ABSTRACT
Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m²). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.
Subject(s)
Blood Platelets/drug effects , Coronary Artery Disease/therapy , Kidney/physiopathology , Percutaneous Coronary Intervention/instrumentation , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation/drug effects , Renal Insufficiency, Chronic/physiopathology , Stents , Aged , Aged, 80 and over , Blood Platelets/metabolism , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Coronary Artery Disease/mortality , Coronary Thrombosis/mortality , Coronary Thrombosis/prevention & control , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Myocardial Infarction/mortality , Myocardial Infarction/prevention & control , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Platelet Aggregation Inhibitors/adverse effects , Platelet Function Tests , Predictive Value of Tests , Prospective Studies , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/mortality , Risk Factors , Severity of Illness Index , Stroke/mortality , Stroke/prevention & control , Time Factors , Treatment OutcomeABSTRACT
AIM: The aim of this study was to compare the effects of 300 mg or 600 mg clopidogrel loading dose, prior to carotid artery stenting (CAS) on the number of transcranial Doppler (TCD)-detected microembolic signals (MES) and to investigate the relationship between the magnitude of platelet reactivity and MES. METHODS: In this prospective randomized, double-blind study, 35 consecutive asymptomatic patients (17.1% females), scheduled for CAS and cardiac surgery were included. The primary endpoint was the number of TCD-detected MES. The secondary endpoints were the absolute magnitude of on-treatment platelet reactivity and the adverse cerebral events. Negative binomial regression to find predictors for sum of single emboli, the student's t-test to assess the association between platelet function tests and randomized dose of 300 mg or 600 mg clopidogrel, and the R2 calculation for the assessment of the association between platelet function tests and embolic load, were used. RESULTS: No statistically significant difference in the number of TCD-detected MES, in the sum of all the single emboli or showers and platelet aggregation measurements between the two groups was observed (aggregometry: 21.7±18.3 versus 23±18%, P=0.8499 and 45.8±17.5 versus 46.5±14.5%, P=0.9003) (verifyNow P2Y12 assay: 231±93 PRU versus 222±86 PRU, P=0.7704). In one patient a transient ischemic attack occurred. CONCLUSION: A loading dose of 300 mg of clopidogrel in combination with aspirin is as effective as 600 mg of clopidogrel in achieving adequate platelet inhibition and preventing periprocedural events in asymptomatic patients undergoing CAS prior to cardiac surgery.
Subject(s)
Cardiac Surgical Procedures , Carotid Stenosis/surgery , Drug-Eluting Stents , Intracranial Embolism/prevention & control , Ischemic Attack, Transient/prevention & control , Ticlopidine/analogs & derivatives , Ultrasonography, Doppler, Transcranial , Aged , Carotid Stenosis/complications , Carotid Stenosis/diagnostic imaging , Clopidogrel , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Heart Diseases/surgery , Humans , Intracranial Embolism/complications , Intracranial Embolism/diagnostic imaging , Ischemic Attack, Transient/diagnostic imaging , Ischemic Attack, Transient/etiology , Male , Platelet Aggregation Inhibitors/administration & dosage , Prognosis , Prospective Studies , Ticlopidine/administration & dosageABSTRACT
OBJECTIVES: Aim of this study was to assess the effect of early initiation of high bolus dose tirofiban on top of dual antiplatelet therapy on angiographic outcome before and after primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infraction patients. BACKGROUND: Glycoprotein IIb/IIIa inhibitors are effective inhibitors of platelet aggregation, and have shown to reduce thrombotic complications in patients undergoing PCI. METHODS: This is a pre-specified angiographic analysis of the On-TIME 2 trial (N = 984) and its open label run-in phase (N = 414). All angiographic parameters, including quantitative coronary angiography (QCA) were performed in an independent angiographic core lab. RESULTS: Of the 1,398 patients, 709 patients (50.7%) were randomized to pre-hospital tirofiban. An open infarct related vessel (TIMI 2 or 3 flow) at initial angiography was more often present in the tirofiban group as compared to the no tirofiban group (58.3% vs. 49.7%, P = 0.002). Tirofiban also reduced initial thrombus burden (P for trend = 0.035) as well as thrombus grade 5 (46.9% vs. 54.3%, P = 0.016) and showed a trend toward a reduction in large thrombus burden (LTB) (69.4% vs. 74.5%, P = 0.055). After PCI, a trend towards a lower corrected TIMI frame count (cTFC) in the tirofiban group was found. A significant interaction was found with time of initiation of study drug, with highest efficacy of tirofiban when given within 76 min after symptom onset, with a significantly lower cTFC after PCI (21.9 ± 17.6 vs. 23.9 ± 18.5, P = 0.008, P for interaction P = 0.006). CONCLUSION: In patients undergoing primary PCI, pre-hospital administration of tirofiban reduces initial thrombus burden and improves initial patency of the infarct related vessel before PCI. Initiation of tirofiban seems to be most effective when given very early after the onset of symptoms; however, this finding needs confirmation in other studies. CLINICAL TRIAL REGISTRATION: The On-TIME 2 trial is registered, at http://isrctn.org, number ISRCTN06195297.
Subject(s)
Angioplasty, Balloon, Coronary , Coronary Angiography , Coronary Thrombosis/therapy , Emergency Medical Services , Myocardial Infarction/therapy , Platelet Aggregation Inhibitors/administration & dosage , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tyrosine/analogs & derivatives , Aged , Angioplasty, Balloon, Coronary/adverse effects , Aspirin/administration & dosage , Clopidogrel , Coronary Circulation/drug effects , Coronary Thrombosis/blood , Coronary Thrombosis/diagnostic imaging , Coronary Thrombosis/drug therapy , Coronary Thrombosis/physiopathology , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Predictive Value of Tests , Prospective Studies , Severity of Illness Index , Ticlopidine/administration & dosage , Ticlopidine/analogs & derivatives , Time Factors , Tirofiban , Treatment Outcome , Tyrosine/administration & dosage , Vascular Patency/drug effectsABSTRACT
BACKGROUND: Previous studies have suggested that women do not accrue equal therapeutic benefit from antiplatelet medication as compared with men. The physiological mechanism and clinical implications behind this gender disparity have yet to be established. METHODS: On-treatment platelet reactivity was determined in 717 men and 234 women on dual antiplatelet therapy, undergoing elective coronary stent implantation. Platelet function testing was performed using arachidonic acid and adenosine diphosphate-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 and Aspirin assays. Also the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke was evaluated. RESULTS: Women had higher baseline platelet counts than men. Women exhibited a higher magnitude of on-aspirin platelet reactivity using LTA, but not using the VerifyNow Aspirin assay. The magnitude of on-clopidogrel platelet reactivity was significantly higher in women as compared with men with both tests used. The cut-off value to identify patients at risk as well as the incidence of clinical endpoints was similar between women and men (16/234[6.8%] vs. 62/717[8.6%], p = 0.38). CONCLUSION: Although the magnitude of platelet reactivity was higher in women, the absolute difference between genders was small and both the cut-off value to identify patients at risk and the incidence of the composite endpoint were similar between genders. Thus, it is unlikely that the difference in platelet reactivity accounts for a worse prognosis in women.
ABSTRACT
BACKGROUND: The carriage of CYP2C19*2 and the use of proton-pump inhibitors (PPIs) and calcium-channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response. OBJECTIVES: The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on-treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting. METHODS: In a prospective, follow-up study, on-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all-cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting. RESULTS: Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty-four events occurred during follow-up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)(adj) 2.2 95% CI, 1.0-5.3, P = 0.044 and HR(adj) 3.3 95% CI, 1.1-9.8, P = 0.032, respectively]. CONCLUSIONS: The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.
Subject(s)
Angioplasty, Balloon, Laser-Assisted/adverse effects , Aryl Hydrocarbon Hydroxylases/genetics , Calcium Channel Blockers/therapeutic use , Platelet Activation/drug effects , Proton Pump Inhibitors/therapeutic use , Thrombosis/prevention & control , Aged , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/pharmacology , Clopidogrel , Cytochrome P-450 CYP2C19 , Drug Interactions , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/pharmacology , Risk Factors , Thrombosis/enzymology , Ticlopidine/administration & dosage , Ticlopidine/analogs & derivatives , Ticlopidine/pharmacology , Ticlopidine/therapeutic useABSTRACT
BACKGROUND: The TRITON-TIMI 38 study has identified three subgroups of patients with a higher risk of bleeding during treatment with the thienopyridine prasugrel: patients with a history of stroke or transient ischaemic attack (TIA), patients ≥75 years and patients with a body weight <60 kg. However, the underlying pathobiology leading to this increased bleeding risk remains to be elucidated. The higher bleeding rate may be due to a stronger prasugrel-induced inhibition of platelet aggregation in these subgroups. The aim of the present study was to determine whether on-treatment platelet reactivity is lower in these risk subgroups as compared with other patients in a large cohort on the thienopyridine clopidogrel undergoing elective coronary stenting. METHODS: A total of 1069 consecutive patients were enrolled. On-clopidogrel platelet reactivity was measured in parallel by light transmittance aggregometry, the VerifyNow® P2Y12 assay and the PFA-100 collagen/ADP cartridge. RESULTS: Fourteen patients (1.5%) had a prior history of stroke or TIA, 138 patients (14.5%) were older than 75 years and 30 patients (3.2%) had a body weight <60 kg. Age ≥ 75 years and a history of stroke were independent predictors of a higher on-treatment platelet reactivity. In contrast, a body weight <60 kg was significantly associated with a lower on-treatment platelet reactivity. CONCLUSION: In two high-risk subgroups for bleeding, patients ≥ 75 years and patients with previous stroke, on-clopidogrel platelet reactivity is increased. In contrast, in patients with a low body weight, on-clopidogrel platelet reactivity is decreased, suggesting that a stronger response to a thienopyridine might only lead to more bleeds in patients with low body weight.
ABSTRACT
BACKGROUND: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. OBJECTIVES: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. PATIENTS/METHODS: Pretreatment and on-treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA-100 Innovance P2Y* cartridge, the flow cytometric vasodilator-stimulated phosphoprotein assay and urine 11-dehydrothromboxane B(2) measurement before and after the administration of a 600-mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. RESULTS: Patients with a history of early ST clearly demonstrated higher on-clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on-aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. CONCLUSIONS: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on-aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.
Subject(s)
Aspirin/pharmacology , Blood Platelets/cytology , Coronary Thrombosis/pathology , Ticlopidine/analogs & derivatives , Aged , Case-Control Studies , Clopidogrel , Female , Flow Cytometry/methods , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/pharmacology , Platelet Function Tests , Stents , Ticlopidine/pharmacology , Treatment Outcome , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: Early coronary stent thrombosis occurs most frequent after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To identify the specific predictors of, respectively, acute and subacute stent thrombosis in patients after primary PCI for STEMI. PATIENTS/METHODS: Consecutive STEMI patients with angiographically confirmed early stent thrombosis were enrolled and compared in a 2 : 1 ratio with a matched control group. Clinical outcome was collected up to 1 year. RESULTS: Of 5842 STEMI patients treated with primary PCI, 201 (3.5%) presented with a definite early stent thrombosis. Of these, 97 (1.7%) had acute stent thromboses and 104 (1.8%) had subacute stent thromboses. Postprocedurally discovered dissection, undersizing and smaller stent diameter were the strongest predictors for acute stent thrombosis. No glycoprotein IIb/IIIa therapy and the use of drug-eluting stents were also associated with acute stent thrombosis. Lack of clopidogrel therapy in the first 30 days after the index PCI was the strongest predictor for subacute stent thrombosis. Mortality rates at 1-year follow-up were lower for acute stent thrombosis than for subacute stent thrombosis (8.3% vs. 13.2%, P = 0.294). The incidence of definite recurrent stent thrombosis at 1-year follow up was significantly lower after a first definite acute stent thrombosis than after a first definite subacute stent thrombosis (6.4% vs. 19.3%, P = 0.007 at 1 year). CONCLUSIONS: The specific risk factors for, respectively, acute and subacute stent thrombosis after primary PCI vary greatly. Mortality rates are high for both categories of stent thrombosis. However, recurrent stent thrombosis occurs more frequently after subacute stent thrombosis.
Subject(s)
Angioplasty, Balloon, Coronary/methods , Myocardial Infarction/therapy , Thrombosis/complications , Thrombosis/etiology , Aged , Clopidogrel , Female , Humans , Incidence , Male , Middle Aged , Myocardial Infarction/epidemiology , Netherlands , Platelet Aggregation Inhibitors/therapeutic use , Registries , Risk Factors , Stents/adverse effects , Thrombosis/therapy , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic use , Treatment OutcomeSubject(s)
Angioplasty, Balloon, Coronary/methods , Blood Platelets/cytology , Platelet Count/methods , Aspirin/administration & dosage , Clopidogrel , Cohort Studies , Humans , Ischemia , Odds Ratio , Platelet Aggregation Inhibitors/therapeutic use , Prospective Studies , ROC Curve , Thrombosis , Ticlopidine/administration & dosage , Ticlopidine/analogs & derivativesABSTRACT
BACKGROUND: High on-aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase-1 inhibition that best predicts atherothrombotic events. METHODS AND RESULTS: Nine hundred and fifty-one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On-aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)-induced light transmittance aggregometry (AA-induced LTA), the VerifyNow® Aspirin Assay (VerifyNow® Aspirin Assay), the arachidonic acid prestimulated IMPACT-R (IMPACT-R AA) and the PFA-100 collagen/epinephrine cartridge (PFA COL/EPI). Cut-offs for HAPR were established by receiver-operator characteristic curve analysis. At 1-year follow-up, the composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P=0.020 (n=925)] and VerifyNow(®) [13.3% vs. 5.9%, P=0.015 (n=422)]. The VerifyNow(®) ASA assay (AUC=0.78) and, to a lesser extent, AA-induced LTA (AUC=0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT-R (n=791) and the PFA Collagen/Epinephrine (n=719) were unable to discriminate between patients with and without primary endpoint at 1-year follow-up. None of the platelet function tests was able to identify patients at risk for bleeding. CONCLUSIONS: AA-induced LTA and the VerifyNow(®) ASA test were able to identify aspirin-treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow(®) Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding.
Subject(s)
Aspirin/pharmacology , Cyclooxygenase 1/chemistry , Cyclooxygenase Inhibitors/pharmacology , Thrombosis/diagnosis , Aged , Angioplasty, Balloon, Coronary/methods , Female , Humans , Male , Middle Aged , Myocardial Infarction/etiology , Platelet Function Tests , Prospective Studies , ROC Curve , Reproducibility of Results , Research Design , Risk , Stents , Thrombosis/prevention & controlABSTRACT
Novel P2Y12 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used P2Y12 inhibitor clopidogrel. Cangrelor is an intravenously administered P2Y12 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action, and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel. It was the objective of this study to determine the contribution of variation in the P2Y12 receptor gene to platelet aggregation after in vitro partial P2Y12 receptor blockade with the direct antagonist cangrelor. Optical aggregometry was performed at baseline and after in vitro addition of 0.05 and 0.25 microM cangrelor to the platelet-rich plasma of 254 healthy subjects. Five haplotype-tagging (ht)-SNPs covering the entire P2Y12 receptor gene were genotyped (rs6798347C>t, rs6787801T>c, rs9859552C>a, rs6801273A>g and rs2046934T>c [T744C]) and haplotypes were inferred. The minor c allele of SNP rs6787801 was associated with a 5% lower 20 microM ADP-induced peak platelet aggregation (0.05 microM cangrelor, p<0.05). Aa homozygotes for SNP rs9859552 showed 20% and 17% less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes (0.05 and 0.25 microM cangrelor respectively; p<0.05). Results of the haplotype analyses were consistent with those of the single SNPs. Polymorphisms of the P2Y12 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the P2Y12 antagonist cangrelor.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Platelet Aggregation/drug effects , Polymorphism, Single Nucleotide/physiology , Receptors, Purinergic P2/genetics , Adenosine Monophosphate/pharmacology , Adult , Blood Platelets , Female , Genotype , Humans , Middle Aged , Pharmacogenetics , Platelet Aggregation Inhibitors/pharmacology , Platelet Function Tests , Purinergic P2 Receptor Antagonists , Receptors, Purinergic P2Y12ABSTRACT
BACKGROUND: Multiple platelet function tests claim to be P2Y12-pathway specific and capable of capturing the biological activity of clopidogrel. OBJECTIVES: The aim of the present study was to determine which platelet function test provides the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel (AMC). PATIENTS/METHODS: Clopidogrel-naive patients scheduled for elective percutaneous coronary intervention (PCI) received a 600 mg loading dose of clopidogrel and 100 mg of aspirin. For pharmacokinetic analysis, blood was drawn at 0, 20, 40, 60, 90, 120, 180, 240 and 360 min after clopidogrel loading and peak plasma concentrations (C(max)) of the AMC were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet function testing was performed at baseline and 360 min after the clopidogrel loading. RESULTS: The VASP-assay, the VerifyNow P2Y12-assay and 20 micromol L(-1) adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) showed strong correlations with C(max) of the AMC (VASP: R(2) = 0.56, P < 0.001; VerifyNow platelet reactivity units (PRU): R(2) = 0.48, P < 0.001; VerifyNow %inhibition: R(2) = 0.59, P < 0.001; 20 micromol L(-1) ADP-induced LTA: R(2) = 0.47, P < 0.001). Agreement with C(max) of the AMC was less evident for 5 micromol L(-1) ADP-induced LTA or whole blood aggregometry (WBA), whereas the IMPACT-R ADP test did not show any correlation with plasma levels of the AMC. CONCLUSION: The flow cytometric VASP-assay, the VerifyNow P2Y12 assay and, although to a lesser extent, 20 micromol L(-1) ADP-induced LTA correlate best with the maximal plasma level of the AMC, suggesting these may be the preferred platelet function tests for monitoring the responsiveness to clopidogrel.
Subject(s)
Angioplasty, Balloon, Coronary , Blood Platelets/drug effects , Coronary Artery Disease/therapy , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation/drug effects , Platelet Function Tests , Ticlopidine/analogs & derivatives , Adenosine Diphosphate , Aged , Biotransformation , Blood Platelets/metabolism , Cell Adhesion Molecules/blood , Chromatography, Liquid , Clopidogrel , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Drug Resistance , Female , Flow Cytometry , Humans , Linear Models , Male , Microfilament Proteins/blood , Middle Aged , Phosphoproteins/blood , Platelet Aggregation Inhibitors/blood , Predictive Value of Tests , Receptors, Purinergic P2/blood , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2Y12 , Tandem Mass Spectrometry , Ticlopidine/blood , Ticlopidine/pharmacokineticsABSTRACT
BACKGROUND: No randomized comparisons are yet available evaluating the effect of pre-hospital high dose tirofiban on the incidence of early stent thrombosis after primary percutaneous coronary intervention (PCI). OBJECTIVES: The aim of this analysis was to evaluate whether routine pre-hospital administration of high-dose tirofiban in ST-segment elevation myocardial infarction (STEMI) decreases the incidence of early stent thrombosis after primary PCI. PATIENTS/METHODS: The Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial was a prospective multicenter study of consecutive STEMI patients referred for primary PCI in which patients were randomized to pre-hospital no high-dose tirofiban/placebo. We examined the incidence of Academic Research Consortium definite and probable early stent thrombosis and determined predictors and outcome of early stent thrombosis. RESULTS: Primary PCI was performed in 1203 out of 1398 patients (86.1%). In 1073 patients (89.2%) a coronary stent was placed. Early stent thrombosis occurred in 39 patients (3.6%). Pre-hospital initiation of high-dose tirofiban significantly reduced early stent thrombosis (2.1% vs. 5.2%, P = 0.006) and was associated with a lower incidence of urgent repeat PCI (1.9% vs. 5.2%, P = 0.005). Early stent thrombosis, as well as pre-hospital initiation of high-dose tirofiban, was independently associated with 30-day mortality. CONCLUSIONS: Pre-hospital initiation of high-dose tirofiban reduces the 30-day incidence of stent thrombosis in STEMI patients treated with primary PCI and stenting. Early stent thrombosis and pre-hospital initiation of high-dose tirofiban were independent predictors of 30-day mortality.
Subject(s)
Angioplasty, Balloon, Coronary , Coronary Thrombosis/prevention & control , Emergency Medical Services , Fibrinolytic Agents/therapeutic use , Myocardial Infarction/drug therapy , Stents , Thrombolytic Therapy , Tyrosine/analogs & derivatives , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Aspirin/administration & dosage , Aspirin/adverse effects , Aspirin/therapeutic use , Clopidogrel , Disease-Free Survival , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Electrocardiography , Emergency Medical Services/methods , Emergency Medical Services/statistics & numerical data , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Heparin/administration & dosage , Heparin/adverse effects , Heparin/therapeutic use , Humans , Male , Middle Aged , Myocardial Infarction/therapy , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Recurrence , Thrombolytic Therapy/adverse effects , Ticlopidine/administration & dosage , Ticlopidine/adverse effects , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic use , Tirofiban , Tyrosine/administration & dosage , Tyrosine/adverse effects , Tyrosine/therapeutic useABSTRACT
BACKGROUND: Inadequate platelet inhibition despite aspirin and clopidogrel therapy during and after a percutaneous coronary intervention is associated with an impaired clinical outcome. Cangrelor, a direct and reversible P2Y(12) inhibitor that is currently in development, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than clopidogrel. The aim of the present study was to compare the magnitude of platelet inhibition in clopidogrel-pretreated patients before and after the in vitro addition of a subtherapeutic dose of cangrelor. METHODS: Blood samples were drawn from patients pretreated with clopidogrel and aspirin who were undergoing elective percutaneous coronary intervention (n=39). Platelet function analysis with 'classical' light transmittance aggregometry (both peak and late aggregation [at 6 min]) was performed before and after the in vitro addition of cangrelor (0.25 mumol/l) to platelet-rich plasma (PRP). After an incubation period of five minutes, platelet aggregation was induced by 5 and 20 mumol/l ADP. RESULTS: The in vitro addition of 0.25mumol/l cangrelor to the PRP from clopidogrel-treated subjects resulted in an additional reduction in ADP-induced platelet aggregation. For ADP concentrations of 5 and 20 mumol/l, peak aggregation showed a decrease of 75 and 85%, respectively (p<0.001 for both), while late aggregation was almost completely diminished (p=0.003 and p<0.001, respectively). Furthermore, the interindividual variation in inhibition of ADP-induced platelet aggregation by clopidogrel was greatly reduced after the addition of cangrelor. CONCLUSION: We demonstrate that the in vitro addition of even a subtherapeutic dose of cangrelor to the PRP of clopidogrel-pretreated patients results in an additional reduction of ADP-induced platelet aggregation. Moreover, cangrelor was able to diminish the interindividual variation observed in clopidogrel-inhibited platelet aggregation. (Neth Heart J 2009;17:195-8.).
ABSTRACT
Multiple studies have demonstrated the effectiveness of dual or triple antiplatelet therapy with aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa therapy in patients with acute coronary syndromes as well as in patients undergoing coronary stent implantation. In the last few years, it is becoming clear that not all patients receive the full benefits with the current standard dosages of antiplatelet therapy. Specifically, numerous studies have revealed a wide interindividual variability in the response to these antiplatelet agents and, more importantly, both nonresponsiveness as well as a heightened residual platelet reactivity have been linked to the occurrence of adverse cardiovascular events. Therefore, assays that identify those patients with an impaired responsiveness or a heightened platelet reactivity despite dual antiplatelet therapy may contribute to better risk stratification and will probably improve clinical outcome when appropriate action is initiated. Likewise, a considerable number of patients do not achieve the minimal inhibition of aggregation threshold with the current recommended weight-adjusted dosages of GP IIb/IIIa therapy. Identifying and optimizing the absolute degree of platelet inhibition in this subgroup of patients will probably improve clinical outcome. The VerifyNow platform is one of the most user friendly point-of-care platelet function test systems because it produces rapid results at the patient bedside. The purpose of the present paper is to give insight into the principal mechanisms of the VerifyNow system, to discuss its clinical utility for the monitoring of antiplatelet therapy and to discuss the proposed cut-off levels to segregate responders from non-responders for the different types of antiplatelet therapy.
Subject(s)
Drug Monitoring/methods , Platelet Aggregation Inhibitors/therapeutic use , Platelet Function Tests/methods , Acute Coronary Syndrome/drug therapy , Humans , Point-of-Care SystemsABSTRACT
In the absence of randomized trials, the optimal management of patients who present with concomitant carotid and coronary artery disease remains an enduring controversy, with much of the debate revolving around whether staged or synchronous carotid endarterectomy (CEA) will reduce peri-operative morbidity and mortality after cardiac surgery. Although encouraging results have been reported using either strategy, there remains no consensus as to which is preferable. More recently, however, carotid artery angioplasty with stenting (CAS) has emerged as a potential alternative to CEA. In 'high-risk for CEA' patients, CAS has shown comparable short and long-term outcome rates to CEA. Accordingly, CAS followed by cardiac surgery could offer a less invasive (and safer) therapeutic option in cardiac patients. This paper reviews the evidence to date supporting the use of CAS+CABG, while highlighting potential situations where such a strategy might be harmful. In particular, it will focus on how the need for dual antiplatelet therapy after CAS can be balanced with avoiding unnecessary bleeding complications after cardiac surgery.
Subject(s)
Angioplasty, Balloon , Coronary Artery Bypass , Endarterectomy, Carotid , Stents , Carotid Stenosis/complications , Carotid Stenosis/surgery , Coronary Artery Disease/complications , Coronary Artery Disease/surgery , HumansSubject(s)
Anticoagulants/therapeutic use , Aspirin/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation , Ticlopidine/analogs & derivatives , Aged , Angioplasty, Balloon, Coronary/methods , Blood Platelets/drug effects , Citrates/pharmacology , Clopidogrel , Female , Humans , Male , Middle Aged , Platelet Count , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Sodium Citrate , Ticlopidine/administration & dosageABSTRACT
Since recent studies have linked an impaired response to antiplatelet therapy with a higher incidence of atherothrombotic events, the monitoring of the efficacy of antiplatelet therapy in the individual patient has attracted much attention. In the present report, we demonstrate that platelet function testing with several point-of-care assays results in ambiguous and conflicting results: some assays indicated that the patient's platelets were insufficiently inhibited by clopidogrel whereas other assays reported an adequate response. Therefore, platelet function assays should not be used solely to guide treatment decisions, and tailor-made antithrombotic treatment has to wait for the most predictive platelet function test to emerge for measuring the risk for thrombotic complications after stenting. Until then, daily clinical practice should not be guided by point-of-care platelet function testing. (Neth Heart J 2007;15:299-305.).