Routine Versus Selective Protamine Administration to Reduce Bleeding Complications After Transcatheter Aortic Valve Implantation (POPular ACE TAVI)

Routine Versus Selective Protamine Administration to Reduce Bleeding Complications After Transcatheter Aortic Valve Implantation

Heparin reversal by protamine administration after transcatheter aortic valve implantation (TAVI) may reduce bleeding events. However, protamine can also cause life-threatening allergic reactions. High-quality evidence regarding the clinical safety and efficacy of routine protamine administration after TAVI is lacking.

The aim of this clinical trial is to determine if routine protamine administration, compared with selective protamine administration, reduces the risk of all-cause mortality or clinically relevant bleeding within 30 days after transcatheter aortic valve implantation.

Study Overview

• Status: Completed
• Conditions: Aortic Valve Stenosis
• Intervention / Treatment: Drug: Protamine sulfate; Drug: Protamine sulfate

• Study Type: Interventional
• Enrollment (Actual): 1000
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium
    • A.S.Z. Aalst
  • Leuven, Belgium
    • University Hospitals Leuven
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam University Medical Center
  • Limburg
    • Maastricht, Limburg, Netherlands
      • Maastricht UMC
  • South Holland
    • Leiden, South Holland, Netherlands
      • Leiden University Medical Center
  • Utrecht
    • Nieuwegein, Utrecht, Netherlands
      • St. Antonius Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged > 18 years
• Undergoing transfemoral TAVI with any commercially available transcatheter heart valve
• Provided written informed consent

Exclusion Criteria:

• Documented protamine allergy or anaphylaxis
• Recent PCI (< 3 months before TAVI)
• Planned arterial access via surgical cut-down

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Selective protamine administration; Selective protamine administration, in case of (threatening) bleeding.	Drug: Protamine sulfate; Selective protamine administration, in case of (threatening) bleeding; Other Names: Selective heparin reversal; Drug: Protamine sulfate; Routine protamine administration in a ratio of 1 IE per 1 IE of unfractionated heparin.; Other Names: Routine heparin reversal
Active Comparator: Routine protamine administration; Routine protamine administration in a ratio of 1 IE per 1 IE of unfractionated heparin.	Drug: Protamine sulfate; Selective protamine administration, in case of (threatening) bleeding; Other Names: Selective heparin reversal; Drug: Protamine sulfate; Routine protamine administration in a ratio of 1 IE per 1 IE of unfractionated heparin.; Other Names: Routine heparin reversal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of all-cause mortality or type 1-4 bleeding	According to the VARC-3 criteria	30 days after TAVI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All bleeding	According to the VARC-3 criteria type 1-4 bleeding	30 days after TAVI
Major, life-threatening or fatal bleeding	According to the VARC-3 criteria type 2-4 bleeding	30 days after TAVI
Major vascular complications	According to the VARC-3 criteria	30 days after TAVI
Cardiovascular mortality	According to the VARC-3 criteria	30 days after TAVI
All-cause mortality	According to the VARC-3 criteria	30 days after TAVI

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for transfusion	Any bleeding requiring transfusion of 1 or more units of whole blood/RBC	30 days after TAVI
Safety endpoint: Anaphylaxis	According to the National Institute of Allergy and Infectious Disease criteria	30 days after TAVI
Safety endpoint: Thromboembolic events	Composite of myocardial infarction, ischaemic stroke, transient ischaemic attack or non-cerebral distal embolization according to the VARC-3 criteria	30 days after TAVI
Neurologic events	According to the VARC-3 criteria	30 days after TAVI
Hospitalization	According to the VARC-3 criteria	30 days after TAVI
Vascular and access-related complications	According to the VARC-3 criteria	30 days after TAVI
Cardiac structural complications	According to the VARC-3 criteria	30 days after TAVI
Other procedural or valve-related complications	According to the VARC-3 criteria	30 days after TAVI
New conduction disturbances and arrhythmias	According to the VARC-3 criteria	30 days after TAVI
Acute kidney injury	According to the VARC-3 criteria	30 days after TAVI
Myocardial infarction	According to the VARC-3 criteria	30 days after TAVI
Bioprosthetic valve dysfunction	According to the VARC-3 criteria	30 days after TAVI
Leaflet thickening and reduced motion	According to the VARC-3 criteria	30 days after TAVI
Clinically significant valve thrombosis	According to the VARC-3 criteria	30 days after TAVI
Haemoglobin level		30 days after TAVI
Delayed haemostasis failure	The occurrence of bleeding requiring prolonged manual compression or alternative interventions (new pressure bandage, fem-stop device, endovascular or surgical repair) after initial haemostasis was achieved and patient is no longer in the catheterization laboratory.	30 days after TAVI
Post-procedural length of stay	Post-procedural length of stay will be measured in the time (days) from procedure to discharge.	30 days after TAVI
Freedom from mortality	According to the VARC-3 criteria	30 days after TAVI
Successful access, delivery of the device, and retrieval of the delivery system	According to the VARC-3 criteria	30 days after TAVI
Correct positioning of a single prosthetic heart valve into the proper anatomical location	According to the VARC-3 criteria	30 days after TAVI
Freedom from surgery or intervention related to the device or to a major vascular or access-related, or cardiac structural complication	According to the VARC-3 criteria	30 days after TAVI
Technical success	According to the VARC-3 criteria	30 days after TAVI
Freedom from surgery or intervention related to the device or to a major vascular or access-related or cardiac structural complication	According to the VARC-3 criteria	30 days after TAVI
Intended performance of the valve (mean gradient <20 mmHg, peak velocity <3 m/s, Doppler velocity index ≥0.25, and less than moderate aortic regurgitation)	According to the VARC-3 criteria	30 days after TAVI
Freedom from all-cause mortality	According to the VARC-3 criteria	30 days after TAVI
Freedom from all stroke	According to the VARC-3 criteria	30 days after TAVI
Freedom from VARC type 2-4 bleeding	According to the VARC-3 criteria	30 days after TAVI
Freedom from major vascular, access-related, or cardiac structural complication	According to the VARC-3 criteria	30 days after TAVI
Freedom from acute kidney injury stage 3 or 4	According to the VARC-3 criteria	30 days after TAVI
Freedom from moderate or severe aortic regurgitation	According to the VARC-3 criteria	30 days after TAVI
Freedom from new permanent pacemaker due to procedure-related conduction abnormalities	According to the VARC-3 criteria	30 days after TAVI
Freedom from surgery or intervention related to the device	According to the VARC-3 criteria	30 days after TAVI
Time to hemostasis	Is defined as elapsed time after sheath removal and first observed and confirmed arterial hemostasis.	30 days after TAVI
Procedural haemostasis failure	Procedural haemostasis failure is defined as failure to achieve haemostasis at the arteriotomy site within 20 minutes or leading to alternative treatment (e.g. fem-stop device, or adjunctive endovascular ballooning/stenting).	30 days after TAVI

Collaborators and Investigators

• Sponsor: St. Antonius Hospital
• Collaborators: St. Antonius Research Fund

Publications and helpful links

General Publications

• Overduin DC, van Ginkel DJ, Dubois C, Lesizza P, Broeze GM, Montero-Cabezas JM, Rosseel L, van der Kley F, van Nuland PJ, Smits TP, Hemelrijk KI, Aarts HM, Rensing BJWM, Timmers L, Swaans MJ, Sonker U, Veenstra L, van 't Hof AWJ, Peper J, Tijssen JGP, Delewi R, Vriesendorp PA, Ten Berg JM. Routine versus selective protamine administration to reduce bleeding after TAVI: Rationale and design of the POPular ACE TAVI trial. Am Heart J. 2026 Mar;293:107296. doi: 10.1016/j.ahj.2025.107296. Epub 2025 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2023
• Primary Completion (Actual): January 2, 2026
• Study Completion (Actual): January 2, 2026

Study Registration Dates

• First Submitted: March 3, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 20, 2023

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Allergy; Protamine; Mortality; Bleeding; TAVI; TAVR
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Immune System Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Pathological Conditions, Signs and Symptoms; Aortic Valve Stenosis; Hypersensitivity; Hemorrhage; Amino Acids, Peptides, and Proteins; Proteins; Nuclear Proteins; Nucleoproteins; Protamines
• Other Study ID Numbers: 2023-504205-36-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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