Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass (PRODOSE)

Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass (PRODOSE)

The PRODOSE trial is investigating a bespoke pharmacokinetic algorithm that calculates a tailored dose of protamine, required after cardiopulmonary bypass to reverse the action of heparin, based on individual patients and their actual bypass time.

The PRODOSE trial aims to demonstrate that the algorithm can be used to define a protamine dose that will more reliably return coagulation parameters to pre-heparin levels as well as decreasing the risk of post-operative bleeding and transfusion.

The trial aims to recruit 200 patients who will be randomised to either a bespoke or standard dose of protamine. The randomisation ratio will be 1:1 in the first instance but the trial uses an adaptive design and an interim analysis will be conducted after 100 patients have been randomised. The randomisation ratio could then be updated after the interim analysis to favour a superior arm whilst preserving statistical power levels.

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Cardiovascular Diseases
• Intervention / Treatment: Procedure: Standard Care; Procedure: PRODOSE Algorithm

Detailed Description

Open-heart surgery is routinely conducted using a heart-lung machine. In order to conduct operations involving heart-lung machines a patient's coagulation system needs to be reliably suppressed to avoid clot formation. Clot in the extracorporeal circuit generally has fatal consequences.

In the vast majority of cases (>99%) the desired suppression of the blood clotting system is achieved by administering heparin. Although relatively short acting, with a half-life of about 150min for a full adult dose, heparin needs to be reversed after weaning from the heart-lung machine in order to avoid catastrophic bleeding post-operatively.

Heparin reversal is achieved by using protamine. This drug is derived from salmon sperm and is generally safe to use. However, in a reasonable number of cases it can have severe side effects, ranging from dangerous hypotension to high blood pressure in the lung circulation with adequately oxygenate the patient. Severe anaphylactic reactions have also been described. There is also increasing evidence that inadequately high doses of protamine may lead to an increased bleeding tendency.

There is controversy about the right dosing of protamine. Traditionally a pragmatic and empirical '1:1' formula is used reversing 100 Units of heparin with 1mg of protamine. This dosing regime does not take the decay of heparin during the time spent on the heart-lung machine into account and potentially exposes patients to unnecessarily high doses of protamine.

The research team was previously able to demonstrate in a pilot project that using a pharmacokinetic algorithm, which takes heparin decay into account, can reduce the protamine dose given to patients without increased bleeding or transfusion requirements.

The team have continued to develop this algorithm into a 2 compartmental model and are seeking to test the hypothesis that using the new formula can reduce patients' risk of the unwanted side-effects of protamine by reducing its dose.

• Study Type: Interventional
• Enrollment (Actual): 228
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
      • Royal Papworth Hospital NHS Foundation Trust

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 scheduled to undergo elective cardiac surgery

Exclusion Criteria:

• Emergency surgery
• Age < 18 years
• Known or suspected coagulopathy or platelet dysfunction
• Adenosine diphosphate (ADP)-receptor antagonists within 7 days of surgery (clopidogrel, ticlopidine, prasugrel)
• Total body weight > 130kg
• End stage renal failure requiring dialysis
• Plan for severe hypothermia (< 28°C) or deep hypothermic circulatory arrest
• Complex cardiac surgery (redo sternotomy, surgery on the thoracic aorta [excluding root])
• Transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Standard Care; At the conclusion of cardiopulmonary bypass, protamine administration will be undertaken at surgical request. For patients in the control group, protamine will be dosed on a 1:1 ratio according to the total dose of heparin initially required to establish a therapeutic activated clotting time (ACT) (i.e. if 30,000 IU were required prior to initiating cardiopulmonary bypass, then the protamine dose will be 300mg).	Procedure: Standard Care; Protamine administered according to Standard Care
Experimental: Algorithm; For patients in the intervention group, protamine will be administered according to the PRODOSE algorithm, which has been incorporated into an Excel spread sheet for ease of use (Microsoft Corporation).	Procedure: PRODOSE Algorithm; Protamine administered according to PRODOSE algorithm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Return to normal coagulation after cessation of cardiopulmonary bypass and reversal of heparin	Kaolin Thrombelastography (TEG) r-time	3 minutes post-protamine administration after cessation of cardiopulmonary bypass.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood loss	Intercostal drain output	4 hours post-surgery
Blood products usage	Use of blood products	24 hours post-surgery

Collaborators and Investigators

• Sponsor: Papworth Hospital NHS Foundation Trust
• Collaborators: Austin Health
• Investigators: Principal Investigator: Florian Falter, FRCA, Royal Papworth Hospital NHS Foundation Trust; Principal Investigator: Lachlan Miles, FRCA, Austin Health

Publications and helpful links

General Publications

• Miles LF, Burt C, Arrowsmith J, McKie MA, Villar SS, Govender P, Shaylor R, Tan Z, De Silva R, Falter F. Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial. PLoS Med. 2021 Jun 7;18(6):e1003658. doi: 10.1371/journal.pmed.1003658. eCollection 2021 Jun.

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2018
• Primary Completion (Actual): October 30, 2019
• Study Completion (Actual): January 30, 2020

Study Registration Dates

• First Submitted: April 26, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): June 23, 2020
• Last Update Submitted That Met QC Criteria: June 21, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Protamine; Cardiopulmonary Bypass; Heparin Antagonists
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases
• Other Study ID Numbers: P02337

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: No
• Studies a U.S. FDA-regulated device product: No