Pieter A. Vriesendorp
Interventional cardiologist, Maastricht University Medical Center
“Once that study is done, I think we can put the issue to rest if it also shows a beneficial effect, and then everyone should use protamine.”
News Coverage ↗ESC 2026View all trials
POPular ACE TAVIStructural HeartOpen Access
Routine versus selective protamine administration after transcatheter aortic valve implantation
Christiaan Overduin
What happened
Routine protamine after TAVI cuts death or clinically relevant bleeding by ~37% versus selective use.
- risk difference −10.9 pts
- P<0.001
- n=966
- 18.5% vs 29.4%
Key points
- Context & question: Determine whether routine protamine administration is superior to selective administration in reducing death and clinically relevant bleeding following transfemoral transcatheter aortic valve implantation.
- Methods & population: Investigator-initiated, double-blind, multicenter, randomized superiority trial; 966 patients undergoing transfemoral TAVI at 6 centres (Netherlands/Belgium); Routine protamine after TAVI vs selective (placebo-first) protamine.
- Finding & limits: The primary composite of all-cause death or clinically relevant bleeding occurred in 18.5% of the routine protamine arm versus 29.4% of the selective arm, primarily driven by lower VARC-3 type 1 bleeding. Design limitations: The composite was driven mainly by VARC-3 type 1 (minor) bleeding rather than death, and the follow-up duration and primary endpoint's ascertainment window are not reported in this conference-only record.
Discussion
Expert perspectives 4
Ritu Thamman
Endpoint critiqueUniversity of Pittsburgh
Routine protamine cut minor bleedings, but 83% of selective-arm patients never needed it
X post ↗Gilbert Tang
Practice takeCardiac surgeon, Mount Sinai Health, New York
“The more minor vascular issues are not benign. These patients have [better] mobilization and especially if they're at low surgical risk, they want to be recovering faster.”
News Coverage ↗Show 1 more perspectivesShow fewer perspectives
Stefano Garzon
Results readoutInterventional / Structural Cardiology · Hospital Israelita Albert Einstein
Less minor bleeding as expected, but no evidence yet for routine protamine use
X post ↗Outstanding questions
Open questions from this trial that would benefit from expert input.
Full evidence
Why the trial, tables, limitations, PICO, abstract, media & sources
Full evidence
Why the trial, tables, limitations, PICO, abstract, media & sources
Why the trial?
Heparin reversal with protamine after TAVI varies widely between centres, balancing access-site bleeding against possible thrombotic risk with no randomised evidence to guide practice. POPular ACE TAVI compared routine against selective protamine administration.
Does routine protamine administration reduce the composite of all-cause death or clinically relevant bleeding in patients undergoing transfemoral TAVI compared to selective administration?
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Evidence details
What drove the result?
| Outcome | Routine | Selective |
|---|---|---|
| All-cause death or clinically relevant bleeding Primary composite · risk difference 10.9 pp (p<0.001), driven mainly by VARC-3 type 1 bleeding | Routine 18.5% | Selective 29.4% |
Limitations & tradeoffs
- Safety
- Anaphylactic reactions occurred in 6 patients (1.3%) in the routine-protamine arm, while thromboembolic events were ~4% in both arms.
- Design limitations
- The composite was driven mainly by VARC-3 type 1 (minor) bleeding rather than death, and the follow-up duration and primary endpoint's ascertainment window are not reported in this conference-only record.
- Statistical certainty
- No per-arm event counts or confidence intervals are available.
Structured PICO
Does routine protamine administration reduce the composite of all-cause death or clinically relevant bleeding in patients undergoing transfemoral TAVI compared to selective administration?
Population
966 patients undergoing transfemoral TAVI.
Intervention
Routine protamine administration at the end of the TAVI procedure.
Comparator
Selective administration (placebo first, with protamine only for ongoing bleeding after 10 minutes).
Outcome
Composite of all-cause death or clinically relevant bleeding.composite endpoint
Main Result
Absolute Risk Reduction10.9
Absolute Event Rate18.5% vs 29.4%
Absolute Risk Reduction10.9%
p-valuep=<0.001
Routine administration of protamine after transfemoral TAVI significantly reduces bleeding complications without increasing thromboembolic risk compared to a selective administration strategy.
Where experts stand
Transcatheter aortic valve replacement evidence still formingExperts see routine protamine after TAVI as a simple win on bleeding but flag that the earlier dataset was underpowered for thromboembolic safety, leaving full adoption an open question until the definitive trial confirms the benefit.
The trial showed routine protamine cuts death and bleeding after transfemoral TAVI, and most experts accept the direction of the result. However, several voices note that earlier data reduced mainly minor bleedings and that the study was not powered to rule out thromboembolic risk. The live question is whether a confirmatory trial will settle the safety concern and move protamine into routine practice.
2 takes classified by contention axis so far — the map appears as more land.
Still unclear
Experts note the study was not powered to assess thromboembolic risk, leaving uncertainty about whether routine protamine could raise clotting events in a larger or longer-follow-up cohort. Whether a confirmatory trial will replicate the benefit and settle the question of universal adoption remains open.
Implication
Routine protamine reversal after TAVI reduces death or bleeding; supports immediate adoption as standard and closes a prior evidence gap.
Abstract
POPular ACE TAVI was an investigator-initiated, randomised, double-blind superiority trial that enrolled 966 patients undergoing transfemoral TAVI at 6 centres in the Netherlands and Belgium between November 2023 and September 2025. Patients were randomised to routine protamine administration at the end of the procedure or selective administration (placebo first, with protamine only for ongoing bleeding after 10 minutes). The primary composite of all-cause death or clinically relevant bleeding occurred in 18.5% with routine protamine versus 29.4% with selective administration (risk difference 10.9 percentage points; p<0.001), driven mainly by a reduction in VARC-3 type 1 bleeding. Anaphylactic reactions occurred in six patients (1.3%) given routine protamine; thromboembolic event rates were low and comparable at roughly 4% in both arms. In the selective arm, protamine was given to only about 18% of patients. Presented by Christiaan Overduin in Hot Line 7 at ESC Congress 2026; no simultaneous journal publication. Sources: herzmedizin.de (DGK) and ESC 365 (presentation 335391).
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Christiaan Overduin (2026) conducted an RCT in transfemoral TAVI (n=966). Routine protamine administration vs. Selective administration was evaluated on composite of all-cause death or clinically relevant bleeding (risk difference 10.9 percentage points, p=<0.001). Routine protamine administration after TAVI reduced all-cause death or clinically relevant bleeding compared to selective administration.