Strategies for Protamine Dosing After Anticoagulation in Cardiovascular Surgery (SEPARATION)

Comparison of Two Strategies for Protamine Dosing After Anticoagulation in Cardiovascular Surgery Regarding Postoperative Bleeding: Total Heparin Administered Versus Residual Heparin Determined by a Pharmacokinetic Model

In cardiovascular surgery, patients are anticoagulated with heparin during cardiopulmonary bypass, subsequently, anticoagulation is reversed with protamine to reduce bleeding due to residual heparin-induced coagulopathy, which can last more than four hours. Protamine reverses the effect of heparin by binding to each heparin molecule, therefore an amount of protamine equivalent to residual heparin is required at the time that anticoagulation is desired to be reversed, but generally, the dose of protamine is calculated from the total dose of heparin, ignoring that heparin is metabolized and cleared during of the extracorporeal circulation, this excess of protamine produces anticoagulant effects that increase postoperative bleeding. Residual heparin can be estimated from heparin pharmacokinetic models and therefore, from these models, a dose closer to the amount necessary to reverse the effect of heparin can be estimated, avoiding protamine excess. In this study, a protamine dosage strategy based on residual heparin determined by a pharmacokinetic model of heparin versus total administered heparin will be compared regarding bleeding and use of blood components in the postoperative period.

Study Overview

• Status: Unknown
• Conditions: Anticoagulant Antagonist Toxicity
• Intervention / Treatment: Drug: Conventional dose; Drug: Dosing according residual heparin

• Study Type: Interventional
• Enrollment (Anticipated): 136
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Fabian Cortez, MSc; Phone Number: +57 (1) 593 8210; Email: fabian.cortes@shaio.org

Study Locations

• Colombia
  • Bogotá, Colombia
    • Recruiting
    • Fundacion ABOOD Shaio
    • Contact: Mauricio Abello; Phone Number: +57 3103218780; Email: mauricio.abello@shaio.org
    • Principal Investigator: David Ramirez

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients over 18 years of age who undergo scheduled cardiovascular surgery or scheduled urgency at the Shaio clinical foundation in the city of Bogotá, who require extracorporeal circulation.
• ASA classification, between 1 - 4
• Informed consent read and signed by the patient
• No history of known blood dyscrasia, with INR values <1.5
• Platelet count greater than 100,000
• No history of heparin-induced thrombocytopenia
• No history of adverse reaction to protamine
• No use of dual anti-aggregation therapy acetylsalicylic acid (ASA) + ADP receptor inhibitors (Clopidogrel) at the time of surgery
• Suspension of ADP receptor inhibitor drugs (Clopidogrel) according to institutional protocol.
• No use of bridging therapy with tirofiban
• Patient with chronic use of oral anticoagulants (warfarin, dabigatran), complete the suspension time according to the institutional protocol,
• No requirement for renal replacement therapy in the last month
• Patient with BMI between 18 - 41 kg / cm2
• Not pregnant

Exclusion Criteria:

• Emergency surgery
• Anticoagulated patient at the time of the intervention
• Procedure not performed under extracorporeal circulation.
• Procedure requiring circulatory arrest and / or profound hypothermia
• Intraoperative death before protamine administration
• Inability to complete data collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Protamine dosing according the total heparin administrated; The protamine dose will be calculated according to the total heparin administered including the heparin dose add during the pump purge, 1 mg of protamine for each 100 IU of heparin	Drug: Conventional dose; Conventional dose used to calculated the protamine dose
EXPERIMENTAL: Protamine dosing according the residual heparin determined by a pharmacokinetic model; The protamine dose will be calculated according to the residual heparin estimated before the separation of the cardiopulmonary bypass using a pharmacokinetic model, 1 mg of protamine for each 100 IU of residual heparin	Drug: Dosing according residual heparin; In this group the heparin doses will be simulated using a pharmacokinetic model to estimated the residual heparin amount at the end of the surgery, the protamine dose will be calculated using the residual heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
postoperative mediastinal bleeding	total blood collected from the mediastinal chest tubes during the first 24 hours	first 24 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
total blood products transfused	red blood cells, plasma, cryoprecipitate, platelets, fibrinogen, and prothrombin complexes	first 24 hours after surgery

Collaborators and Investigators

• Sponsor: Fundación Clínica Shaio
• Collaborators: Universidad El Bosque, Bogotá
• Investigators: Study Chair: Mauricio Abello, Fundacion ABOOD Shaio; Principal Investigator: David Ramez, Universidad del bosque

Publications and helpful links

General Publications

• Puis L, Milojevic M, Boer C, De Somer FMJJ, Gudbjartsson T, van den Goor J, Jones TJ, Lomivorotov V, Merkle F, Ranucci M, Kunst G, Wahba A; EACTS/EACTA/EBCP Committee Reviewers. 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery. Interact Cardiovasc Thorac Surg. 2020 Feb 1;30(2):161-202. doi: 10.1093/icvts/ivz251. No abstract available.
• Delavenne X, Ollier E, Chollet S, Sandri F, Lanoiselee J, Hodin S, Montmartin A, Fuzellier JF, Mismetti P, Gergele L. Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass. Br J Anaesth. 2017 May 1;118(5):705-712. doi: 10.1093/bja/aex044.
• Meesters MI, Veerhoek D, de Jong JR, Boer C. A Pharmacokinetic Model for Protamine Dosing After Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 2016 Oct;30(5):1190-5. doi: 10.1053/j.jvca.2016.04.021. Epub 2016 Apr 28.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 15, 2020
• Primary Completion (ANTICIPATED): November 20, 2021
• Study Completion (ANTICIPATED): November 22, 2021

Study Registration Dates

• First Submitted: November 9, 2020
• First Submitted That Met QC Criteria: November 9, 2020
• First Posted (ACTUAL): November 16, 2020

Study Record Updates

• Last Update Posted (ACTUAL): December 1, 2020
• Last Update Submitted That Met QC Criteria: November 28, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: cardiopulmonary bypass; dose; heparin; extracorporeal circulation; protamine
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin
• Other Study ID Numbers: DIB-20-34

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes