Volume 293, March 2026, 107296Author links open overlay panel, , , , , , , , , , , , , , , , , , , …ABSTRACTBackground

Unfractionated heparin is routinely used during transcatheter aortic valve implantation (TAVI) to reduce catheter thrombosis and thromboembolism. Protamine reverses the effect of heparin and may lower bleeding risk, but it can also trigger severe allergic reactions. Robust data on the safety and efficacy of routine protamine administration after TAVI is lacking.

Methods

The ``routine versus selective protamine administration to reduce bleeding complications after transcatheter aortic valve implantation (POPular ACE TAVI)'' is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. A total of 1000 patients will be randomized 1:1 to routine versus selective protamine administration, stratified by study site and antithrombotic therapy. Primary and secondary outcomes are defined according to the Valve Academic Research Consortium-3 (VARC-3) criteria. The primary outcome is a composite of all-cause mortality and clinically relevant bleeding (type 1-4) within 30 days after TAVI. Ranked secondary outcomes include clinically relevant bleeding; major, life-threatening or fatal bleeding (type 2-4); major vascular complications; cardiovascular mortality; and all-cause mortality. Safety outcomes include anaphylaxis and thromboembolic events defined as the composite of myocardial infarction, ischemic stroke, transient ischemic attack, or noncerebral distal embolization. Recruitment began in November 2023 and will continue until 1,000 patients are randomized. The trial will end after 30‑day follow‑up of the last patient.

Conclusion

The POPular ACE TAVI trial (NCT05774691) will evaluate whether routine protamine administration reduces all-cause mortality or clinically relevant bleeding after TAVI compared with selective use.

Section snippetsBackground

Transcatheter aortic valve implantation (TAVI) is an established treatment for patients with severe aortic stenosis.1,2 Despite technical advances in recent years, procedure-related bleeding complications remain frequent.3., 4., 5. Bleeding complications have been reported in up to 35% of the patients.6., 7., 8. These events are inherently related to the vascular access site and route.3,5 Also, higher age, female sex, peripheral artery disease, renal insufficiency, anemia, and antithrombotic

Study design

POPular ACE TAVI (NCT05774691) is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The trial tests the hypothesis that routine protamine administration reduces all-cause mortality or clinically relevant bleeding within 30 days after TAVI compared with selective protamine administration. A total of 1,000 patients will be randomized 1:1 to routine versus selective protamine administration and followed for 30 days (Figure 1).

Study population

Patients undergoing

Discussion

According to international expert consensus documents, heparin reversal by the administration of protamine before vascular closure can be considered to prevent bleeding complications after TAVI.11,16 However, concerns remain: protamine may provoke life‑threatening allergic reactions and, at higher doses, paradoxically inhibit coagulation. Because these recommendations are largely based on expert opinion, clinical practice varies widely among centers and even operators. Strategies range from

Conclusion

Protamine may lower bleeding events after TAVI without increasing thromboembolic risk. However, current evidence is limited by observational designs and underpowered trials. The POPular ACE TAVI trial will address these gaps by randomizing 1,000 patients in a double-blind, placebo-controlled study to evaluate whether routine protamine administration reduces all-cause mortality or clinically relevant bleeding within 30 days after TAVI. The results will guide clinicians regarding the appropriate

CRediT authorship contribution statement

Daniël C. Overduin: Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing. Dirk Jan van Ginkel: Methodology, Writing – original draft, Writing – review & editing, Funding acquisition. Christophe Dubois: Investigation, Writing – review & editing. Pierluigi Lesizza: Investigation, Writing – review & editing. Gijs M. Broeze: Conceptualization, Investigation, Writing – review & editing. Jose M. Montero-Cabezas: Investigation, Writing – review & editing.

Conflict of interest

Dr Montero-Cabezas has received lecturer fees from Penumbra, Inc., and a research grant from ShockWave Medical, Inc.; Dr van der Kley has received consulting/lecturer fees from Edwards Lifesciences, Boston Scientific, and Abbott; Dr Swaans has received consulting/lecturer fees from Abbott Vascular, Bioventrix Inc., Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, GE Healthcare, Medtronic, Philips Healthcare, and Siemens Healthcare; Dr Van ‘t Hof has received institutional research

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