Clinical trial NCT03532594: Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass
Official title: Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass (PRODOSE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Diseases
Cardiovascular Diseases
Keywords: Protamine
Heparin Antagonists
Cardiopulmonary Bypass
Lead sponsor: Papworth Hospital NHS Foundation Trust
Sponsor class: OTHER_GOV
Collaborators: name: Austin Health
First posted: 2018-05-22
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Return to normal coagulation after cessation of cardiopulmonary bypass and reversal of heparin
timeFrame: 3 minutes post-protamine administration after cessation of cardiopulmonary bypass.
Secondary outcomes:
measure: Blood loss
timeFrame: 4 hours post-surgery
measure: Blood products usage
timeFrame: 24 hours post-surgery
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Royal Papworth Hospital NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Royal Papworth Hospital NHS Foundation Trust
name: Florian Falter, FRCA
role: PRINCIPAL_INVESTIGATOR
affiliation: Austin Health
name: Lachlan Miles, FRCA
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.