Influence of Anticoagulants and Heparin Contaminants on the Suitability of MMP-9 as a Blood-Derived Biomarker.

In contrast to other common anticoagulants such as citrate and low-molecular-weight heparin (LMWH), high-molecular-weight heparin (HMWH) induces the expression of matrix metalloproteinase (MMP)-9, which is also measured as a biomarker for stroke in blood samples. Mechanistically, HMWH-stimulated T cells produce cytokines that induce monocytic MMP-9 expression. Here, the influence of further anticoagulants (Fondaparinux, Hirudin, and Alteplase) and the heparin-contaminating glycosaminoglycans (GAG) hyaluronic acid (HA), dermatan sulfate (DS), chondroitin sulfate (CS), and over-sulfated CS (OSCS) on MMP-9 was analyzed to assess its suitability as a biomarker under various conditions. Therefore, starved Jurkat T cells were stimulated with anticoagulants/contaminants. Subsequently, starved monocytic THP-1 cells were incubated with the conditioned Jurkat supernatant, and MMP-9 mRNA levels were monitored (quantitative (q)PCR). Jurkat-derived mediators secreted in response to anticoagulants/contaminants were also assessed (proteome profiler array). The supernatants of HMWH-, Hirudin-, CS-, and OSCS-treated Jurkat cells comprised combinations of activating mediators and led to a significant (in the case of OSCS, dramatic) MMP-9 induction in THP-1. HA induced MMP-9 only in high concentrations, while LMWH, Fondaparinux, Alteplase, and DS had no effect. This indicates that depending on molecular weight and charge (but independent of anticoagulant activity), anticoagulants/contaminants provoke the expression of T-cell-derived cytokines/chemokines that induce monocytic MMP-9 expression, thus potentially impairing the diagnostic validity of MMP-9.

Antithrombotic Therapy in Patients with Complex Percutaneous Coronary Intervention and Cardiogenic Shock.

Managing antithrombotic therapy in patients undergoing complex and high-risk in indicated patients, including those treated with complex percutaneous coronary intervention (PCI) or presenting with cardiogenic shock (CS), is challenging. This review highlights the critical role of antithrombotic therapy, during and after PCI, to optimize the efficacy while minimizing risks. Unfractionated heparin remains the mainstay anticoagulant for complex PCI and CS, with bivalirudin as a potential safer alternative. Cangrelor offers consistent antiplatelet effects, especially when timely absorption of oral agents is uncertain.

Bivalirudin versus heparin in patients with or without bail-out GPI use: a pre-specified subgroup analysis from the BRIGHT-4 trial.

BACKGROUND: Conflicting results comparing bivalirudin versus heparin anticoagulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), in part due to the confounding effect of glycoprotein IIb/IIIa inhibitors (GPI). The aim of the study was to compare the safety and effectiveness of bivalirudin plus a post-PCI high-dose infusion vs heparin with or without bail-out GPI use. METHODS: We conducted a pre-specified subgroup analysis from the BRIGHT-4 trial that randomized 6016 STEMI patients who underwent primary PCI to receive either bivalirudin plus a post-PCI high-dose infusion for 2-4 h or heparin monotherapy. GPI use was only reserved as bail-out therapy for procedural thrombotic complications. The primary outcome was a composite of all-cause death or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding at 30 days. RESULTS: A total of 5250 (87.4%) patients received treatment without GPI while 758 (12.6%) received bail-out GPI. Bail-out GPI use was associated with an increased risk of the primary outcome compared to non-GPI use (5.28% vs. 3.41%; adjusted hazard ratio (aHR), 1.62; 95% confidence interval (CI), 1.13-2.33; P = 0.009) and all-cause death (5.01% vs. 3.12%; aHR, 1.74; 95% CI, 1.20-2.52; P = 0.004) but not in the risk of BARC types 3-5 bleeding (0.53% vs. 0.48%; aHR, 0.90; 95% CI, 0.31-2.66; P = 0.85). Among patients without GPI use, bivalirudin was associated with lower rates of the primary outcome (2.63% vs. 4.21%; aHR, 0.55; 95% CI, 0.39-0.77; P = 0.0005), all-cause death (2.52% vs. 3.74%; aHR, 0.58; 95% CI, 0.41-0.83; P = 0.003), and BARC types 3-5 bleeding (0.15% vs. 0.81%; aHR, 0.19; 95% CI, 0.06-0.57; P = 0.003) compared with heparin. However, among patients requiring bail-out GPI, there were no significant differences observed in the rates of the primary outcome (5.76% vs. 4.87%; aHR, 0.77; 95% CI, 0.36-1.66; P = 0.50; Pinteraction = 0.07) or its individual components between bivalirudin and heparin groups. CONCLUSIONS: Bivalirudin plus a post-PCI high-dose infusion was associated with significantly reduced 30-day composite rate of all-cause death or BARC types 3-5 bleeding compared with heparin monotherapy in STEMI patients undergoing primary PCI without GPI use. However, these benefits might be less pronounced in patients requiring bail-out GPI due to thrombotic complications during primary PCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT03822975.

Recombinant hirudin and PAR-1 regulate macrophage polarisation status in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant tumour. Although some standard therapies have been established to improve the cure rate, they remain ineffective for specific individuals. Therefore, it is meaningful to find more novel therapeutic approaches. Macrophage polarisation is extensively involved in the process of tumour development. Recombinant hirudin (rH) affects macrophages and has been researched frequently in clinical trials lately. Our article validated the regulatory role of rH in macrophage polarisation and the mechanism of PAR-1 by collecting clinical samples and subsequently establishing a cellular model to provide a scientifically supported perspective for discovering new therapeutic approaches. METHOD: We assessed the expression of macrophage polarisation markers, cytokines and PAR-1 in clinical samples. We established a cell model by co-culture with THP-1 and OCI-Ly10 cell. We determined the degree of cell polarisation and expression of validation cytokines by flow cytometry, ELISA, and RT-qPCR to confirm the success of the cell model. Subsequently, different doses of rH were added to discover the function of rH on cell polarisation. We confirmed the mechanism of PAR-1 in macrophage polarisation by transfecting si-PAR-1 and pcDNA3.1-PAR-1. RESULTS: We found higher expression of M2 macrophage markers (CD163 + CMAF+) and PAR-1 in 32 DLBCL samples. After inducing monocyte differentiation into M0 macrophages and co-culturing with OCI-Ly10 lymphoma cells, we found a trend of these expressions in the cell model consistent with the clinical samples. Subsequently, we discovered that rH promotes the polarisation of M1 macrophages but inhibits the polarisation of M2 macrophages. We also found that PAR-1 regulates macrophage polarisation, inhibiting cell proliferation, migration, invasion and angiogenic capacity. CONCLUSION: rH inhibits macrophage polarisation towards the M2 type and PAR-1 regulates polarisation, proliferation, migration, invasion, and angiogenesis of DLBCL-associated macrophages.

Hirudin delays the progression of diabetic kidney disease by inhibiting glomerular endothelial cell migration and abnormal angiogenesis.

BACKGROUND: In the early stages of diabetic kidney disease (DKD), the pathogenesis involves abnormal angiogenesis in the glomerulus. Hirudin, as a natural specific inhibitor of thrombin, has been shown in previous studies to inhibit the migration of various tumor endothelial cells and abnormal angiogenesis. However, its role in DKD remains unclear. METHODS: The effects of hirudin in DKD were studied using spontaneous type 2 diabetic db/db mice (which develop kidney damage at 8 weeks). Network pharmacology was utilized to identify relevant targets. An in vitro high glucose model was established using mouse glomerular endothelial cells (MGECs) to investigate the effects of hirudin on the migration and angiogenic capacity of MGECs. RESULTS: Hirudin can ameliorate kidney damage in db/db mice. Network pharmacology suggests its potential association with the VEGFA/VEGFR2 pathway. Western blot and immunohistochemistry demonstrated elevated protein expression levels of VEGFA, VEGFR2, AQP1, and CD31 in db/db mice, while hirudin treatment reduced their expression. In the MGECs high glucose model, hirudin may reverse the enhanced migration and angiogenic capacity of MGECs in a high glucose environment by altering the expression of VEGFA, VEGFR2, AQP1, and CD31. Moreover, the drug effect gradually increases with higher concentrations of hirudin. CONCLUSIONS: This study suggests that hirudin can improve early-stage diabetic kidney disease kidney damage by inhibiting the migration and angiogenesis of glomerular endothelial cells, thereby further expanding the application scope of hirudin. Additionally, the study found increased expression of AQP1 in DKD, providing a new perspective for further research on the potential pathogenesis of DKD.

Comparison of sample materials for S100b analysis.

Head injury is a potentially lethal and frequently occurring condition in the emergency department (ED). Reliable and fast diagnosis is important both for patients and flow in the ED. Circulating S100B is used to rule out the need for head computer tomography in low-risk patients with mild head injury. The flow of these patients through the ED would benefit from shorter turn-around time. Standard serum clotting tubes require 30-60 min clotting time, followed by an analysis time of 45 min. Here, we evaluated the performance of two alternative blood collection tubes; a rapid serum tube (RST) with a recommend clotting time of 5 min and a hirudin tube (HIR) for instant anticoagulation. S100B measurement was performed on paired blood samples from 221 subjects using a Roche Cobas 602 analyser. The performances of the alternative tubes were evaluated by method comparison to the standard serum clotting tube, repeatability and agreement of results obtained from alternative tubes compared with the standard clotting tube. Both alternative tubes had a minor positive bias (RST = 0.011 µg/L, HIR = 0.008 µg/L). The repeatability was 2% for RST and 10% for HIR, while being 4% for the standard clotting tube. In the agreement analysis, the positive and negative predictive values for RST were 62% and 100% while being 73% and 99% for HIR respectively. Our study suggests that RST is a feasible alternative to reduce laboratory turn-around time in S100b analysis.

The impact of heparin and direct thrombin inhibitors on cell-penetrating polymer siRNA transfection.

Gene therapy using siRNA has become a promising strategy to achieve targeted gene knockdown for treatment of cardiovascular pathologies. However, efficient siRNA transfection often relies on cationic delivery vectors such as synthetic cell-penetrating polymers which are susceptible to interference by negatively charged molecules. Anticoagulants such as heparin, which is negatively charged and widely used in cardiovascular applications, may pose a significant barrier to effective siRNA delivery. We therefore conducted in vitro studies utilizing human smooth muscle and endothelial cells transfected with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ß2-microglobulin (B2M) siRNA in the presence of heparin, argatroban, and bivalirudin in order to determine which anticoagulant therapy is most compatible for siRNA delivery. We observed that while heparin, at clinical doses, decreases the efficiency of siRNA targeted mRNA knockdown, mRNA knockdown is not inhibited in the presence of either argatroban or bivalirudin. Our data suggests that heparin should be avoided during siRNA therapy with cationic transfection agents, and argatroban and bivalirudin should be used in its stead.

Therapeutic Potentials of Medicinal Leech in Chinese Medicine.

The use of medicinal leeches in clinical therapy has been employed for a long time, as it was originally recognized for exerting antithrombin effects. These effects were due to the ability of the leech to continuously suck blood while attached to human skin. According to Chinese Pharmacopoei, leeches used in traditional Chinese medicine mainly consist of Whitmania pigra Whitman, Hirudo nipponia Whitman, and Whitmania acranulata, but the latter two species are relatively scarce. The main constituents of leeches are protein and peptide macromolecules. They can be categorized into two categories based on their pharmacological effects. One group consists of active ingredients that directly target the coagulation system, such as hirudin, heparin, and histamine, which are widely known. The other group comprises protease inhibitor components like Decorsin and Hementin. Among these, hirudin secreted by the salivary glands of the leech is the most potent thrombin inhibitor and served as the sole remedy for preventing blood clotting until the discovery of heparin. Additionally, leeches play a significant role in various traditional Chinese medicine formulations. In recent decades, medicinal leeches have been applied in fields including anti-inflammatory treatment, cardiovascular disease management, antitumor treatment, and many other medical conditions. In this review, we present a comprehensive overview of the historical journey and medicinal applications of leeches in various medical conditions, emphasizing their pharmaceutical significance within traditional Chinese medicine. This review offers valuable insights for exploring additional therapeutic opportunities involving the use of leeches in various diseases and elucidating their underlying mechanisms for future research.

Combined drug anti-deep vein thrombosis therapy based on platelet membrane biomimetic targeting nanotechnology.

After orthopedic surgeries, such as hip replacement, many patients are prone to developing deep vein thrombosis (DVT), which in severe cases can lead to fatal pulmonary embolism or major bleeding. Clinical intervention with high-dose anticoagulant therapy inevitably carries the risk of bleeding. Therefore, a targeted drug delivery system that adjusts local DVT lesions and potentially reduces drug dosage and toxic side effects important. In this study, we developed a targeted drug delivery platelet-derived nanoplatform (AMSNP@PM-rH/A) for DVT treatment that can simultaneously deliver a direct thrombin inhibitor (DTI) Recombinant Hirudin (rH), and the Factor Xa inhibitor Apixaban (A) by utilizing Aminated mesoporous silica nanoparticles (AMSNP). This formulation exhibits improved biocompatibility and blood half-life and can effectively eliminate deep vein thrombosis lesions and achieve therapeutic effects at half the dosage. Furthermore, we employed various visualization techniques to capture the targeted accumulation and release of a platelet membrane (PM) coating in deep vein thrombosis and explored its potential targeting mechanism.

Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.

Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.

Layer-by-Layer Construction of Antibacterial and Anticoagulant Blood Contacting Materials.

Vascular transplantation is a common treatment for Cardiovascular disease (CVD). However, the mismatch of mechanical, structural, or microenvironmental properties of materials limits the clinical application. Therefore, the functional construction of artificial vessels or other blood contact materials remains an urgent challenge. In this paper, the composite nanofibers of polycaprolactone (PCL) with dopamine and polyethylenimine (PEI) coating are first prepared, which are further self-assembled by anticoagulant hirudin (rH) and antimicrobial peptide (AMP) of HHC36 through layer-by-layer (LBL) method. The results of FTIR and XPS analysis show that hirudin and AMP are successfully loaded on PEI-PDA/PCL nanofibers and the hydrophilicity is improved. They also show good mechanical properties that the ultimate tensile strength and elongation at break are better than natural blood vessels. The antibacterial results show that the antibacterial effect is still 93% against E. coli on the fifth day because of the stable and continuous release of HHC36 and rH. The performance of anticoagulant activity also exhibited the same results, which APTT is even 9.7s longer in the experimental group than the control group on the fifth day. The novel materials would be effectively solve the formation of thrombosis around artificial blood vessel grafts and the treatment of inflammation.

Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022.

OBJECTIVES: The activated partial thromboplastin time (aPTT) is the most frequently used monitoring assay for bivalirudin in children and young adults on mechanical circulatory support including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO). However, intrinsic variability of the aPTT complicates management and risks bleeding or thrombotic complications. We evaluated the utility and reliability of a bivalirudin-calibrated dilute thrombin time (Bival dTT) assay for bivalirudin monitoring in this population. DESIGN: Retrospective analysis of clinical data (including aPTT, dilute thrombin time [dTT]) and results of residual plasma samples from VAD patients were assessed in two drug-calibrated experimental assays. One assay (Bival dTT) was validated for clinical use in VAD patients, and subsequently used by clinicians in ECMO patients. Pearson correlation and simple linear regression were used to determine R2 correlation coefficients between the different laboratory parameters using Statistical Package for Social Sciences (Armonk, NY). SETTING: ICUs at Cincinnati Children's Hospital Medical Center. SUBJECTS: Children on VAD or ECMO support anticoagulated with bivalirudin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fifteen plasma samples from 11 VAD patients were analyzed. Both drug-calibrated experimental assays (anti-IIa and Bival dTT) showed excellent correlation with each other ( R2 = 0.94) and with the dTT ( R2 = 0.87), but poor correlation with aPTT ( R2 = 0.1). Bival dTT was selected for validation in VAD patients. Subsequently, clinically ordered results (105) from 11 ECMO patients demonstrated excellent correlation between the Bival dTT and the standard dTT ( R2 = 0.86) but very poor correlation with aPTT ( R2 = 0.004). CONCLUSIONS: APTT is unreliable and correlates poorly with bivalirudin's anticoagulant effect in ECMO and VAD patients. A drug-calibrated Bival dTT offers superior reliability and opportunity to standardize results across institutions. Additional studies are needed to determine an appropriate therapeutic range and correlation with clinical outcomes.

Recombinant hirudin suppresses angiogenesis of diffuse large B-cell lymphoma through regulation of the PAR-1-VEGF.

Hirudin is one of the specific inhibitors of thrombin, which has been confirmed to have strong bioactivities, including inhibiting tumors. However, the function and mechanism of hirudin and protease-activated receptor 1 (PAR-1) in diffuse large B-cell lymphoma (DLBCL) have not been clear. Detecting the expression PAR-1 in DLBCL tissues and cells by RT-qPCR and IHC. Transfected sh-NC, sh-PAR-1, or pcDNA3.1-PAR-1 in DLBCL cells or processed DLBCL cells through added thrombin, Vorapaxar, Recombinant hirudin (RH), or Na2S2O4 and co-culture with EA.hy926. And built DLBCL mice observed tumor growth. Detecting the expression of related genes by RT-qPCR, Western blot, IHC, and immunofluorescence, measured the cellular hypoxia with Hypoxyprobe-1 Kit, and estimated the cell inflammatory factors, proliferation, migration, invasion, and apoptosis by ELISA, CCK-8, flow cytometry, wound-healing and Transwell. Co-immunoprecipitation and pull-down measurement were used to verify the relationship. PAR-1 was highly expressed in DLBCL tissues and cells, especially in SUDHL2. Na2S2O4 induced SUDHL2 hypoxia, and PAR-1 did not influence thrombin-activated hypoxia. PAR-1 could promote SUDHL2 proliferation, migration, and invasion, and it was unrelated to cellular hypoxia. PAR-1 promoted proliferation, migration, and angiogenesis of EA.hy926 or SUDHL2 through up-regulation vascular endothelial growth factor (VEGF). RH inhibited tumor growth, cell proliferation, and migration, promoted apoptosis of DLBCL, and inhibited angiogenesis by down-regulating PAR-1-VEGF. RH inhibits proliferation, migration, and angiogenesis of DLBCL cells by down-regulating PAR-1-VEGF.

Exploring a Hirudin variant from nonhematophagous leeches: Unraveling full-length sequence, alternative splicing, function, and potential as a novel anticoagulant polypeptide.

ETHNOPHARMACOLOGICAL RELEVANCE: Leeches exhibit robust anticoagulant activity, making them useful for treating cardiovascular diseases in traditional Chinese medicine. Whitmania pigra, the primary source species of leech-derived medicinal compounds in China, has been demonstrated to possess formidable anticoagulant properties. Hirudin-like peptides, recognized as potent thrombin inhibitors, are prevalent in hematophagous leeches. Considering that W. pigra is a nonhematophagic leech, the following question arises: does a hirudin variant exist in this species? AIM OF THE STUDY: In this study we identified the hirudin-encoding gene (WP_HV1) in the W. pigra genome. The goal of this study was to assess its anticoagulant activity and analyze the related mechanisms. MATERIALS AND METHODS: In this study, a hirudin-encoding gene, WP_HV1, was identified from the W. pigra genome, and its accurate coding sequence (CDS) was validated through cloning from cDNA extracted from fresh W. pigra specimens. The structure of WP_HV1 and the amino acids associated with its anticoagulant activity were determined by sequence and structural analysis and prediction of its binding energy to thrombin. E. coli was used for the expression of WP_HV1 and recombinant proteins with various structures and mutants. The anticoagulant activity of the synthesized recombinant proteins was then confirmed using thrombin time (TT). RESULTS: Validation of the WP_HV1 gene was accomplished, and three alternative splices were discovered. The TT of the blank sample exceeded that of the recombinant WP_HV1 sample by 1.74 times (0.05 mg/ml), indicating positive anticoagulant activity. The anticoagulant activity of WP_HV1 was found to be associated with its C-terminal tyrosine, along with the presence of 9 acidic amino acids on both the left and right sides. A significant reduction in the corresponding TT was observed for the mutated amino acids compared to those of the wild type, with decreases of 4.8, 6.6, and 3.9 s, respectively. In addition, the anticoagulant activity of WP_HV1 was enhanced and prolonged for 2.7 s when the lysine-67 residue was mutated to tryptophan. CONCLUSION: Only one hirudin-encoding variant was identified in W. pigra. The active amino acids associated with anticoagulation in WP_HV1 were resolved and validated, revealing a novel source for screening and developing new anticoagulant drugs.

Hirudin enhances perforator flap survival: Clinical application report and mechanistic exploration.

BACKGROUND AND PURPOSE: Hirudin, a potent anticoagulant, is used in traditional Chinese medicine (TCM) to treat thrombotic conditions and prevent postoperative thrombosis. Coagulation-related vascular complications are a common cause of perforator flaps failure. This study explores hirudin's potential to enhance flap growth by mitigating coagulation-related issues. MATERIALS AND METHODS: Patients were divided into GroupⅠ(hirudin group) and GroupⅡ(control). Laboratory tests covered red blood cell count (RBC), hematocrit (HCT), platelet count (PLT), monocyte count (MONO), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-Dimer. Clinical parameters, including capillary refill time (CRT), flap swelling, and survival status, were evaluated. Animal experiments used Sprague-Dawley (SD) rats to establish random skin flaps. The experimental side received hirudin injection, while the control side received saline. Flaps were photographed to calculate survival rate, and CD31 immunohistochemical (IHC) analysis was performed to calculate microvessel density (MVD). RESULTS: The study, with 29 patients, found significant CRT differences between groups on postoperative days 2 and 6 (p = 0.027; p = 0.019), favoring GroupⅠ. Swelling severity varied significantly over time; GroupⅡhad more pronounced swelling. GroupⅠshowed superior flap growth with fewer complications, statistically significant (p = 0.033). Specific lab indicators (MONO, PT, and FIB) were significant at certain times. In animal experiments, the experimental side consistently had higher flap survival and slightly increased CD31 expression at various times, with higher MVD on days 2 and 6. CONCLUSIONS: Hirudin enhances flap survival through diverse mechanisms, supporting its role as a complementary approach in perforator flap surgeries.

Differential Use of Glycoprotein IIb/IIIa Inhibitors with Bivalirudin in Patients with STEMI Undergoing PCI: A Systematic Review and Meta-Analysis.

AIM: The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. METHODS: Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72-0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57-0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66-0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72-0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13-2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24-0.65; P = 0.0003). CONCLUSION: Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.

Bivalirudin versus heparin in ST and non-ST-segment elevation myocardial infarction-Outcomes at two years.

BACKGROUND: The registry-based randomized VALIDATE-SWEDEHEART trial (NCT02311231) compared bivalirudin vs. heparin in patients undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI). It showed no difference in the composite primary endpoint of death, MI, or major bleeding at 180 days. Here, we report outcomes at two years. METHODS: Analysis of primary and secondary endpoints at two years of follow-up was prespecified in the study protocol. We report the study results for the extended follow-up time here. RESULTS: In total, 6006 patients were enrolled, 3005 with ST-segment elevation MI (STEMI) and 3001 with Non-STEMI (NSTEMI), representing 70 % of all eligible patients with these diagnoses during the study. The primary endpoint occurred in 14.0 % (421 of 3004) in the bivalirudin group compared with 14.3 % (429 of 3002) in the heparin group (hazard ratio [HR] 0.97; 95 % confidence interval [CI], 0.85-1.11; P = 0.70) at one year and in 16.7 % (503 of 3004) compared with 17.1 % (514 of 3002), (HR 0.97; 95 % CI, 0.96-1.10; P = 0.66) at two years. The results were consistent in patients with STEMI and NSTEMI and across major subgroups. CONCLUSIONS: Until the two-year follow-up, there were no differences in endpoints between patients with MI undergoing PCI and allocated to bivalirudin compared with those allocated to heparin. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02311231.

Bivalirudin as a substitute for heparin in neurointervention for patients with heparin-induced thrombocytopenia.

OBJECTIVES: Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS: Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients. RESULTS: Bivalirudin was safely and effectively used in the case reported, with no thrombotic or hemorrhagic complications. Our literature review revealed a paucity of studies on the use of heparin alternatives, including bivalirudin, in neuroendovascular procedures in patients with heparin-induced thrombocytopenia. CONCLUSIONS: Heparin-induced thrombocytopenia is an important iatrogenic disease process in patients undergoing neuroendovascular procedures, and developing protocols to diagnose and manage heparin-induced thrombocytopenia is important for healthcare systems. While further research needs to be done to establish the full range of anticoagulation options to substitute for heparin, our case indicates bivalirudin as a potential candidate.