Control ligands (albumin-FITC and IgG-phycoerythrin) were used to detect nonspecific association and permit definition of a threshold for activation dependent binding. Fluorescent intensity greater than threshold was used to identify "positive" platelets with respect to either fibrinogen binding or P-selectin expression.

Aggregation of platelets is prevented by dilution of blood (5 µL of blood plus 60 µL of reaction mixture). Platelet aggregates can be identified with flow cytometry (large particles based on forward and side scatter with associated CD61 antibody). Aggregation was not identified in assays performed on patients enrolled in the present study.

We previously characterized both intra-assay and intraindividual variability.^11,13 Intra-assay coefficient of variation (ie, assay of multiple aliquots from the same individual at the same time) is 9% of mean for capacity to bind fibrinogen in response to 0.2 µmol/L ADP and 3% of mean in response to 1 µmol/L ADP. Intra-assay coefficient of variation is 11% of mean for P-selectin expression in response to 0.2 µmol/L ADP and 6% of mean in response to 1 µmol/L ADP. Intra-individual variability (ie, assay of multiple samples from the same individual at different times) is 9% (SD) for capacity to bind fibrinogen in response to 0.2 µmol/L ADP and 7% (SD) in response to 1 µmol/L ADP. Similarly, intra-individual variability is 6% (SD) for P-selectin expression in response to 0.2 µmol/L ADP and 13% (SD) in response to 1 µmol/L ADP.

End Points
Primary end point was a composite of myocardial infarction, urgent revascularization, or repeat revascularization during 90 days after PCI. Myocardial infarction during index hospitalization was defined as elevation of CK-MB to >3 times upper limit of normal or development of pathological Q waves in 2 contiguous ECG leads. Myocardial infarction after discharge from the hospital was defined on the basis of elevation of CK and CK-MB above upper limit of normal or development of pathologic Q waves in 2 contiguous ECG leads. Urgent revascularization was defined as severe myocardial ischemia that required coronary artery bypass surgery or repeat PCI during index hospitalization. Repeat revascularization was defined as any other coronary revascularization procedure during 90 days of follow up.

Statistical Analysis
Descriptive statistics were implemented for all measures. Comparison between high- and low-reactivity groups were conducted with the use of 2x2 contingency table methods and Fisher’s Exact Test for dichotomous measures, likelihood ratio methods for 2x2 contingency tables, and 2 sample t tests for more continuous measures. Comparison of incidence of clinical outcomes within the 90-day study period between high- and low-reactivity groups was examined with the use of logistic regression methods and adjustment for potential confounding measures. Regression coefficients and 95% confidence intervals for each model measure were obtained to facilitate interpretation. A backward-stepping process was used to examine model parsimony among reactivity grouping and potential confounding measures. Cox regression models were used to examine time-to-event data to complement the logistic regression models. A 5% level was used for statistical significance. All statistical computations were conducted with the use of Systat (version 8.0) software.

	Results

Top Abstract Introduction Methods Results Discussion References

 
We identified 120 patients between October 1999 and March 2000; 8 were excluded (4 because of incomplete assessment of CK or CK-MB and 4 because of technical limitations in results of the platelet assay). Table 1 shows characteristics of the 112 patients in the 2 groups studied. The 2 groups were similar with respect to age, sex, risk factors, and presenting diagnosis. Moreover, both groups were similar with respect to frequency of stents implanted, activated clotting time results, and use of GP IIb/IIIa inhibitors during PCI (after blood was obtained for platelet assay). Patients with low platelet reactivity were more likely to have been treated with clopidogrel before PCI (65% in low-reactivity group versus 35% in high-reactivity group; P=0.002). Prevalence of diabetes was comparable in both groups. However, diabetic patients treated with insulin were more likely to be in the high platelet reactivity group (17% compared with 3.6%, P=0.026).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Patients Studied

We previously determined that fibrinogen associates with platelets that are not activated.¹⁷ This association reflects uptake into -granules.¹⁷ Accordingly, we use surface expression of P-selectin to identify activation of platelets in absence of added agonists. Activation was not apparent in the absence agonist (basal P-selectin expression, 0.5±1.1% of platelets). Similar to previous results,^13,14 7±9% of platelets had associated fibrinogen in the absence of agonists.

Marked interindividual variability in activation of GP IIb/IIIa was seen in response to exposure of the platelet to 0.2 µmol/L ADP. GP IIb/IIIa activation ranged from 0% to 77%, with a median of 24.9% (Figure 1). Patients with platelet GP IIb/IIIa activation 24.9% were classified into the low-reactivity group and those with activation >24.9% were in the high-reactivity group. The 90 days’ follow up was completed in all 112 patients studied. The primary end point of myocardial infarction, urgent revascularization, or repeat revascularization in the 90-day follow-up interval occurred in 26.8% of patients in the high- and 7.1% in the low-reactivity group (OR, 4.8; P=0.01; Figure 2). Each component of the primary end point was more prevalent in the high- versus low-reactivity group. The incidence of repeat revascularization during the 90 days was significantly different between groups (17.9% versus 3.6%; P=0.027).

View larger version (20K): [in this window] [in a new window]   Figure 1. Distribution of patients with respect to activation of GP IIb/IIIa in response to 0.2 µmol/L ADP. Percentage of platelets that bound fibrinogen in response to 0.2 µmol/L ADP was determined by use of flow cytometry in blood obtained before PCI. Median response for entire cohort was 24.9% of platelets. Thus, patients classified as having low platelet reactivity were those in whom 0% to 24.9% of platelets bound fibrinogen, and patients classified in the high reactivity group were those in whom 25% to 77% of platelets bound fibrinogen.

View larger version (15K): [in this window] [in a new window]   Figure 2. Incidence of adverse events for 90 days after PCI. Composite end point (all events) was incidence of myocardial infarction, urgent revascularization, and repeat revascularization. Platelet reactivity was assessed by flow-cytometric determination of binding of fibrinogen to platelets in response to 0.2 µmol/L ADP. Patients were classified as exhibiting high or low platelet reactivity on the basis of median response for entire cohort (*P<0.05).

A multivariate logistic regression model was developed to examine the joint effect of the reactivity grouping, age, clopidogrel treatment, and use of insulin, because univariate results (Table 1) indicated that the high- and low-reactivity groups differed significantly with respect to age, treatment with clopidogrel, and use of insulin. Thus, these parameters could potentially confound comparison of the composite end point in those with either high or low platelet reactivity. Use of multivariate logistic regression models to adjust for covariates that may differ significantly between groups has been described previously.¹⁸ The overall logistic regression model was developed with reactivity group and the 3 potentially confounding variables (Table 2). This regression model improved fit (²; P=0.016) compared with the null model and a McFadden ² (P=0.121). Reactivity grouping remained statistically significant (P=0.035) after simultaneous adjustment for age, clopidogrel treatment, and use of insulin (Table 2). Adjusted odds of observing a negative clinical outcome for the high-reactivity group were 3.78-fold greater than adjusted odds of observing a negative outcome in the low-reactivity group. The adjusted odds ratio was reduced in magnitude compared with the unadjusted odds ratio of 4.80. Accordingly, this reduction provides an indication of the usefulness of the multivariate logistic regression model to adjust for covariates in this case. In addition, logistic regression models that started with the measures identified in Table 2 and were obtained from the backward stepwise process consistently identified reactivity grouping as the most highly related measure associated with negative clinical outcome.

View this table: [in this window] [in a new window]   Table 2. Logistic Regression Predicting Composite End Point

Kaplan-Meier curves of the probability of freedom from composite end point diverged during the initial 24 hours after PCI (Figure 3). In addition, a significant difference in the incidence of events was apparent between 30 and 90 days after PCI, under conditions in which clopidogrel was not given to any patient in either group. During this interval, the incidence of the composite end point was 1.9% in patients with low platelet reactivity and 16.7% in those with high platelet reactivity (P=0.02).

View larger version (14K): [in this window] [in a new window]   Figure 3. Kaplan-Meier curves of probability of freedom from composite end point at 90 days. Composite end point included myocardial infarction, urgent revascularization, and repeat revascularization. Platelet reactivity was assessed by flow-cytometric determination of binding of fibrinogen to platelets in response to 0.2 µmol/L ADP. Patients were classified as exhibiting high or low platelet reactivity on the basis of median response for the entire cohort. Curves diverged during the initial 24 hours and again from 30 to 90 days after PCI. Divergence of the curves during the initial 24 hours reflects a predominantly higher incidence of periprocedural myocardial infarction in those with high platelet reactivity; from 30 to 90 days after PCI, a predominantly higher incidence of repeat revascularization in those with high platelet reactivity. Cox regression models were used to examine time to first end point with respect to the platelet reactivity group, in combination with other confounding measures (age, sex, clopidogrel, and insulin). Platelet reactivity was the only significant measure for all models (P<0.05).

Platelet activation with respect to P-selectin expression was less effective for identification of low- and high-risk patients (Table 3). Activation of GP IIb/IIIa in response to 1 µmol/L ADP or 25 µmol/L TRAP was less sensitive than activation with 0.2 µmol/L ADP for predicting outcome. However, significant correlation was seen between repeat revascularization and reactivity group in response to 1 µmol/L ADP or 25 µmol/L TRAP (Table 4).

View this table: [in this window] [in a new window]   Table 3. Incidence of Composite End Point Through 90 Days in Groups Segregated by Median for P-Selectin Expression

View this table: [in this window] [in a new window]   Table 4. Incidence of End Points Through 90 Days in Groups Segregated by Median Activation of GP IIb/IIIa

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our results indicate that platelet reactivity can be used prospectively to differentiate patients with low versus high risk of adverse events and repeat revascularization after PCI. Assessment of platelet reactivity by flow-cytometric analysis and assay of activation of GP IIb/IIIa in response to a low concentration of ADP (0.2 µmol/L) provided the most robust prognostic information.

Although recent technical advances have improved outcomes after PCI, periprocedural myocardial infarction and the need for repeat revascularization continue to be problematic.^19–21 Characteristics of atherosclerotic lesions and clinical presentation can often predict risk of adverse events.²² Diabetic patients have a substantially increased risk of repeat revascularization.²³ Platelets, specifically GP IIb/IIIa activation, are pivotal in pathogenesis of atherosclerosis and acute coronary syndromes.^1,24 Contribution of platelets to development of adverse outcomes after PCI is evident, as judged from the benefit derived from pretreatment with GP IIb/IIIa inhibitors.

Our results extend those of Tschoepe and colleagues,²⁵ who characterized the association of ischemic events and platelet activation over a 24-hour interval after PCI. The assay used in the present study characterizes platelet reactivity by inducing activation rather than identifying activated platelets in blood. Furthermore, platelet reactivity determined before PCI accurately identified subjects at low and high risk from 30 to 90 days after PCI. Thus, platelet reactivity not only portends cardiac risk during the periprocedural interval but also from 30 to 90 days after PCI.

As expected, patients who had been treated with clopidogrel were more likely to have less reactive platelets. Accordingly, logistic regression models were used to examine the combined effect of clopidogrel and platelet reactivity on the composite end point. Despite greater representation in the low-reactivity group, clopidogrel did not appear to influence the association between clinical outcome and platelet reactivity. This conclusion is consistent with 2 other observations. First, patients were treated with clopidogrel for only 4 weeks after placement of intracoronary stents, but the incidence of the composite end point between 30 and 90 days was 8-fold higher in those with increased platelet reactivity. Second, platelet reactivity in response to TRAP also identified subjects at high risk for subsequent adverse outcome.

Diabetic patients treated with insulin in the present study were more likely to be in the high platelet reactivity group. This subset of patients may represent those who have long-standing diabetes with extensive vascular disease: a group in whom increased platelet reactivity has been described.^26,27 Alternatively, treatment with insulin may potentiate activation of platelets, as suggested by the effect of insulin on thrombin activity.²⁸

Conclusion
Patients undergoing PCI exhibit marked interindividual variability in platelet GP IIb/IIIa activation in response to 0.2 µmol/L ADP. This permits stratification of patients into low- and high-risk groups with respect to adverse events during the first 3 months after PCI. Thus, assessment of platelet reactivity should facilitate selection and implementation of long-term diverse antiplatelet agents.

Received March 16, 2001; revision received April 10, 2001; accepted April 19, 2001.

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