The toxicity assessment of neorudin in cynomolgus monkeys.

In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

Analysis of Wholesale Drug Acquisition and Laboratory Assessment Costs Between Heparin Compared With Bivalirudin-Based Systemic Anticoagulation Strategies in Adult Extracorporeal Membrane Oxygenation.

OBJECTIVES: To assess the wholistic costs of systemic anticoagulation delivery in heparin versus bivalirudin-based maintenance of adult patients supported on extracorporeal membrane oxygenation (ECMO). DESIGN: Single-center retrospective cohort study. SETTING: Large academic ECMO center. PATIENTS: Adults on ECMO receiving heparin or bivalirudin for primary maintenance systemic anticoagulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electronic data were abstracted from a database maintained by our ECMO center, which transitioned to a preferred bivalirudin-based anticoagulation management in 2017. The pretransition group consisted of 126 patients (123 heparin and three bivalirudin), whereas the posttransition group included 275 patients (82 heparin and 193 bivalirudin). Drug costs were estimated using the wholesale acquisition cost, and laboratory assays costs were estimated using reimbursement fee schedules. Cost data were normalized to the duration of the ECMO run and reported in U.S. Dollar per ECMO day. Following the practice change, bivalirudin patients were less likely to receive AT supplementation (31.0 vs 12.4%; p < 0.0001) and had fewer coagulation assays ordered (6.1 vs 5.4 per ECMO day; p = 0.0004). After the transition, there was a dramatic decrease in costs related to AT assay assessments ($11.78 [interquartile range {IQR}, $9.48-$13.09] vs $1.03 [IQR, $0-$5.75]; p < 0.0001) and AT supplementation ($0 [IQR, $0-$312.82] vs $0 [IQR, $0-$0]; p < 0.0001) per ECMO day. Unadjusted survival at 28 days was higher posttransition (64.3 vs 74.9%; p = 0.0286). CONCLUSIONS: Antithrombin assays and supplementation compromise a significant proportion of heparin-based anticoagulation costs in ECMO patients and is substantially reduced when a bivalirudin-based anticoagulation strategy is deployed. A favorable association exists between the aggregate cost of administration of bivalirudin compared with heparin-based systemic anticoagulation in adults supported on ECMO driven by reductions in antithrombin activity assessments and the cost of antithrombin replacement.

Cost-effectiveness of bivalirudin in pediatric ventricular assist devices.

BACKGROUND: Despite recent data suggesting improved outcomes with bivalirudin vs heparin in pediatric Ventricular assist devices (VAD), higher costs remain a barrier. This study quantified trends in bivalirudin use and compared outcomes, resource utilization, and cost-effectiveness associated with bivalirudin vs heparin. METHODS: Children age 0 to 6 year who received VAD from 2009 to 2021 were identified in Pediatric Health Information System. Bivalirudin use was evaluated using trend analysis and outcomes were compared using Fine-Gray subdistrubtion hazard ratios (SHR). Daily-level hospital costs were compared due to differences in length of stay. Cost-effectiveness was evaluated using incremental cost-effectiveness ratio (ICER). RESULTS: Of 691 pediatric VAD recipients (median age 1 year, IQR 0-2), 304 (44%) received bivalirudin with 90% receiving bivalirudin in 2021 (trend p-value <0.01). Bivalirudin had lower hospital mortality (26% vs 32%; adjusted SHR 0.57, 95% CI 0.40-0.83) driven by lower VAD mortality (20% vs 27%; adjusted SHR 0.46, 95% CI 0.32-0.77) after adjusting for year, age, diagnosis, and center VAD volume. Post-VAD length of stay was longer for bivalirudin than heparin (median 91 vs 64 days, respectively, p < 0.001). Median daily-level costs were lower among bivalirudin (cost ratio 0.87, 95% CI 0.79-0.96) with higher pharmacy costs offset by lower imaging, laboratory, supply, and room/board costs. Estimated ICER for bivalirudin vs heparin was $61,192 per quality-adjusted life year gained with a range of $27,673 to $131,243. CONCLUSIONS: Bivalirudin use significantly increased over the past decade and is now used in 90% young pediatric VAD recipients. Bivalirudin was associated with significantly lower hospital mortality and an ICER <$65,000, making it a cost-effective therapy for pediatric VAD recipients.

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.

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.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin.

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.

Anticoagulation with heparin The art of simplicity even in patients on dialysis.

In current PCI practice, anticoagulation with either bivalirudin or unfractionated heparin in patients with ACS share comparable efficacy and safety. Nonetheless, their individual performance in patients on dialysis remains unclear. This observational PCI study reported in-hospital clinical outcome in patients on dialysis undergoing PCI according to drug regimen: bivalirudin versus heparin. Similar clinical outcome was observed with both drug regimens.

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.

Toxicology Assessment of a Dual-Function Peptide 5rolGLP-HV in Mice.

5rolGLP-HV had an ideal therapeutic potential in the prevention of hyperglycemia in type 2 diabetes and delay of the thrombosis. The objective of the study was to investigate the toxicology effects of 5rolGLP-HV and guarantee its safety. In acute toxicity test, the mice were orally receiving 5rolGLP-HV at a single dose of 300 mg/kg or 2000 mg/kg. For sub-chronic toxicity study, the mice received 5rolGLP-HV at doses of 800 mg/kg or 1600 mg/kg for 9 weeks. No significant adverse effects were evident in acute and sub-chronic toxicity tests, indicating that the LD50 value is greater than 2000 mg/kg. Although the liver and kidney exhibited a little abnormal in sub-chronic toxicity study, they could recovery to normal after withdrawal 5rolGLP-HV for 2 weeks. In micronucleus assay, the mice received 5rolGLP-HV at doses of 250, 500, or 1000 mg/kg for two consecutive days. The micronucleus numbers and the polychromatic erythrocytes to normochromatic erythrocytes (PCE/NCE) ratios among 5rolGLP-HV groups were within the normal range. Similarly, sperm aberration test demonstrated that 5rolGLP-HV had no teratogenic effect on the mice sperm. In conclusion, the combined results clearly demonstrated the safety of 5rolGLP-HV and support its use as a drug to treat diabetes and thrombosis.

Optimal P2Y12 Inhibitor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Network Meta-Analysis.

OBJECTIVES: The study sought to compare the clinical efficacy and safety of P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention (PPCI). BACKGROUND: Limited data exist regarding the comparative efficacy and safety of P2Y12 inhibitors in STEMI patients undergoing PPCI. METHODS: Clinical trials enrolling STEMI patients were identified and relevant data was extracted. Major adverse cardiovascular events (MACE) were defined as the composite of all cause mortality, MI, and target vessel revascularization. Network meta-analysis was performed using Bayesian methods. RESULTS: A total of 37 studies with 88,402 STEMI patients and 5,077 MACE were analyzed. Outcomes at 1 month (22 studies and 60,783 patients) suggest that prasugrel was associated with: lower MACE than clopidogrel (standard dose odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.50 to 0.69; high-dose OR: 0.60, 95% CI: 0.51 to 0.71; upstream OR: 0.79, 95% CI: 0.66 to 0.94), and ticagrelor (standard dose OR: 0.69, 95% CI: 0.56 to 0.84; upstream OR: 0.72, 95% CI: 0.50 to 1.05); lower mortality and MI than clopidogrel and standard ticagrelor; lower stroke risk than standard clopidogrel and standard or upstream ticagrelor; and lower stent thrombosis than standard or upstream clopidogrel. At 1-year (10 studies, n = 40,333) prasugrel was associated with lower mortality and MACE than other P2Y12 inhibitors. MACE was particularly lower with prasugrel in studies where patients received bivalirudin, drug-eluting stents, and but not glycoprotein IIb/IIIa inhibitor. CONCLUSIONS: In STEMI patients undergoing PPCI, prasugrel and ticagrelor are more efficacious than clopidogrel; in addition, prasugrel was superior to ticagrelor particularly in conjunction with bivalirudin and drug-eluting stents.

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.

The comparative efficacy of bivalirudin is markedly attenuated by use of radial access: insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

AIM: The purpose of our study was to evaluate the relative impact of bivalirudin on bleeding outcomes associated with trans-radial interventions (TRI) in real world practice. METHODS AND RESULTS: Data for patients undergoing percutaneous coronary intervention (PCI) between January 2010 and March 2014 at the 47 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) were utilized. Propensity matching was used within cohorts defined by access site. The impact of bivalirudin use on in-hospital outcomes was evaluated with Fisher's exact tests. Among patients undergoing trans-femoral interventions (TFI), use of bivalirudin was associated with a reduction in bleeding compared with both glycoprotein IIb/IIIa inhibitors (GPI; 1.67 vs. 3.46%, absolute risk reduction (ARR) 1.79%, odds ratio, OR, 0.47, confidence interval, CI, 0.41-0.54, number needed to treat, NNT 56, P < 0.001) and heparin (1.26 vs. 1.76%, ARR 0.5%, OR 0.71, CI 0.61-0.82, NNT 197, P < 0.001). Among patients undergoing TRI, there was a more modest absolute reduction in bleeding with bivalirudin compared with GPI (0.79 vs. 1.41%, ARR 0.62%, OR 0.56, CI 0.34-0.90, NNT 161, P = 0.016) and no difference in bleeding compared with heparin (0.46 vs. 0.46%, OR 1, CI 0.54-1.84, P = 1). CONCLUSION: Bivalirudin is markedly efficacious in reducing bleeding in patients undergoing TFI. The reduction in bleeding associated with bivalirudin use is minimal to absent in patients undergoing TRI. Given its lower cost and comparable outcomes, heparin should be the preferred anticoagulation strategy in those undergoing radial PCI.

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.

Beneficial effects of a point-of-care bleeding risk calculator on anticoagulant selection in the coronary catheterization laboratory.

STUDY OBJECTIVES: To estimate periprocedural bleeding risk before elective percutaneous coronary intervention (PCI) by using a point-of-care bleeding risk calculator and to document changes in anticoagulant use and bleeding complications after implementation of use of this calculator. DESIGN: Prospective observational pilot study with a historical control cohort. SETTING: Tertiary care medical center. PATIENTS: The pilot cohort consisted of 100 patients undergoing ad hoc PCI during elective cardiac catheterization procedures between January and May 2013, whose bleeding risk and accompanying PCI anticoagulant recommendations were determined by the use of a pre-PCI point-of-care bleeding risk calculator. The historical control cohort consisted of all patients who underwent elective PCI at the same facility between April 1, 2011, and March 31, 2012, before implementation of use of the bleeding risk calculator. MEASUREMENTS AND MAIN RESULTS: The pre-PCI bleeding risk calculator distinguished patients in the pilot cohort as high risk (score 12 or higher) or low risk (lower than 12) for bleeding after a PCI procedure. The primary outcome was bivalirudin use in the pilot cohort compared with its use in the historical control cohort. Implementation of the bleeding risk calculator significantly decreased bivalirudin use compared with bivalirudin use in the historical control cohort (87% in the control cohort vs 60% in the pilot cohort, p<0.01). Bivalirudin use remained high in patients at high bleeding risk (82.2% in the pilot cohort vs 87.4% in the control cohort, p=0.3) and its use was decreased in patients at low bleeding risk (41.8% in the pilot cohort vs 87.1% in the control cohort, p<0.01). The incidence of bleeding complications in the pilot cohort was comparable with that in the control cohort (1% vs. 0.4%, p=0.37), although this pilot study was underpowered to potentially detect a significant change in the incidence of bleeding complications. CONCLUSION: A simple bleeding risk calculator can substantially reduce overall bivalirudin use by specifically decreasing its use among patients at low bleeding risk while maintaining its use among patients at high bleeding risk. The incidence of bleeding complications remained unchanged despite decreasing bivalirudin use among patients undergoing elective coronary catheterization who were at low risk for bleeding.

[Alternatives to heparin and protamine anticoagulation for cardiopulmonary bypass in cardiac surgery]. / Les différentes alternatives d'anticoagulation au couple héparine/protamine en chirurgie cardiaque sous circulation extra-corporelle.

PURPOSE: Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB) cardiac procedures, but this strategy has some limitations. The primary objective of this study was to determine the reliable alternatives for anticoagulation during CPB for cardiac surgery. For each drug proposed, the secondary objectives were to outline the main advantages and disadvantages, to propose a therapeutic protocol, and to provide a cost-benefit analysis. SOURCE: A systematic review of the literature was performed between September 2012 and December 2013. It was based on the protocol established by the "Cochrane collaboration Handbook". Twenty articles were analyzed. The Thériaque database from the University Hospital of Grenoble made the economic analysis possible. PRINCIPAL FINDINGS: Seven alternative anticoagulation strategies were considered: danaparoid sodium, lepirudin, argatroban, bivalirudin, ancrod, idraparinux, and EP217609. Danaparoid sodium has issues with individual variability. Several studies (EVOLUTION-ON, CHOOSE-ON) proposed a reliable therapeutic protocol for bivalirudin. Ancrod resulted in an increase in the transfusion of blood products. Direct thrombin inhibitors offer a promising alternative. EP217609 is a synthetic anticoagulant currently undergoing Phase IIa clinical trials. It is an indirect inhibitor of factor Xa, a direct inhibitor of free and bound thrombin, and can be neutralized by avidin. CONCLUSIONS: The ideal anticoagulation strategy for cardiac surgery with CPB does not exist. Heparin and protamine remain the gold standard for anticoagulation therapy. To date, bivalirudin is the most promising molecule despite its high cost and lack of a readily available antagonist.

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.