Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass

NCT ID: NCT03532594

Last Updated: 2020-06-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 228 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-16
• Study Completion Date: 2020-01-30

Brief Summary

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.

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.

Conditions

Heart Diseases; Cardiovascular Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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).

Group Type: OTHER

Standard Care

Intervention Type: PROCEDURE

Protamine administered according to Standard Care

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).

Group Type: EXPERIMENTAL

PRODOSE Algorithm

Intervention Type: PROCEDURE

Protamine administered according to PRODOSE algorithm

Interventions

PRODOSE Algorithm

Protamine administered according to PRODOSE algorithm

Intervention Type: PROCEDURE

Standard Care

Protamine administered according to Standard Care

Intervention Type: PROCEDURE

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Austin Health

OTHER_GOV

Sponsor Role: collaborator

Papworth Hospital NHS Foundation Trust

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Florian Falter, FRCA

Role: PRINCIPAL_INVESTIGATOR

Royal Papworth Hospital NHS Foundation Trust

Lachlan Miles, FRCA

Role: PRINCIPAL_INVESTIGATOR

Austin Health

Locations

Royal Papworth Hospital NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom

Countries

United Kingdom

References

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.

Reference Type: DERIVED

PMID: 34097705 (View on PubMed)

Other Identifiers

P02337

Identifier Type: -

Identifier Source: org_study_id