bivalirudin and Critical-Illness

To assess the effect of anticoagulation with bivalirudin administered intravenously on gas-exchange in patients with COVID-19 and respiratory failure using invasive mechanical ventilation.. This is a single centre parallel group, superiority, randomized (1:1 allocation ratio) controlled trial.. All patients admitted to the Hamad Medical Corporation -ICU in Qatar for COVID-19 associated respiratory distress and in need of mechanical ventilation are screened for eligibility.. all adult patients admitted to the ICU who test positive for COVID-19 by PCR-test and in need for mechanical ventilation are eligible for inclusion. Upon crossing the limit of D-dimers (1.2 mg/L) these patients are routinely treated with an increased dose of anticoagulant according to our local protocol. This will be the start of randomization.. pregnancy, allergic to the drug, inherited coagulation abnormalities, no informed consent.. The intervention group will receive the anticoagulant bivalirudin intravenously with a target aPTT of 45-70 sec for three days while the control group will stay on the standard treatment with low-molecular-weight heparins /unfractionated heparin subcutaneously (see scheme in Additional file 1). All other treatment will be unchanged and left to the attending physicians.. As a surrogate parameter for clinical improvement and primary outcome we will use the PaO2/FiO2 (P/F) ratio.. After inclusion, the patients will be randomized using a closed envelope method into the conventional treatment group, which uses the standard strategy and the experimental group which receives anticoagulation treatment with bivalirudin using an allocation ratio of 1:1.. Due to logistical and safety reasons (assessment of aPTT to titrate the study drug) only the data-analyst will be blinded to the groups.. We performed a sample size calculation and assumed the data for P/F ratio (according to literature) is normally distributed and used the mean which would be: 160 and SD is 80. We expect the treatment will improve this by 30%. In order to reach a power of 80% we would need 44 patients per group (in total 88 patients). Taking approximately 10% of dropout into account we will include 100 patients (50 in each group).. The local registration number is MRC-05-082 with the protocol version number 2. The date of approval is 18th June 2020. Recruitment started on 28. The protocol is registered before starting subject recruitment under the title: "Anticoagulation in patients suffering from COVID-19 disease. The ANTI-CO Trial" in ClinicalTrials.org with the registration number: NCT04445935 . Registered on 24 June 2020.. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 2). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Topics: Anticoagulants; Antithrombins; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Critical Illness; Fibrin Fibrinogen Degradation Products; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pandemics; Partial Thromboplastin Time; Peptide Fragments; Pneumonia, Viral; Qatar; Recombinant Proteins; Respiration, Artificial; Respiratory Distress Syndrome; SARS-CoV-2

Direct thrombin inhibitors offer potential advantages over unfractionated heparin but have been poorly studied in children.. To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration.. The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children aged 6 months to 18 years. Drug initiation consisted of a bolus dose (0.125 mg kg(-1) ) followed by continuous infusion (0.125 mg kg h(-1) ). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 h and 25-35 days.. Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. The infusion rate bivalirudin correlated more closely with drug concentration than the APTT. At 48-72 h, nine (50%) patients had complete or partial thrombus resolution, increasing to 16 (89%) at 25-35 days. No major and one minor bleeding event occurred.. Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT.

Topics: Adolescent; Age Factors; Antithrombins; Biomarkers; Child; Child, Preschool; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hemorrhage; Hirudins; Humans; Infant; Infusions, Intravenous; Injections, Intravenous; Male; Partial Thromboplastin Time; Peptide Fragments; Prospective Studies; Recombinant Proteins; Venous Thrombosis

To evaluate the safety and efficacy of bivalirudin compared with heparin for preventing hemofilter occlusion during continuous venovenous hemofiltration (CVVH).. Prospective, randomized, double-blind study.. University-affiliated hospital.. Ten critically ill adults (median age 58 yrs, 70% male) with acute renal failure who, without anticoagulation, experienced hemofilter survival time of 24 hours or less during CVVH.. Patients were randomized to receive bivalirudin 2 mg/hour (five patients) or heparin 400 units/hour (five patients) administered prefilter into the extracorporeal circuit.. Patients had a median Acute Physiology and Chronic Health Evaluation (APACHE) II score of 24, Sequential Organ Failure Assessment (SOFA) score of 11, and reduced antithrombin activity (75.5 units/dl). Baseline characteristics were not significantly different between groups. Study drug was administered in 40 hemofilters (18 from bivalirudin-treated patients, 22 from heparin-treated patients). The primary efficacy outcome was hemofilter survival time, defined as the interval of time between commencement of CVVH with a new extracorporeal circuit (hemofilter) and hemofilter failure. Compared with no anticoagulation, the addition of bivalirudin or heparin significantly improved hemofilter survival time (mean ± SD 10 ± 5 hrs with no anticoagulation vs 22 ± 18 hrs with anticoagulation, p=0.0005). Hemofilter survival time was significantly increased in patients receiving bivalirudin versus those receiving heparin (29.6 ± 20.7 vs 16.5 ± 13.6 hrs, p=0.045). Independent predictors of hemofilter survival were use of bivalirudin therapy and increased antithrombin III activity. No patients randomized to bivalirudin experienced any bleeding or thrombosis events; one patient who received heparin developed alveolar hemorrhage, and one developed a lower extremity deep vein thrombosis.. Compared with heparin, bivalirudin was more efficacious in prolonging hemofilter survival time and was well tolerated. Additional studies of bivalirudin for prevention of hemofilter occlusion during continuous renal replacement therapy are warranted.

Topics: Acute Kidney Injury; Anticoagulants; Antithrombins; Critical Illness; Double-Blind Method; Female; Hemofiltration; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Recombinant Proteins; Time Factors

Thromboelastography (TEG) offers a more dynamic assessment of hemostasis over activated partial thromboplastin time (aPTT). However, the clinical utility of TEG in monitoring bivalirudin during extracorporeal membrane oxygenation (ECMO) remains unknown. The purpose of this study was to evaluate the correlation between aPTT and TEG in adult ECMO patients anticoagulated with bivalirudin.. Multicenter, retrospective, cohort study conducted over a 2-year period.. Two academic university medical centers (Banner University Medical Center) in Phoenix and Tucson, AZ.. Adult patients requiring ECMO and bivalirudin therapy with ≥1 corresponding standard TEG and aPTT plasma samples drawn ≤4 h of each other were included. The primary endpoint was to determine the correlation coefficient between the standard TEG reaction (R) time and bivalirudin aPTT serum concentrations.. A total of 104 patients consisting of 848 concurrent laboratory assessments of R time and aPTT were included. A moderate correlation between TEG R time and aPTT was demonstrated in the study population (r = 0.41; p < 0.001). Overall, 502 (59.2%) concurrent assessments of TEG R time and aPTT values showed agreement on whether they were sub-, supra-, or therapeutic according to the institution's classification for bivalirudin. The 42.2% (n = 271/642) discordant TEG R times among "therapeutic" aPTT were almost equally distributed between subtherapeutic and supratherapeutic categories.. Moderate correlation was found between TEG R time and aPTT associated with bivalirudin during ECMO in critically ill adults. Further research is warranted to address the optimal test to guide clinical decision-making for anticoagulation dosing in ECMO patients.

Topics: Adult; Anticoagulants; Cohort Studies; Critical Illness; Extracorporeal Membrane Oxygenation; Heparin; Hirudins; Humans; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombelastography

There is a paucity of data regarding the use of direct thrombin inhibitors such as bivalirudin for children on extracorporeal life support (ECLS). We sought to compare the outcomes of children on ECLS anticoagulated with bivalirudin versus heparin. Patients transitioned from heparin to bivalirudin were treated as a separate group. A single-institution, retrospective review of all consecutive children (neonate to 18 years) placed on ECLS in the cardiac or pediatric intensive care units was performed (June 2018-December 2019). Data collected included demographics, anticoagulation strategy, number of circuit interventions, blood product use on ECLS, survival to decannulation, and survival to discharge. Fifty-four children were placed on ECLS for a total of 56 runs. Demographics and venovenous versus venoarterial ECLS were similar. The bivalirudin group had longer median duration of support compared to the heparin group--11.0 days [IQR 6.2, 23.1] versus 3.3 days [2.1, 6.2], P < .001. Patients switched from heparin to bivalirudin had a similar duration of support (10.3 days [8.3, 18.3]) as those on bilvalirudin alone. However, there was no difference in red blood cell, fresh frozen plasma, or platelet transfusions. There was no difference in the number of circuit interventions, survival to decannulation or discharge. The freedom to first circuit intervention was longer with bivalirudin compared to heparin. Our data suggest that even with longer pediatric ECLS runs on bivalirudin, there were no differences in the outcomes between the heparin and bivalirudin groups, with longer freedom from first circuit intervention with bivalirudin. While this is the largest reported series comparing children on ECLS anticoagulated with heparin versus bivalirudin, larger studies are needed to determine the optimal anticoagulation strategy for this diverse and complicated group of children.

Topics: Adolescent; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Critical Illness; Drug Substitution; Extracorporeal Membrane Oxygenation; Female; Hemorrhage; Heparin; Hirudins; Hospitals, High-Volume; Humans; Infant; Intensive Care Units, Pediatric; Male; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Stroke; Thrombosis

CytoSorb is a promising tool to treat severe inflammatory status with multiple mechanisms in the acute care setting. Its effect on drugs is, however, poorly documented in vivo, although removal of small molecules might translate into decreased blood levels of life-saving medications. The aim of this study was to assess the impact of CytoSorb on vancomycin and bivalirudin clearance in a large population of critically ill patients. We performed a single-center analysis of CytoSorb treatments performed between January 2018 and March 2019 in critically ill patients admitted to our intensive care unit. A total of 109 CytoSorb treatments were performed in 89 patients. A decrease in lactate dehydrogenase (P = .007), troponin T (P = .022), and creatine phosphokinase (P = .013) was reported during treatment. Vancomycin dose required significant adjustments during treatment (P < .001), but no significant change was necessary after the first 3 days. Similarly, the requirements of bivalirudin significantly changed over days (P < .001), but no dose adjustment was needed after the first 3 days of treatment. No differences in terms of vancomycin and bivalirudin dose need was observed between patients on extracorporeal membrane oxygenation and those who were not (P = .6 and P = .6, respectively), between patients with and without continuous veno-venous hemofiltration (P = .9 and P = .9, respectively), and between CytoSorb responders or not (P = .4 and P = .7, respectively). CytoSorb is effective in mitigating the systemic inflammatory response and safe with respect to vancomycin and bivalirudin administration. These preliminary data further support the use of CytoSorb as adjunct therapy in critically ill patients.

Topics: Anti-Bacterial Agents; Antithrombins; Biomarkers; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Hemadsorption; Hirudins; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Vancomycin

Anticoagulation with unfractionated heparin (UFH) in critically ill cardiac surgery patients has several limitations, including the risk of heparin-induced thrombocytopenia. The use of a direct thrombin inhibitor, such as bivalirudin, might either treat this complication or completely eliminate it. The aim of the present study was to analyze the use of bivalirudin in this setting, as either a secondary drug switching from heparin or as the primary anticoagulant, and to evaluate clinical outcomes.. Propensity-matching retrospective analysis.. A cardiac surgery intensive care unit.. One hundred propensity-matched patients who received heparin or bivalirudin.. Bivalirudin was administered as a first-line or second-line drug after heparin discontinuation in case of thrombocytopenia and suspicion of heparin-induced thrombocytopenia. Twenty-six patients (52%) received bivalirudin as a primary anticoagulant, while 24 patients (48%) received bivalirudin after switching from heparin.. Bivalirudin treatment was associated with a reduction of major bleeding (p=0.05) compared with the control group. Interestingly, in an intention-to-treat analysis, patients receiving primary bivalirudin showed significant reductions in minor bleeding (p=0.04), and mortality (p=0.01) compared with the secondary bivalirudin group and, similarly, compared with the rest of the study population (UFH and secondary bivalirudin patients, p=0.01 and p=0.05, respectively). Predictors of hospital mortality by multivariate analysis included urgent admission (odds ratio [OR]=2.7; 95 confidence interval [CI], 1.03-7.2; p=0.04), ;septic shock (OR=8.0; 95 CI, 2.26-28.7; p<0.005) and primary therapy with UFH (OR=19.2; 95 CI, 2.2-163.9; p=0.007).. Novel anticoagulant strategies might play a crucial role in critically ill cardiac surgery patients. In a propensity-matched population, results of the present study showed that primary bivalirudin anticoagulation may reduce bleeding complications and mortality.

Topics: Antithrombins; Cardiac Surgical Procedures; Critical Illness; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hirudins; Humans; Injections, Intravenous; Italy; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Propensity Score; Recombinant Proteins; Retrospective Studies; Survival Rate; Thrombosis

Topics: Adrenal Insufficiency; Adrenergic alpha-Agonists; Adult; Anti-Inflammatory Agents; Antihypertensive Agents; Aspirin; Bisoprolol; Critical Illness; Epinephrine; Fibrinolytic Agents; Hirudins; Humans; Hydrocortisone; Male; Peptide Fragments; Piperazines; Prasugrel Hydrochloride; Ramipril; Recombinant Proteins; Shock, Cardiogenic; Thiophenes; Treatment Outcome

To evaluate the safety, effectiveness, and dosing of bivalirudin for treatment of heparin-induced thrombocytopenia (HIT) in critically ill patients with hepatic and/or renal dysfunction.. Retrospective cohort study.. University-affiliated medical center. Eighteen patients older than 18 years who were admitted to the intensive care unit (ICU), had hepatic and/or renal dysfunction, and were treated with bivalirudin for the diagnosis of HIT between January 1, 2004, and March 31, 2005.. Patient records were reviewed for dosage and duration of bivalirudin therapy, occurrence of thrombosis, and clinically significant adverse effects. Of the 18 patients identified, 12 had both hepatic and renal dysfunction (group 1), four had hepatic dysfunction (group 2), and two had renal dysfunction (group 3). Demographics were similar among the groups. Mean +/- SD age was 54 +/- 15 years and weight was 82 +/- 14 kg, 67% were male, 83% were Caucasian, and 56% were receiving renal replacement therapy. Mean bivalirudin doses were 0.06 +/- 0.15 mg/kg/hour (median 0.03 mg/kg/hr), 0.14 +/- 0.05 mg/kg/hour (median 0.14 mg/kg/hr), and 0.05 +/- 0.01 mg/kg/hour (median 0.05 mg/kg/hr) for patients in groups 1, 2, and 3, respectively. Ten patients receiving continuous venovenous hemofiltration with or without dialysis received a mean dose of 0.04 +/- 0.03 mg/kg/hour (median 0.03 mg/kg/hr). In the 18 patients, mean bivalirudin duration was 15 +/- 17 days, activated partial thromboplastin time (aPTT) was 69 +/- 22 seconds, and international normalized ratio was 2.2 +/- 0.8. Supratherapeutic aPTTs were most common on days 1 (22%) and 2 (28%) when bivalirudin doses were highest. Clinically significant bleeding did not occur in any patient. Thrombosis occurred in one patient (6%) while receiving bivalirudin.. Patients in the ICU who have hepatic and/or renal dysfunction require low doses of bivalirudin to achieve aPTT values 1.5-2.5 times baseline. Bivalirudin can be safely started at 0.14 mg/kg/hour in patients with hepatic dysfunction, 0.03-0.05 mg/kg/hour in those with renal or combined hepatic and renal dysfunction, and 0.03-0.04 mg/kg/hour in patients receiving continuous renal replacement therapy.

Topics: Adult; Aged; Anticoagulants; Cohort Studies; Critical Illness; Female; Heparin; Hirudins; Humans; Intensive Care Units; Kidney Diseases; Liver Diseases; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombin; Thrombocytopenia