Mary V. Jacoski

A clinical risk score for prediction of stent thrombosis.

The aim was to develop a clinically useful patient risk score predictive for stent thrombosis (ST). Using readily available baseline clinical and angiographic characteristics, a Cox proportional hazards multivariate model was used to identify significant (p <0.10) predictors of ST through 1 year in 2,487 patients receiving a TAXUS Express (Boston Scientific Corp., Natick, Massachusetts) drug-eluting stent (DES) in the ARRIVE 1 registry. Hazard ratios of significant predictors were rounded to an integer value ranging from 2 to 5. These values were summed for a maximum possible score of 24. The model was validated using 1-year data from a similar DES data set (ARRIVE 2, n = 4,820 patients). The 8 significant predictors found were thienopyridine therapy discontinuation before 6 months, insulin-requiring diabetes, smoker at baseline, left main stent placement, multiple stent placement, lesion length >28 mm, moderate to severe lesion calcification, and reference vessel diameter <3 mm. Model discrimination was high, indicated by an area under the receiver-operator characteristic curve of 0.819. Stratification of patients into low-, medium-, and high-risk groups showed that ST developed in 0.8% of patients with a score <6, 3.6% of patients with a score of 7 to 13, and 12.6% of patients with a score >or=14. In conclusion, using 8 readily available clinical and angiographic characteristics, we defined an ST risk score for patients receiving a DES during the first year. Analysis of patients from ARRIVE 1 and 2 showed that most (73%) were in the lowest risk category, with 25% in the moderate risk category. Less than 2% were at highest risk of developing ST.

The use of the point of care Helena ICHOR/Plateletworks and the Accumetrics Ultegra RPFA for assessment of platelet function with GPIIB-IIIa antagonists.

AbstractObjective: To evaluate a newly modified rapid platelet function analysis system (ICHOR/ Plateletworks®) and to compare the results obtained with those of traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Background: Anti-platelet therapy is standard of care for patients as an adjunct to percutaneous coronary intervention (PCI) or for medical management of non-ST elevation acute coronary syndromes (NSTE ACS). Recent clinical trial results suggest that the three currently approved platelet GPIIb-IIIa receptor antagonists, eptifibatide, tirofiban and abciximab, may vary in extent of inhibition of platelet aggregation (IPA) at the approved doses. Thus, pharmacodynamic evaluations of these agents to determine the extent of platelet function inhibition, especially during the periprocedural time of a cardiac intervention, are necessary. A rapid measurement method as a surrogate for LTA, the current gold standard, would be ideal in order to have the option for dose monitoring or adjustment prior to or during an intervention. The Helena ICHOR/ Plateletworks® may be useful for point of care testing. Methods: Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Results: This study demonstrated that platelet inhibition measured by the ICHOR/Plateletworks® mirrored the level of IPA obtained with LTA. In contrast, the Ultegra® system had less correlation when compared to LTA at inhibition levels < 90%. Conclusions: Based on these data, the ICHOR/ Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary.Abbreviated AbstractA rapid platelet function measurement method as a surrogate for light transmission aggregometry (LTA), the current gold standard, is ideal in order to have the option for GPIIb-IIIa antagonist dose monitoring or adjustment prior to or during a coronary intervention. A newly modified rapid platelet function analysis system (ICHOR/Plateletworks® was evaluated and compared to the results obtained with traditional light transmission aggregometry (LTA), and the Ultegra/RPFA® system. Blood samples collected in D-Phe-Pro-Arg-chloromethyl ketone dihydrochloride (PPACK) anticoagulant were treated with increasing concentrations of eptifibatide, tirofiban or abciximab. LTA was carried out in conjunction with the ICHOR/Plateletworks®, using a modified method, and Accumetrics Ultegra® with RPFA cartridges. Based on these data, the ICHOR/Plateletworks® utilized under modified guidelines may serve as a surrogate for LTA when rapid measurements are necessary.

A clinical risk score for the prediction of very late stent thrombosis in drug eluting stent patients.

AIMS Very late stent thrombosis (VLST; >1 year) is an infrequent but potentially serious complication, whose risk factors have not been fully elucidated. This investigation sought to develop a clinically useful risk stratification score for VLST following drug eluting stent (DES) placement. METHODS AND RESULTS A Cox proportional hazards multivariate model of VLST was developed based on follow-up into a second year of patients enrolled in the ARRIVE registries, utilising readily available baseline clinical and angiographic characteristics. ST predictors between one and two years were identified among 7,459 consecutively enrolled patients who received a TAXUS® Express2™ (Boston Scientific, Natick, MA, USA) DES. Six significant predictors were found: presence of renal disease, prior myocardial infarction, multiple stenting, bifurcation lesions, prior CABG, and smoking at baseline. Each predictor was assigned a score, then summed for a maximum possible score of 10. Stratification into low and high risk groups revealed that VLST developed in 0.5% of 6,759 patients with scores<5, and 2.6% of 700 patients with scores≥5. CONCLUSIONS We defined a VLST risk score for patients during the second year post DES-placement that provides a useful tool for risk stratification.

Comparative Pharmacodynamic Evaluation of Eptifibatide and Abciximab in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: The TAM2 Study

Background: The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided >80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had <80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS.Methods: We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/0.2) and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 μM ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients.Results: Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p < 0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%.Conclusion: These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used.Abbreviated abstract. We compared platelet aggregation inhibition (PAI) with the glycoprotein IIb-IIIa inhibitors eptifibatide and abciximab in patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS), using light transmission aggregometry assays with D-phenylalanyl-L-propyl-L-arginine chloromethylketone (PPACK) as the anticoagulant and 20 μmol adenosine diphosphate (ADP) as the platelet agonist. Mean PAI with eptifibatide during the entire 24-hour infusion period was >80%, and it was significantly higher than the mean PAI achieved with abciximab (p < 0.0001). Mean PAI with abciximab was <80% at 6, 8, 12, 18, and 24 hr. Most patients in the eptifibatide arm had >80% PAI at all time points, whereas many patients treated with abciximab had <80% PAI throughout the infusion period, particularly at later times (6 hr and beyond). Mean GPIIb-IIIa receptor occupancy with eptifibatide was also higher than with abciximab. These pharmacodynamic differences may have contributed to differing clinical effects of eptifibatide and abciximab in large clinical trials in patients with NSTE ACS.

Pharmacodynamic effects of clopidogrel in pediatric cardiac patients: A comparative study of platelet aggregation response

Little data on pediatric percent platelet aggregation (%PA) exist in the literature, particularly in cardiac patients and in response to clopidogrel. The objectives were to estimate the %PA range expected in pediatric patients and to measure the clopidogrel effect on %PA in the PICOLO (Platelet Inhibition in Children on Clopidogrel) trial. To estimate a neonatal/infant %PA response range, %PA induced by 5 µM adenosine diphosphate (ADP) was assessed using light transmission aggregometry in 16 cord and 11 normal adult blood samples and prior to clopidogrel therapy in 49 neonatal and 49 infant/toddler cardiac patients enrolled in PICOLO. The %PA induced by 5 µM thrombin receptor-activating peptide (TRAP) was also assessed for 10 neonates and 21 infants/toddlers enrolled in PICOLO and compared with 11 adult samples. Percent inhibition of platelet aggregation (%IPA) induced by 5 µM ADP at steady-state clopidogrel levels was assessed in 33 neonates and 39 infants/toddlers. ADP-induced %PA was lowest in cord blood samples, intermediate in study neonates and infants/toddlers, and highest in adults. Similarly, TRAP-induced platelet aggregation was lower in neonates and infants/toddlers than adults. For all groups, %PA and %IPA were highly variable, with 11% of neonates and 13% of infants/toddlers showing <10% IPA. In conclusion, ADP- and TRAP-induced %PA is lower in pediatric cardiac patients than normal adults, but highly variable in both. The lower baseline %PA may explain why the pediatric clopidogrel dose providing 30–50% IPA (0.20 mg/kg/day) is lower than a simple weight-based extrapolation of the adult dose (75 mg/day) providing similar inhibition.