Glycoprotein Inhibitors Research Articles

0456: Reperfusion in elderly patients with acute ST-elevation myocardial infarction: results from the RENAU-RESURCOR STEMI network

Elderly patients with acute ST-elevation myocardial infarction (STEMI) remain undertreated. To evaluate the management of elderly STEMI patients treated in a formal regional network of care. This prospective analysis, based on data from the ongoing RESURCOR coronary emergency network, involved 6169 patients presenting with an acute STEMI between 2002 and 2011 in the north French Alps. Patients were divided into age groups: <65, 65-74, 75-84 and ≥85 years. Reperfusion rates, types, timing and adjunctive medications were compared. The RESURCOR network advocates primary percutaneous coronary intervention (PPCI) over fibrinolysis and bivalirudin over glycoprotein inhibitors (GPI) in the elderly. Lack of reperfusion therapy increased with age (Table). The rate of fibrinolysis was higher than that for PPCI in younger patients whereas the situation was reversed in elderly patients. In patients who had PPCI, use of bivalirudin increased and GPI decreased with age, system delays were similar. These regional French data indicate that elderly STEMI patients receive appropriate management with timely delivered PPCI and bivalirudin; however, a substantial proportion are still undertreated. Abstratct 0456 – Table: Reperfusion rates, types, timing and adjunctive medications among the age groups Age groups <65 years n=3476 65-74 years n=1238 75-84 years n=1147 ≥85 years n=308 P-value No reperfusion, n (%) 3.8 5.6 8.0 13.6 <0.001 Fibrinolysis, n (%) 1853 (53.3) 593 (47.9) 449 (39.2) 87 (28.3) <0.001 Primary PCI, n (%) 1492 (42.9) 576 (46.5) 606 (52.8) 179 (58.1) <0.001 Delay (first medical contact to PPCI), median (IQR), min 80 (58-123) 85 (60-125) 85 (64-130) 84 (60-124) 0.1 Bivalirudin * , n/N (%) 81/1197 (6.8) 30/429 (7.0) 48/373 (12.9) 28/121(23.1) <0.001 GPI * , n/N (%) 1375/2695 (51.0) 493/963 (51.2) 435/879 (49.5) 85/222 (38.3) 0.003 * Calculated among patients undergoing a coronarography. Bivalirudin has been used since 2008.

Bivalirudin, glycoprotein inhibitor, and heparin use and association with outcomes of primary percutaneous coronary intervention in the United Kingdom.

The HORIZONS trial reported a survival advantage for bivalirudin over heparin-with-glycoprotein inhibitors (GPIs) in primary PCI for ST elevation myocardial infarction. This drove an international shift in clinical practice. Subsequent studies have produced divergent findings on mortality benefits with bivalirudin. We investigated this issue in a larger population than studied in any of these trials, using the United Kingdom national PCI registry. 61 136 primary PCI procedures were performed between January 2008 and January 2012. Demographic and procedural data were obtained from the registry. Mortality information was obtained through the UK Office of National Statistics. Multivariable logistic regression and propensity analysis modelling were utilized to study the association of different anti-thrombotic strategies with outcomes. Unadjusted data demonstrated near-identical survival curves for bivalirudin and heparin-plus-GPI groups. Significantly higher early and late mortality was found in patients treated with heparin alone ( ITALIC! P < 0.0001) but this group had a markedly higher baseline risk. After propensity matching, the bivalirudin vs. heparin-plus-GPI groups still demonstrated very similar adjusted mortality (odds ratio 1.00 at 30 days, and 0.96 at 1 year). Patients treated with heparin alone continued to show higher mortality after adjustment, although effect size was considerably diminished (odds ratio vs. other groups 1.17-1.24 at 30 days). Analysis of recent UK data showed no significant difference in short- or medium-term mortality between ST elevation myocardial infarction patients treated with bivalirudin vs. heparin-plus-GPI at primary PCI.

Anticoagulation Strategies for Primary Percutaneous Coronary Intervention

Mortality rates for acute ST-segment–elevation myocardial infarction (STEMI) have improved dramatically over the past 3 decades: effective reperfusion therapy has been the cornerstone of this improvement, with recent trends showing growth in primary percutaneous coronary intervention (PCI).1 Although mortality rates for routine risk STEMI patients are now ≈5%,2,3 process and procedure challenges remain prevalent. A key area of persistent controversy is optimal anticoagulation during the primary PCI procedure.4–8 Four anticoagulant options are available for primary PCI: heparin, enoxaparin, fondaparinux, and bivalirudin. Clinical practice is heterogeneous in terms of anticoagulant choices, timing, and context of delivery. In a recent study of primary PCI for STEMI performed between 2007 and 2010, US practice reflected this heterogeneity—among over 66 000 primary PCI patients included in the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) registry, 80% received unfractionated heparin, 11% received low–molecular weight heparin, 23% received bivalirudin, and none received fondaparinux.9 Although glycoprotein inhibitors (GPI) are not anticoagulants, it is not possible to discuss primary PCI anticoagulant strategies without mentioning these potent antiplatelet agents—of note, the ACTION registry confirms the relevancy of this drug class, demonstrating that 79% of primary PCI patients in the United States received GPI agents in the first 24 hours of their hospitalization.9 This review will address the issues and controversy of anticoagulation for primary PCI in 4 sections: (1) thrombin generation during primary PCI and the individual characteristics of each anticoagulant, (2) the changing context of primary PCI anticoagulants with respect to other interventional approaches and therapies, (3) an overview of recent controversial trials, and (4) recommended anticoagulation for the clinical practice of primary PCI. ### Pathophysiology Anticoagulation for primary PCI addresses 2 pathophysiologic processes: initial thrombin generation caused by spontaneous coronary plaque rupture and secondary thrombin generation caused by iatrogenic introduction …

Abstract W P61: Safety and E fficacy of I ntravenous E ptifibatide as S tandalone T herapy for select A cute Ischemic Stroke Patients (SIESTA-I trial)

Background and Objective: There is existence of data on the successful application of Eptifibatide, a cyclic heptapeptide inhibitor of glycoprotein IIb/IIIa receptor with its short half-life in coronary interventions. There is minimal literature in the application of stroke treatment. Our objective was to report the results of an open labeled retrospective registry to evaluate the safety (in regards to hemorrhagic complications) and efficacy (regarding discharge NIHSS) of administering high dose IV Eptifibatide as a standalone therapy for acute stroke in patients ineligible for IV r-tPa or neurointervention. Methods: All patients with acute ischemic events between 2010-13 were included that presented to our university affiliated comprehensive stroke center. Patients that received Eptifibatide as standalone therapy were reviewed. Eptifibatide was administered intravenously as a 135-μg/kg single-dose bolus, then a 0.5-μg/kg/min infusion. Charts were reviewed for all patients to assess for primary safety and efficacy endpoint. The primary safety endpoint was bleeding. Bleeding complications were classified as major (symptomatic intracranial hemorrhage and hemoglobin decrease by &gt;5mg/dl), minor (hemoglobin decrease 3-5 mg/dl) and insignificant as proposed by the TIMI score (Thrombolysis in Myocardial Infarction). The primary efficacy end point was neurological improvement/deterioration as defined by a change in discharge NIHSS by &gt; 4 points compared to initial NIHSS respectively. Results: Of a total patient population of 2,329, total of 20 patients (mean age of 73, 50% male (n=10)) received Eptifibatide administered intravenously for a mean duration of 32.5 hours (range 17-67 hours). No major or minor bleeding was observed except for a patient who exhibited minor complication of knee hemarthroses. 9 patients demonstrated early neurological improvement with only 2 exhibiting neurological deterioration related to extension of ischemic core. Conclusion: Application of IV Eptifibatide in achieving recanalization and preventing extension may be a safe standalone therapy in acute ischemic stroke patients ineligible for other neurological interventions. Larger randomized trials are required to corroborate our findings.

A Pilot Clinical Trial to Evaluate the Efficacy of a Topical Antiviral Osmotically Active Hypertonic Solution for The Treatment of Influenza Virus Induced Sore Throat

Objectives: The presence of free virus particles and bacteria on the surface of the throat is the main cause of initiating and maintaining viral throat infection. In the absence of any topical antiviral treatment, the objectives of this study were to evaluate the efficacy and safety of some specific virus glycoprotein neutralizing and proteolytic enzyme binding plant tannins in an osmotically active hypertonic solution (VB-Th4) for the treatment of sore throat. Methods: 60-patients having acute sore throat were treated with VB-Th4 spray for a maximum period of 14-consecutive days. 43 patients in the Standard treatment (ST) group received other commonly used treatments. Effect on clinical signs, duration of recovery and requirement for the use of antibiotics was evaluated. Results: VB-Th4 significantly reduced the signs of sore throat, bacterial load as well as throat pain, irritation and inflammation immediately after the first treatment with complete recovery in 90% patients within 7-days. The time required for complete recovery and the use of antibiotics was significantly reduced in the VB-Th4 compared to the ST group. Conclusion: In the absence of any topical antiviral drug, topical virus glycoprotein and protease inhibitors open a new therapeutic approach to treat throat viral infections.

Alpha-1 Antitrypsin and SERPINA1 gene Mutation As New Biomarker in Sickle Cell Disease

Sickle cell disease (SCD) has heterogeneous clinical picture and there are several pathway involved in SCD pathogenesis, and chronic inflammation and hemolysis are important hallmarks of the disease. Based on such points, there is a search for prognostic markers to establish possible sub-genotypes of the disease. The present study investigated the alpha-1 antitrypsin (AAT) levels, a serum glycoprotein inhibitor of proteases responsible for trigger inflammatory reactions, describing its associations with SERPINA1 gene polymorphisms, hematological and chemistry biomarkers, and clinical history in a group of SCD children in steady-state. The study was approved at FIOCRUZ research board and followed the principle of Declaration of Helsinki. A total of 356 steady state unrelated SCD patients were included at the present study and a control group (CG) compound by 100 unrelated healthy individuals sex and age matched with the patients group, which were from the same geographical origin. Patients age ranging 13.96+9.91 years of age, the AAT levels higher than the 50th percentile (158.0 mg/mL) had significantly lower red blood cells (RBC) count (p=0.003), hemoglobin (Hb) (p=0.0002) and hematocrit (Hct) (0.0002) concentration, and higher white blood cells (WBC) (p=0.004) and neutrophils (p=0.0001) counts, and higher C-reactive protein (CRP) levels (p<0.0001), and lower urea levels (p=0.0003). AAT had significant negative correlation with RBC (r=-0.205, p=0.0001), Hb (r=-0.203, p=0.0001), Hct (r=-0.256, p<0.0001), high density lipoprotein cholesterol (HDL-C) (r=-0.205, p=0.0001), urea (r=-0.184, p=0.0005), creatinine (r=-134, p=0.012), and albumin (r=-0.135, p=0.011), and significant positive correlation with WBC (r=0.18, 0.0007), neutrophils (r=0.2297, p<0.0001), HbS (r=0.2874), total bilirubin (r=0.137, p=0.01), direct bilirubin (r=0.136, p=0.001), indirect bilirubin (r=0.115, p=0.032), lactate dehydrogenase (r=0.159, p=0.003), ferritin (r=0.1353, 9=0.011), CRP (r=0.355, p<0.0001). Patients with higher levels of AAT had clinical history of more than three infection episodes (OR=1.71, CI:1.05-2.65, p=0.02), gallstones presence (OR=1.75, CI:1.03-2.97, p=0.02), and received more blood therapy (OR=2.35, CI:1.51-3.65, p=0.0001).The SERPINA1 gene polymorphisms were analyzed in 126 SCD patients and 100 CG individuals, the protease inhibitor (Pi)*MM or wide type genotype was find in 115 (91.3%) of SCD patients and 92 (92%) of CG; the PI*SS genotype was find in 2 (1.6%) SCD patients and in none individual of the CG; the PI*MS genotype was find in 9 (7.1%) SCD patients and in 6 (6%) CG individuals; and the PI*MZ genotype was find in 2 (2%) CG individuals. Ours results suggest that the AAT may be considerer as a marker of SCD patients’ outcome, once increased levels is related to stress situation, anti-inflammatory and inhibitory proteases properties and may act as a physiological and cytoprotective regulator influencing the severity of SCD. Our results related to SERPINA1 genotypes emphasize the role of the mutant allele in decrease the AAT production what may represent a risk factor. Additional studies should be carried out in order to investigate mechanisms throughout the AAT can induce several important events in the SCD pathogenesis. DisclosuresNo relevant conflicts of interest to declare.

Abstract 17927: Bayesian Hierarchical Meta-Analysis Clarifies the Trade-Off Between Bleeding and Stent Thrombosis in Trials Comparing Bivalirudin with Heparin During Percutaneous Coronary Intervention

Introduction: Calculating the net benefit between bleeding risks and ischemic complications of antithrombotic therapy remains challenging. Hypothesis: Hierarchical meta-analyses may allow inferences to be made about the parameter θ, which reflects the underlying hypothesis that one therapy is superior to another conditional on the types of risks associated with various end points in clinical trials. Methods: We employed Bayesian hierarchical meta-analyses of 10 randomized clinical trials randomizing 34,658 patients to either bivalirudin or heparin, with or without platelet glycoprotein inhibitors, during percutaneous coronary intervention (PCI). Results: No difference was seen in the rate of death 30 days after using bivalirudin or heparin (OR 1.01, 95% Bayesian credible interval [BCI] 0.79-1.28), but the risk of major bleeding was lower (OR 0.58, 95% BCI 0.38-0.84) and the risk of definite stent thrombosis (ST) was higher (OR 1.86, 95% BCI 1.19-2.94) after using bivalirudin than after using heparin. For every 100 patients, using bivalirudin in place of heparin prevented 4.1 episodes of major bleeding episodes but caused 0.8 episode of definite ST. (Figure Legend: Probability density functions normalized to 1 for risk of major bleeding, death and definite stent thrombosis at 30 days after treatment with bivalirudin or heparin, with or without platelet glycoprotein inhibitors.) Conclusions: Neither bivalirudin nor heparin emerges as a preferred strategy in an analysis that accounts for mortality differences. Because bivalirudin reduces major bleeding at the cost of increased stent thrombosis, decisions between bivalirudin and heparin based on baseline bleeding risk and ST risk are likely to maximize net clinical benefit.

TCT-825 Bleeding events are reduced and survival improved by use of radial access during primary percutaneous coronary intervention for patients receiving glycoprotein inhibitors

access during primary percutaneous coronary intervention for patients receiving glycoprotein inhibitors Control Number: 2917 Submission Type: Abstract Presentation Format: Poster Only New Device/Innovation: No Author(s): Adam J Brown, Nikil K Rajani, Liam M McCormick, Stephen P Hoole, Nick E West Institution(s): University of Cambridge, Cambridge, United Kingdom, Papworth Hospital, Cambridge, United Kingdom Presenter Poster: Dr Adam J Brown, MB BChir View Disclosure University of Cambridge Background: Use of glycoprotein IIb/IIIa inhibitors (GPI) during primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) is known to improve myocardial perfusion and reduce further ischemic events, but is associated with an increase in bleeding risk. Performing PPCI via radial access (rPPCI) is thought to reduce post-procedural bleeding complications and may improve overall survival. We sought to assess whether rPPCI is associated with improved outcomes in patients receiving GPI at our institution. Methods: Consecutive patients undergoing PPCI for STEMI over a four-year period were included. All patients were preloaded with 600mg clopidogrel and 300mg aspirin en-route to PPCI. Interventional strategy and GPI use were left to operator discretion. Patient data and outcome measures were obtained by interrogation of notes and national databases. Bleeding complications were categorized using Bleeding Academic Research Consortium (BARC) definitions. Results: 2,019 patients were included in the analysis (mean age 64.2±12.4yrs, 75.9% male), with 863 receiving GPI. Patients that received GPI were younger (62.7±11.8yrs vs. 64.8±12.6yrs, p< 0.001), more likely to be male (80.5% vs. 73.9%, p< 0.001) but had a higher incidence of cardiogenic shock (5.6% vs. 2.7%, p=0.002). Other baseline demographics were similar. Overall, BARC defined bleeding was more prevalent in those receiving GPI (BARC ≥2 3.0% vs. 0.7%, p< 0.001; BARC ≥3 2.6% vs. 0.2%, p< 0.001). However, patients undergoing rPPCI with GPI had lower bleeding rates when compared with femoral access (0.8% vs. 3.7%, p=0.05). For patients receiving GPI, rPPCI resulted in a significant improvement in 1-year survival (99.2% vs. 93.5%, p=0.01; OR 0.12, 95%CI 0.02-0.87, p=0.04). However, in patients not receiving GPI, no survival benefit for rPPCI was observed (94.4% vs. 93.7%, p=0.70; OR 0.87, 95%CI 0.44-1.71, p=0.69). Conclusions: rPPCI results in lower rates of bleeding and improved survival in patients receiving GPI during PPCI. rPPCI should be considered in patient groups where subsequent use of GPI is likely. CORONARY: STEMI and NSTEMI

A pilot double-blind trial using verapamil as adjuvant therapy for refractory seizures

Given verapamil's property as a glycoprotein inhibitor, this drug could increase the effective concentration of antiepileptic drugs (AEDs) in the epileptic foci, reducing the number of seizures. This pilot study was designed to evaluate the safety and efficacy of verapamil as adjunct therapy in pharmacoresistant patients with focal onset seizures. This was a single-centered, randomized, double-blind and placebo-controlled trial evaluating verapamil as an add-on therapy for adult patients with refractory epilepsy. Twenty-two patients were randomized, but five of them withdrew and one patient passed away after consent, having no exposure to either verapamil or placebo; four patients withdrew during or after the double-blind phase due to side effects. From these four patients, only one patient was in the verapamil group. Twelve patients (59%) finished the study. Some patients experienced lower seizure frequencies, but none of them reached 50% reduction. In addition, there was no statistically significant decrease in the seizure frequency of patients receiving verapamil. When comparing the verapamil with the placebo at the double-blind or the open label study phases, the average difference in seizure range also failed to show significance (p=0.41 and p=0.98, respectively). No significant cardiovascular effects were observed, and side effects unique to verapamil were skin rashes and feet edema. Throughout the study, carbamazepine, valproic acid and clobazam levels increased following verapamil intake; minor dosage adjustment was required in one patient on carbamazepine. This pilot study has shown mild benefits of verapamil use in comparison to placebo as an add-on therapy for a group of non-selected patients with refractory epilepsy. A partial response in a subset of patients was seen. No significant safety problems happened, but adjustments on AEDs may be required during verapamil use.

Effects of HM30181, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers

HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Evaluation of the effect of curcumin capsules on glyburide therapy in patients with type-2 diabetes mellitus.

This study aimed to assess the possible beneficial effects of curcumin capsules as lipid-lowering effects and as a permeability glycoprotein (P-gp) inhibitor on the pharmacokinetics and pharmacodynamics of glyburide and as a P-gp substrate with glyburide in patients with type-2 diabetes mellitus. Open-label, randomized control trial was carried out for 11 days on eight type-2 diabetic patients on glyburide therapy. On the first day of the study, following the administration of 5 mg of glyburide, blood samples were collected from the patients at various time intervals ranging from 0.5 to 24 h. Blood sampling was repeated on the 11th day of the study, after treating the patients with curcumin for ten consecutive days. Glyburide concentrations changed at the second hour, Cmax was unchanged, the glucose levels were decreased, Area Under first Movement Curre (AUMC) was increased, and no patient has experienced the hypoglycaemia. The low-density lipoprotein, very-low-density lipoprotein and triglycerides were decreased significantly, and the high-density lipoprotein content increased. The co-administration of curcumin capsules with glyburide may be beneficial to the patients in better glycaemic control. The lipid lowering and antidiabetic properties of the curcumin show as a potential future drug molecule.

MR-proANP improves prediction of mortality and cardiovascular events in patients with STEMI.

Atrial natriuretic peptide (ANP) is released from the atria (on cleavage of proANP) in response to elevated intra-atrial pressure and wall stretch. Clinical data on proANP are still limited, mainly due to limitations in assaying the protein, which recently have been solved. ProANP is elevated in cardiovascular disease and predicts outcome in heart failure. However, knowledge of the prognostic value in acute myocardial infarction remains limited. We prospectively included 680 patients with STEMI treated with primary-PCI, from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma MR-proANP was measured using an automated processing assay. Endpoints were all-cause mortality (n = 137) and the combined endpoint (n = 170) of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and admission due to recurrent MI, ischaemic stroke or heart failure. During 5-year follow-up, MR-proANP was associated with increased risk of all-cause mortality and MACE (both p < 0.001). After adjustment for confounding risk factors (age, gender, hypertension, diabetes, hypercholesterolaemia, smoking, previous MI, BMI, eGFR, CRP, peak-TnI, symptom-to-balloon time, multivessel disease, complex lesion, LAD-lesion and use of glycoprotein inhibitor), MR-proANP remained an independent predictor of all-cause mortality and MACE - hazard ratio: 1.68 (95% CI 1.35-2.10; p < 0.001) and 1.68 (95% CI 1.39-2.03; p < 0.001) per standard deviation increase in MR-proANP. MR-proANP significantly increased C-statistics and reclassified 26% of the patients for all-cause mortality and 34% for MACE into higher or lower risk categories, matching actual event rates more accurately. Plasma MR-proANP independently predicts all-cause mortality and MACE in patients with STEMI.

Interaction between access choice and pharmacotherapy for coronary intervention: the results of a UK survey

IntroductionPercutaneous coronary intervention (PCI) has changed significantly over the past decade with the uptake of radial access and the development of newer and more potent antiplatelets and safer antithrombins. This...

Balancing the risks of stent thrombosis and major bleeding during primary percutaneous coronary intervention

This editorial refers to ‘Bivalirudin is superior to heparins alone with bailout GPIIb/IIIa Inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX trial’[†][1], by U. Zeymer et al ., on page 2460. Two feared peri-procedural complications of primary percutaneous coronary intervention (PCI) are stent thrombosis (ST) and major bleeding. Although rare, ST is associated with high rates of myocardial infarction and death.1 Potent antithrombotic therapy around the time of PCI markedly reduces the risk of ST, but increases bleeding hazard ( Figure 1 ). Historically, the anticoagulant of choice for PCI has been unfractionated heparin (UFH). Glycoprotein inhibitors (GPI) added to heparin significantly reduce peri-procedural ischaemic complications, but increase major bleeding and the need for transfusions. There has been a consistent association between major bleeding and increased mortality.2 In PCI for elective indications and across the spectrum of acute coronary syndrome (ACS), the direct thrombin inhibitor bivalirudin is non-inferior to heparin plus GPI with respect to overall ischaemic complications, but significantly decreases major bleeding. Figure 1 Balancing reductions in stent thrombosis with increases in major bleeding. PCI, percutaneous coronary intervention. In this issue of European Heart Journal , an important pre-specified analysis by Zeymer et al. uses the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) study population to compare patients receiving bivalirudin with patients receiving heparins [UFH or low-molecular weight heparin (LMWH)] with routine GPI use (defined as initiation before or during coronary angiography) and patients receiving heparins with only bailout GPI use (defined as initiation after the start of PCI). This study expands on the original EUROMAX findings by reporting a significant difference in the composite primary endpoint of death or major bleeding that favours bivalirudin over heparins with routine GPI use and heparins with bailout GPI use (5.1 vs. … [1]: #fn-1

Enhanced uptake and transport of (+)-catechin and (-)-epigallocatechin gallate in niosomal formulation by human intestinal Caco-2 cells.

The aim of this study was to evaluate (+)-catechin and (−)-epigallocatechin gallate (EGCG) cellular uptake and transport across human intestinal Caco-2 cell monolayer in both the absence and presence of niosomal carrier in variable conditions. The effect of free drugs and drug-loaded niosomes on the growth of Caco-2 cells was studied. The effects of time, temperature, and concentration on drug cellular uptake in the absence or presence of its niosomal delivery systems were investigated. The intestinal epithelial membrane transport of the drug-loaded niosomes was examined using the monolayer of the human Caco-2 cells. The kinetics of transport, and the effect of temperature, adenosine triphosphate inhibitor, permeability glycoprotein inhibitor, multidrug resistance-associated protein 2 inhibitor, and the absorption enhancer on transport mechanism were investigated. It was found that the uptake of catechin, EGCG, and their niosomes by Caco-2 cells was 1.22±0.16, 0.90±0.14, 3.25±0.37, and 1.92±0.22 μg/mg protein, respectively (n=3). The apparent permeability coefficient values of catechin, EGCG, and their niosomes were 1.68±0.16, 0.88±0.09, 2.39±0.31, and 1.42±0.24 cm/second (n=3) at 37°C, respectively. The transport was temperature- and energy-dependent. The inhibitors of permeability glycoprotein and multidrug resistance-associated protein 2 and the absorption enhancer significantly enhanced the uptake amount. Compared with the free drugs, niosomal formulation significantly enhanced drug absorption. Additionally, drug-loaded niosomes exhibited stronger stability and lower toxicity. These findings showed that the oral absorption of tea flavonoids could be improved by using the novel drug delivery systems.

Bivalirudin in percutaneous coronary intervention: The EUROpean BiValIrudin UtiliSatION in Practice (EUROVISION) Registry

PurposeThe prospective EUROVISION Registry was designed to capture patterns of use and short term outcomes in consecutive patients undergoing PCI with bivalirudin (BIV) in European centres. MethodsA total of 2018 consecutive BIV-treated patients were included from 58 sites in 5 countries (Germany, Italy, France, Austria, United Kingdom). In-hospital and 30-day outcomes were prospectively collected and included: death, myocardial infarction (MI), stroke, urgent revascularization (URV), major and minor bleeding, stent thrombosis (ST) and thrombocytopenia (TCP). ResultsIn this all-comer population, indication for PCI included STEMI (34%), NSTEMI (25%), unstable angina (16%) and stable angina (26%). Diabetes was present in 24% of patients and 30% of cases were performed via radial access. Preloading with a P2Y12 inhibitor was frequent (74%) while procedural glycoprotein inhibitor (GPI) use was low at 4.2%. Almost half (45%) of patients had received at least one additional anticoagulant prior to receiving BIV for PCI. The overall 30-day mortality was 1.0%, with low rates of MI (1.1%), URV (0.8%), ST (0.3%) and stroke (0.2%). The rate of ACUITY major bleeding was 1.6% and no TCP was reported. Dosing variations representing possible under- or over-dosing of BIV were frequent at 35%. ConclusionIn this prospective registry of consecutive patients intended for PCI, use of BIV was associated with low rates of ischemic complications and excellent safety.

Does the Inhibition of the Final Common Pathway of Platelet Aggregation Reduce the No-Reflow Phenomenon During Primary Percutaneous Coronary Intervention? Tirofiban no Infarto Agudo do miocárdio e a não Reperfusão (TIARA)

ABSTRACT Background Primary percutaneous coronary intervention is currently the preferred method to treat patients with STsegment elevation acute myocardial infarction. The no-reflow phenomenon, which is the inability to reperfuse a region of the myocardium after restoration of patency of a previously occluded epicardial coronary artery, is observed in a considerable proportion of these patients. The benefit of IIb/IIIa glycoprotein inhibitors, blocking the final common pathway of platelet aggregation, has been suggested in studies of acute coronary syndromes, but their actual efficacy in the context of no-reflow in patients treated with primary percutaneous coronary intervention remains unclear. Methods The aim of this multicenter, double-blinded, placebo controlled study is to assess the impact of the early administration of the low molecular weight glycoprotein IIb/ IIIa inhibitor tirofiban on the incidence of no-reflow using angiographic and electrocardiographic methods to determine: (1) the epicardial coronary flow, using the TIMI score, and the microcirculatory flow, using the MBG score of opacification and myocardial flow; (2) the resolution of the ST segment elevation, as the final index of the success of reperfusion. Conclusions If the decrease in no-reflow incidence at 90 minutes and 24 hours after primary percutaneous coronary intervention is confirmed, this pilot study should guide the implementation of a larger study to investigate the possible impact of the systematic inhibition of the final common pathway of platelet aggregation on the mortality of ST-segment elevation acute myocardial infarction patients.

Bivalirudin use during percutaneous coronary intervention in patients on chronic warfarin therapy

About 5 to 8 % of patients referred for percutaneous coronary intervention (PCI) have an indication for long-term oral anticoagulation (OAC), mainly due to atrial fibrillation (AF) [1]. Intravenous direct thrombin inhibitor, bivalirudin (Angiox, The Medicines company LTD, UK), is increasingly used in the setting of primary PCI for ST elevation myocardial infarction, and acute coronary syndromes, since it has provided a similar reduction in major adverse cardiac events but lower bleeding events, when compared to heparin and heparin plus glycoprotein inhibitors (GPIs) [2,3].

Patients undergoing PCI from the femoral route by default radial operators are at high risk of vascular access-site complications

Radial artery (RA) access for PCI has a lower incidence of vascular access-site (VAS) complications than the femoral artery (FA) approach. However, even for default radial operators certain patients are intervened upon from the FA. We examined the demographics and incidence of VAS complications when default radial operators resort to the FA for PCI. The demographics and VAS complications were compared by access site retrospectively for all PCI cases performed by default radial operators (n=1,392). A modified ACUITY trial definition of major VAS complication was used. FA puncture occurred in 25.2% (351/1,392) of cases. Patients were more likely to be female, older and weigh less than patients undergoing PCI from the RA. The FA procedure was likely to be more complex with larger sheaths, more left main stem, graft and multivessel intervention, and there was a greater proportion of emergency cases. Despite increased case complexity, glycoprotein inhibitors were used less frequently in femoral cases (26.5% vs. 36.8%, p<0.001). A VAS complication occurred in 12.5% (44/351) of cases. The risk factors for access-site bleeding are disproportionately high in the population requiring FA puncture by default radial operators, and as a result such patients have a high rate of vascular access-site complications.

The β-Prism Lectin Domain of Vibrio cholerae Hemolysin Promotes Self-assembly of the β-Pore-forming Toxin by a Carbohydrate-independent Mechanism

Vibrio cholerae cytolysin/hemolysin (VCC) is an amphipathic 65-kDa β-pore-forming toxin with a C-terminal β-prism lectin domain. Because deletion or point mutation of the lectin domain seriously compromises hemolytic activity, it is thought that carbohydrate-dependent interactions play a critical role in membrane targeting of VCC. To delineate the contributions of the cytolysin and lectin domains in pore formation, we used wild-type VCC, 50-kDa VCC (VCC(50)) without the lectin domain, and mutant VCC(D617A) with no carbohydrate-binding activity. VCC and its two variants with no carbohydrate-binding activity moved to the erythrocyte stroma with apparent association constants on the order of 10(7) M(-1). However, loss of the lectin domain severely reduced the efficiency of self-association of the VCC monomer with the β-barrel heptamer in the synthetic lipid bilayer from ∼83 to 27%. Notably, inactivation of the carbohydrate-binding activity by the D617A mutation marginally reduced oligomerization to ∼77%. Oligomerization of VCC(50) was temperature-insensitive; by contrast, VCC self-assembly increased with increasing temperature, suggesting that the process is driven by entropy and opposed by enthalpy. Asialofetuin, the β1-galactosyl-terminated glycoprotein inhibitor of VCC-induced hemolysis, promoted oligomerization of 65-kDa VCC to a species that resembled the membrane-inserted heptamer in stoichiometry and morphology but had reduced global amphipathicity. In conclusion, we propose (i) that the β-prism lectin domain facilitated toxin assembly by producing entropy during relocation in the heptamer and (ii) that glycoconjugates inhibited VCC by promoting its assembly to a water-soluble, less amphipathic oligomer variant with reduced ability to penetrate the bilayer.