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J Am Coll Cardiol, 2007; 49:657-666, doi:10.1016/j.jacc.2006.10.050
(Published online 25 January 2007). © 2007 by the American College of Cardiology Foundation |
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Sinai Center for Thrombosis Research, Baltimore, Maryland.
Manuscript received July 28, 2006; revised manuscript received September 29, 2006, accepted October 1, 2006.
* Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 West Belvedere Avenue, Baltimore, Maryland 21215. (Email: pgurbel{at}lifebridgehealth.org).
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Abstract |
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Background: Patients exhibiting heightened platelet reactivity to adenosine diphosphate (ADP) might be at increased risk for recurrent ischemic events after coronary stenting.
Methods: A total of 100 consecutive patients receiving chronic antiplatelet therapy consisting of aspirin (325 mg qd) and clopidogrel (75 mg qd) were studied before undergoing nonemergent stenting. Patients were followed for 1 year after coronary stenting for the occurrence of death, myocardial infarction, stent thrombosis, stroke, or ischemia requiring a hospital stay.
Results: All patients were aspirin responsive. Patients with ischemic events (23 of 100, 23%) within 1 year had greater on-treatment prestent ADP-induced platelet aggregation than patients without ischemic events by aggregometry and TEG (p < 0.001 for both measurements). Of patients with an ischemic event, 70% and 87% displayed high on-treatment platelet reactivity at baseline by aggregometry and TEG, respectively. High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p < 0.001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.
Conclusions: Patients receiving chronic clopidogrel therapy undergoing nonemergent percutaneous coronary intervention who exhibit high on-treatment ADP-induced platelet aggregation are at increased risk for postprocedural ischemic events. These findings might have implications for the alteration in clopidogrel maintenance dose and use of glycoprotein IIb/IIIa inhibitors in selected patients.
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A relationship between clopidogrel nonresponsiveness and post-PCI ischemic events in clopidogrel-naïve patients has been recently suggested (5,9–11). Clinical studies indicated that postprocedural heightened platelet reactivity is associated with increased myocardial necrosis and inflammation marker release (3,12). Furthermore, increased post-treatment platelet reactivity has been associated with recurrent ischemic events and stent thrombosis (4,5,11). These studies emphasize the potentially sizeable risks associated with inadequate platelet inhibition from current antiplatelet therapy.
Among patients receiving maintenance dose clopidogrel therapy, a certain percentage display heightened platelet reactivity to ADP (4,6,13). Despite this evidence, there is no established recommendation for clopidogrel loading in patients receiving chronic clopidogrel therapy undergoing PCI. Furthermore, there are no sufficient data correlating heightened platelet reactivity with adverse cardiovascular events in these patients. The goal of the present study was to quantify this relationship. We hypothesized that patients receiving chronic clopidogrel therapy undergoing non-emergent PCI who display high preprocedural platelet reactivity, as measured by standard light transmittance aggregometry (LTA) and thrombelastography (TEG), are at increased risk for post-PCI ischemic events.
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Methods |
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1 month before undergoing non-emergent coronary stenting were enrolled after giving informed consent. A clopidogrel loading dose was not administered. All patients had received at least 81 mg aspirin for 7 days before the procedure. Patients were >18 years old. The exclusion criteria were: a history of bleeding diathesis, acute myocardial infarction within 48 h, elevated cardiac markers (above upper limits normal for the respective assay), cerebrovascular event within 3 months, illicit drug or alcohol abuse, prothrombin time >1.5 times control, platelet count <100,000/mm3, hematocrit <30%, creatinine >4.0 mg/dl, and glycoprotein (GP) IIb/IIIa use before the procedure. On the day of the procedure and daily thereafter, 325 mg aspirin was administered. Eptifibatide was administered at the discretion of the treating physician with the ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) study protocol as a double bolus (180 µg/kg) followed by an infusion (2 µg/kg/min) for 18 to 24 h after procedure. Unfractionated heparin was administered according to the ESPRIT dosing regimen (60 U/kg) as a bolus to all patients in the catheterization laboratory immediately before stenting (14). Clopidogrel was prescribed in all patients for at least 6 months after procedure.
Blood sampling. Baseline blood samples were obtained from patients in a fasting state in the catheterization laboratory through the indwelling femoral vessel sheath. Samples were transferred to separate vacutainer blood collecting tubes (Becton-Dickinson, Franklin Lakes, New Jersey) containing 3.8% trisodium citrate or lithium heparin. After discarding the first 2 to 3 ml of free flowing blood, the vacutainer tubes were filled to capacity and gently inverted 3 to 5 times to ensure complete mixing of the anticoagulant. Baseline samples were obtained before coronary intervention and at 3 h and 18 to 24 h after stenting. In patients treated with eptifibatide, the 18 to 24 h blood draw was performed within 1 h after completion of the eptifibatide infusion.
Platelet aggregation. The blood-citrate tubes were centrifuged at 120 g for 5 min to recover platelet rich plasma (PRP) and further centrifuged at 850 g for 10 min to recover platelet poor plasma (PPP). The PRP and PPP were stored at room temperature to be used within 2 h. Platelet aggregation was assessed as described previously (3). Briefly, platelets were stimulated with 5 µmol/l ADP and 1 mmol/l arachidonic acid (AA). Aggregation was assessed with a Chronolog Lumi-Aggregometer (Model 490-4D) with the Aggrolink software package (Chronolog, Havertown, Pennsylvania). Aggregation was expressed as the maximum percent change in light transmittance from baseline, with PPP as a reference.
Thrombelastograph Hemostasis Analyzer With PlateletMapping. The Food and Drug Administration-approved Thrombelastograph Hemostasis Analyzer With PlateletMapping assay (Haemoscope Corp., Niles, Illinois) relies on the measurement of thrombin-induced clot strength to enable a quantitative analysis of platelet function (15,16). The assay uses heparin as an anticoagulant to eliminate thrombin activity in the sample. Reptilase and factor XIIIa (activator F) are used to generate a cross-linked fibrin clot to isolate the fibrin contribution to clot strength (17). The contribution of P2Y12 receptor or cyclooxygenase pathways to the clot formation can be measured by the addition of the appropriate agonist, ADP or AA.
Blood was analyzed according to the manufacturer’s instructions. One milliliter heparinized blood was transferred to a vial containing kaolin and mixed by inversion. Five hundred microliters of the activated blood were then transferred to a vial containing heparinase and mixed to neutralize heparin. The neutralized blood (360 µl) was immediately added to a heparinase-coated cup and assayed in the TEG analyzer to measure the thrombin-induced clot strength (MAthrombin). Heparinized blood (340 µl) was added to a noncoated cup containing reptilase and activator F to generate a whole blood crosslinked clot in the absence of thrombin generation or platelet stimulation (MAfibrin). A third sample (340 µl) of heparinized blood was added to a nonheparinase-coated cup in the presence of the activator F and ADP (2 µmol) or AA (1 mmol/l) to generate a whole blood-crosslinked clot with platelet activation (MAADP or MAAA). Platelet aggregation in response to ADP or AA is calculated with computerized software on the basis of the formula: %Aggregation = [(MAADP or AA– MAfibrin)/(MAthrombin – MAfibrin)] x 100 (Fig. 1).
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50% ADP-induced platelet aggregation after stimulation with 5-µmol ADP at baseline as measured by LTA or 70% ADP-induced aggregation with 2-µmol ADP at baseline as measured by TEG (17). All patients below these cut points were defined as exhibiting normal on-treatment platelet reactivity (NPR). All tables are representative of 5 µmol/l ADP-induced LTA aggregation values.
Aspirin resistance
Aspirin resistance was defined as >20% platelet aggregation after stimulation by 1-mmol/l AA as measured by LTA or more than 50% platelet aggregation after stimulation by 1-mmol/l AA as measured by TEG (18).
Clinical outcomes
Patients were contacted by telephone at 1, 6, and 12 months to identify the occurrence of adverse events. Patient records including electronic source documents were obtained and reviewed by 2 physicians blinded to the study who adjudicated events. Ischemic events were defined as: death secondary to any cardiovascular cause, stroke, myocardial infarction (in-hospital and after discharge), ischemia requiring a hospital stay, and target vessel revascularization (TVR), nontarget vessel revascularization (NTVR), or medical management. Myocardial infarction was defined as the occurrence of ischemic symptoms and a troponin-I value > upper limits of normal (>1.5 ng/ml). Unstable angina was defined as the occurrence of ischemic symptoms requiring a hospital stay. Bleeding was quantified according to the Thrombolysis In Myocardial Infarction (TIMI) criteria (19). In brief, minor bleeding was defined as clinically overt bleeding accompanied by a fall in hemoglobin of 3.0 to 5.0 g/dl or a fall in hematocrit of 9% to <15%. Major bleeding occurred when the hemoglobin decreased >5 g/dl or the hematocrit decreased 15%.
Statistical analysis. Categorical variables are expressed as n (%), and continuous variables are expressed as mean ± SD with p < 0.05 considered statistically significant. The Fischer Exact test and Mann-Whitney Rank Sum test were used for comparison of categorical and continuous variables between platelet reactivity groups. Multivariate Cox regression analysis was used to evaluate the significance of the following variables concerning ischemic events within 1 year of follow-up: HPR (measured by TEG and LTA), age, history of diabetes, history of hypertension, smoking (current), bare-metal stent (BMS) versus drug-eluting stent (DES), and patients presenting post-acute coronary syndrome. Pearson product moment correlation was used to measure the correlation between LTA and TEG assays. All statistical calculations for the aforementioned analyses were performed with SigmaStat software (Point Richmond, California). A receiver operator curve (ROC) analysis was used to determine the ability of LTA and TEG to predict ischemic events. This analysis was performed with MedCalc software (Mariakerke, Belgium).
Determination of sample size. It has been demonstrated that approximately 20% of patients with a history of prior coronary revascularization undergoing repeat PCI will experience a recurrent ischemic event within 1 year of repeat coronary intervention (20). We have previously demonstrated that patients in the upper quartile of platelet reactivity are at approximately 3 times greater risk for repeat ischemic events (17). Therefore, we hypothesized that 30% and 10% of patients with HPR and NPR in the current study will experience a recurrent ischemic event, respectively. With the sample size calculation from SigmaStat software, it is estimated that the sample size required for 95% power with the alpha of 0.05 is approximately 100 patients.
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Results |
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1 month) and aspirin therapy were enrolled. Among these patients, 12 were admitted with myocardial infarction (enrolled 48 h after infarction) and 13 had unstable angina. The remainder of the patients had stable angina, and the procedures were nonemergent. A total of 30 patients received treatment with GP IIb/IIIa inhibitors at the discretion of the physician. Serial platelet assays were completed for all subjects.
Demographics.
Patient demographics and procedural characteristics are shown in Tables 1 and 2,
respectively. Briefly, cardiovascular risk factors and multivessel interventions using drug-eluting stents were common. No significant differences in age, gender, ethnicity, body mass index, baseline medications or hematological data existed between reactivity groups. Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium-channel blockers.
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Discussion |
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50% ADP-induced aggregation) or TEG (70% ADP-induced aggregation) are at increased risk for recurrent ischemic events. Of 23 patients suffering recurrent ischemic events, 16 patients displayed HPR as measured by LTA, whereas 20 patients displayed HPR as measured by TEG. Moreover, mean platelet aggregation was significantly higher in patients suffering recurrent ischemic events than in patients without recurrent events. Of further interest was the observation that patients not treated with eptifibatide displayed an 18% increase in mean platelet aggregation from baseline to 3 h after procedure as measured by LTA. These findings suggest that selected patients exhibiting preprocedural platelet inhibition during chronic clopidogrel therapy might nevertheless remain at risk for periprocedural thrombotic events due to heightened platelet reactivity to ADP that occurs after stenting. A possible explanation for the absence of an increase in platelet reactivity to ADP when studied by TEG involves the use of whole blood as compared with platelet-rich plasma. Heptinstall et al. (21) have demonstrated the important effects that leukocytes and erythrocytes have on adenine nucleotide metabolism that modify the overall response of platelets to ADP.
Our results are concordant with several previous studies that have demonstrated the relationship between insufficient platelet inhibition, postcoronary stent thrombosis, and ischemic cardiovascular events (4,5,10,11). The recent CREST study (Clopidogrel Effect on Platelet Reactivity in Patients With Stent Thrombosis) demonstrated significantly higher 5 µmol/l and 20 µmol/l LTA ADP-induced platelet aggregation in patients with stent thrombosis as compared with patients without stent thrombosis (4), and the PREPARE POST-STENTING (Platelet Reactivity in Patients and Recurrent Events Post-Stenting) study reported increased ADP-induced aggregation measured by TEG in patients suffering ischemic events compared with patients without events (5). Furthermore, Matetzky et al. (10) reported that patients in the highest quartile of ADP-induced aggregation who were stented for acute ST-segment elevation myocardial infarction had a 40% likelihood for a recurrent cardiovascular event within 6 months. A similar study by Barragan et al. (11) showed high P2Y12 receptor reactivity as measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation levels in patients with stent thrombosis. Each of these studies supports the notion that inadequate platelet inhibition, the occurrence of stent thrombosis, and recurrent ischemic events are significantly related.
This study is the first to correlate the occurrence of ischemic events with platelet reactivity to ADP in patients receiving chronic clopidogrel therapy undergoing non-emergent PCI. There is currently no existing standard of treatment for clopidogrel loading in these patients. The possibility of further inhibiting platelet reactivity in patients receiving chronic clopidogrel therapy with an additional 600-mg loading dose was demonstrated by Kastrati et al. (22), suggesting routine reloading with clopidogrel in all patients undergoing PCI regardless of ongoing clopidogrel treatment. In addition, Kastrati (22) has also suggested increasing the current clopidogrel maintenance dose to 150 mg qd to further inhibit ADP-induced aggregation. Moreover, our current study demonstrated that the administration of eptifibatide reduced periprocedural elevation in platelet reactivity measured by LTA. Because further platelet inhibition is attainable in patients receiving chronic clopidogrel therapy, and a reduction in platelet reactivity is associated with a decrease in ischemic complications, an additional loading dose of clopidogrel (300 mg or 600 mg), the use of a GP IIb/IIIa inhibitor or an increase in maintenance dose therapy to 150 mg qd are all therapeutic considerations for patients receiving chronic therapy undergoing non-emergent PCI.
Thrombelastography was implemented in the current study to assess its reliability as a monitoring tool for analyzing the response to antiplatelet therapy. The TEG, combined with the PlateletMapping assay, was able to identify a subtherapeutic response that highly correlated with the more labor intensive method of LTA. Eighty-seven percent of patients encountering recurrent ischemic events exhibited HPR that was identified by TEG. These findings are concordant with the results of the PREPARE POST-STENTING study (5). Therefore, this assay might affect the delivery of individualized antiplatelet therapy.
Study limitations. Although the study strongly suggests that HPR is associated with increased ischemic events after PCI, the results overall are limited by a small sample size. Therefore, larger randomized clinical trials in this subset of patients are necessary to confirm our findings. A second limitation of the study is that patients were not given an additional loading dose of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose remains unclear. Moreover, inherent differences within our study population by virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity. In addition, flow cytometric platelet surface P-selectin and GP IIb/IIIa expression were not measured for additional indicators of platelet reactivity to ADP. Finally, medication was not provided and distributed by our study. Therefore, clopidogrel noncompliance might have contributed to pre-PCI high platelet reactivity and could have affected long-term outcomes, because no additional loading dose was administered. However, preprocedural compliance to clopidogrel and aspirin was verified by nursing staff, and postprocedural compliance was assured through repetitive telephone contacts and outpatient source documentation.
In conclusion, patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by LTA or the TEG point-of-service device, are at increased risk for postprocedural ischemic events. Our data support a mechanistic link between the platelet physiologic response and clinical outcomes. The results of this study have potential implications for clinicians who do not administer additional clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy. Platelet function testing might improve patient outcomes by assessing the risk for recurrent ischemic events and adjusting subsequent antiplatelet treatment. These treatments might include reloading with a dose of 300 mg or 600 mg of clopidogrel, additional antiplatelet treatment with a GP IIb/IIIa inhibitor, or an increased clopidogrel maintenance dose. Future prospective studies are required to determine the efficacy of these regimens in patients with HPR.
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Footnotes |
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1 Dr. Gurbel has received research funding from Haemoscope and NIH to study the physical properties of clot formation with respect to recurrent ischemic events postelective stenting; research funding from Schering and Millennium to study antiplatelet effects of clopidogrel and eptifibatide in elective stenting; and research grant funding from Bayer to study the antiplatelet effects of aspirin in outpatients. 
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p = 0.0004 for platelet aggregation 3 h after PCI in patients receiving eptifibatide versus baseline. (B) Graph demonstrating mean 2 µmol/l ADP-induced platelet aggregation with and without eptifibatide measured by TEG at baseline, 3 h and 18 to 24 h after PCI. *p < 0.0001 for change in platelet aggregation in patients receiving eptifibatide versus no eptifibatide. Abbreviations as in