Evaluation of Recombinant Factor VIIa Utilization and Development of a Cost-Effective Dose Minimization Protocol in Adult Cardiac Surgery Patients at an Academic Medical Center

Abstract Background: Although recombinant factor VIIa is often utilized to mitigate critical bleeding following cardiac surgery, the optimal dosing strategy in this population is not well-established. At our institution, hospital guidelines recommend administration of recombinant factor VIIa 60 mcg/kg for all off-label indications. However, available data suggest doses as low as 17 mcg/kg have been efficacious in cardiac surgery patients with critical bleeding. Additionally, although low-dose recombinant factor VIIa (< 40 mcg/kg) and high-dose (50-109 mcg/kg) dosing strategies have been reported equally efficacious according to retrospective, observational studies, higher doses may be associated with increased incidence of adverse events. Therefore, we aimed to evaluate the safety of recombinant factor VIIa in cardiac surgery patients with critical bleeding, and estimate potential cost-savings associated with implementation of a low-dose recombinant factor VIIa protocol in this population. Methods: All adult cardiac surgery patients who received one or more doses of recombinant factor VIIa during a 1-year period (July 1, 2016 to June 30, 2017) were included. Thromboembolic event rates documented within 14 days following recombinant factor VIIa administration were evaluated in patients alive at discharge. An average wholesale price of 2.59 USD per mcg was utilized for recombinant factor VIIa cost calculations. Results: A total of 16 patients received 24 doses of recombinant factor VIIa during the study period. The median weight-based dose administered was 55 mcg/kg (utilizing actual body weight), and the median dose was 5 mg. The median cost per recombinant factor VIIa dose was 12,950 USD, resulting in a total expenditure of 277,174 USD. Nine of sixteen patients (56%) survived to hospital discharge. Five of nine (56%) patients alive at discharge experienced thromboembolic complications following recombinant factor VIIa administration, three (60%) of which were central nervous system (CNS) thromboembolic events. Based on data supporting low-dose strategies, a proposed weight-based recombinant factor VIIa dose-minimization protocol was developed by leadership in the departments of pharmacy, hematology, cardiac surgery, and cardiac anesthesia (Table 1). Implementation of this protocol would result in an estimated annual cost-avoidance of 168,376 USD. Conclusions: Recombinant factor VIIa administration at a dose of 55 mcg/kg in adult cardiac surgery patients with critical bleeding is associated with a high rate of thromboembolic events, including CNS thromboembolism. Additionally, this recombinant factor VIIa dosing strategy is associated with significant cost, which can be substantially reduced with implementation of a low-dose recombinant factor VIIa protocol in the cardiac surgery population. Disclosures No relevant conflicts of interest to declare.

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Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients

Critical Care ◽

10.1186/s13054-020-03375-7 ◽

2020 ◽

Vol 24 (1) ◽

Cited By ~ 1

Author(s):

Sandra Jonmarker ◽

Jacob Hollenberg ◽

Martin Dahlberg ◽

Otto Stackelberg ◽

Jacob Litorell ◽

...

Keyword(s):

Body Weight ◽

Confidence Intervals ◽

Critically Ill ◽

Low Dose ◽

Cox Proportional Hazards ◽

High Dose ◽

Thromboembolic Events ◽

Risk Of Death ◽

Dosing Strategy ◽

Medium Dose

Abstract Background A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. Method In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. Results A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13–0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43–1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Conclusions Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. Trial registration Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

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Patients with Severe Factor XI Deficiency Who Have An Inhibitor or IgA Deficiency Can Undergo Uneventful Major Surgery by a Single Infusion of Low Dose Recombinant Factor VIIa and Use of Tranexamic Acid.

Blood ◽

10.1182/blood.v112.11.1215.1215 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1215-1215 ◽

Cited By ~ 1

Author(s):

Ophira Salomon ◽

Ilia Tamarin ◽

Tami Livnat ◽

Zeev Horovitz ◽

Joseph Kuriansky ◽

...

Keyword(s):

Tranexamic Acid ◽

Low Dose ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Iga Deficiency ◽

Major Surgery ◽

High Dose ◽

Single Infusion ◽

Factor Xi ◽

Factor Xi Deficiency

Abstract Inhibitors to factor XI (FXI) can develop following exposure to plasma products in 33% of patients with severe FXI deficiency who are homozygous for the type II nonsense mutation prevalent in Jews (Salomon et al. Blood2003;101:4783). Hemostasis in five such patients was previously achieved during surgery by infusion of recombinant factor VIIa (rFVIIa) and tranexamic acid, but two patients experienced arterial thrombosis following surgery (Schulman et al. Hemophilia2006; 12:223). Conceivably, the rather high dose of rFVIIa used was responsible for the thrombotic events in these patients. In a previous in vitro study, we showed that low concentrations of rFVIIa can correct thrombin generation in plasma of patients with severe FXI deficiency and an inhibitor to FXI (Livnat et al. J Thromb Hemost2006; 4:192). In the present study we addressed the question whether low doses of rFVIIa and use of tranexamic would be hemostatically effective and less thrombogenic during and after major surgery in patients with severe FXI deficiency in whom plasma derivatives could not be used. Three patients (two with FXI inhibitor and one with severe IgA deficiency) underwent major surgery managed by a single low dose infusion of rFVIIa and administration of tranexamic acid 1 G q.i.d for 7 days (Table). In patient 1 the infusion was given immediately prior to surgery and in patients 2 and 3 at the end of surgery. Hemostasis was achieved in all patients and no thrombosis occurred. No. Sex/age FXI (U/dL) FXI inhibitor (B.U) Operation Single dose rVIIa (uG/Kg) Adverse events * IgA deficiency 1 M/62 < 0.01 5.0 Laparoscopic cholecystectomy 30 None 2 M/61 < 0.01 5.0 Transuretheral prostatectomy 16 None 3 M/63 0.02 0* Parathyroidectomy 15 None These observations suggest that a single infusion of low dose rFVIIa and use of tranexamic acid can be a safe modality of treatment in patients with severe FXI deficiency who cannot receive blood products. Furthermore, the protocol outlined here may be used to avoid inhibitor formation in patients with extremely severe FXI deficiency who undergo surgery.

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148: A COMPARISON OF LOW- AND HIGH-DOSE RECOMBINANT FACTOR VIIA AFTER CARDIAC SURGERY

Critical Care Medicine ◽

10.1097/01.ccm.0000618952.87315.ce ◽

2020 ◽

Vol 48 (1) ◽

pp. 57-57

Author(s):

Megan Van Berkel Patel ◽

Lauren Caldwell ◽

Cimaron Blalock

Keyword(s):

Cardiac Surgery ◽

Recombinant Factor Viia ◽

Factor Viia ◽

High Dose

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DOSING OF THROMBOPROPHYLAXIS AND MORTALITY IN CRITICALLY ILL COVID-19 PATIENTS

10.1101/2020.09.17.20195867 ◽

2020 ◽

Author(s):

Sandra Jonmarker ◽

Jacob Hollenberg ◽

Martin Dahlberg ◽

Otto Stackelberg ◽

Jacob Litorell ◽

...

Keyword(s):

Body Weight ◽

Confidence Intervals ◽

Critically Ill ◽

Low Dose ◽

Cox Proportional Hazards ◽

High Dose ◽

Thromboembolic Events ◽

Bleeding Events ◽

Risk Of Death ◽

Dosing Strategy

Background: A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association of initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. Method: All critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500−4500 IU tinzaparin or 2500−5000 IU dalteparin), medium (>4500 IU but <175 IU/kilogram, kg, of body weight tinzaparin or >5000 IU but <200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body-mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. Results: A total of 152 patients were included; 67 received low, 48 medium, and 37 high dose thromboprophylaxis. Baseline characteristics did not differ between groups. Mortality was lower in high (13.5%) vs medium (25.0%) and low dose thromboprophylaxis (38.8%) groups, p≡0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13 − 0.87) among those who received high dose, respectively 0.88 (95% confidence intervals 0.43 − 1.83) among those who received medium dose, as compared with those who received low dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low dose thromboprophylaxis (17.9%) groups, p≡0.04, but no difference in the proportion of bleeding events, p≡0.16. Conclusions: Among critically ill COVID-19 patients with respiratory failure, high dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.

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Antithrombotic and hemostatic stewardship: evaluation of clinical outcomes and adverse events of recombinant factor VIIa (Novoseven®) utilization at a large academic medical center

Therapeutic Advances in Cardiovascular Disease ◽

10.1177/1753944720924255 ◽

2020 ◽

Vol 14 ◽

pp. 175394472092425 ◽

Cited By ~ 1

Author(s):

Kassandra Marsh ◽

David Green ◽

Veronica Raco ◽

John Papadopoulos ◽

Tania Ahuja

Keyword(s):

Cardiac Surgery ◽

Adverse Events ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Academic Medical Center ◽

Blood Bank ◽

Thromboembolic Events ◽

Blood Products ◽

New York University ◽

Off Label

Background: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. Methods: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. Results: A total of 63 patients [pediatric ( n = 6), adult ( n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. Conclusion: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

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High-dose versus low-dose opioid anesthesia in adult cardiac surgery: A meta-analysis

Journal of Clinical Anesthesia ◽

10.1016/j.jclinane.2019.03.009 ◽

2019 ◽

Vol 57 ◽

pp. 57-62

Author(s):

Lisa Q. Rong ◽

Mohamed K. Kamel ◽

Mohamed Rahouma ◽

Ajita Naik ◽

Kritika Mehta ◽

...

Keyword(s):

Cardiac Surgery ◽

Low Dose ◽

Meta Analysis ◽

High Dose ◽

Adult Cardiac Surgery

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Low-Dose Recombinant Factor VIIa in the Management of Uncontrolled Postoperative Hemorrhage in Cardiac Surgery Patients

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1053/j.jvca.2005.06.005 ◽

2006 ◽

Vol 20 (4) ◽

pp. 573-575 ◽

Cited By ~ 12

Author(s):

Ewoudt M.W. van de Garde ◽

Leo J. Bras ◽

Robin H. Heijmen ◽

Catherijne A.J. Knibbe ◽

Eric P.A. van Dongen ◽

...

Keyword(s):

Cardiac Surgery ◽

Low Dose ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Postoperative Hemorrhage

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Comparison of the in-vivo Effect of Two Tranexamic Acid Doses on Fibrinolysis Parameters in Adults Undergoing Valvular Cardiac Surgery with Cardiopulmonary Bypass - A Pilot Investigation

10.21203/rs.3.rs-65365/v1 ◽

2020 ◽

Author(s):

Zhen-feng ZHOU ◽

Wen Zhai ◽

Li-na YU ◽

Kai SUN ◽

Li-hong SUN ◽

...

Keyword(s):

Cardiac Surgery ◽

Placebo Group ◽

Cardiopulmonary Bypass ◽

Plasminogen Activator ◽

Dose Group ◽

Low Dose ◽

High Dose Group ◽

High Dose ◽

Pai 1

Abstract Background: The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB, which has not been systematically elucidated.Methods: A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T1), 5 min after the TXA bolus (T2), 5 min after the initiation of CPB (T3), 5 min before the end of CPB (T4) and 5 min after the protamine administration (T5). A Thrombelastography (TEG) and standard coagulation test were also performed.Results: Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (p <0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (p <0.05); TAFI concentrations also decreased at the T5 in low-dose group (p <0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. No significant differences were observed in the levels of the coagulation proteins at any points between the groups.Conclusions: The vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass, and we recommend a low dose TXA regimen for those patients.Clinical trial number and registry URL: ChiCTR-IPR-17010303; http://www.chictr.org.cn, Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.

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