A meta-analysis and cost-minimization analysis of bivalirudin versus heparin in high-risk patients for percutaneous coronary intervention.

This meta-analysis was performed to compare the safety, efficacy, and pharmacoeconomic of bivalirudin versus heparin in high-risk patients for percutaneous coronary interventions (PCI). Earlier meta-analysis comparing bivalirudin and heparin during PCI demonstrated that bivalirudin caused less bleeding with more stent thrombosis. However, little data were available on the safety of bivalirudin versus heparin in high-risk patients for PCI. Thus, we performed a meta-analysis to evaluate the efficacy and safety in the "high-risk" patients. A systematic search of electronic databases was conducted up to July 30, 2020. The Cochrane Risk of Bias assessment tool was used to assess the quality of included studies. The primary outcomes were all-cause death and major adverse cardiac events (MACE); secondary outcomes were major and minor bleeding, followed by a cost-minimization analysis comparing bivalirudin and heparin using a local drug and medical costs reported in China. Subgroup analysis was based on the type of disease of the high-risk population. Finally, a total of 10 randomized controlled trials involved 42,699 patients were collected. The Cochrane Risk of Bias Tool was employed to appraise the research quality. No significant difference was noted between bivalirudin and heparin regarding all-cause death and MACE. However, subgroup analysis showed that bivalirudin caused less major bleeding in female (OR:0.65, 95% CI:0.53-0.79), diabetes (OR:0.55, 95%CI:0.42-0.73), and CKD (OR:0.59, 95%CI:0.63-1.65). The scatterers of the included literature were approximately symmetrical, and no research was outside the funnel plot. Additionally, cost-minimization analysis showed that heparin was likely to represent a cost-effective option compared with bivalirudin in China, with potential savings of 2129.53 Chinese Yuan (CNY) per patient for one PCI. Overall, the meta-analysis showed that although bivalirudin appeared to have a lower risk of major bleeding rate, the overall effectiveness and safety between the two groups showed no significant difference in high-risk patients for PCI. But the results of the cost-minimization analysis showed that heparin could be a potential cost-saving drug than bivalirudin in patients for PCI in China.

Description of Bivalirudin Use for Anticoagulation in Pediatric Patients on Mechanical Circulatory Support.

BACKGROUND: Although heparin has previously been the anticoagulant of choice during mechanical circulatory support (MCS), there is a lack of consistency in dose-response in pediatric patients. Bivalirudin offers more consistent dose-response in adults; however, there are limited data for pediatrics use. OBJECTIVE: The purpose was to characterize the usage, dosage, and safety profile of bivalirudin when used for pediatric MCS in a tertiary care pediatric hospital. METHODS: A retrospective review of pediatric patients receiving bivalirudin for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) anticoagulation was conducted. The primary outcome was the average dose of bivalirudin. Additional outcomes included initial and maximum bivalirudin dose, time to first therapeutic activated partial thromboplastin time (aPTT), time within goal aPTT range, bleeding and clotting complications, and cost. Data were compared between ECMO and VAD patients. RESULTS: Thirty-four patients were included. The median dose of bivalirudin was 0.37 mg/kg/h (interquartile range [IQR] = 0.21-0.56), with a maximum dose of 0.62 mg/kg/h (IQR = 0.33-0.91). VAD patients had a higher median and maximum dose as compared with ECMO patients. Patients achieved their therapeutic goal in a median of 6.1 hours and averaged 61.9% time within therapeutic aPTT. One patient had significant hemorrhage, whereas 3 patients had clotting requiring a circuit change. Bivalirudin acquisition cost was higher than heparin. CONCLUSION AND RELEVANCE: Bivalirudin dosing in ECMO and VAD patients is consistent with dosing seen in previous reports but may be higher in VAD patients. Comparative studies between heparin and bivalirudin are necessary to compare cost-effective outcomes for pediatric patients.

Development of peptide therapeutics: A nonclinical safety assessment perspective.

Novel peptide drugs continue to gain interest as effective modalities against previously undruggable targets. As with any other technology, development and safety assessment of peptides presents with various complex challenges. Additionally, there is a lack of specific regulatory guidance for peptide development, with the industry relying mainly on associating existing small molecule [ICH M3(R2)] and biologic [ICH S6(R1)] guidance. To gain insights into regulatory requirements for therapeutic peptides, we developed a dataset of peptides approved in the United States from 1998 through 2019 for which the summary basis of approval (SBA) packages are publicly available. The dataset comprises a total of 47 peptides (22 chemically synthesized, 6 semi-synthetic, 18 recombinant, and 1 natural). This article summarizes our learnings from the dataset in regards to the development paradigm, guidances followed, strategies for selection of toxicology species; requirements and/or value of genotoxicity and immunogenicity assessment; impurity, metabolite, and safety pharmacology assessment; and safety assessment of peptides containing non-proteogenic amino acids. In the context of the learnings from the dataset, the authors provide their recommendations for improvement of strategies to develop peptide drugs.

Assessment of residual thrombus burden in patients with ST-segment elevation myocardial infarction undergoing bivalirudin versus unfractionated heparin infusion: The MATRIX (minimizing adverse hemorrhagic events by transradial access site and angioX) OCT study.

BACKGROUND: Residual stent strut thrombosis after primary percutaneous coronary intervention (PCI), negatively affects myocardial perfusion, may increase stent thrombosis risk, and it is associated with neointima hyperplasia at follow-up. OBJECTIVES: To study the effectiveness of any bivalirudin infusion versus unfractionated heparin (UFH) infusion in reducing residual stent strut thrombosis in patients with ST-elevation myocardial infarction (STEMI). METHODS: Multi-vessel STEMI patients undergoing primary PCI and requiring staged intervention were selected among those randomly allocated to two different bivalirudin infusion regimens in the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) Treatment-Duration study. Those receiving heparin only were enrolled into a registry arm. Optical coherence tomography (OCT) of the infarct-related artery was performed at the end of primary PCI and 3-5 days thereafter during a staged intervention. The primary endpoint was the change in minimum flow area (ΔMinFA) defined as (stent area + incomplete stent apposition [ISA] area) - (intraluminal defect + tissue prolapsed area) between the index and staged PCI. RESULTS: 123 patients in bivalirudin arm and 28 patients in the UFH arm were included. Mean stent area, percentage of malapposed struts, and mean percent thrombotic area were comparable after index or staged PCI. The ΔMinFA in the bivalirudin group was 0.25 versus 0.05 mm2 in the UFH group, which resulted in a between-group significant difference of 0.36 [95% CI: (0.05, 0.71); p = .02]. This was mostly related to a decrease in tissue protrusion in the bivalirudin group (p = .03). There was a trend towards more patients in the bivalirudin group who achieved a 5% difference in the percentage of OCT frames with the area >5% (p = .057). CONCLUSIONS: The administration of bivalirudin after primary PCI significantly reduces residual stent strut thrombosis when compared to UFH. This observation should be considered hypothesis-generating since the heparin-treated patients were not randomly allocated.

The comparative safety and effectiveness of bivalirudin versus heparin monotherapy in patients on dialysis undergoing percutaneous coronary intervention: Insights from the Blue Cross Blue Shield of Michigan cardiovascular consortium.

BACKGROUND: Dialysis patients are at a higher risk of bleeding after percutaneous coronary intervention (PCI); however, due to their exclusion from randomized clinical trials, the optimal antithrombotic regimen for this population remains unknown. We sought to evaluate the comparative safety and effectiveness of bivalirudin monotherapy versus unfractionated heparin (UFH) monotherapy in dialysis patients undergoing PCI. METHODS: We included dialysis patients who underwent PCI in a multicenter registry between January 2010 and September 2015 at 47 Michigan hospitals. We compared in-hospital outcomes between bivalirudin versus UFH; excluding those treated with glycoprotein IIb/IIIa inhibitors. Optimal full matching was used to account for the nonrandom use of these drugs. RESULTS: Of 177,963 patients who underwent PCI, 4,303 (2.4%) were on dialysis. Among those, 1,257 (29.2%) received bivalirudin monotherapy and 2,112 (49.1%) received UFH monotherapy. Patients treated with bivalirudin had fewer comorbidities. After matching, there were no significant differences in outcomes between those who received bivalirudin versus UFH: bleeding (adjusted odds ratio: 0.67; 95% confidence interval: 0.41-1.07; P = 0.093); major bleeding (0.81; 0.19-3.50; P = 0.77); transfusion (1.01; 0.77-1.33; P = 0.96); repeat PCI (0.57; 0.14-2.24; P = 0.42); stent thrombosis (0.56; 0.05-5.83; P = 0.63); and death (0.84; 0.46-1.51; P = 0.55). CONCLUSIONS: We found no significant differences in in-hospital outcomes between bivalirudin and UFH monotherapy among dialysis patients undergoing PCI. Randomized clinical trials are needed to determine the optimal anticoagulant regimen for this population. © 2017 Wiley Periodicals, Inc.

Association Of Bleeding Avoidance Strategies with age-related bleeding and In-hospital mortality in patients undergoing percutaneous coronary Interventions.

BACKGROUND: The association of bleeding avoidance strategy (BAS) (consisting of a combination of radial access, bivalirudin [rather than heparin +/- glycoprotein GPIIb/IIIa antagonists], and/or vascular closure devices after femoral access) with bleeding and in-hospital outcomes has not been evaluated among elderly patients undergoing percutaneous coronary interventions (PCI). METHODS: We studied BAS use, bleeding and in-hospital mortality among 121,635 patients categorized by age (<50, 50-59, 60-69, 70-79, and ≥80years) undergoing PCI from the BMC2 registry (1/2010-12/2013). RESULTS: The use of BAS decreased marginally with age and despite improved utilization over time, remained lower among the elderly. BAS was used in a much lower risk cohort among all age groups. Nonetheless, compared with no BAS, the use of this strategy was associated with lower bleeding (adjusted OR 0.984, 95% CI 0.980-0.985) and in-hospital mortality (adjusted OR 0.996, 95% CI 0.994-0.997) among all age-groups. Similar relative reduction in the risk of bleeding was observed among all age groups with BAS use with lowest risk (thus greatest absolute risk reduction given their highest risk for bleeding) for the oldest cohort. CONCLUSIONS: BAS use decreased with age among patients undergoing PCI despite its association with lower in-hospital mortality. Although overall utilization improved over time, it still remained lower in the elderly cohort, a group likely to benefit most from it. These data identified an opportunity to design strategies to improve BAS use particularly among high-risk elderly patients undergoing PCI so as to decrease bleeding and reduce related adverse events and costs.

Bivalirudin is associated with improved clinical and economic outcomes in heart failure patients undergoing percutaneous coronary intervention: Results from an observational database.

BACKGROUND: Outcomes with bivalirudin compare favorably with heparin ± GPIIb/IIIa receptor inhibition (heparin ± GPI) during percutaneous coronary intervention (PCI). Patients with congestive heart failure (CHF) have increased risk for complications. The objective was to investigate clinical and economic outcomes for bivalirudin ± GPI vs. heparin ± GPI among PCI patients with CHF. METHODS: Using the Premier Hospital Database, PCI patients with CHF were stratified by anticoagulant: bivalirudin, bivalirudin ± GPI, heparin and heparin ± GPI. The probability of receiving bivalirudin ± GPI was estimated using individual and hospital variables. Using propensity scores, each bivalirudin ± GPI patient was matched to a heparin ± GPI patient. The primary outcome was in-hospital death. Bleeding rates, transfusion, length of stay and in-hospital cost were ascertained. RESULTS: Overall, 116,313 patients at 315 hospitals received bivalirudin (n = 45,559) bivalirudin + GPI (n = 8,115), heparin (n = 27,972) or heparin + GPI (n = 34,667). Patients had STEMI (21.2%), NSTEMI (29.1%), unstable angina (16.6%), stable angina (5.7%) or other ischemic heart disease (24.2%). Of these, 79.1% of bivalirudin patients matched, resulting in 84,948 analyzed patients. Compared with heparin ± GPI patients, bivalirudin ± GPI patients had fewer deaths (3.3% vs. 3.9%; p < 0.0001), less clinically apparent bleeding (10.2% vs. 11.4%; p < 0.0001), clinically apparent bleeding with transfusion (2.7% vs. 3.2%, p <0.0001), and transfusion (8.5% vs. 9.8%, p < 0.0001). Patients receiving bivalirudin had shorter length of stay (6.3 vs. 6.8 days; p < 0.0001) and lower in-hospital cost (mean $26,706 vs. $27,166 [median $19,414 vs. $19,798]; p < 0.0001). In conclusion, this is the largest retrospective analysis of PCI patients with CHF and demonstrates bivalirudin ± GPI compared with heparin ± GPI is associated with lower inpatient rates of death, bleeding, and cost.

In vitro assessment of allergenicity features and localization of probable IgE binding regions.

Rice is cultivated as a staple grain crop in many countries, especially in Asia. In the present study, recombinant rice chitinase was expressed, purified and characterized by in silico and immunobiochemical methods. Rice chitinase was affinity purified and it resolved at 24 kDa on SDS-PAGE. Purified protein was analyzed for pepsin resistance, heat stability, and IgE binding using atopic patients' sera. Chitinase was resistant to pepsin digestion and heat treatment at 90 °C for 1 h. It showed significant IgE binding with 7 of 110 patients' sera positive to different food allergens. Homology modeled 3D structure of rice chitinase was used for B cell epitope prediction. In silico predicted B cell peptides were assessed for IgE binding by ELISA using food allergic patients' sera, epitope RC2 showed IgE binding comparable to chitinase. In conclusion, chitinase was identified as a potential allergen and may share cross reactive epitopes with food allergens.

Bivalirudin in percutaneous coronary intervention, is it the anticoagulant of choice?

For decades, unfractionated heparin (UFH) has been widely used in catheterization laboratories for anticoagulation for percutaneous coronary intervention (PCI). The direct thrombin inhibitors, bivalirudin, has emerged as an alternative to UFH for PCI procedures, due to its lower bleeding risk. More recently, randomized trials and meta-analyses questioned the efficacy of bivalirudin, and demonstrated that bivalirudin might be associated with a higher incidence of ischemic events and in particular stent thrombosis. In this review, we discuss the pharmacology of bivalirudin along with the clinical evidence comparing bivalirudin versus UFH in patients undergoing PCI for various indications.

A regional pharmacoinvasive PCI strategy incorporating selected bleeding avoidance strategies.

BACKGROUND: Pharmacoinvasive therapy (PIT) is a potential treatment for ST-segment elevation myocardial infarction patients who are not able to achieve primary percutaneous intervention (PCI) within guideline-recommended time limits. The risk for bleeding complications with PIT has not been studied in the setting of routine use of two selected bleeding avoidance strategies (BAS): bivalirudin and vascular closure devices. METHODS: We analyzed a contemporary multicenter registry (2009-2013) of consecutive patients undergoing PCI as part of a 10-hospital regional algorithm involving one PCI center and nine transfer centers: PIT for hospitals greater than 60 min (N=140), and primary PCI if less than 60-min travel time to the PCI center (N=346). We compared the risk for Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS) major bleeding among patients undergoing PIT versus primary PCI in the setting of routine use of selected BAS and determined the independent predictors of major bleeding in the entire cohort. RESULTS: The PIT patients had a median travel time of 103±49 min, were more frequently female, had a higher incidence of renal failure, and had a lower frequency of cardiogenic shock compared with the primary PCI group. BAS were routine and similar in both groups. Rates of death, stroke, and ischemic and major bleeding outcomes were similar between the two groups, and the length of stay was shorter in the PIT group. Multivariate logistic models indicated that two independent predictors of major bleeding were cardiac arrest [odds ratio (OR)=3.89, 95% confidence interval (CI): 1.2-12.1, P=0.02] and bailout glycoprotein IIb/IIIa inhibitor utilization (OR=3.29, 95% CI: 1.1-9.6, P=0.03). The PIT strategy in conjunction with selected BAS did not predict major bleeding (OR=2.1, 95% CI: 0.85-5.44, P=0.11). CONCLUSION: Bleeding and ischemia rates were similar between the PIT and primary PCI strategies in the setting of routine use of selected BAS; further study on a broader range of BAS including the radial approach may be warranted. Cardiac arrest and bailout glycoprotein IIb/IIIa inhibitor, but not PIT in conjunction with selected BAS, are independent predictors of bleeding risk in a regional ST-segment elevation myocardial infarction population.

Bivalirudin for acute coronary syndromes: premises, promises and doubts.

Bivalirudin is a valuable anticoagulant option in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Advantages over heparin as a parenteral anticoagulant include more predictable pharmacokinetics and pharmacodynamics, shorter half-life, no need for cofactors, some degree of antiplatelet effect, and the ability to inhibit clot-bound thrombin. Clinical evidence supporting the use of bivalirudin over heparin in current ACS guidelines, however, derives mostly from early randomised trials that may no longer reflect current management patterns, now including the use of oral antiplatelet agents more potent than clopidogrel (i.e. prasugrel or ticagrelor) and a broader implementation of strategies to reduce bleeding (i.e. radial access for percutaneous coronary intervention, and use of glycoprotein IIb/IIIa inhibitors only in bailout situations). Defining the fine balance between bivalirudin efficacy and safety over heparins in the context of other antithrombotic treatments remains a challenge in clinical practice, particularly in a fast-evolving scenario, such as ACS, where numerous new trials have been presented in very recent times. Here we provide an up-to-date overview of the evidence on the use of bivalirudin in ACS, with focus on new data, open issues, and future directions.

An investigation into the ameliorating effect of black soybean extract on learning and memory impairment with assessment of neuroprotective effects.

BACKGROUND: The physiological effects of the non-anthocyanin fraction (NAF) in a black soybean seed coat extract on Aß-induced oxidative stress were investigated to confirm neuroprotection. In addition, we examined the preventive effect of NAF on cognitive defects induced by the intracerebroventricular (ICV) injection of Aß. METHODS: Levels of cellular oxidative stress were measured using 2',7'-dichlorofluorescein diacetate (DCF-DA). Neuronal cell viability was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. To investigate in vivo anti-amnesic effects of NAF by using Y-maze and passive avoidance tests, the learning and memory impairment in mice was induced by Aß. After in vivo assays, acetylcholinesterase (AChE) activity and level of malondialdehyde (MDA) in the mouse brain were determined to confirm the cognitive effect. Individual phenolics of NAF were qualitatively analyzed by using an ultra-performance liquid chromatography (UPLC) Accurate-Mass Quadrupole Time of-Flight (Q-TOF) UPLC/MS. RESULTS: A NAF showed cell protective effects against oxidative stress-induced cytotoxicity. Intracellular ROS accumulated through Aß1-40 treatment was significantly reduced in comparison to cells only treated with Aß1-40. In MTT and LDH assay, the NAF also presented neuroprotective effects on Aß1-40-treated cytotoxicity. Finally, the administration of this NAF in mice significantly reversed the Aß1-40-induced cognitive defects in in vivo behavioral tests. After behavioral tests, the mice brains were collected in order to examine lipid peroxidation and AChE activity. AChE, preparation was inhibited by NAF in a dose-dependent manner. MDA generation in the brain homogenate of mice treated with the NAF was decreased. Q-TOF UPLC/MS analyses revealed three major phenolics from the non-anthocyanin fraction; epicatechin, procyanidin B1, and procyanidin B2. CONCLUSIONS: The results suggest that the NAF in black soybean seed coat extracts may improve the cytotoxicity of Aß in PC12 cells, possibly by reducing oxidative stress, and also have an anti-amnesic effect on the in vivo learning and memory deficits caused by Aß. Q-TOF UPLC/MS analyses showed three major phenolics; (-)-epicatechin, procyanidin B1, and procyanidin B2. Above results suggest that (-)-epicatechins are the major components, and contributors to the anti-amnesic effect of the NAF from black soybean seed coat.

Effect of ocriplasmin on the management of macular holes: assessment of the clinical relevance of ocriplasmin.

IMPORTANCE: Assessing the effect of ocriplasmin availability on the management of full-thickness macular holes (MHs) is important for vitreoretinal surgeons and their patients. Such an assessment can indicate whether the use of ocriplasmin will bring a paradigm shift in treating MHs or will be just an additional option relevant to a small group of patients. OBJECTIVES: To classify the MHs evaluated in our institute by their stage and the presence of vitreomacular adhesion (VMA) and to identify eyes that were suitable candidates for ocriplasmin injection according to guidelines published by the Microplasmin for Intravitreous Injection-Traction Release Without Surgical Treatment (MIVI-TRUST) study group. DESIGN, SETTING, AND PARTICIPANTS: All optical coherence tomographic studies of eyes with MHs performed between 2009 and 2013 were retrospectively reviewed. The scans were interpreted by 2 individuals, and for each hole the stage, size, and vitreomacular relationship were defined according to the definitions used in the MIVI-TRUST studies. One hundred thirty-five patients with full-thickness MHs evaluated at a public hospital were included in the study series. There were 82 women and 53 men, and the mean (SD) age was 67.3 (12.8) years. MAIN OUTCOMES AND MEASURES: The stage, size, and presence or absence of VMA were documented for each MH. The suitability for ocriplasmin intravitreal injection was determined according to the criteria described in the MIVI-TRUST reports. RESULTS: Vitreomacular adhesion was present in 19 eyes with MH (14.1%). Of these, the hole size was 400 µm or less in only 9 eyes (6.7% of the series). Using the criteria of the MIVI-TRUST study exclusively, only these eyes were candidates for ocriplasmin injection. Assuming a closure success rate of 40%, as described in that study, only 2.7% of the patients in our series would have benefited from ocriplasmin injection. CONCLUSIONS AND RELEVANCE: Our findings indicate that ocriplasmin injection is an adequate choice for few patients with MHs. Pars plana vitrectomy will probably remain the treatment of choice for most eyes with MHs. This situation could change if MHs are detected earlier and treated while they are still small and have vitreomacular traction.

Impact of worsening renal dysfunction on the comparative efficacy of bivalirudin and platelet glycoprotein IIb/IIIa inhibitors: insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

BACKGROUND: Use of bivalirudin has been associated with a reduction in the incidence of bleeding in patients undergoing percutaneous coronary intervention. Patients with chronic kidney disease, a known predictor of post-percutaneous coronary intervention bleeding, are under-represented in clinical trials. METHODS AND RESULTS: We evaluated the outcome of 64,052 patients who underwent percutaneous coronary intervention from 2007 to 2009 at 33 hospitals in Michigan and were treated with bivalirudin (28,378) or with heparin and glycoprotein IIb/IIIa inhibitors (35,674). Propensity-matched analysis was adjusted for the nonrandomized use of the 2 strategies. Patients treated with bivalirudin were older, had a lower glomerular filtration rate, and had more comorbidities. Use of bivalirudin was associated with fewer transfusions (2.8% versus 4.2%; P<0.0001), gastrointestinal bleeds (0.5% versus 1.3%; P<0.0001), and vascular complications (1.0% versus 2.5%; P<0.0001), with no difference in survival. Bleeding complications were more common with worsening renal function, but use of bivalirudin was associated with less bleeding across the continuum of renal dysfunction. CONCLUSIONS: The risk of bleeding after percutaneous coronary intervention increases with worsening chronic kidney disease. Bivalirudin was associated with a dramatically reduced risk of bleeding across all categories of renal dysfunction. Our study findings suggest that bivalirudin monotherapy is an acceptable, if not the more appropriate alternative, to heparin and glycoprotein IIb/IIIa inhibitors in patients with chronic kidney disease.

The clinical and economic impact of bivalirudin for percutaneous coronary intervention.

Bivalirudin (BVR) is a direct thrombin inhibitor used as an adjunctive antithrombotic agent in combination with aspirin and an ADP-receptor blocker in patients with acute coronary syndrome undergoing percutaneous coronary intervention. When compared to a strategy of heparin plus a glycoprotein IIb/IIIa inhibitor, BVR has been shown in a number of randomized clinical trials to be at least as effective at reducing ischemic endpoints and to have a consistently lower rate of bleeding complications. In addition, various economic analyses have shown it to be cost-effective compared to heparin plus a glycoprotein IIb/IIIa inhibitor and this, coupled with its proven clinical efficacy, has led to the incorporation of BVR into both EU and US clinical guidelines. Previous studies with BVR have mostly assessed its use in patients treated with aspirin and clopidogrel and further studies are ongoing to determine its role in combination with newer, more potent oral antiplatelet agents.

Bivalirudin for the treatment of ST-segment elevation myocardial infarction: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer (The Medicines Company) of bivalirudin to submit evidence for its clinical and cost effectiveness within its licensed indication for the treatment of adults with ST-segment elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention (PPCI), as part of NICE's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG), which produced a review of the evidence within the manufacturer's submission to NICE. This article describes the manufacturer's submission, the ERG review and NICE's subsequent decisions. The main evidence was derived from one randomized controlled trial (RCT) of STEMI patients intended for PPCI, comparing bivalirudin with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). Bivalirudin was associated with a significant reduction in cardiac mortality at 30 days (p = 0.03) and at 1-year follow-up (p = 0.005), and a significant reduction in major bleeding at 30 days (p < 0.001) and 1 year (p < 0.0001), compared with heparin plus GPI. Stent thrombosis up to 24 hours following PPCI was significantly (p < 0.001) more common with bivalirudin. However, there was no significant treatment effect for stent thrombosis from 1 to 30 days (p = 0.28), or at 1-year follow-up (p = 0.53). There were no significant treatment group differences at 30 days and at 1 year in stroke (p = 0.68 and p = 0.99, respectively), in myocardial infarction [MI] (p = 0.90 and p = 0.22, respectively), or in the need for the revascularization of the target vessel for ischaemia (p = 0.18 and p = 0.12, respectively). There were two decision-analytic models: the base-case scenario used 1-year follow-up data from the RCT; and a sensitivity analysis used 3-year follow-up data. Resource use was primarily drawn from this RCT. Health-related quality-of-life (HR-QOL) estimates were drawn from a UK cohort study. Both models evaluated the incremental costs and outcomes of bivalirudin compared with heparin plus GPI for patients with STEMI intended for PPCI. The analysis adopted a UK NHS perspective over a lifetime horizon. Unit costs were based on year 2009-2010 prices. The model adopted a decision-tree structure to reflect initial events for the initial period (stroke, repeat MI, minor/major bleeding events, repeat revascularization and death) and a two-state Markov component to simulate longer-term survival. The economic analysis suggested that bivalirudin is expected to dominate the heparin plus GPI strategy. This finding was consistent across the probabilistic sensitivity analysis and the vast majority of deterministic sensitivity analyses undertaken. Three exceptions to this finding were observed for the following sensitivity analyses: (1) the exclusive use of eptifibatide as the GPI (incremental cost-effectiveness ratio [ICER] = £1,764); (2) the combination of 100 % eptifibatide use, 100 % radial arterial access and no differential length between strategies for initial hospital stay (ICER = £4,106); and (3) a longer length of ward stay (increase of 0.33 days) for the initial hospitalization (ICER = £415). The Appraisal Committee (AC) gave a positive recommendation for bivalirudin for the treatment of adults with STEMI undergoing PPCI.

Hypoallergenicity of various miso pastes manufactured in Japan.

Miso paste (miso), a fermented soybean food, is popular in Japan and other Asian countries. However, the soybean is known to induce an allergenic response in some individuals. In the present study, we evaluated the allergenicity of various kinds of miso available in Japan. Total proteins were extracted from Amakuti-kome miso, Karakuti-kome miso, Mugi-miso and Mame-miso, and the protein profiles were analyzed. The major protein bands detected in the intact soybean extract were not present in any of the miso samples, which instead showed various low molecular weight protein bands of approximately 10-25 kDa. The existence levels of six major soybean allergens were determined by Western blotting using specific antibodies. We found that the allergen levels varied among miso and allergen types; however, allergen levels were consistently lower in miso than in the soybean extract. We obtained similar results for IgE-ELISA experiments using serum IgE from soybean allergy patients. Taken together, these results indicate that compared to soybean extract, various types of miso contain small quantities of intact soybean allergens. Additionally, several lines of evidence indicated that the allergen levels were exceptionally low in the dark-colored Karakuti-kome miso and Mame-miso, which are produced with relatively long fermentation periods, suggesting that the duration of fermentation might be a key factor in the hypoallergenicity of miso.

Bivalirudin for primary percutaneous coronary interventions: outcome assessment in the Ottawa STEMI registry.

BACKGROUND: Data from randomized trials has demonstrated the superiority of bivalirudin to glycoprotein IIb/IIIa inhibitors plus heparin in patients undergoing primary percutaneous coronary intervention. Real-world performance of bivalirudin in primary percutaneous coronary intervention and the benefit of bivalirudin over heparin remain unknown in an era of routine dual antiplatelet therapy. METHODS AND RESULTS: From July 2004 to December 2010, 2317 consecutive patients were indexed in the University of Ottawa Heart Institute ST-segment-elevation myocardial infarction registry. During this period 748 patients received bivalirudin, 699 patients received glycoprotein IIb/IIIa inhibitors, and 676 patients received unfractionated heparin alone. The primary outcome was the rate of noncoronary artery bypass graft related thrombolysis in myocardial infarction major bleeding. Bivalirudin significantly reduced the primary outcome compared with heparin plus glycoprotein IIb/IIIa inhibitors (2.7% versus 7.3%, adjusted OR 2.96, 95% CI: 1.61-5.45, P<0.001) and the composite end point of death, stroke, reinfarction and major bleed (OR 1.66, 95% CI: 1.12-2.45, P=0.01). Compared with heparin alone, a reduction in major bleeds (OR 1.21, 95% CI: 0.60-2.44, P=0.59) or the composite end point (1.05, 95% CI: 0.68-1.63, P=0.83) with bivalirudin could not be demonstrated. Notably, major bleeding was associated with a 5-fold increase in the risk of mortality both in-hospital (3.5% versus 20.6%) and out to 180 days (5.6% versus 25.8%). CONCLUSIONS: Bivalirudin use compared with glycoprotein IIb/IIIa inhibitors plus heparin as an antithrombotic strategy in primary percutaneous coronary intervention results in less major bleeding in contemporary practice. A benefit of bivalirudin over heparin could not be established with this registry and requires additional investigations to either confirm or refute.