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- P2Y12 Receptor Blockade Augments Glycoprotein IIb-IIIa Antagonist Inhibition of Platelet Activation, Aggregation, and Procoagulant Activity. [Journal Article]
- J Am Heart Assoc 2013; 2(3):e000026.
New antiplatelet agents that provide greater, more consistent inhibition of the platelet ADP receptor P2Y12 may be used in combination with glycoprotein (GP) IIb-IIIa antagonists, but their combined effect on platelet function and procoagulant activity is not well studied. Therefore, the objective of this study was to evaluate the independent and complementary effects of P2Y12 and GPIIb-IIIa inhibition on platelet function and procoagulant activity.Healthy donor blood was treated with the active metabolite of prasugrel (R-138727 5 μmol/L), GPIIb-IIIa antagonists (abciximab 3 μg/mL or eptifibatide 0.9 μg/mL), and combinations thereof, exposed to physiologically relevant agonists (collagen and ADP) and then evaluated for markers of platelet activation and procoagulant activity. Significant interactions between R-138727 and GPIIb-IIIa antagonists were observed. R-138727 and the GPIIb-IIIa antagonists had additive inhibitory effects on collagen-stimulated platelet aggregation and on the collagen plus ADP-stimulated level of activated platelet surface GPIIb-IIIa. R-138727 and abciximab each inhibited collagen plus ADP-stimulated platelet phosphatidylserine expression and prothrombin cleavage, and the combination produced greater inhibition than achieved with abciximab alone. In contrast, eptifibatide did not inhibit, but instead enhanced, collagen plus ADP-stimulated prothrombin cleavage. Addition of R-138727 reduced prothrombin cleavage in eptifibatide-treated samples, suggesting a novel mechanism for potential benefit from combined prasugrel and eptifibatide treatment.The complementary effects of abciximab and R-138727 on platelet activation, aggregation, and procoagulant activity suggest their combined use may, to a greater degree than with either agent alone, reduce thrombus formation in vivo.
- Intra-Arterial Infusion of a Glycoprotein IIb/IIIa Antagonist for the Treatment of Thromboembolism During Coil Embolization of Intracranial Aneurysm: A Comparison of Abciximab and Tirofiban. [JOURNAL ARTICLE]
- AJNR Am J Neuroradiol 2013 May 9.
BACKGROUND AND PURPOSE:Abciximab and tirofiban are commonly used for the treatment of thromboembolisms that form during coiling of intracranial aneurysms; however, it is not known which of these inhibitors is safer and more effective. We report the safety and the recanalization rates for intra-arterial abciximab and intra-arterial tirofiban infusion for the treatment of thromboembolisms that form during coiling.
MATERIALS AND METHODS:Between March 2004 and April 2011, 346 intracranial aneurysms were treated with coiling. Thromboembolisms developed in 22 of these patients and were treated by use of intra-arterial tirofiban (n = 11) or abciximab (n = 11) infusion.
RESULTS:In the abciximab group, the thromboembolisms were completely (n = 1) or partially (n = 7) resolved in 8 cases (72.7%) at the time of the final control angiography. Complete (n = 9) or partial (n = 2) resolution was achieved in all cases at the time of follow-up angiography (<3 days after the procedure). In the tirofiban group, thromboembolisms were completely (n = 4) or partially (n = 6) resolved in 10 cases (90.9%) at the time of the final control angiography. Complete (n = 9) or partial (n = 2) resolution was observed in all cases at the time of the follow-up angiography. There were no statistically significant differences between the 2 groups with respect to thrombus resolution (final angiography, P = .311; follow-up angiography, P = .707). No hemorrhagic complications developed in either group.
CONCLUSIONS:These results suggest that tirofiban is more effective than abciximab for the immediate resolution of thromboembolisms, with no statistical significance. Both intra-arterial tirofiban and abciximab exhibited similar safety and recanalization rates.
- Lack of effect of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on platelet function. [JOURNAL ARTICLE]
- J Sci Food Agric 2013 May 3.
BACKGROUND:The health benefits of fruit and vegetable-rich diets may be partly due to modulation of platelet activity bioactive phytochemicals. The aim of this study was to investigate effects of bioactive-rich plant extracts and isolated bioactive metabolites on platelet function. Blood samples (n=15 subjects) were treated with extracts of bioactive-rich plants consumed as traditional foods in the Black Sea region, or with human metabolites of the bioactives quercetin and sulforaphane. Platelet function was assessed using the PFA-100.
RESULTS:None of the extracts containing various flavonoids, glucosinolates and other bioactives, or isolated bioactive metabolites of quercetin or sulforaphane, caused significant changes in PFA-100 closure time (CT). In contrast, the positive controls (aspirin and Abciximab) consistently caused significant increases in CT for the platelet agonists epinephrine and ADP, respectively.
CONCLUSION:These data do not support the notion that these plant bioactives can improve human platelet function.
- Primary percutaneous coronary intervention in nonagenarians: six-month outcomes from a single-center registry. [Journal Article]
- J Invasive Cardiol 2013 May; 25(5):242-5.
Little is known about the efficacy and medium-term outcomes of primary percutaneous coronary intervention (PCI) in very old patients. We evaluated in-hospital and 6-month outcomes in a retrospective cohort of nonagenarian patients presenting at our hospital with ST-segment elevation myocardial infarction (STEMI) and treated by primary PCI from January 2003 to May 2012. During this period, primary PCI was performed in 1598 consecutive patients; twenty-seven patients (age, 92.5 ± 2.5 years) were enrolled in the study. Four patients (15%) were in advanced Killip class at presentation. STEMI location was anterior in 44%. Patients received aspirin, 300 mg clopidogrel loading dose, and heparin. Abciximab was given to 41% of patients. Coronary angiography showed multivessel disease in 52% of patients. Pain-to-balloon and door-to-balloon times were 375.0 ± 410.2 minutes and 107.3 ± 47.6 minutes, respectively. Intra-aortic balloon pump was implanted in 1 patient. An average of 1.3 ± 0.7 stents (95% bare-metal stents) were implanted per patient. Procedural success rate, defined as Thrombolysis in Myocardial Infarction (TIMI) flow grade ≥2 and residual stenosis <20%, was 89%. Hospital mortality was 18.5%. TIMI major bleeding and acute renal failure, defined as an absolute increase of 0.5 mg/dL serum creatinine, occurred in 7% and 22% of patients, respectively. Overall 6-month survival rate was 67%. Our data suggest that primary PCI can be performed in nonagenarian patients with high success rate and with an acceptable bleeding risk, even when aggressive antithrombotic drugs, such as glycoprotein IIb/IIIa inhibitors, are given.
- Intracoronary abciximab and local anti-inflammatory effects. [JOURNAL ARTICLE]
- Int J Cardiol 2013 Apr 20.
- Impact of multivessel disease on myocardial perfusion and survival among patients undergoing primary percutaneous coronary intervention with glycoprotein IIb/IIIa inhibitors. [Journal Article]
- Arch Cardiovasc Dis 2013 Mar; 106(3):155-61.
Although primary angioplasty achieves thrombolysis in myocardial infarction (TIMI) 3 flow in most patients with ST-elevation myocardial infarction, epicardial recanalization does not guarantee optimal perfusion in a large proportion of patients. The influence of multivessel disease on myocardial reperfusion and survival after primary angioplasty has not been extensively investigated.To evaluate the impact of multivessel disease on myocardial perfusion and survival in a large cohort of patients with ST-elevation myocardial infarction treated with angioplasty and glycoprotein (GP) IIb/IIIa inhibitors.This analysis is based on 1494 patients undergoing primary angioplasty included in the EGYPT database. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase-MB (CK-MB). Follow-up data were collected between 30 days and 1 year after primary angioplasty.Multivessel disease was observed in 870 patients (58.2%). The extent of coronary artery disease was associated with age, diabetes, hypertension, previous myocardial infarction, previous revascularization, abciximab treatment and longer ischaemic time, and was independently associated with impaired angiographic myocardial perfusion (adjusted odds ratio 1.18, 95% confidence interval [CI] 1.01-1.40, P=0.049). At 208±160 days, the extent of coronary artery disease was independently associated with higher mortality (adjusted hazard ratio 1.54, 95% CI 1.06-2.24, P=0.022).Among patients with ST-elevation myocardial infarction undergoing primary angioplasty with GP IIb/IIIa inhibitor treatment, the extent of coronary artery disease was independently associated with impaired myocardial perfusion and survival.
- Integrin αIIbβ3: From Discovery to Efficacious Therapeutic Target. [Journal Article]
- Circ Res 2013 Apr 12; 112(8):1189-200.
From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.
- Transport Limitations of Nitric Oxide Inhibition of Platelet Aggregation under Flow. [JOURNAL ARTICLE]
- Ann Biomed Eng 2013 Apr 6.
Nitric oxide (NO) inhibits platelet aggregation at and near the site of a vascular injury by upregulation of cyclic guanosine monophosphate, which reduces the dimerization of the integrin α IIb β 3. The magnitude of NO flux from the vessel wall and the NO concentration that is necessary to inhibit platelet aggregation under physiological flow conditions is unknown. In this study, a NO releasing polymer, diazeniumdiolated dibutylhexanediamine, was integrated into a microfluidic flow assay to determine the relationship between NO wall flux and collagen mediated platelet adhesion, activation and aggregation. A NO flux equal to or greater than 2.5 × 10(-10) mol cm(-2) min(-1) was found to abrogate aggregation, but not initial platelet adhesion, on collagen at 200 and 500 s(-1) as effectively as the α IIb β 3 antagonist abciximab. The dynamic range of NO fluxes found to induce measurable inhibition of platelet aggregation spanned from 0.33 × 10(-10) to 2.5 × 10(-10) mol cm(-2) min(-1) at 200-500 s(-1). These fluxes correspond to near-wall NO concentrations of 3-90 nM based on a computational model of NO transport. The model predicts that NO concentration in the platelet rich layer near the wall is kinetically limited, while NO penetration into the lumen is mass transfer limited.
- Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction. [JOURNAL ARTICLE]
- Catheter Cardiovasc Interv 2013 Apr 1.
BACKGROUND:Previous studies on gender differences in outcome in patients with ST segment elevation myocardial infarction (STEMI) have been performed, but most of those are from before the current era of PCI technique and medical therapy and have a short duration of follow-up. The objective of our study is to assess the influence of gender on long-term outcome in patients with STEMI who underwent primary percutaneous intervention (PCI) between January 2006 and May 2008.
METHODS:Two-year follow-up data from 202 female and 668 male patients undergoing primary PCI for STEMI were available from the DEBATER (A Comparison of Drug Eluting and Bare Metal Stents for Primary Percutaneous Coronary Intervention with or without Abciximab in ST-segment elevation Myocardial Infarction: The Eindhoven Reperfusion Study) trial database. The primary endpoint was major adverse cardiac events (MACE), defined as the composite of death, myocardial infarction, and target vessel revascularization.
RESULTS:Women were older (64.7 ± 11.7 vs. 59.0 ± 10.7; P < 0.001), and had more often diabetes mellitus (15% vs. 9%; P = 0.01) and hypertension (44% vs. 25%; P < 0.001). At two years, the rate of MACE was significantly higher in women (21% vs. 14%; P = 0.02). The mortality rate in women was 8% versus 2.6% in men (P < 0.001). However, multivariate analysis after adjustment for age and the baseline characteristics hypertension, smoking, diabetes mellitus, stent diameter, and time between onset of symptoms and arrival of the ambulance showed similar MACE and mortality rates in men and women.
CONCLUSION:Women have higher rates of both MACE and mortality after primary PCI for STEMI compared to men because of higher age with higher baseline risk profiles.© 2013 Wiley Periodicals, Inc.
- Clinical outcomes and cost implications of routine early PCI after fibrinolysis: one-year follow-up of the Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) study. [Journal Article, Research Support, Non-U.S. Gov't]
- Am Heart J 2013 Apr; 165(4):630-637.e2.
In patients with ST-elevation myocardial infarction treated with fibrinolysis, routine early percutaneous coronary intervention (r-PCI) improves clinical outcomes at 30 days compared with a more standard approach of performing early PCI only for failed fibrinolysis (s-PCI).We report prespecified secondary clinical outcomes and cost implications of r-PCI compared with s-PCI from the Canadian TRANSFER-AMI trial. Average cost per patient in each arm was calculated based on a microcosting approach. Bootstrap method (5,000 samples) was used to calculate standard errors and 95% CI.At 1 year, rates of death or reinfarction (10.3% vs 11.6%, P = .50), hospital readmission (15.4% vs 16.5%, P = .64) and subsequent revascularization after index hospitalization (6.9% vs 8.7%, P = .30) were similar between the r-PCI and s-PCI arms. The difference in cost per patient between r-PCI and s-PCI was CAD $1,003 (95% CI, -$247 to $2,211). Since a greater proportion of patients were transported by air (vs land) in the r-PCI arm (9.4% vs 3%), and the ratio of abciximab to eptifibatide use was higher in the r-PCI arm compared with s-PCI (2:1 vs 4:5), we undertook additional post hoc cost scenario analyses. In a scenario where patients are transported by land only and eptifibatide is used as the sole GPIIb/IIIa inhibitor, the difference in cost per patient between r-PCI and s-PCI was estimated to be CAD $108 (95% CI, -$1,114 to $1,344).At 1 year, there is no difference in the clinical composite outcome of death or reinfarction between r-PCI and s-PCI strategies. Greater cost with r-PCI, although statistically insignificant, is economically important.