Aortic Valve StenosisPhase 3ATLANTIS-ProtaNCT06215378
Antagonization of Heparin With Protamine Sulfate After TAVI
A Phase 3 study testing Antagonization of heparin with protamine sulfate in people with Aortic Valve Stenosis and Heart Valve Diseases, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
Transcatheter aortic valve replacement (TAVR) is now the first therapeutic option offered to high and intermediate risk patients with symptomatic aortic stenosis but even to low-risk, when the aortic valve is tricuspid and the transfemoral approach is suitable. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Aortic Valve Stenosis, Heart Valve Diseases
- What is being tested?
- Antagonization of heparin with protamine sulfate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 940 participants
- Where
- 1 siteFrance
- Study dates
- 25 May 2025to 1 Mar 2027
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women ≥18 years of age
- Any patient eligible for transfemoral TAVI, irrespective of the chronic antithrombotic treatment
- Written informed consent
- Registered at the French social healthcare
Who cannot join
- Any major protamine sulfate exposure contraindications defined as a history of severe pulmonary hypertension, acute pulmonary edema or history of bronchospasm related to protamine sulfate administration
- Known allergy to protamine sulfate
- Hypersensitivity to protamine sulfate including protamine contained as an excipient in NPH [Neutral Protamine Hagedorn] insulin, known protamine or protamine-heparine complex antibodies
- Non-femoral approach for the TAVI procedure
- Protamine sulfate exposure within 24h of randomization
- Fish allergy
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- Mechanical valves
- For men: Sterile or Vasectomy
- Women of childbearing potential
- Pregnancy and breast feeding women
- Contemporaneous enrolment in an interventional clinical trial
- Patient under guardianship or curatorship
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
Pitié Salpêtrière hospital
Paris, Île-de-France Region, 75013
Paul GUEDENEY, MD, PHD
About this study
Official title: Antagonization of Heparin With Protamine Sulfate to Lower All Neurological Ischemic and Hemorrhagic Events After Transcatheter Aortic Valve Implantation for Aortic Stenosis
Transcatheter aortic valve replacement (TAVR) is now the first therapeutic option offered to high and intermediate risk patients with symptomatic aortic stenosis but even to low-risk, when the aortic valve is tricuspid and the transfemoral approach is suitable. Vascular and bleeding complications are the most frequent procedure-related unwanted events associated with increased short-term morbidity and mortality. Selection of the appropriate vascular access site and pre-closing devices as well as stent implantation mitigate these complications.
ACT-guided heparin reaching a target of 300 seconds or more is recommended prior to the placement of the guiding sheath in the common femoral artery. Protamine sulfate is the heparin antidote, which antagonizes 100% of its anti-IIa activity and 60% of its anti-Xa activity. Reversal of heparin using protamine sulfate is recommended for transapical and complicated transfemoral aortic valve placement.However, there is a great heterogeneity of protamine use in daily practice and supportive evidence for the prevention of bleeding complications as well as its safety is lacking. In addition, the radial approach for the second vascular access is more commonly used as well as the use of echo-guided femoral puncture further questioning reversal of heparin when the procedure has been successfully completed without overt bleeding complications.
Our study aims to demonstrate the superiority of a strategy of systematic ACT-guided heparin administration followed by systematic antagonization with protamine sulfate over usual of care to reduce in-hospital mortality, vascular/bleeding complications, stroke and transcient ischemic attack, myocardial infarction or red blood cell transfusion, from randomization to hospital discharge
- Conditions
- Aortic Valve Stenosis, Heart Valve Diseases
- Being tested
- Antagonization of heparin with protamine sulfate
- Keywords
- TAVI, Protamine, Heparine, Antagonization, Aortic stenosis
- Medical subject headings
- Aortic Valve Stenosis, Heart Valve Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Antagonization of heparin with protamine sulfateDrug
A systematic use at the end of procedure of Protamine Sulfate for antagonization of heparine.1 mg of protamine sulfate neutralizes approximately 100 heparin unit. To be administered in slow infusion (10 min) not exceeding 50mg of protamine sulfate to reverse 100% of the anti-IIa activity of heparin sodium. If the ACT is not back to the baseline value after the end of this infusion, additional doses of protamine should be performed depending on the ACT value to obtain complete antagonization of anti-IIa activity of heparin sodium
| Study group | Role | What they receive |
|---|---|---|
| Systematic heparine antagonization with protamine sulphate | Experimental | Complete reversal of the Heparin administered during the TAVI achieved through the infusion of a protamine solution until the ACT returns to its baseline level. Receives: Drug: Antagonization of heparin with protamine sulfate |
| No Systematic heparine antagonization with protamine sulphate | No intervention | No administration of protamine solution unless a participant encounters a bleeding event requiring a surgery or percutanous intervention. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite of ischemic and bleeding events
The primary endpoint is defined as the first occurrence, of any event of the composite of all-cause mortality, type 2, 3 or 4 bleeding, major or minor vascular complications, stroke or TIA, myocardial infarction or any redblood transfusion. The primary endpoint will be blindly determined by a clinical event committee according to the valve Academic Research Consortium-3 (VARC-3 classifications)
Measured: From procedure to hospital discharge (or at 30 days whichever comes first)
Secondary outcomes (5)
In hospital stay
Assessment of length of in-hospital stay in days post TAVI procedure
Measured: From procedure to hospital discharge, assessed up to 30 days
Bleeding complication
Assessment of the occurrence of:
- Type 2, 3 or 4 bleeding according to the VARC 3 criteria or any red blood cell transfusion of minor or vascular complications.
- Type 2, 3 or 4 bleedings or red blood cell transfusion.
- Any red blood cell transfusion
- Type 2, 3 or 4 bleedings
Measured: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of interaction
Assessment of an interaction in the impact of systematic antagonization according to the use or not of an echo-guided femoral puncture and/or arterial radial access. These subgroups are defined at the time of randomization by stratification.
Measured: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of adverse outcome
Assessment of the occurrence of:
- Death or type 2, 3 or 4 bleedings
- Any kidney injury, stage 2 to 4 according to the KDIGO definition
- Death, type 2, 3 or 4 bleedings or stroke
- Death, VARC 3 type 2-3-4 bleeding or Any red blood cell transfusion, MI or stroke Or TIA
- Any myocardial infarction, stroke or TIA
- Type 3 or 4 bleeding
- Type 2 bleeding
- Minor vascular complications
- Access site and access related vascular injury according to VARC-3 criteria
Measured: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of long term adverse outcome
Assessment of the composite of: Death, stroke, TIA, MI and bleeding VARC type 2 or more as well as each individual endpoint
Measured: From procedure 12 months post procedure
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2024
- Study start25 May 2025
- Primary completion1 Mar 2027 (estimated)
- Study completion1 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Aortic Valve StenosisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase III, national, multicenter, controlled, randomized open label study in 2 parallel groups at a 1:1 ratio
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 940 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- Action Research Group
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06215378
- Sponsor's protocol ID
- APHP211046
- Acronym
- ATLANTIS-Prota
- Status last verified
- Jan 2025
- First submitted
- 22 Dec 2023
- Last updated
- 22 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antagonization of Heparin With Protamine Sulfate to Lower All Neurological Ischemic and Hemorrhagic Events After Transcatheter Aortic Valve Implantation for Aortic Stenosis
- ClinicalTrials.gov ID
- NCT06215378
- Acronym / sponsor ID
- ATLANTIS-Prota / APHP211046
- Conditions
- Aortic Valve Stenosis, Heart Valve Diseases
- Keywords
- TAVI, Protamine, Heparine, Antagonization, Aortic stenosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 940 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- Action Research Group
- Study start
- 25 May 2025 (actual)
- Primary completion
- 1 Mar 2027 (estimated)
- Study completion
- 1 Mar 2027 (estimated)
- First posted
- 22 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Transcatheter aortic valve replacement (TAVR) is now the first therapeutic option offered to high and intermediate risk patients with symptomatic aortic stenosis but even to low-risk, when the aortic valve is tricuspid and the transfemoral approach is suitable. Vascular and bleeding complications are the most frequent procedure-related unwanted events associated with increased short-term morbidity and mortality. Selection of the appropriate vascular access site and pre-closing devices as well as stent implantation mitigate these complications.
ACT-guided heparin reaching a target of 300 seconds or more is recommended prior to the placement of the guiding sheath in the common femoral artery. Protamine sulfate is the heparin antidote, which antagonizes 100% of its anti-IIa activity and 60% of its anti-Xa activity. Reversal of heparin using protamine sulfate is recommended for transapical and complicated transfemoral aortic valve placement.However, there is a great heterogeneity of protamine use in daily practice and supportive evidence for the prevention of bleeding complications as well as its safety is lacking. In addition, the radial approach for the second vascular access is more commonly used as well as the use of echo-guided femoral puncture further questioning reversal of heparin when the procedure has been successfully completed without overt bleeding complications.
Our study aims to demonstrate the superiority of a strategy of systematic ACT-guided heparin administration followed by systematic antagonization with protamine sulfate over usual of care to reduce in-hospital mortality, vascular/bleeding complications, stroke and transcient ischemic attack, myocardial infarction or red blood cell transfusion, from randomization to hospital discharge
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Phase III, national, multicenter, controlled, randomized open label study in 2 parallel groups at a 1:1 ratio
| Arm | Type | Receives |
|---|---|---|
| Systematic heparine antagonization with protamine sulphate | Experimental | Drug: Antagonization of heparin with protamine sulfateComplete reversal of the Heparin administered during the TAVI achieved through the infusion of a protamine solution until the ACT returns to its baseline level. |
| No Systematic heparine antagonization with protamine sulphate | No intervention | –No administration of protamine solution unless a participant encounters a bleeding event requiring a surgery or percutanous intervention. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Men and women ≥18 years of age
- Any patient eligible for transfemoral TAVI, irrespective of the chronic antithrombotic treatment
- Written informed consent
- Registered at the French social healthcare
Key exclusion criteria (12 listed)
- Any major protamine sulfate exposure contraindications defined as a history of severe pulmonary hypertension, acute pulmonary edema or history of bronchospasm related to protamine sulfate administration
- Known allergy to protamine sulfate
- Hypersensitivity to protamine sulfate including protamine contained as an excipient in NPH [Neutral Protamine Hagedorn] insulin, known protamine or protamine-heparine complex antibodies
- Non-femoral approach for the TAVI procedure
- Protamine sulfate exposure within 24h of randomization
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Antagonization of heparin with protamine sulfateA systematic use at the end of procedure of Protamine Sulfate for antagonization of heparine.1 mg of protamine sulfate neutralizes approximately 100 heparin unit. To be administered in slow infusion (10 min) not exceeding 50mg of protamine sulfate to reverse 100% of the anti-IIa activity of heparin sodium. If the ACT is not back to the baseline value after the end of this infusion, additional doses of protamine should be performed depending on the ACT value to obtain complete antagonization of anti-IIa activity of heparin sodium | Drug | Systematic heparine antagonization with protamine sulphate |
Primary outcome
Composite of ischemic and bleeding events
Time frame: From procedure to hospital discharge (or at 30 days whichever comes first)
The primary endpoint is defined as the first occurrence, of any event of the composite of all-cause mortality, type 2, 3 or 4 bleeding, major or minor vascular complications, stroke or TIA, myocardial infarction or any redblood transfusion. The primary endpoint will be blindly determined by a clinical event committee according to the valve Academic Research Consortium-3 (VARC-3 classifications)
5 secondary outcomes
In hospital stay
Time frame: From procedure to hospital discharge, assessed up to 30 days
Bleeding complication
Time frame: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of interaction
Time frame: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of adverse outcome
Time frame: From procedure to hospital discharge (or at 30 days whichever comes first)
Assessement of long term adverse outcome
Time frame: From procedure 12 months post procedure
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2025.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Antagonization of heparin with protamine sulfate in people with Aortic Valve Stenosis and Heart Valve Diseases, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Paul Dr GUEDENEY, MD (0184827619 ext. +33, paul.guedeney@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite of ischemic and bleeding events (time frame: From procedure to hospital discharge (or at 30 days whichever comes first)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2025.