CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Bivalirudin and Clopidogrel With and Without Eptifibatide for Elective Stenting: Effects on Platelet Function, Thrombelastographic Indexes, and Their Relation to Periprocedural InfarctionResults of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) Study
Paul A. Gurbel, MD*,*,
Kevin P. Bliden, BS*,
Jorge F. Saucedo, MD ,
Thomas A. Suarez, MD*,
Joseph DiChiara, BS*,
Mark J. Antonino, BS*,
Elisabeth Mahla, MD*,
Anand Singla, MD*,
William R. Herzog, MD*,
Ashwani K. Bassi, MD*,
Thomas A. Hennebry, MB, BCh, BAO,
Tania B. Gesheff, RN* and
Udaya S. Tantry, PhD*
* Sinai Center for Thrombosis Research, Baltimore, Maryland
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Manuscript received August 11, 2008;
revised manuscript received October 17, 2008,
accepted October 26, 2008.
* Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Shapiro Building, Suite 209, 2401 West Belvedere Avenue, Baltimore, Maryland 21215 (Email: pgurbel{at}lifebridgehealth.org).
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Abstract
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Objectives: The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction.
Background: Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown.
Methods: Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined.
Results: In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-µM adenosine diphosphate–induced, and 15- and 25-µM thrombin receptor activator peptide–induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002).
Conclusions: For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045
Key Words: eptifibatide • clopidogrel • bivalirudin • platelets • myonecrosis • stents
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Abbreviations and Acronyms
| | ADP = adenosine diphosphate | | B = bivalirudin | | C = clopidogrel | | CK-MB = creatinine kinase-myocardial band | | CN = clopidogrel naïve | | E = eptifibatide | | GP = glycoprotein | | MT = clopidogrel maintenance treatment/therapy | | PCI = percutaneous coronary intervention | | PPACK = D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone | | PR = platelet reactivity | | R = time to initial platelet-fibrin clot formation | | TEG = thrombelastography | | TIP-FCS = thrombin-induced platelet-fibrin clot strength | | TRAP = thrombin receptor activator peptide | | UFH = unfractionated heparin |
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Ischemic complications during and after percutaneous coronary interventions (PCIs) are strongly influenced by platelet function (1). High post-PCI platelet reactivity (PR) to adenosine diphosphate (ADP) has been correlated with clinical events including periprocedural myocardial infarction and stent thrombosis (2–4). In a pharmacodynamic study, eptifibatide administered with clopidogrel and heparin at the time of elective stenting produced consistent and superior platelet inhibition that was associated with lower periprocedural myonecrosis and inflammation marker release than was a strategy of clopidogrel and heparin alone (5,6). In addition to high PR to ADP, elevated maximum tensile strength of a thrombin-induced platelet-fibrin clot (TIP-FCS) measured by thrombelastography has also been strongly correlated with the occurrence of a 6-month post-PCI ischemic event (7).
Platelet function measurements were not performed in clinical trials that reported a noninferior anti-ischemic effect of bivalirudin therapy alone compared with heparin plus a glycoprotein (GP) IIb/IIIa inhibitor in patients treated with PCI (8,9). There are few studies reporting conflicting results regarding the potential antiplatelet effects of bivalirudin (10–13). In a recent study of PCI patients pretreated with a 600-mg clopidogrel load, administration of bivalirudin produced significant immediate additional suppression of ADP-induced platelet aggregation compared with that of unfractionated heparin (UFH) (12). In another study, therapy with bivalirudin or UFH in addition to eptifibatide and clopidogrel resulted in the same degree of platelet inhibition. Moreover, no significant differences occurred in the platelet inhibition between the bivalirudin and UFH alone groups (13). Thus, the effect of bivalirudin with and without a GP IIb/IIIa inhibitor on platelet function in PCI patients is unclear. Moreover, the effect of the latter regimens on TIP-FCS and the relation of TIP-FCS to periprocedural myonecrosis are completely unknown.
Therefore, the primary objective of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and TIP-FCS measured by thrombelastography in PCI patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction. Patients on long-term clopidogrel maintenance treatment (MT) and clopidogrel naïve (CN) patients loaded with high-dose clopidogrel immediately after stenting were studied, as both clinical scenarios are commonly encountered in daily practice in the U.S.
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Methods
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Patients.
Two hundred consecutive stable patients undergoing PCI were enrolled in a 2-center, randomized, open-label study between March 2006 and December 2007. The study was approved by each of the local institutional review boards and was registered under http://www.clinicaltrials.gov
NCT00370045
[ClinicalTrials.gov]
). The exclusion criteria were as follows: age <18 years old, a history of bleeding diathesis, acute myocardial infarction within 48 h, elevated cardiac markers (above upper limits of normal for the respective assay), cerebrovascular event within 3 months, chronic vessel occlusion, visible thrombus, illicit drug or alcohol abuse, prothrombin time >1.5 times control, platelet count <100,000/mm3, hematocrit <30%, creatinine >2.0 mg/dl, and anticoagulation therapy or GP IIb/IIIa blocker use before the procedure.
Subjects were stratified according to clopidogrel therapy before PCI and randomized by a computer-generated assignment to eptifibatide plus bivalirudin (n = 98) or bivalirudin alone (n = 102), thus providing 4 treatment groups: 1) 600-mg clopidogrel plus bivalirudin (600 mg C + B); 2) 75-mg clopidogrel plus bivalirudin (75 mg C + B); 3) 600-mg clopidogrel plus bivalirudin plus eptifibatide (600 mg C + B + E); and 4) 75-mg clopidogrel plus bivalirudin plus eptifibatide (75 mg C + B + E). Clopidogrel naïve patients (n = 128) received treatment with 600-mg clopidogrel in the catheterization laboratory immediately after stenting, whereas patients currently on 75-mg MI (n = 72) did not receive a load. All patients on maintenance therapy had received daily clopidogrel for at least 2 weeks before enrollment. All patients were treated with at least 81-mg daily aspirin for at least 7 days before enrollment followed by 325-mg daily aspirin and 75-mg clopidogrel. Eptifibatide was administered using the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy) study protocol as a double bolus (180 µg/kg) followed by an infusion (2 µg/kg/min) for 18 h after the procedure (14). Bivalirudin was administered according to the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2) study protocol as a 0.75-mg/kg bolus followed by a 1.75-mg/kg/h infusion for the duration of the intervention (8).
Blood sampling.
Baseline blood samples were obtained in the catheterization laboratory through the indwelling femoral vessel sheath and transferred to tubes anticoagulated with 75 µM D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK) (BIOMOL, Plymouth Meeting, Pennsylvania) for aggregation and flow cytometry studies. Blood samples for myocardial necrosis marker analyses and for thrombelastography were collected in Vacutainer tubes (Becton Dickinson, Franklin Lakes, New Jersey) containing 1.8-mg/ml dipotassium ethylene diamine tetraacetate and 3.8% trisodium citrate, respectively. Post-PCI blood samples were obtained at 2 h, 6 to 8 h, and 18 h.
Platelet aggregation.
The PPACK tubes were centrifuged at 120 g for 5 min to recover platelet-rich plasma and further centrifuged at 850 g for 10 min to recover platelet-poor plasma. The platelet-rich and platelet-poor plasma were stored at room temperature to be used within 2 h. Briefly, platelets were stimulated with ADP (5 and 20 µM), thrombin receptor activator peptide (TRAP [15 and 25 µM]), collagen (2 µg/ml), and arachidonic acid (2 mM); and aggregation was assessed using a Chronolog Lumi-Aggregometer (Model 490-4D) with the AGGRO/LINK control software (Chronolog, Havertown, Pennsylvania). Aggregation was expressed as the maximum percent change in light transmittance from baseline, using platelet-poor plasma as a reference.
Whole blood flow cytometry.
The ADP-induced surface expression of platelet receptors was determined by whole blood flow cytometry using the 3-color analysis method (Immunocytometry Systems, Cytometry Source Book, Becton Dickinson) with the following monoclonal antibodies: FITC-conjugated PAC-1 (recognizes activated GP IIb/IIIa receptors), R-phycoerythrin (R-PE)-conjugated CD41a (recognizes total GP IIb/IIIa receptors), and CY-Chrome-conjugated CD62P (recognizes p-selectin [BD Biosciences, San Diego, California]), as previously described (6). The p-selectin was expressed as percent positive cells (i.e., the ratio of CD62P [CY-Chrome] vs. CD41a [R-PE] positive cells), and activated GP IIb/IIIa was expressed as mean fluorescence intensity (6).
Thrombelastography (TEG).
Thrombin-Induced Platelet-Fibrin Clot Strength and Time to Initial Platelet-Fibrin Clot Formation
The TEG hemostasis analyzer (Haemoscope Corp., Niles, Illinois) provides quantitative and qualitative measurements of the physical properties of a clot (7,15). The TEG analyzer is a viscoelastic monitor that measures platelet-fibrin clot strength. Briefly, 1,000 µl of citrated blood were transferred to a vial containing kaolin and mixed by inversion. Then, 340 µl of the activated blood was transferred to a reaction cup to which 20 µl of 200-mM calcium chloride was added. The sample was assayed in the TEG analyzer according to the manufacturer's instructions to generate the platelet-fibrin clot. Maximum TIP-FCS was recorded and expressed in millimeters. The time to initial platelet-fibrin clot formation (R), an indicator of rate of thrombin generation, was expressed in minutes (16).
Myonecrosis markers.
Troponin I, creatinine kinase-myocardial band (CK-MB), and myoglobin were determined using the Triage Cardiac Panel with a Triage Meter (Biosite Inc., San Diego, California). The method is based on a fluorescence immunoassay. The upper limit of normal value for troponin I is 1.0 ng/ml; for myoglobin, it is 107 ng/ml; and for CK-MB, it is 4.3 ng/ml. The sensitivity of each assay is 0.05 ng/ml for troponin I, 1.0 ng/ml for CK-MB, and 5 ng/ml for myoglobin (data on file, Biosite Inc. [June, 2008]).
Clinical follow-up and definitions.
Adverse ischemic and bleeding events were determined in-hospital, and at 1 and 6 months after PCI. A physician blinded to the study results adjudicated all end points by reviewing medical record source documents. Ischemic events were defined as death secondary to any cardiovascular cause, myocardial infarction (the occurrence of ischemic symptoms and a troponin I value greater than upper limits of normal and/or CK-MB >3 times the upper limits of normal) (17), definite subacute (<30 days) and late (>30 days) stent thrombosis (18), unplanned target vessel revascularization, unplanned non–target vessel revascularization, and stroke.
Bleeding was quantified according to the TIMI (Thrombolysis In Myocardial Infarction) trial criteria. Minor bleeding was defined as clinically overt bleeding accompanied by a fall in hemoglobin of 3.0 to 5.0 g/dl (or, when hemoglobin was not available, a fall in hematocrit of 9% to 15%). Major bleeding occurred when the hemoglobin decreased by >5 g/dl (or, when hemoglobin was not available, a fall in hematocrit of >15%) (19). Mean platelet reactivity and mean TIP-FCS were calculated as the average of measurements recorded at 2, 6 to 8, and 18 h after PCI.
Sample size and statistical analysis.
A previous study using PPACK as the anticoagulant has shown that the addition of eptifibatide to bivalirudin and clopidogrel therapy produced  80% inhibition of baseline aggregation in response to 5-µM TRAP, whereas bivalirudin and clopidogrel therapy produced 55% inhibition of baseline aggregation (13). We estimated that the eptifibatide plus bivalirudin would produce 25% greater inhibition of baseline aggregation as compared with bivalirudin alone. Using SigmaStat (Systat Software, Inc., San Jose, California) the sample size required to detect 25% greater inhibition with 95% power and with an alpha = 0.05 was 97 patients per group.
Categorical variables were reported as percentages and compared using the Fisher exact test. Continuous variables were reported as mean ± SD and compared using either the unpaired t test or Wilcoxon rank sum test after analyzing the normal distribution. Analysis of platelet aggregation and thrombelastography data at different time points for the treatment groups (600 mg C + B vs. 600 mg C + B + E; 75 mg C + B vs. 75 mg B + E) were performed by 2-way repeated measures analysis of variance to evaluate the effect of group, time, and group-time interactions. If significant, post-hoc testing between baseline and post-treatment time points and between different groups at the same time point was carried out using Bonferroni correction for multiple testing. A p value <0.05 was considered significant (Systat Software).
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Results
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Demographics and procedural characteristics.
Two hundred patients were enrolled and had platelet assays performed. Clopidogrel naïve patients treated with eptifibatide had a higher prevalence of prior coronary artery bypass grafting, more vessels treated, fewer de novo lesions, smaller reference vessel diameter, and less frequent angiotensin-converting enzyme inhibitor use as compared with CN patients not treated with eptifibatide (Table 1). Patients on maintenance clopidogrel therapy treated with eptifibatide were more often male, more often treated with angiotensin-converting enzyme inhibitors and less often received calcium blockers, and less frequently were smokers than were patients on maintenance clopidogrel therapy not treated with eptifibatide. There were no significant differences in hematologic indices and creatinine concentrations between groups (data not shown).
Platelet inhibition.
Overall, platelet inhibition was markedly greater at 2, 6 to 8, and 18 h after PCI in patients treated with bivalirudin and eptifibatide compared with bivalirudin alone, as demonstrated by 15-µM TRAP-induced aggregation (3 ± 15% vs. 53 ± 22%, 7 ± 13% vs. 58 ± 17%, and 7 ± 10% vs. 50 ± 22%, respectively; p < 0.001 for all comparisons) and 25-µM TRAP-induced aggregation (0 ± 8% vs. 55 ± 22%, 6 ± 13% vs. 59 ± 17%, and 5 ± 11% vs. 49 ± 21%, respectively; p < 0.001 for all comparisons). Platelet inhibition was similarly much greater in patients treated with bivalirudin and eptifibatide as assessed by 5- and 20-µM ADP-induced and collagen-induced aggregation (p < 0.001 for comparisons at all times; data not shown).
Platelet reactivity in CN patients.
Figures 1A to 1E show platelet aggregation in the CN group. There was significantly lower overall platelet aggregation in patients treated with eptifibatide versus patients not treated with eptifibatide (p < 0.001), a decrease in platelet aggregation over time (p < 0.001), and a different time course of platelet aggregation between the 2 groups (interaction, p < 0.001). Post-hoc analysis indicated that eptifibatide therapy resulted in markedly lower platelet aggregation assessed by all agonists that was immediate and persistent at all times (p < 0.001 for all agonists). In patients treated with bivalirudin alone, the maximum effect of clopidogrel on platelet reactivity was observed at 6 to 8 h (p  0.01 vs. baseline for all agonists); the effect on TRAP-induced aggregation was modest compared with aggregation stimulated by the other agonists. At 2 h, there was no effect of the clopidogrel load on collagen or TRAP-induced aggregation compared with baseline in patients treated with bivalirudin alone.
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Figure 1 Platelet Reactivity in Response to ADP, TRAP, and Collagen in CN Patients
Platelet reactivity in response to adenosine diphosphate (ADP) (5 and 20 µM) (A and B), thrombin receptor activator peptide (TRAP) (15 and 25 µM) (C and D), and collagen (2 µg/l) (E) at baseline and at 2, 6 to 8, and 18 h after percutaneous coronary intervention in clopidogrel naïve (CN) patients. Group "600 mg C + B" (orange lines) received 600-mg clopidogrel and bivalirudin, and group "600 mg C + B + E" (green lines) received 600-mg clopidogrel, bivalirudin, and eptifibatide. *p < 0.001, +p < 0.01 versus baseline; #p < 0.001 between groups at the same time point (Bonferroni correction).
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Platelet reactivity in patients on maintenance clopidogrel therapy.
Figures 2A to 2E show platelet aggregation in patients on maintenance clopidogrel therapy. There was a significantly lower overall platelet aggregation in patients treated with eptifibatide versus patients not treated with eptifibatide (p < 0.001), a decrease in platelet aggregation over time (p < 0.001), and a different time course of platelet aggregation between the 2 groups (interaction, p < 0.001, except for collagen-induced aggregation). Post-hoc analysis indicated that eptifibatide therapy resulted in an immediate and significantly marked reduction in platelet aggregation stimulated by all agonists that persisted for the duration of the infusion (at all times, p < 0.001 vs. baseline and between groups, except for collagen-induced aggregation).
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Figure 2 Platelet Reactivity in Response to ADP, TRAP, and Collagen in MT Patients
Platelet reactivity in response to ADP (5 and 20 µM) (A and B), TRAP (15 and 25 µM) (C and D), and collagen (2 µg/L) (E) at baseline and at 2, 6 to 8, and 18 h after percutaneous coronary intervention in patients treated with maintenance clopidogrel therapy (MT). Group "75 mg C + B" (orange lines) received 75-mg clopidogrel and bivalirudin, and group "75 mg C + B + E" (green lines) received 75-mg clopidogrel, bivalirudin, and eptifibatide. *p < 0.001 versus baseline; #p < 0.001 between groups at the same time point (Bonferroni correction). Abbreviations as in Figure 1.
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Flow cytometry.
p-selectin and GP IIb/IIIa Expression
Baseline stimulated p-selectin and GP IIb/IIIa expression were lower in clopidogrel pre-treated patients than in CN patients (p < 0.001 for both measurements) (Figs. 3A and 3B). In CN patients and patients on maintenance therapy, p-selectin and GP IIb/IIIa expression were lower at 18 h than at baseline (p < 0.001). At 18 h, GP IIb/IIIa and p-selectin expression did not differ among the 4 groups.
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Figure 3 ADP-Stimulated P-Selectin and GP IIb/IIIa Receptor Expression
(A) Adenosine diphosphate (ADP)-stimulated p-selectin and (B) active glycoprotein (GP) IIb/IIIa expression at baseline (orange bars) and 18 h after percutaneous coronary intervention (green bars).
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TIP-FCS.
In both CN patients and patients on maintenance clopidogrel therapy there was significantly lower overall TIP-FCS in patients treated with eptifibatide versus patients not treated with eptifibatide (p < 0.001), and a significant change in TIP-FCS over time (p = 0.001) (Figs. 4A and 4B).
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Figure 4 TIP-FCS and R in CN and MT Patients
(A and B) Thrombin-induced platelet-fibrin clot strength (TIP-FCS). (C and D) Time to initial platelet-fibrin clot formation (R) measured by thrombelastography. +p < 0.01, ++p < 0.05 versus baseline; #p < 0.001 between groups at the same time point (Bonferroni correction). (A, C) Orange lines = 600-mg C + B; green lines = 600-mg C + B + E. (B, D) Orange lines = 75-mg C + B; green lines = 75-mg C + B + E. B = bivalirudin; C = clopidogrel; E = eptifibatide.
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Time to initial thrombin-induced platelet-fibrin clot formation.
There was a significant change in R over time, with a maximum effect observed at 2 h in patients treated with eptifibatide and patients not treated with eptifibatide in both the CN group and the MT group (p < 0.001). (Figs. 4C and 4D).
Mean 18-h post-PCI platelet aggregation and TIP-FCS.
Patients treated with eptifibatide had lower mean 18-h post-PCI platelet aggregation in response to all agonists (p < 0.001) and lower mean TIP-FCS (p < 0.03) than patients treated with bivalirudin alone (Table 2). Among patients treated with bivalirudin therapy alone, mean 18-h post-PCI platelet aggregation was higher in the CN group (p < 0.02 for all agonists) and there was no difference in mean TIP-FCS between clopidogrel therapy groups.
Mean 18-h post-PCI platelet aggregation (5 and 20 µM ADP, 15 and 25 µM TRAP) was lowest in CN patients treated with eptifibatide (p < 0.02). In patients treated with eptifibatide, mean 18-h post-PCI TIP-FCS was lower in the CN group compared with MT patients (p = 0.09).
Periprocedural myocardial necrosis marker release.
The addition of eptifibatide to bivalirudin in CN patients and MT patients was associated with lower peak myonecrosis marker release (p < 0.05 for all markers in CN patients) (Table 3). Patients treated with eptifibatide had a lower incidence of periprocedural myocardial infarction (Fig. 5). Ejection fraction; procedure duration; total stent length; vessel diameter; number of vessels treated; frequency of de novo, calcified, and bifurcation lesions; and stent types did not differ between patients with and without periprocedural infarction (data not shown). There was a higher prevalence of circumflex intervention in patients with periprocedural infarction (56% vs. 23%, p = 0.006).
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Figure 5 Periprocedural Myocardial Infarctions
Incidence of periprocedural myocardial infarction measured by creatinine kinase-myocardial band (CK-MB), troponin-I, and myoglobin. Orange bars = 75-mg C + B; yellow bars = 600-mg C + B; light green bars = 75-mg C + B + E; dark green bars = 600-mg C + B + E. ULN = upper limit of normal; other abbreviations as in Figure 4.
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Relation of myonecrosis to mean post-PCI aggregation and TIP-FCS.
Figures 6A and 6B demonstrate that patients with periprocedural myocardial infarction had higher mean 5-µM ADP-induced platelet aggregation and TIP-FCS than patients without necrosis marker release. Among the 11 patients with periprocedural infarction diagnosed by CK-MB, 9 had mean 5-µM ADP-induced platelet aggregation >40%, and 10 of 11 had TIP-FCS >67 mm.
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Figure 6 Relation of Necrosis Marker Release to ADP-Induced Aggregation and TIP-FCS
(A) Relation of necrosis marker release to mean 5-µM adenosine diphosphate (ADP)-induced aggregation 18 h after percutaneous coronary intervention (PCI). (B) Relation of necrosis marker release to mean 18-h post-PCI platelet-fibrin clot strength (TIP-FCS). NL = normal limit; other abbreviations as in Figures 4 and 5.
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Clinical outcomes.
There was 1 sudden cardiovascular death (Table 3). One definite stent thrombosis occurred in the bivalirudin-alone group within 30 days that resulted in a myocardial infarction and unplanned target vessel revascularization. Thirteen infarctions were periprocedural. Both patients having unplanned target vessel revascularization at 31 to 180 days also had an initial periprocedural infarction. All major bleeding events within the first 30 days occurred in the eptifibatide-treated group; 2 were vascular access site related and 1 was secondary to a gastric ulcer. The 1 major bleeding event occurring beyond 30 days was an intracranial hemorrhage. All minor bleeding within the first 30 days was access site related.
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Discussion
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The CLEAR PLATELETS-2 study demonstrated that for elective coronary stenting, the addition of eptifibatide to bivalirudin therapy in both CN patients and MT patients: 1) produced an immediate and marked reduction in periprocedural platelet aggregation stimulated by multiple agonists; and 2) reduced overall maximum TIP-FCS measured ex vivo by TEG. The CLEAR PLATELETS-2 study is the first to examine the pharmacodynamic effect of bivalirudin with and without eptifibatide in patients on clopidogrel maintenance therapy. The CLEAR PLATELETS-2 study is also the first demonstration of a link between high levels of platelet aggregation and platelet-fibrin clot strength in bivalirudin-treated patients, and high peak necrosis marker release and the occurrence of periprocedural infarctions. Patients who had periprocedural infarction had 25% greater TIP-FCS compared with patients who had normal cardiac markers.
Thus, the CLEAR PLATELETS-2 study further supports the observations of the CLEAR PLATELETS study linking periprocedural myonecrosis to high platelet aggregation where heparin was used as the anticoagulant (5). Interestingly, mean platelet reactivity in CLEAR PLATELETS-2 was unexpectedly lowest after in-laboratory loading in CN patients treated with eptifibatide. In contrast, in patients treated with bivalirudin therapy alone, mean platelet reactivity was lower in MT patients than in CN patients. These data suggest that eptifibatide therapy with in-laboratory loading is associated with a synergistic antiplatelet effect. Moreover, the synergistic antiplatelet effect was further suggested by lower mean TIP-FCS occurring in CN patients treated with eptifibatide. Finally, these physiological observations translated into a low incidence of periprocedural infarction and a comparatively low average peak level of necrosis marker release. Our results are consistent with the demonstration by Lev et al. (11) of a more pronounced reduction in ex vivo platelet-thrombus formation in PCI patients who were administered eptifibatide plus UFH compared with bivalirudin alone.
Our data again support the concept that selected patients have a poor antiplatelet response to clopidogrel that is associated with an increased risk for periprocedural myocardial infarction. This observation holds true for CN patients and for those on chronic clopidogrel therapy who receive anticoagulation therapy alone in the catheterization laboratory. Because wide response variability has been observed in patients treated with a 600-mg clopidogrel loading dose, with 10% exhibiting nonresponsiveness determined 24 h after loading, the addition of a GP IIb/IIIa inhibitor may decrease the occurrence of periprocedural infarction in these otherwise unrecognized high-risk patients undergoing elective PCI (20). Among patients who experienced periprocedural myocardial infarction measured by CK-MB in the CLEAR PLATELETS-2 study, 85% had mean post-treatment 5-µM ADP-induced aggregation >40%, and 100% had mean TIP-FCS >63 mm. These measurements may serve as cutpoints for GP IIb/IIIa administration in future PCI studies. Accordingly, the results of both the CLEAR PLATELETS and the CLEAR PLATELETS-2 studies may facilitate future investigations in patients undergoing elective stenting that are designed to optimize the use of adjunctive GP IIb/IIIa blockade based an assessment of platelet physiology.
The marked platelet inhibition after eptifibatide treatment in the present study is consistent with the observations of Saucedo et al. (13), the only prior pharmacodynamic investigation of bivalirudin therapy with and without eptifibatide in elective stenting. The Saucedo study differs from the CLEAR PLATELETS-2 study in the use of a 300-mg clopidogrel loading dose administered 15 to 30 min before PCI. In a recent study of patients treated with a 600-mg clopidogrel loading dose at least 2 h before PCI, bivalirudin therapy was associated with 4% reduction in 5-µM ADP-induced platelet aggregation immediately after the procedure (12). In the CLEAR PLATELETS-2 study, we observed a significant decrease (mean absolute change of 6% to 8%) in 5- and 20-µM ADP-induced platelet aggregation at 2 h after PCI in CN patients treated with bivalirudin alone and a clopidogrel loading dose. However, in clopidogrel pre-treated patients in the CLEAR PLATELETS-2 trial, bivalirudin therapy alone was not associated with reduced platelet aggregation between 2 and 18 h after administration, suggesting that the effect observed by Sibbing et al. (12) was transient.
In a small study, Schneider et al. (21) reported decreased platelet reactivity measured by flow cytometry immediately after PCI in patients treated with bivalirudin and a 600-mg clopidogrel load administered immediately after PCI. In the CLEAR PLATELETS-2 study, p-selectin expression fell at 24 h in all groups. The observation of decreased p-selectin in clopidogrel pre-treated patients in the CLEAR PLATELETS-2 trial is consistent with the observations of Schneider et al (21). Although the mechanism for this observation is unclear, these findings suggest that bivalirudin administered at the time of PCI modifies the activation of the platelet by ADP as measured by p-selectin expression.
Study limitations.
Although the current study is the largest pharmacodynamic investigation of the comparative antiplatelet effects of bivalirudin with and without eptifibatide in patients treated with clopidogrel, and is the only study to evaluate the effects on TIP-FCS, the study was not intended to assess clinical outcomes including bleeding. Therefore, definitive statements regarding the relation of treatment to long-term patient outcomes will require larger investigations. In addition, the effect of GP IIb/IIIa therapy on bleeding may counterbalance the benefits of reduced periprocedural infarction (22). Previous large-scale studies demonstrated noninferiority in the occurrence of long-term ischemic end points in patients treated with bivalirudin alone compared with patients treated with GP IIb/IIIa inhibitor plus UFH (8,9).
The translational research in the present study focused on periprocedural myonecrosis and its relation to platelet function and platelet-fibrin clot strength. Our study was not powered to assess the relation of long-term clinical outcomes to treatment strategies.
Currently, it is common practice to treat patients with anticoagulant therapy alone and to administer a loading dose of clopidogrel at the time of, or immediately after, stenting even in high-risk scenarios. In the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, in patients not pretreated with a thienopyridine loading dose, therapy with heparin plus a GP IIb/IIIa blocker was associated with a trend toward fewer 30-day ischemic events (p = 0.08) than was treatment with bivalirudin alone, whereas patients pre-treated with clopidogrel had the same composite ischemic event rate irrespective of GP IIb/IIIa blocker use (9). The CLEAR PLATELETS-2 study supports the role of GP IIb/IIIa blockade in reducing periprocedural infarction in CN patients and in patients receiving a maintenance dose of clopidogrel for at least 2 weeks before PCI who did not get pre-stent loading. However, it remains unknown from the data of the CLEAR PLATELETS-2 study whether the strategies of in-laboratory clopidogrel loading plus eptifibatide plus bivalirudin and clopidogrel loading 6 to 24 h before the procedure plus bivalirudin therapy are associated with similar effects on myonecrosis occurrence.
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Conclusions
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An important relation exists between platelet aggregation, TIP-FCS, and the occurrence of post-PCI myonecrosis in patients treated with bivalirudin. The inhibitory effect of eptifibatide added to bivalirudin therapy on the physical characteristics of the thrombin-induced platelet-fibrin clot is a new observation. Patients with high thrombin-induced platelet-fibrin clot strength and platelet aggregation identified by ex vivo testing are at greatest risk for periprocedural infarction. Future studies of PR and TIP-FCS measurements may facilitate personalized antiplatelet therapy with the appropriate selection of patients for GP IIb/IIIa blockade in elective stenting.
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Footnotes
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Dr. Gurbel has received research grants and honoraria from Schering-Plough, Haemoscope, AstraZeneca, Medtronic, Lilly/Sankyo, Sanofi, Boston Scientific, and Bayer. Dr. Saucedo received a research grant and honorarium from Schering-Plough. This study is supported by a research grant from Integrated Therapeutics Group, Inc., a subsidiary of Schering-Plough Corporation.
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References
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